WO2009085223A1

WO2009085223A1 - Combination of metformin r-(+)-lipoate and antihyperglycemic agents for the treatment of diabetic hyperglycemia and diabetic complications

Info

Publication number: WO2009085223A1
Application number: PCT/US2008/013924
Authority: WO
Inventors: Banavara L. Mylari
Original assignee: Indigene Pharmaceuticals, Inc.
Priority date: 2007-12-20
Filing date: 2008-12-19
Publication date: 2009-07-09

Abstract

Disclosed are phaπnaceutical compositions, methods of treatment, and kits for the treatment of Type 2 diabetic hyperglycemia and diabetic complications using combination treatments comprising metformin R-(+)-lipoate and antihyperglycemic agents.

Description

COMBINATION OF METFORMIN R-(+)-LIPOATE AND

ANTIHYPERGLYCEMIC AGENTS FOR THE TREATMENT OF DIABETIC

HYPERGLYCEMIA AND DIABETIC COMPLICATIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U S Provisional Patent Application Seπal No 61/008,787 filed on December 20, 2007 The specification of this application is incorporated herein by reference in its entirety

FIELD OF THE INVENTION

The disclosure is directed to methods, phaπnaceutical compositions and kits comprising metformin R-(+)-hpoate [MR-(+) LA] and an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug The disclosure further relates to methods of using those pharmaceutical compositions for the treatment of Type 2 diabetes and complications associated with Type 2 diabetes

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 hyperhpidemia The long-term consequences of these co-morbidities include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and diabetic cataracts Metformin R-(+)-hpoate has been descπbed and claimed as novel treatment for control of chronic hyperglycemia in a pending application The disclosure relates to combinations of metformin R-(+)-hpoate and antihyperglycemic agents to treat diabetes and diabetes exacei bated complications in diabetic patients

SUMMARY OF THE INVENTION In one aspect the disclosure relates to combinations of metformin R-(+)-hpoate and antihypeiglycemic agents to tieat diabetes and diabetes complications in diabetic patients In one aspect, the disclosure relates to methods, pharmaceutical compositions and kits comprising metformin R-(+)-lipoate, and an antihyperglycemic agent, or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug. The disclosure further relates to methods of using such pharmaceutical compositions for the treatment of diabetic complications including, but not limited to, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.

Antihyperglycemic agents that may be used in accordance with the disclosure may include, for example, sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP IV inhibitors, and pharmaceutically-acceptable salts and prodrug thereof, and pharmaceutically-acceptable salts of said prodrug, and others.

In one aspect, the disclosure is directed to pharmaceutical compositions comprising metformin R-(+)-lipoate, an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug; and a pharmaceutically-acceptable carrier, vehicle or diluent.

In certain embodiments, the antihyperglycemic agent is a sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP IV inhibitor, or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug. In certain embodiments the pharmaceutically acceptable salt is selected from the group consisting of a propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l ,4-dioate, hexyne-l ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 - sulfonate, naphthalene-2-sulfonate, mandelate, hippurate, gluconate, or lactobionate.

In certain embodiments, the metformin R-(+) lipoate 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 l OO 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 antihyperglycemic agent is present in the amount ranging from 2.5 mg to I 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 pharmaceutical composition is formulated as a tablet

In certain embodiments, the pharmaceutical composition is administered once, twice, or three times daily

In certain embodiments, the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdeπnal, transmucosal, lontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administiation The disclosure also provides methods of treating diabetic complications in a mammal compπsing administering the mammal a pharmaceutical composition provided herein Such diabetic complications may include, for example, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy

In one embodiment, the disclosure provides methods of treating a diabetic complication in a mammal comprising administering to the mammal metformin R-(+)-hpoate and an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug

In another the disclosure embodiment provides methods wherein the metformin R- (+)-hpoate and the antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, are administered separately

In one aspect, the disclosure is directed to methods wherein the metformin R-(+)- hpoate and the antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, are administered together

