WO2009085198A2

WO2009085198A2 - Combination of metformin r-(+)-lipoate and antiobesity agents for the treatment of diabetic hyperglycemia and diabetic complications

Info

Publication number: WO2009085198A2
Application number: PCT/US2008/013878
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
Also published as: WO2009085198A3

Abstract

Disclosed are pharmaceutical 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 antiobesity agents.

Description

COMBINATION OF METFORMIN R-(+)-LIPOATE AND ANTIOBESITY 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 Serial No. 61/008,922 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, pharmaceutical compositions and kits comprising metformin R-(+)-lipoate [MR-(+) LA], and an antiobesity 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 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, obesity 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 antiobesity agents to treat diabetes and obesity exacerbated diabetic complications in diabetic patients.

SUMMARY OF THE INVENTION

In one aspect, the disclosure relates to combinations of metformin R-(+)-lipoate and antiobesity agents to treat diabetes and obesity exacerbated diabetic complications in diabetic patients. In one aspect, the disclosure relates to methods, pharmaceutical compositions, and kits comprising metformin R-(+)-lipoate and an antiobesity 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.

Antiobestiy agents include cannabinoid receptor 1 (CB 1) antagonists, serotonin and norepinephrine reuptake inhibitors and lipase inhibitors, and pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.

In certain embodiments, the disclosure provides for pharmaceutical compositions comprising metformin R-(+)-lipoate; and an antiobesity 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 other embodiments, the antiobesity agent is a cannabinoid receptor 1 (CB-I) antagonist (e.g., rimonabant and CP-945,598, preferably rimonabant) or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.

In alternative embodiments, the antiobesity agent is a serotonin and norepinephrine reuptake inhibitor (e.g., sibutramine, WAY 163909, and APD-356, preferably sibutramine) or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.

In certain embodiments, the antiobesity agent is a lipase inhibitor (e.g., Orlistat and ATL-962, preferably Orlistat) or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug. In certain embodiments, the antiobesity agent is a cannabinoid receptor 1 (CB-I ) antagonist (e.g., rimonabant and CP-945,598), a serotonin and norepinephrine reuptake inhibitor (e.g., sibutramine, WAY 163909, and APD-356), or a lipase inhibitor (e.g., Orlistat and ATL-962), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug derivative thereof. 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, lnethylbenzoate, 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, 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 antiobesity 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 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, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.

In one aspect, the disclosure provides for methods of treating diabetic complications in a mammal comprising administering to the mammal a pharmaceutical composition of the disclosure. In particular, 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 certain embodiments, the metformin R-(+)-lipoate and the antiobesity agent, or a pharmaceutically-acceptable salt or prodrug of the antiobesity agent, or a pharmaceutically-acceptable salt of said prodrug, may be administered separately. In certain embodiments, the metformin R-(+)-lipoate and the antiobesity agent, or a pharmaceutically-acceptable salt or prodrug of the antiobesity agent, or a pharmaceutically-acceptable salt of said prodrug, may be administered together.

In certain embodiments, the antiobesity agent is a cannabinoid receptor 1 (CB- I ) antagonist (e.g., rimonabant and CP-945,598), a serotonin and norepinephrine reuptake inhibitor (e.g., sibutramine, WAY 163909, and APD-356), or a lipase inhibitor (e.g., Orlistat and ATL-962), 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 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 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 antiobesity 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 one aspect, the disclosure provides for methods wherein metformin R-(+)-lipoate and the antiobesity agent, or a pharmaceutically-acceptable salt or prodrug of the antiobesity agent, or a pharmaceutically-acceptable salt of said prodrug, are administered in a single dosage form, (e.g., a tablet, a capsule or a caplet). In one aspect, the disclosure provides for kits 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 antiobesity 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.

In certain embodiments, the antiobesity agent is a cannabinoid receptor 1 (CB- I ) antagonist (e.g., rimonabant and CP-945,598), a serotonin and norepinephrine reuptake inhibitor (e.g., sibutramine, WAY 163909, and APD-356), or a lipase inhibitor (e.g., Orlistat and ATL-962), 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 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.