In one aspect, the disclosure is directed to methods wherein the metformin R-(+)- hpoate and the antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof or a pharmaceutically-acceptable salt of said prodiug aie administered in a single dosage foπn, foi example, a tablet, a capsule oi a caplet

In certain embodiments of methods as disclosed heiein, the antihyperglycemic agent is a sulfonylurea, meglitinide, thiazolidinedione alpha-glucosidase inhibitoi, DPP IV inhibitoi , or a pharmaceutically-acceptable salt oi pi odiug thcicof oi a phannaccutically- acceptable salt of said prodrug In certain embodiments the pharmaceutically acceptable salt is selected from the group consisting of a propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l ,4-dioate, hexyne-l ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, hippurate, gluconate, or lactobionate

In certain embodiments of methods as disclosed herein, the metformin R-(+) hpoate 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 antihyperglycemic agent is present in the 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 yet another aspect, the disclosure provides kits comprising a) a first unit dosage form comprising metformin R-(+)-hpoate, and a pharmaceutically- acceptable earner, vehicle or diluent, b) a second unit dosage form comprising an antihyperglycemic agent, or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, and a pharmaceutically-acceptable carπei , vehicle or diluent, and c) a container

In certain embodiments, the antihyperglycemic agent is a sulfonylurea, meghtinide, thiazohdinedione, alpha-glucosidase inhibitor, DPP IV inhibitor, or a pharmaceutically- acceptable salt or prodrug thereof, oi a pharmaceutically-acceptable salt of said prodrug In certain embodiments the phaimaceutically acceptable salt is selected from the group consisting of a propionate decanoate. capi ylate, acrylate, formate, isobutyrate, caprate, heptanoate, piopiolate, oxalate, malonate, succinate suberate, sebacate. fumarate, maleate, butyne- 1 4-dioate, hexyne- l ,6-dioatc, bcn/oatc chloiobenzoate, methylbenzoate, dinitiobenzoate hydioxybcn/ioatc metho\ybcn/oate phthalate terephathalate, sulfonate, xylenesulfonate phenylacetate, phenylpiopionate, phenylbutyiate, citi ate, lactate, β- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1- sulfonate, naphthalene-2-sulfonate, mandelate, hippurate, gluconate, or lactobionate

In certain embodiments, the metformin R-(+) lipoate 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 antihyperglycemic agent is present in the 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 the compositions, methods, and kits of the disclosure, it is preferred that the antihyperglycemic agent be a compound selected fiom the following classes of antihyperglycemic agents sulfonylureas, meghtinides, biguanides, thiazohdinediones, alpha- glucosidase inhibitors, and DPP-IV inhibitors, pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs Preferred sulfonylureas include, but are not limited to, acetohexamide, 1 - butyl- 3- methanilyl urea, carbutamide, chlorpropamide, ghbornuπde, gliclazide, glipizide, ghquidone, ghsoxepid, glybuπde, glybuthiazole, glybuzole, glyhexamide, ghmipiπde, glymidine, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, repaghnide, D- phenylalanine deπvative- nateghnide, meghtinide analogue- mitighnide, non-sulphonylurea moiety of glibenclamide, meghtinide, pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs Especially preferred sulfonylureas include chlorpropamide, tolazamide, tolbutamide, glybuπde, glipizide, glimepiπde, repaghnide, and nateghnide prodrugs thereof and pharmaceutically-acceptable salts of said sulfonylureas, and said prodrugs Preferred meghtinides include, but are not limited to, benzoic acid deπvative- repaghnide, D-phenylalanine derivative- nateghnide, meghtinide analogue- mitighnide, non- sulphonylurea moiety of glibenclamide, meghtinide and others, pharmaceutically-acceptable salts and piodiugs thereof, and pharmaceutically-acceptable salts of said piodrugs Especially pi eten ed meghtinides include repaghnide, nateghnide and others, pharmaceutically-acceptable salts and prodrugs theieof, and pharmaceutically-acceptable salts of said prodrugs Preferred thiazohdinediones include pioghtazone and rosightazone, pharmaceutically- acceptable salts or a prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs Preferred alpha-glucosidase inhibitors include, but are not limited to, acarbose, vaghbose, and miglitol, pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically- acceptable salts of said prodrugs

Preferred DPP-IV inhibitors include, but are not limited to, sitagliptin and vildaghptin, saxaghptin, SYR-322, and PSN9301 , pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs

DETAILED DESCRIPTION OF THE INVENTION

The methods, compositions, and kits of the 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 antihyperglycemic agents that may be used in accordance with the disclosure are members of different classes of antihyperglycemic agents (e g , sulfonylureas, meghtinides, biguanides, thiazohdinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors and others) pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs

The term "sulfonylureas ^" refers to a class of compounds that stimulate insulin release by binding to the sulfonylurea receptor, a subunit of the KATP channel complex This binding leads to closure of the channel, resulting in voltage change in the beta-cell membiane and, in turn, influx of Ca²⁺ ions causing exocytosis of insulin granules For a discussion on sulfonylureas see, for example, Metabolism, 55, 20 (2006) and references cited therein, and Lancet, 358, 1709 (2001 ) and references cited therein The term " thiazohdinediones refers to a class of compounds that are selective agonists for the peioxisome piohfeiator-activated ieccptoi gamma (PPARγ), a membei of the family of nuclear hormone receptors that function as hgand-activated transcπption factors For a review on thiazolidinediones see, for example, Trends Endocrin Met , 10, 9 (1999) and references cited therein

The term "alpha-glucosidase inhibitors" refers to a class of compounds having the ability to competitively inhibit brush border enzyme alpha-glucosidase in the GI tract, which has the ability to cleave complex carbohydrates into sugars For a review on alpha- glucosidase inhibitors see, for example, Diabetes Res Clin Pr , 40, S51 (1998) and references cited therein

The term "DPP IV inhibitors^" refers to a class of compounds that have the ability to selectively inactivate the enzyme DPP-IV, and those which have the ability to rapidly inactivate incretin hormones (e g , glucagon-hke peptide-1 (GLP-I ) and insulinotropic polypeptide (GIP)), that are released by the intestine throughout the day, and whose levels are increased after a meal For a review on DPP-IV inhibitors see, for example, Expert Opin Inv Drug, 12, 87 (2003) and references cited therein In the practice of the compositions and methods of the disclosure, any sulfonyluiea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, or DPP-IV inhibitor, or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or any combination thereof, may be employed

Sulfonylureas that may be used in accordance with the disclosure include, but are not limited to, acetohexamide, which may be prepared as disclosed in U S Patent No 3,013,072, 1- Butyl-3-methanilyl urea, which may be prepared as disclosed in U S Patent No 3,183,260, carbutamide, which may be prepared as disclosed in U S Patent No 4,324,796, chlorpropamide, which may be prepared as disclosed in U S Patent No 4,381 ,304, glibornuπde, which may be prepared as disclosed in U S Patent No 4,153,710, ghclazide, which may be prepared as disclosed in U S Patent No 6,733,782, glipizide, which may be prepared and its use as oral administration as disclosed in U S Patent No 5,545,413, ghquidone, has been described and its use as disclosed in U S Patent No 4,708,868, glybuiide oi glibenclamide, which may be prepared and its use as disclosed in U S Patent No 6,830,760, glybuthiazole, which may be described as disclosed in U S Patent No 7, 144,900, glybuzole, which may be prepared and its use as disclosed in U S Patent No