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 term "cannabinoid receptor 1 (CB-I) antagonist" refers to a compound that has the ability to compete selectively for the cannabinoid- 1 receptors. For a review of cannabinoid receptor 1 (CB-I) antagonists see, for example, Nat. Rev. Drug Discov., 5, 919 (2006) and J. Pharmacol. Exp. Ther., 277, 586 (1996).

The term "serotonin and norepinephrine reuptake inhibitor" refers to a compound that has the ability to block the reuptake of both serotonin and norepinephrine. For a review of serotonin and norepinephrine reuptake inhibitors see, for example, Nat. Rev. Drug Discov., 5, 919 (2006) and Ann. Pharmacother., 33, 968 (1999). The term "lipase inhibitors" refers to a compound that has the ability to block the enzyme lipase. For a review of lipase inhibitors see, for example, Nat. Rev. Drug Discov., 5, 919 (2006) and Obes. Res. 9, 599 (2001).

The antiobesity agents, which may be used in accordance with the disclosure, may be members of different classes of antiobesity agents, including cannabinoid receptor 1 (CB-I) antagonists, serotonin and norepinephrine reuptake inhibitors and lipase inhibitors, and pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs. Cannabinoid receptor 1 (CB-I) antagonists which are within the scope of disclosure include, but are not limited to: rimonabant, which may be prepared as disclosed in U.S. Pat. No .6, 825,209; and CP-945,598, which may be prepared as disclosed in U.S. Pat. Nos. 7,129,239 and 7,145,012. The disclosures thereof are incorporated herein by reference.

Serotonin and norepinephrine reuptake inhibitors which are within the scope of disclosure include, but are not limited to: sibutramine, which may be prepared as disclosed in U.S. Pat. No. 6,610,887; APD-356, which may be prepared as disclosed in U.S. Pat. No. 6,953,787; and WAY 163909, which may be prepared as disclosed in U.S. Pat. Nos.

7,129,237 and 7,012,089. The disclosures thereof are incorporated herein by reference.

Lipase inhibitors which are within the scope of the disclosure include, but are not limited to: orlistat, which may be prepared as disclosed in U.S. Pat. No. 4,983,746 and U.S. Pat. No. 6, 734,314; and ATL- 962, which may be prepared as disclosed in U.S. Pat. No. 6,624,161. 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, 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. Preferred 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 relates to methods of treatment in which metformin R-

(+)-lipoate and an antiobesity agent, or a pharmaceutically-acceptable salt or prodrug of the antiobesity agent, or a pharmaceutically-acceptable salt of said prodrug, are administered together, as part of the same pharmaceutical composition.

In one aspect, the disclosure relates to methods of treatment in which metformin R- (+)-lipoate and an antiobesity agent, or a pharmaceutically-acceptable salt or prodrug of the antiobesity agent, or a pharmaceutically-acceptable salt of said prodrug, 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 metformin R-(+)-lipoate and the antiobesity 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 metformin R-(+)-lipoate is in the range of about 5 mg/kg/day to about 100 mg/kg/day in single or divided doses, preferably about 5 mg/kg/day to about 60 mg/kg/day in single or divided doses and the antiobesity agent will be administered in single or divided doses. Antiobesity 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 about 10 mg/kg/day to about 300 mg/kg/day for an average subject, depending upon the antiobesity 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 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 antiobesity 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 antiobesity 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, 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. Antiobesity agents will generally be administered in amounts ranging from about 2.5 mg to about 1 g per day in single or divided doses, for example, about 2.5 mg to about 750 mg per day for an average 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 antiobesity 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 can be via any method which delivers it preferentially 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. 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 are administered in single (e.g., once daily) or multiple doses or via constant infusion.

Pharmaceutical compositions comprising metformin R-(+)-lipoate, and an antiobesity 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 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.