7,084,123. glyhexamide. which may be descnbed and its use as disclosed in U S Patent No 5859037, glimepn idc, which may be prepaied and its use as disclosed in U S Patent No 4,379,785; glymidine, which may be prepared and its use as disclosed in U.S. Patent No. 4,007,201 ; tolazamide, which may be prepared as disclosed in U.S. Patent No. 3,583,979; tolbutamide, which may be prepared as disclosed in U.S. Patent No.3,452,014; repaglinide, which may be prepared as disclosed in U.S. Patent No. 7,148,355, 5,216,167; D- phenylalanine derivative: nateglinide, which may be prepared as disclosed in U.S. Patent No. 6,861,553; and meglitinide analogue mitiglinide, which may be prepared as disclosed in U.S. Patent No.7,084,123. The disclosures thereof are incorporated herein by reference.

Meglitinides that may be used in accordance with the disclosure include, but are not limited to: benzoic acid derivative: repaglinide, which may be prepared as disclosed in U.S. Patent No. 7,148,355, 5,216,167; D-phenylalanine derivative nateglinide, which may be prepared as disclosed in U.S. Patent No. 6,861 ,553; and meglitinide analogue mitiglinide, which may be prepared as disclosed in U.S. Patent No.7,084,123. The disclosures thereof are incorporated herein by reference.

Thiazolidinediones that may be used in accordance with the disclosure include, but are not limited to, rosiglitazone, which may be prepared as disclosed in U.S. Patent No. 6,515,132; and pioglitazone, which may be prepared as disclosed in U.S. Patent No. 7,009,057. The disclosures thereof are incorporated herein by reference.

Alpha-glucosidase inhibitors that may be used in accordance with the disclosure include, but are not limited to, acarbose, which may be prepared as disclosed in U.S. Patent No. 4,904,769; voglibose, which may be prepared as disclosed in Published PCT Application No. WO 2005/030698, miglitol, which may be prepared as disclosed in U.S. Patent No. 4,639,436. The disclosures thereof are incorporated herein by reference.

DPP-IV inhibitors that may be used in accordance with the disclosure include, but are not limited to, sitagliptin, which may be prepared as disclosed in U.S. Patent No. 6,699,871 ; vildagliptin, which may be prepared as disclosed in U.S. Patent No. 6,432,969; saxagliptin, which may be prepared as disclosed in the U.S. Patent No. 6,395,767; SYR-322, which may be prepared as disclosed in U.S. Published Patent Application No. US20050070531 ; and PSN9301 , which maybe prepared as disclosed in U.S. Patent No. 6,303,661. The disclosures thereof are incorporated herein by reference. 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, ethyl enediamine, meglumine (N-methylglucamine), benethamine (N- benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl- 1 ,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, such as aliphatic mono or dicarboxylic acids, hydroxyalkanoic or hydroxyl alkanedioic acids, e.g. acetic, propanoic, hydroxyacetic, 2-hydroxy propanoic, 2-oxopropanoic, ethanedioic, propanediol, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3- dihydroxybutanedioic, or 2-hydroxy- 1 ,2,3-propanetricarboxylic acid; phenylsubstituted alkanoic acids; or suitable aromatic acids, such as 2-hydroxybenzoic, or 4-amino-2- hydroxybenzoic acid; or suitable sulfonic acids, such as alkanesulfonic acids, e.g. methanesulfonic, or ethanesulfonic acid, or aromatic sulfonic acids, e.g. benzenesulfonic, or 4-methylbenzenesulfonic acid; or cyclohexanesulfamic acid. Preferred acids are e.g. hydrobromic acid, sulphuric acid, phosphoric acid, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, dobesilic, methanesulfonic, ethanesulfonic, laurylsulfonic, benzene sulfonic, and para-toluenesulfonic acids.

In one aspect, the disclosure relates to methods of treating diabetic complications in which metfoπnin R-(+)-lipoate and a antihyperglycemic agent are administered together, as part of the same pharmaceutical composition. In another aspect, the disclosure relates to methods of treating diabetic complications in which metformin R-(+)-lipoate and a antihyperglycemic agent 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 metfoπnin R-(+)-lipoate and the antihyperglycemic agent used, the type of pharmaceutical formulations used, the characteristics of the subject being treated and the seventy of the complications. Generally, in carrying out the methods of this disclosure, an effective dosage for the treatment of a warm-blooded animal, including a mammal, such as a human, for metformin R-(+)-hpoate is in the range of about 5 mg/kg/day to about 100 mg/kg/day in single or divided doses, preferably 5 mg/kg/day to 100 mg/kg/day in single or divided doses, Similarly, the antihyperglycemic agent may be administered in single or divided doses Antihyperglycemic agents will generally be administered in amounts ranging from about 0 01 mg/kg/day to about 500 mg/kg/day in single or divided doses, preferably 10 mg/kg/day to about 300 mg/kg/day for an average subject, depending upon the antihyperglycemic agent and the route of administration Some variation in dosage may necessarily occur depending on the condition of the subject being treated The prescribing physician may determine the appropriate dose for the individual subject

In addition, MR-(+)-LA may occur as hydrates or solvates Said hydrates and solvates are also within the scope of the disclosure In one aspect, the disclosure provides for methods of treating diabetic complications in which the MR-(+) LA and antihyperglycemic 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 appropπate 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 antihyperglycemic agent being used, the type of pharmaceutical formulations being used, the characteristics of the subject being treated and the seventy of the complications Generally, in carrying out the methods, an effective dosage for the treatment of a wann-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, 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 or about 2 5 mg per day to about 5 mg per day Antihypeiglycemic agents will genei ally be administei ed in amounts ranging from about 2 5 mg to about 1 g per day in single oi divided doses, for example, about 2 5 mg to about 750 mg pei day tor an aveiage subject, such as about 2 5 mg to about 500 mg per day; about 2.5 mg to about 250 mg per day; or about 2.5 mg to about 200 mg per day; about 2.5 mg to about 150 mg per day; about 2.5 mg to about 100 mg per day; about 2.5 mg to about 50 mg per day; about 2.5 mg to about 25 mg per day; about 2.5 mg to 20 about mg per day; about 2.5 mg to about 10 mg or about 2.5 mg to about 5 mg per day, depending upon the antihyperglycemic agent and the route of administration. 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. Administration of the pharmaceutical compositions of the disclosure may be via any method which delivers a composition of the disclosure preferentially to the desired tissue (e.g., nerve, kidney, retina and/or cardiac tissues). Such methods include oral routes, parenteral, intraduodenal routes, etc. Generally, the compositions of the present disclosure may be administered in single (e.g., once daily) or multiple doses or via constant infusion.

Pharmaceutical compositions comprising, metformin R-(+)-lipoate, and an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, are hereinafter referred to, collectively, as "the active compositions of the disclosure."

The active compositions of the disclosure may be administered to a subject in need thereof by any 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.

The active compositions of the disclosure 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 foπned by combining the active compositions of the disclosure and the phannaceutically-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 including, but are not limited to, sodium citrate, calcium carbonate and calcium phosphate, may be employed along with various disintegrants (e.g., starch and alginic acid) and certain complex silicates, together with binding agents (e.g., polyvinylpyrrolidone, sucrose, gelatin and acacia). Additionally, lubricating agents (e.g., magnesium stearate, sodium lauryl sulfate and talc) may be useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. Aqueous suspensions or elixirs may be desired for oral administration, including various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions of the active compositions of the disclosure 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.