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 formed by combining the active compositions of this 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 including, 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. Preferred 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.

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) may be 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, 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 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).

The active compositions of the disclosure contain an amount of metformin R-(+)- lipoate, and an antiobesity 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%. 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.

Since the present 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 comprises two separate pharmaceutical compositions: metformin R-(+)-lipoate, and an antiobesity 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 aldose reductase inhibitor may comprise one tablet or capsule while a daily dose of the antiobesity agent may comprise several tablets or capsules and vice versa. The memory aid should reflect this. In another specific embodiment 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 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 are provided for 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 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 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 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 1 18 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 waterjacketed 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 (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 mm of reperfusion Hearts are treated with 1 μM metformin hpoate In the metformin hpoate treated diabetic group (DZ), hearts are subjected to 10 mm of normoxic perfusion with normal Krebs-Henseleit buffer and 10 mm of normoxic perfusion with Krebs-Henseleit buffer containing 1 μM metformin hpoate The hearts are then subjected to 20 mm of zero-flow ischemia followed by 60 mm 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 hpoate 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 hpoate 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, 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, 4,617,312, 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 undei stood that the disclosuie is not limited to the particular embodiments described herein, but that various changes and modifications may be made without departing fiom the spint and scope of the disclosuie 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 antiobesity agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug; and

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

2. The phaπnaceutical composition of claim 1, wherein the antiobesity agent is a cannabinoid receptor 1 (CB- I) antagonist, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.

3. The pharmaceutical composition of claim 1, wherein the antiobesity agent is a serotonin and norepinephrine reuptake inhibitor, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.

4. The pharmaceutical composition of claim 1, wherein the antiobesity agent is a lipase inhibitor, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug.

5. The pharmaceutical composition of claim 2, wherein the cannabinoid receptor 1 (CB-I) antagonist is selected from the group consisting of rimonabant and CP-945,598, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof.

6. The pharmaceutical composition of claim 3, wherein the serotonin and norepinephrine reuptake inhibitor is selected from sibutramine, WAY 163909, and APD-356, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or any combination thereof.

7. The pharmaceutical composition of claim 4, wherein the lipase inhibitor is selected from the group consisting of Orlistat and ATL-962, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or combination thereof.

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

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

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

9. 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; and

10. The method of claim 8, wherein the antiobesity agent is selected from the group consisting of a cannabinoid receptor 1 (CB-I) antagonist, a serotonin and norepinephrine reuptake inhibitor, and a lipase inhibitor, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof.

1 1. The method of claim 9, wherein the diabetic complication is diabetic neuropathy.

12. The method of claim 9, wherein the diabetic complication is diabetic nephropathy.

13. The method of claim 9, wherein the diabetic complication is diabetic cardiomyopathy.

14. The method of claim 9, wherein the diabetic complication is diabetic retinopathy.

15. The method of claim 9, wherein the diabetic complication is cataracts.

16. The method of claim 9, wherein the diabetic complication is myocardial infarction.

17. The method of claim 9, wherein the antiobesity agent is selected from the group consisting of a cannabinoid receptor 1 (CB- I ) antagonist, a serotonin and norepinephrine reuptake inhibitor, and a lipase inhibitor, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or a combination thereof.

18. The method of claim 9, wherein the metformin R-(+)-lipoate and the antiobesity agent, or a pharmaceutically-acceptable salt or prodrug of the antiobesity agent, or a pharmaceutically- acceptable salt of said prodrug, are administered separately.

19. The method of claim 9, wherein the metformin R-(+)-lipoate and the antiobesity agent, or a pharmaceutically-acceptable salt or prodrug of the antiobesity agent, or a pharmaceutically- acceptable salt of said prodrug, are administered together.

20. 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 antiobesity 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.

21. The kit of claim 22 wherein the antiobesity agent is selected from a cannabinoid receptor 1 (CB-I) antagonist, a serotonin and norepinephrine reuptake inhibitor, and a lipase inhibitor, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, or any combination thereof.