For intranasal administration or administration by inhalation, the active compounds of the disclosure (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, trichlorofluoiOmethane, dichlorotetrafluoroethane, 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 steπle, aqueous or partially aqueous solutions (usually in about 0 1 % to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared

Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of the disclosure, to those skilled in the art For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa , 19th Edition (1995) The active compositions of the disclosure contain an amount of metformin R-(+)- lipoate and an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug 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 or condition of the subject being treated

Since the disclosure has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the disclosure also relates to combining separate pharmaceutical compositions in kit form The kit may comprise two separate pharmaceutical compositions metformin R-(+)-hpoate, and an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of said prodrug as described above The kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet Typically the kit comprises directions for the administiation of the separate components The kit form is particularly advantageous when the sepai ate components are preferably administered in different dosage forms (e g , oral and parenteial) ai e administered at different dosage inteivals or when titration of the individual components of the combination is desired by the pi esci ibing 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 mateπal covered with a foil of a preferably transparent plastic mateπal. Duπng 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 mateπal 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 aldose reductase inhibitor can consist of one tablet or capsule while a daily dose of the antihyperglycemic agent can consist of several tablets or capsules and vice versa. The memory aid may reflect this.

In certain embodiments of the disclosure, 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 micio-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

The compositions of the disclosure generally will be administered in a convenient formulation The following examples are produced for illustrative purposes illustrative purposes.

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 hydrochloπde (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-(+)-hpoate; m p 148-150° C, [α]D20 = + 67.7° (c=l , water); C₂H₂₅N₅O₂S₂ 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 that may be used for determination of conditions leading to a method for treatment and prevention of post-ischemic damage of the heart and heart tissue.

Spontaneously diabetic Bio-Bred (BB/W) rats from the colony maintained at the University of Massachusetts Medical Center, Worcester, were used in this study BB/W rats were chosen for the current study because the BB/W rats have been considered a useful model of autoimmune human insulin-dependent diabetes (IDDM) Like human IDDM, spontaneous diabetes appears during adolescence, with an abrupt clinical onset characteπzed by weight loss, hyperglycemia, hypoinsuhnemia, and ketonuπa As in the case of human diabetics, pathological changes in retina, myocardium, livei , 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 pnoi 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 descπbes an isolated perfused rat heart model used in development of the disclosure Studies are performed using an lsovolumic isolated rat heart preparation Acutely diabetic male BB/W rats and non-diabetic age-matched (3-4 months old) control are pretreated with hepaπn (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 ventπcle 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 1 18 mM NaCl, 47 mM KCl, 12 mM CaCl₂, 12 mM MgCl₂, 25 mM

NaHCθ₃, 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 ⁰C. under all conditions The oxygenated perfusate in the room tempeiature reservoir is passed through 25 ft. of thin- walled silicone tubing surrounded by distilled water at 37 ⁰C saturated with 95% oxygen. The perfusate then enters the waterjacketed (37 ⁰C) tubing leading to the heart through a water jacketed bubble trap This prepai ation provides excellent oxygenation that routinely has been stable for 3-4 hours

Model fo> Zero-flow Ischemia

This example descπbes a proccduic used foi study of zcio-flow ischemia in diabetic control, diabetic treated, non-diabetic treated and control isolated hearts Diabetic control (DC) diabetic treated (DZ) normal (C) control and normal treated (CZ) hearts are subjected to 20 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.

Model for 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 noπnal 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, 2004, 45, 292-302. Antidiabetic activity of compounds of Formula I may also be tested according to protocols described in the following patents: U.S. Patent Nos. 4,340,605; 4,342,771 ; 4,367,234; 4,61 7,312; 4,687,777 and 4,703,052. Additional references relevant to this application include the following: French Patent 2796551 and U.S. Published Patent 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: (i) metformin R-(+)-lipoate

(ii) an antihyperglycemic agent, or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug; and

(iii) a pharmaceutically-acceptable carrier, vehicle or diluent.

2. A phaπnaceutical composition of claim 1 , wherein the antihyperglycemic agent is a sulfonylurea or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug.

3. A phaπnaceutical composition of claim 1 , wherein the antihyperglycemic agent is a meglitinide or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug.

4. A pharmaceutical composition of claim 1 , wherein the antihyperglycemic agent is a thiazolidinedione or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.

5. A pharmaceutical composition of claim 1 , wherein the antihyperglycemic agent is an alpha-glucosidase inhibitor or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.

6. A pharmaceutical composition of claim 1 , wherein the antihyperglycemic agent is a DPP- IV inhibitor or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug.

7. A phaπnaceutical composition of claim 2, wherein the sulfonylurea is selected from the group consisting of chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide, glimepiride, repaglinide, nateglinide and glibenclamide, or a phaπnaceutically-acceptable salt or a prodrug thereof, or a phamiaceutically-acceptable salt of said prodrug, or a combination thereof.

8. A pharmaceutical composition of claim 3, wherein the meglitinide is selected from the group consisting of repaglinide, nateglinide and glibenclamide, or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof.

9. A pharmaceutical composition of claim 4, wherein the thiazolidinedione is selected from the group consisting of pioglitazone, and rosightazone, or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof.

10. A pharmaceutical composition of claim 5, wherein the alpha-glucosidase inhibitor is selected from the group consisting of acarbose, vaglibose, and miglitol, or a pharmaceutically- acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or any combination thereof.

1 1. A pharmaceutical composition of claim 6, wherein the DPP-IV inhibitor is selected from the group consisting of sitaghptin, vildagliptin, saxagliptin, SYR-322, and PSN9301 , or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof.

12. A method of treating Type 2 diabetes in a mammal comprising administering to a mammal an anti-diabetically effective amount of:

(i) metformin R-(+)-lipoate

(ii) an antihyperglycemic agent, or a said pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, and

(iii) a pharmaceutically-acceptable carrier, vehicle or diluent.

13 A method of treating a diabetic complication in a mammal comprising administering to said mammal an anti-diabetically effective amount of:

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

(ii) an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said piodrug: and

(iii) a phaπnaceutically-acceptable carrier, vehicle or diluent.

14 The method of claim 12, wherein the antihyperglycemic agent is selected from a sulfonylurea, a meghtinide, a thiazolidinedione, an alpha-glucosidase inhibitor, and a DPP IV inhibitor, or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug, or a combination thereof

15 The method of claim 13, wherein the diabetic complication is diabetic neuropathy

16 The method of claim 13 wherein the diabetic complication is diabetic nephropathy

17 The method of claim 13 wherein said diabetic complication is diabetic cardiomyopathy

18 The method of claim 13, wherein the diabetic complication is diabetic retinopathy

19 The method of claim 13, wherein the diabetic complication is cataracts

20 The method of claim 13, wherein the diabetic complication is myocardial infarction

21 The method of claim 13, wherein the antihyperglycemic agent is selected from the group consisting of a sulfonylurea, a meghtinide, a thiazolidinedione, an alpha-glucosidase inhibitor, and a DPP IV inhibitor, or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof

22 A method of claim 13 wherein the metformin R (+)-lipoate and the antihyperglycemic agent, or a phaimaceutically-acceptable salt or prodrug of the antihyperglycemic agent, or a phaimaceutically-acceptable salt of said prodrug, are administered separately

23 A method of claim 13 wherein the metformin R-(+)-hpoate and the antihyperglycemic agent oi a phai maceutically-acceptable salt or prodrug of the antihyperglycemic agent, or a phaimaceutically-acceptable salt of said prodrug, are administered together

24 A kit comprising a) a first unit dosage form comprising metformin R-(+)-lipoate and a pharmaceutically- acceptable carrier, vehicle or diluent; b) a second unit dosage form comprising an antihyperglycemic agent, or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, and a pharmaceutically-acceptable carrier, vehicle or diluent; and c) a container.

25. The kit of claim 25, wherein the antihyperglycemic agent is selected from the group consisting of a sulfonylurea, a meglitinide, a thiazolidinedione, an alpha-glucosidase inhibitor, and a DPP IV inhibitor, or a pharmaceutically-acceptable salt or a prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof.