WO2008112167A1

WO2008112167A1 - Combination of metformin r-(+) lipoate and antihypertensive agents for the treatment of diabetic hyperglycemia and diabetic complications

Info

Publication number: WO2008112167A1
Application number: PCT/US2008/003095
Authority: WO
Inventors: Banavara L. Mylari; Mary E. Vaman Rao
Original assignee: Indigene Pharmaceuticals Inc
Current assignee: Indigene Pharmaceuticals Inc
Priority date: 2007-03-09
Filing date: 2008-03-07
Publication date: 2008-09-18
Anticipated expiration: 2009-09-09
Also published as: AR065669A1; CL2008000683A1; TW200848012A

Abstract

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

Description

COMBINATION OF METFORMIN R-(+) LIPOATE AND

ANTIHYPERTENSIVE AGENTS FOR THE TREATMENT OF

DIABETIC HYPERGLYCEMIA AND DIABETIC COMPLICATIONS

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

60/905,935 filed on March 9, 2007. The specification of this application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention is directed to methods, pharmaceutical compositions and kits comprising metformin R-(+) lipoate [MR-(+) LA], and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. The invention further relates to methods of using those pharmaceutical compositions for the treatment of Type 2 diabetic hyperglycemia and diabetic complications.

BACKGROUND OF THE INVENTION Metabolic syndrome is intricately intertwined with diabetes, which has become pandemic. Clinical presentation of this syndrome is patient-dependent and the co-morbidities in patients with diabetes (chronic hyperglycemia) include high blood pressure and hyperlipidemia. The long-term consequences of these co-morbidities include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and cataracts. Metformin R-(+) lipoate has been described and claimed as novel treatment for control of chronic hyperglycemia in a pending application. Thus, a need exists in the art for a combination therapy of metformin R-(+)-lipoate and antihypertensive agents to treat diabetes and diabetic complications in diabetic patients.

SUMMARY OF THE INVENTION In one aspect, the disclosure provides for combinations of metformin R-(+) lipoate and antihypertensive agents to treat diabetes and high blood pressure exacerbated diabetic complications in diabetic patients. In one aspect, the disclosure provides for methods, pharmaceutical compositions and kits comprising MR-(+) LA and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. The disclosure further provides for methods of using such pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy.

Antihypertensive agents include renin-angiotensin system (RAS) inhibitors, calcium channel blockers, A-II antagonists, diuretics, beta-adrenergic receptor blockers, neutral endo- peptidase inhibitors, vasodilators and alpha-adrenergic receptor blockers. The term "renin- angiotensin system (RAS) inhibitor" refers to a compound having the ability to inhibit the conversion of the naturally-occurring plasma glycoprotein angiotensinogen into the N-terminal deca-peptide angiotensin I, or the subsequent conversion of angiotensin I to the octa-peptide angiotensin II. While angiotensin I possesses minimal vasoactive properties, angiotensin II is a potent vasoconstrictor, which mediates increased systemic vascular resistance with concomitant deleterious impact on various hemodynamic parameters in dysfunctional states. Angiotensin II further promotes retention of sodium and water through its role in the regulation of renal hemodynamics and release from the adrenal cortex of aldosterone. Thus, the renin-angiotensin system is a known causative factor in hypertension. For a discussion of the mechanisms of action and clinical utilities of various RAS inhibitors, see for example, Drugs, 28:144 (1984), and the references cited therein.

In the practice of the compositions and methods of the disclosure, any RAS inhibitor may be employed, such as a renin inhibitor, an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin II receptor antagonist.

The term "renin inhibitor" refers to a compound having the ability to inhibit the proteolytic conversion of angiotensinogen into angiotensin I, the penultimate precursor to angiotensin II. For a review of renin inhibitors see, for example, Pharm. Res., 4:364 (1987). A variety of renin inhibitors will be known to one of ordinary skill in the art, including those disclosed in U.S. Pat. Nos. 4,814,342, 4,855,303, and 4,895,834.

The term "angiotensin-converting enzyme (ACE) inhibitor" refers to a compound having the ability to inhibit the cleavage of angiotensin I to angiotensin II. For a review of various ACE inhibitors see, for example, Am. J. Cardiol. 66:7D (1990). In one aspect, the disclosure provides for pharmaceutical compositions comprising MR-(+) LA, and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In one aspect, the disclosure provides for methods of treating a diabetic complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth herein below. In 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 one aspect, the disclosure provides for methods of treating a diabetic complication in a mammal comprising administering to said mammal MR-(+) LA, and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In one aspect, the disclosure provides for methods wherein the MR-(+) LA, and an anti-hypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof, are administered separately. In one aspect, the disclosure provides for methods wherein the MR-(+) LA, and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof, are administered in a single dosage form, for example, a tablet, a capsule or a caplet.

In one aspect, the disclosure provides for kits comprising: a) a first unit dosage form comprising MR-(+) LA; b) a second unit dosage form comprising an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof; and c) a container.

In certain embodiments as disclosed herein, the antihypertensive agent is a compound selected from the following classes of antihypertensive agents: renin-angiotensin system (RAS) inhibitors, calcium channel blockers, diuretics, endo-peptidase inhibitors, beta- adrenergic receptor blockers and alpha-adrenergic receptor blockers.

In certain embodiments, ACE inhibitors include benazepril, enalapril, lisinopril, ramipril, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. In certain embodiments, A-II antagonists include losartan, irbesartan and valsartan or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In certain embodiments, calcium channel blockers include verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, amlodipine, nimodipine, nisoldipine, nitrendipine and felodipine, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In certain embodiments, diuretics include amiloride and bendroflumethiazide, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

Endo-peptidase inhibitors may be neutral endo-peptidase inhibitors or may be dual ACE inhibitor/neutral endo-peptidase inhibitors. In certain embodiments, neutral endo- peptidase inhibitors include candoxatril and candoxatrilat, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. In certain embodiments, dual ACE inhibitor/neutral endo-peptidase inhibitors include sampatrilat and omapatrilat, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. Sampatrilat and omapatrilat are dual ACE inhibitor/neutral endo-peptidase inhibitors. Omapatrilat is also known as a vaso-peptidase inhibitor.

In certain embodiments, a beta-adrenergic receptor blocker is carvedilol, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In certain embodiments, alpha-adrenergic receptor blockers include doxazosin, prazosin and trimazosin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In one aspect, the disclosure provides for a pharmaceutical composition comprising metformin R-(+) lipoate, and an angiotensin-converting enzyme (ACE) inhibitor (e.g., benazepril, enalapril, lisinopril or ramipril) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. In certain embodiments, the ACE inhibitor is enalapril 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-1 ,4-dioate, hexyne-1 ,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 ACE inhibitor is enalapril maleate. 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 enalapril 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, metformin R-(+) lipoate is present in the amount of 250 mg and enalapril is present in the amount of 5 mg. In certain embodiments, metformin R-(+) lipoate is present in the amount of 250 mg and enalapril is present in the amount of 10 mg. In certain embodiments, metformin R-(+) lipoate is present in the amount of 500 mg and enalapril is present in the amount of 10 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 certain embodiments, wherein the pharmaceutical composition is a tablet. In one aspect, the disclosure provides for a unit dose formulation comprising:

(i) metformin R-(+) lipoate; and (ii) an ACE inhibitor (e.g., benazepril, enalapril, lisinopril or ramipril) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. In certain embodiments, the ACE inhibitor is enalapril or a pharmaceutically acceptable salt 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, 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 ACE inhibitor is enalapril maleate.

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 enalapril 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 a method of treating a diabetic complication in a human or mammal subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising comprising metformin R-(+) lipoate, and an angiotensin-converting enzyme (ACE) inhibitor (e.g., benazepril, enalapril, lisinopril and ramipril) 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, 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 ACE inhibitor is enalapril maleate.

In certain embodiments, the pharmaceutical composition comprises 250 mg of metformin R-(+) lipoate and 5 mg of enalapril. In certain embodiments, the pharmaceutical composition comprises 250 mg of metformin R-(+) lipoate and 10 mg of enalapril. In certain embodiments, the pharmaceutical composition comprises 500 mg of metformin R-(+) lipoate and 10 mg of enalapril.

In certain embodiments, the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction. In certain embodiments, the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.

In certain embodiments, the pharmaceutical composition is a tablet. In certain embodiments, the subject is dosed on a daily basis, such as once daily or twice daily. In certain embodiments, the subject is dosed twice daily.

In one aspect, the disclosure provides for a method of treating Type 2 diabetes in a human or mammal subject, comprising administering to the human or mammal subject a therapeutically effective amount of a unit dose comprising comprising metformin R-(+) lipoate, and an angiotensin-converting enzyme (ACE) inhibitor (e.g., benazepril, enalapril, lisinopril or ramipril) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. In certain embodiments, the ACE inhibitor is enalapril or a pharmaceutically acceptable salt 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 ACE inhibitor is enalapril maleate.

In certain embodiments, the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.

In certain embodiments, the pharmaceutical composition is a tablet.

In certain embodiments, the subject is dosed on a daily basis, such as once daily or twice daily.

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 anti-hypertensive agents, which may be used in accordance with the disclosure, are members of different classes of antihypertensive agents, including RAS inhibitors, calcium channel blockers, A-II antagonists, diuretics, beta-adrenergic receptor blockers, vasodilators and alpha-adrenergic receptor blockers. ACE inhibitors which may be used in accordance with the disclosure include, but are not limited to: benazepril, which may be prepared as disclosed in U.S. Pat. No. 4,410,520; captopril, which may be prepared as disclosed in U.S. Pat. No. 4,105,776); and enalapril and lisinopril, which may be prepared as disclosed in U.S. Pat. No. 4,374,829 (see Nature 288:280 (1980)) and ramipril, which may be prepared as disclosed in U.S. Pat. No. 4,587,258.

Angiotensin-II receptor antagonists (A-II antagonists) which may be used in accordance with the disclosure include, but are not limited to: candesartan, which may be prepared as disclosed in U.S. Pat. No. 5,196,444; eprosartan, which may be prepared as disclosed in U.S. Pat. No. 5,185,351 ; irbesartan, which may be prepared as disclosed in U.S. Pat. No. 5,270,317; losartan, which may be prepared as disclosed in U.S. Pat. No. 5,138,069; and valsartan, which may be prepared as disclosed in U.S. Pat. No. 5,399,578. The disclosures thereof are incorporated herein by reference.

Calcium channel blockers which may be used in accordance with the disclosure include, but are not limited to: bepridil, which may be prepared as disclosed in U.S. Pat. No. 3,962,238 or U.S. Reissue No. 30,577; clentiazem, which may be prepared as disclosed in

U.S. Pat. No. 4,567,175; diltiazem, which may be prepared as disclosed in U.S. Pat. No.

3,562,257 fendiline, which may be prepared as disclosed in U.S. Pat. No. 3,262,977; gallopamil, which may be prepared as disclosed in U.S. Pat. No. 3,261,859; mibefradil, which may be prepared as disclosed in U.S. Pat. No. 4,808,605; prenylamine, which may be prepared as disclosed in U.S. Pat. No. 3,152,173; semotiadil, which may be prepared as disclosed in U.S. Pat. No. 4,786,635; terodiline, which may be prepared as disclosed in U.S.

Pat. No. 3,371 ,014; verapamil, which may be prepared as disclosed in U.S. Pat. No.

3,261 ,859; amlodipine, which may be prepared as disclosed in U.S. Pat. No. 4,5723,909; aranipine, which may be prepared as disclosed in U.S. Pat. No. 4,572,909; barnidipine, which may be prepared as disclosed in U.S. Pat. No. 4,220,649; benidipine, which may be prepared as disclosed in European Patent Application Publication No. 106,275; cilnidipine, which may be prepared as disclosed in U.S. Pat. No. 4,672,068; efonidipine, which may be prepared as disclosed in U.S. Pat. No.4,885,284; elgodipine, which may be prepared as disclosed in U.S.

Pat. No.4,952,592; felodipine, which may be prepared as disclosed in U.S. Pat. No.

4,264,611 ; isradipine, which may be prepared as disclosed in U.S. Pat. No. 4,466,972; lacidipine, which may be prepared as disclosed in U.S. Pat. No. 4,801,599; lercanidipine, which may be prepared as disclosed in U.S. Pat. No. 4,705,797; manidipine, which may be prepared as disclosed in U.S. Pat. No. 4,892,875; nicardipine, which may be prepared as disclosed in U.S. Pat. No. 3,985,758; nifedipine, which may be prepared as disclosed in U.S.

Pat. No. 3,485,847; nilvadipine, which may be prepared as disclosed in U.S. Pat. No.

4,338,322; nimodipine, which may be prepared as disclosed in U.S. Pat. No. 3,799,934; nisoldipine, which may be prepared as disclosed in U.S. Pat. No. 4,154,839; nitrendipine, which may be prepared as disclosed in U.S. Pat. No. 3,799,934; cinnarizine, which may be prepared as disclosed in U.S. Pat. No. 2,882,271 ; flunarizine, which may be prepared as disclosed in U.S. Pat. No. 3,773,939; lidoflazine, which may be prepared as disclosed in U.S.

Pat. No. 3,267,104; lomerizine, which may be prepared as disclosed in U.S. Pat. No. 4,663,325; bencyclane, which may be prepared as disclosed in Hungarian Pat. No. 151 ,865; etafenone, which may be prepared as disclosed in German Pat. No. 1,265,758; and perhexiline, which may be prepared as disclosed in British Pat. No. 1,025,578. Amlodipine besylate, a salt of amlodipine, is disclosed in U.S. Pat. No. 4,879,303. The disclosures thereof are incorporated herein by reference. Beta-adrenergic receptor blockers (beta -blockers) which may be used in accordance with the disclosure include, but are not limited to: acebutolol, which may be prepared as disclosed in U.S. Pat. No. 3,857,952; alprenolol, which may be prepared as disclosed in Netherlands Patent Application No. 6,605,692; amosulalol, which may be prepared as disclosed in U.S. Pat. No. 4,217,305; arotinolol, which may be prepared as disclosed in U.S. Pat. No. 3,932,400; atenolol, which may be prepared as disclosed in U.S. Pat. Nos. 3,663,607 or 3,836,671 ; befunolol, which may be prepared as disclosed in U.S. Pat. No.3, 853,923; betaxolol, which may be prepared as disclosed in U.S. Pat. No. 4,252,984; bevantolol, which may be prepared as disclosed in U.S. Pat. No.3, 857, 981 ; bisoprolol, which may be prepared as disclosed in U.S. Pat. No. 4,171 ,370; bopindolol, which may be prepared as disclosed in U.S. Pat. No. 4,340,541; bucumolol, which may be prepared as disclosed in U.S. Pat. No. 3,663,570; bufetolol, which may be prepared as disclosed in U.S. Pat. No. 3,723,476; bufuralol, which may be prepared as disclosed in U.S. Pat. No. 3,929,836; bunitrolol, which may be prepared as disclosed in U.S. Pat. Nos. 3,940,489 and 3,961,071 ; buprandolol, which may be prepared as disclosed in U.S. Pat. No. 3,309,406; butiridine hydrochloride, which may be prepared as disclosed in French Pat. No. 1,390,056; butofilolol, which may be prepared as disclosed in U.S. Pat. No. 4,252,825; carazolol, which may be prepared as disclosed in German Pat. No. 2,240,599; carteolol, which may be prepared as disclosed in U.S. Pat. No. 3,910,924; carvedilol, which may be prepared as disclosed in U.S. Pat. No. 4,503,067; celiprolol, which may be prepared as disclosed in U.S. Pat. No. 4,034,009; cetamolol, which may be prepared as disclosed in U.S. Pat. No. 4,059,622; cloranolol, which may be prepared as disclosed in German Pat. No. 2,213,044; dilevalol, which may be prepared as disclosed in Clifton et al., J. Med. Chem., 25:670 (1982); epanolol, which may be prepared as disclosed in European Patent Publication Application No. 41,491; indenolol, which may be prepared as disclosed in U.S. Pat. No. 4,045,482; labetalol, which may be prepared as disclosed in U.S. Pat. No. 4,012,444; levobunolol, which may be prepared as disclosed in U.S. Pat. No. 4,463,176; mepindolol, which may be prepared as disclosed in Seeman et al., HeIv. Chim. Acta, 54:241 (1971); metipranolol, which may be prepared as disclosed in Czechoslovakian Pat. Application No. 128,471; metoprolol, which may be prepared as disclosed in U.S. Pat. No. 3,873,600; moprolol, which may be prepared as disclosed in U.S. Pat. No. 3,501,769; nadolol, which may be prepared as disclosed in U.S. Pat. No. 3,935, 267; nadoxolol, which may be prepared as disclosed in U.S. Pat. No. 3,819,702; nebivalol, which may be prepared as disclosed in U.S. Pat. No. 4,654,362; nipradilol, which may be prepared as disclosed in U.S. Pat. No. 4,394,382; oxprenolol, which may be prepared as disclosed in British Pat. No. 1,077,603; perbutolol, which may be prepared as disclosed in U.S. Pat. No. 3,551,493; pindolol, which may be prepared as disclosed in Swiss Pat. Nos. 469,002 and 472,404; practolol, which may be prepared as disclosed in U.S. Pat. No. 3,408,387; pronethalol, which may be prepared as disclosed in British Pat. No. 909,357; propranolol, which may be prepared as disclosed in U.S. Pat. Nos. 3,337,628 and 3,520,919; sotalol, which may be prepared as disclosed in Uloth et al., Journal of Medicinal Chemistry, 1966, 9, 88; sufinalol, which may be prepared as disclosed in German Pat. No. 2,728,641 ; talindol, which may be prepared as disclosed in U.S. Pat. Nos. 3,935,259 and 4,038,313; tertatolol, which may be prepared as disclosed in U.S. Pat. No.

3,960,891 ; tilisolol, which may be prepared as disclosed in U.S. Pat. No. 4,129,565; timolol, which may be prepared as disclosed in U.S. Pat. No. 3,655,663; toliprolol, which may be prepared as disclosed in U.S. Pat. No. 3,432,545; and xibenolol, which may be prepared as disclosed in U.S. Pat. No. 4,018,824. The disclosures thereof are incorporated herein by reference.

Endo-peptidase inhibitors which may be used in accordance with the disclosure include, but are not limited to sampatrilat, which may be prepared as disclosed in European Pat. Application Publication No. EP 358398; candoxatril and candoxatrilat, each of which may be prepared as disclosed in European Patent Application Publication No. EP 274234; and omapatrϊlat, which may be prepared as disclosed in U.S. Pat. No. 5,508,272. The disclosures thereof are incorporated herein by reference. Alpha-adrenergic receptor blockers (alpha-blockers) which may be used in accordance with the disclosure include, but are not limited to: amosulalol, which may be prepared as disclosed in U.S. Pat. No. 4,217,307; arotinolol, which may be prepared as disclosed in U.S. Pat. No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S. Pat. No. 4,252,721; doxazosin, which may be prepared as disclosed in U.S. Pat. No. 4,188,390; fenspiride, which may be prepared as disclosed in U.S. Pat. No. 3,399,192; indoramin, which may be prepared as disclosed in U.S. Pat. No. 3,527,761 ; labetolol, which may be prepared as disclosed above; naftopidil, which may be prepared as disclosed in U.S. Pat. No. 3,997,666; nicergoline, which may be prepared as disclosed in U.S. Pat. No. 3,228,943; prazosin, which may be prepared as disclosed in U.S. Pat. No. 3,51 1,836; tamsulosin, which may be prepared as disclosed in U.S. Pat. No. 4,703,063; tolazoline, which may be prepared as disclosed in U.S. Pat. No. 2,161,938; trimazosin, which may be prepared as disclosed in U.S. Pat. No. 3,669,968; and yohimbine, which may be isolated from natural sources according to methods well known to those skilled in the art. The disclosures thereof are incorporated herein by reference. The term "vasodilator," where used herein, is meant to include cerebral vasodilators, coronary vasodilators and peripheral vasodilators. Cerebral vasodilators which may be used in accordance with the disclosure include, but are not limited to: bencyclane, which may be prepared as disclosed above; cinnarizine, which may be prepared as disclosed above; citicoline, which may be isolated from natural sources as disclosed in Kennedy et al., J Am. Chem. Soc, 250:77 (1955), or synthesized as disclosed in Kennedy, J. of Biol. Chem., 222:185 (1956); cyclandelate, which may be prepared as disclosed in U.S. Pat. No.

3,663,597; ciclonicate, which may be prepared as disclosed in German Pat. No. 1 ,910,481 ; diisopropylamine dichloroacetate, which may be prepared as disclosed in British Pat. No. 862,248; eburnamonine, which may be prepared as disclosed in Hermann et al., J. Am. Chem. Soc, 101:1540 (1979); fasudil, which may be prepared as disclosed in U.S. Pat. No. 4,678,783; fenoxedil, which may be prepared as disclosed in U.S. Pat. No. 3,818,021 ; flunarizine, which may be prepared as disclosed in U.S. Pat. No. 3,773,939; ibudilast, which may be prepared as disclosed in U.S. Pat. No. 3,850,941 ; ifenprodil, which may be prepared as disclosed in U.S. Pat. No. 3,509,164; lomerizine, which may be prepared as disclosed in U.S. Pat. No.4,663,325; nafronyl, which may be prepared as disclosed in U.S. Pat. No.3,334,096; nicametate, which may be prepared as disclosed in Blicke et al., J. Am. Chem. Soc, 64:1722 (1942); nicergoline, which may be prepared as disclosed above; nimodipine, which may be prepared as disclosed in U.S. Pat. No. 3,799,934; papaverine, which may be prepared as reviewed in Goldberg, Chem. Prod. Chem. News, 17:371 (1954); pentifylline, which may be prepared as disclosed in German Pat. No. 860,217; tinofedrine, which may be prepared as disclosed in U.S. Pat. No. 3,563,997; vincamine, which may be prepared as disclosed in U.S. Pat. No. 3,770,724; vinpocetine, which may be prepared as disclosed in U.S. Pat. No. 4,035,750; and viquidil, which may be prepared as disclosed in U.S. Pat. No. 2,500,444. The disclosures thereof are incorporated herein by reference.

Coronary vasodilators which may be used in accordance with the disclosure include, but are not limited to: amotriphene, which may be prepared as disclosed in U.S. Pat. No. 3,010,965; bendazol, which may be prepared as disclosed in J. Chem. Soc. 2426 (1958); benfurodil hemisuccinate, which may be prepared as disclosed in U.S. Pat. No. 3,355,463; benziodarone, which may be prepared as disclosed in U.S. Pat. No. 3,012,042; chloracizine, which may be prepared as disclosed in British Pat. No. 740,932; chromonar, which may be prepared as disclosed in U.S. Pat. No. 3,282,938; clobenfural, which may be prepared as disclosed in British Pat. No. 1,160,925; clonitrate, which may be prepared from propanediol according to methods well known to those skilled in the art, e.g., see Annalen, 1870, 155, 165; cloricromen, which may be prepared as disclosed in U.S. Pat. No. 4,452,81 1 ; dilazep, which may be prepared as disclosed in U.S. Pat. No. 3,532,685; dipyridamole, which may be prepared as disclosed in British Pat. No. 807,826; droprenilamine, which may be prepared as disclosed in German Pat. No. 2,521 ,1 13; efloxate, which may be prepared as disclosed in British Pat. Nos. 803,372 and 824,547; erythrityl tetranitrate, which may be prepared by nitration of erythritol according to methods well-known to those skilled in the art; etafenone, which may be prepared as disclosed in German Pat. No.1,265,758; fendiline, which may be prepared as disclosed in U.S. Pat. No.3,262,977; floredil, which may be prepared as disclosed in German Pat. No.2,020,464; ganglefene, which may be prepared as disclosed in U.S.S.R. Pat. No.115,905; hexestrol, which may be prepared as disclosed in U.S. Pat. No. 2,357,985; hexobendine, which may be prepared as disclosed in U.S. Pat. No. 3,267,103; itramin tosylate, which may be prepared as disclosed in Swedish Pat. No. 168,308; khellin, which may be prepared as disclosed in Baxter et al., J. Chem. Soc. S 30 (1949); lidoflazine, which may be prepared as disclosed in U.S. Pat. No. 3,267,104; mannitol hexanitrate, which may be prepared by the nitration of mannitol according to methods well-known to those skilled in the art; medibazine, which may be prepared as disclosed in U.S. Pat. No. 3,119,826; nitroglycerin; pentaerythritol tetranitrate, which may be prepared by the nitration of pentaerythritol according to methods well-known to those skilled in the art; pentrinitrol, which may be prepared as disclosed in German Pat. No. 638,422-3; perhexilline, which may be prepared as disclosed above; pimefylline, which may be prepared as disclosed in U.S. Pat. No. 3,350,400; prenylamine, which may be prepared as disclosed in U.S. Pat. No. 3,152,173; propatyl nitrate, which may be prepared as disclosed in French Pat. No. 1,103,113; trapidil, which may be prepared as disclosed in East German Pat. No. 55,956; tricromyl, which may be prepared as disclosed in U.S. Pat. No. 2,769,015; trimetazidine, which may be prepared as disclosed in U.S. Pat. No. 3,262,852; trolnitrate phosphate, which may be prepared by nitration of triethanolamine followed by precipitation with phosphoric acid according to methods well-known to those skilled in the art; visnadine, which may be prepared as disclosed in U.S. Pat. Nos. 2,816,1 18 and 2,980,699. The disclosures thereof are incorporated herein by reference.

Peripheral vasodilators which may be used in accordance with the disclosure include, but are not limited to: aluminum nicotinate, which may be prepared as disclosed in U.S. Pat.

No. 2,970,082; bamethan, which may be prepared as disclosed in Coπϊgan et al., J. Am.

Chem. Soc, 67:1894 (1954); bencyclane, which may be prepared as disclosed above; betahistine, which may be prepared as disclosed in Walter et al.; J Am. Chem. Soc, 63:2771

(1941); bradykinin, which may be prepared as disclosed in Hamburg et al., Arch. Biochem. Biophys., 76:252 (1958); brovincamine, which may be prepared as disclosed in U.S. Pat. No.

4,146,643; bufeniode, which may be prepared as disclosed in U.S. Pat. No. 3,542,870; buflomedil, which may be prepared as disclosed in U.S. Pat. No. 3,895,030; butalamine, which may be prepared as disclosed in U.S. Pat. No. 3,338,899; cetiedil, which may be prepared as disclosed in French Pat. Nos. 1,460,571 ; ciclonicate, which may be prepared as disclosed in German Pat. No. 1,910,481 ; cinepazide, which may be prepared as disclosed in Belgian Pat. No. 730,345; cinnarizine, which may be prepared as disclosed above; cyclandelate, which may be prepared as disclosed above; diisopropylamine dichloroacetate, which may be prepared as disclosed above; eledoisin, which may be prepared as disclosed in British Pat. No. 984,810; fenoxedil, which may be prepared as disclosed above; flunarizine, which may be prepared as disclosed above; hepronicate, which may be prepared as disclosed in U.S. Pat. No. 3,384,642; ifenprodil, which may be prepared as disclosed above; iloprost, which may be prepared as disclosed in U.S. Pat. No. 4,692,464; inositol niacinate, which may be prepared as disclosed in Badgett et al., J. Am. Chem. Soc, 69:2907 (1947); isoxsuprine, which may be prepared as disclosed in U.S. Pat. No. 3,056,836; kallidin, which may be prepared as disclosed in Biochem. Biophys. Res. Commun., 6:210 (1961); kallikrein, which may be prepared as disclosed in German Pat. No. 1,102,973; moxisylyte, which may be prepared as disclosed in German Pat. No. 905,738; nafronyl, which may be prepared as disclosed above; nicametate, which may be prepared as disclosed above; nicergoline, which may be prepared as disclosed above; nicofuranose, which may be prepared as disclosed in Swiss Pat. No. 366,523; nylidrin, which may be prepared as disclosed in U.S. Pat. Nos. 2,661,372 and 2,661,373; pentifylline, which may be prepared as disclosed above; pentoxifylline, which may be prepared as disclosed in U.S. Pat. No.3,422,107; piribedil, which may be prepared as disclosed in U.S. Pat. No. 3,299,067; prostaglandin E₍, which may be prepared by any of the methods referenced in the Merck Index, Twelfth Edition, Budaveri, Ed., New Jersey, 1996, p. 1353; suloctidil, which may be prepared as disclosed in German Pat. No. 2,334,404; tolazoline, which may be prepared as disclosed in U.S. Pat. No. 2,161,938; and xanthinol niacinate, which may be prepared as disclosed in German Pat. No. 1,102,750 or Korbonits et al., Acta. Pharm. Hung., 38:98 (1968). The disclosures thereof are incorporated herein by reference.

The term "diuretic," within the scope of the disclosure, is meant to include diuretic benzothiadiazine derivatives, diuretic organomercurials, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracils and other diuretics such as amanozine, which may be prepared as disclosed in Austrian Pat. No. 168,063; amiloride, which may be prepared as disclosed in Belgian Pat. No. 639,386; arbutin, which may be prepared as disclosed in Tschitschibabin, Annalen, 479:303 (1930); chlorazanil, which may be prepared as disclosed in Austrian Pat. No. 168,063; ethacrynic acid, which may be prepared as disclosed in U.S. Pat. No. 3,255,241 ; etozolin, which may be prepared as disclosed in U.S. Pat. No. 3,072,653; hydracarbazine, which may be prepared as disclosed in British Pat. No. 856,409; isosorbide, which may be prepared as disclosed in U.S. Pat. No. 3,160,641; mannitol; metochalcone, which may be prepared as disclosed in Freudenberg et al., Ber., 90:957 (1957); muzolimine, which may be prepared as disclosed in U.S. Pat. No. 4,018,890; perhexiline, which may be prepared as disclosed above; ticrynafen, which may be prepared as disclosed in U.S. Pat. No. 3,758,506; triamterene which may be prepared as disclosed in U.S. Pat. No. 3,081,230; and urea. The disclosures thereof are incorporated herein by reference.

Diuretic benzothiadiazine derivatives which may be used in accordance with the disclosure include, but are not limited to: althiazide, which may be prepared as disclosed in British Pat. No. 902,658; bendroflumethiazide, which may be prepared as disclosed in U.S. Pat. No. 3,265,573; benzthiazide, McManus et al., 136th Am. Soc. Meeting (Atlantic City, September 1959), Abstract of papers, pp 13-O; benzylhydrochlorothiazide, which may be prepared as disclosed in U.S. Pat. No. 3,108,097; buthiazide, which may be prepared as disclosed in British Pat. Nos. 861,367 and 885,078; chlorothiazide, which may be prepared as disclosed in U.S. Pat. Nos. 2,809,194 and 2,937,169; chlorthalidone, which may be prepared as disclosed in U.S. Pat. No.3, 055,904; cyclopenthiazide, which may be prepared as disclosed in Belgian Pat. No. 587,225; cyclothiazide, which may be prepared as disclosed in Whitehead et al., J. of Org. Chem., 26:2814 (1961); epithiazide, which may be prepared as disclosed in U.S. Pat. No. 3,009,91 1 ; ethiazide, which may be prepared as disclosed in British Pat. No. 861,367; fenquizone, which may be prepared as disclosed in U.S. Pat. No. 3,870,720; indapamide, which may be prepared as disclosed in U.S. Pat. No. 3,565,91 1 ; hydrochlorothiazide, which may be prepared as disclosed in U.S. Pat. No. 3,164,588; hydroflumethiazide, which may be prepared as disclosed in U.S. Pat. No. 3,254,076; methyclothiazide, which may be prepared as disclosed in Close et al., J. Am. Chem. Soc, 82:1 132 (1960); meticrane, which may be prepared as disclosed in French Pat. Nos. M2790 and 1,365,504; metolazone, which may be prepared as disclosed in U.S. Pat. No. 3,360,518; paraflutizide, which may be prepared as disclosed in Belgian Pat. No. 620,829; polythiazide, which may be prepared as disclosed in U.S. Pat. No. 3,009,911 ; quinethazone, which may be prepared as disclosed in U.S. Pat. No. 2,976,289; teclothiazide, which may be prepared as disclosed in Close et al., J. Am. Chem. Soc, 82:1132 (1960); and trichlormethiazide, which may be prepared as dislcosed in deStevens et al., Experientia, 16:1 13 (1960). The disclosures thereof are incorporated herein by reference.

Diuretic sulfonamide derivatives which may be used in accordance with the disclosure include, but are not limited to: acetazolamide, which may be prepared as disclosed in U.S. Pat. No. 2,980,679; ambuside, which may be prepared as disclosed in U.S. Pat. No.

3,188,329; azosemide, which may be prepared as disclosed in U.S. Pat. No. 3,665,002; bumetanide, which may be prepared as disclosed in U.S. Pat. No. 3,634,583; butazolamide, which may be prepared as disclosed in British Pat. No. 769,757; chloraminophenamide, which may be prepared as disclosed in U.S. Pat. Nos. 2,809,194, 2,965,655 and 2,965,656; clofenamide, which may be prepared as disclosed in Olivier, Rec. Trav. Chim., 37:307

(1918); clopamide, which may be prepared as disclosed in U.S. Pat. No. 3,459,756; clorexolone, which may be prepared as disclosed in U.S. Pat. No. 3,183,243; disulfamide, which may be prepared as disclosed in British Pat. No. 851,287; ethoxolamide, which may be prepared as disclosed in British Pat. No. 795,174; furosemide, which may be prepared as disclosed in U.S. Pat. No. 3,058,882; mefruside, which may be prepared as disclosed in U.S.

Pat. No. 3,356,692; methazolamide, which may be prepared as disclosed in U.S. Pat. No.

2,783,241; piretanide, which may be prepared as disclosed in U.S. Pat. No.4,010,273; torasemide, which may be prepared as disclosed in U.S. Pat. No. 4,018,929; tripamide, which may be prepared as disclosed in Japanese Pat. No. 73 05,585; and xipamide, which may be prepared as disclosed in U.S. Pat. No. 3,567,777. 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, ethylenediamine, 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, 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- 1,2,3- 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. In certain embodiments, the acids are selected from hydrobromic acid, sulphuric acid, phosphoric acid, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, dobesilic, methanesulfonic, ethanesulfonic, laurylsulfonic, benzenesulfonic, and para-toluenesulfonic acids. 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 antihypertensive agent are administered together, as part of the same pharmaceutical composition, and to methods in which these two active agents are administered separately, as part of an appropriate dosage regimen designed to obtain the benefits of the combination therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the active agents will depend upon the MR-(+) LA and the antihyperlipidemic agent being used, the type of pharmaceutical formulations being used, the characteristics of the subject being treated and the severity of the complications. Generally, in carrying out the methods, an effective dosage for the treatment of a warm-blooded animal, including a mammal, like a human, for MR-(+) LA is in the range of about 2.5 mg per day to about 1 g per day in single or divided doses, such as about 2.5 mg per day to about 750 mg per day, 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. Antihypertensive 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 antihypertensive 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.

Pharmaceutical compositions comprising, MR-(+) LA, and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof are hereinafter referred to, collectively, as "the active compositions of the disclosure."

In certain embodiments of the disclosure, the active compositions may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the active compositions of the disclosure may be administered intranasally, as a rectal suppository or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. In certain embodiments of the disclosure, the active compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compositions of the disclosure and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. In certain embodiments, 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.

In certain embodiments of the disclosure, a composition may be 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, 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 the 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 MR-(+) LA, and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. The amount of each of those ingredients may independently be, for example, 0.0001%-95% of the total amount of the composition, where the total amount may not, of course, exceed 100%. In any event, the composition or formulation to be administered will contain a quantity of each of the components of the composition according to the disclosure in an amount effective to treat the disease/condition of the subject being treated. In one aspect, the disclosure provides for combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: MR- (+) LA, and an antihypertensive agent, as described above. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . " etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of the MR(+)LA can consist of one tablet or capsule while a daily dose of the antihypertensive agent can consist of several tablets or capsules and vice versa. The memory aid should reflect this. In certain embodients, the disclosure provides for a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken. The compositions of this disclosure generally will be administered in a convenient formulation.

As a particular example, this disclosure provides for the pharmaceutically acceptable acid addition salts of metformin R-(+) lipoate. Since metformin R-(+) lipoate is an amine, it is basic in nature and accordingly reacts with any number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, tartaric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 -sulfonate, naphthalene-2 -sulfonate, mandelate, hippurate, gluconate, lactobionate, and the like salts. In certain embodiments, the pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as fumaric acid, tartaric acid and maleic acid.

The disclosure provides for pharmaceutically acceptable acid addition salts of angiotensin-converting enzyme (ACE) inhibitor. Such compounds may be basic in nature and accordingly react with any number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, tartaric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, hippurate, gluconate, lactobionate, and the like salts. In certain embodimetns, the pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as fumaric acid, tartaric acid and maleic acid.

The following examples illustrate preferred embodiments of the disclosure.

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

Sodium methoxide (0.31 g) was dissolved in methanol (2 mL) and to this solution was added metformin hydrochloride (1 g) while stirring. The stirring was continued for an additional 10 min. Acetone (40 mL) was then added, stirred for 20 min, and the mixture was filtered. To the filtrate, containing metformin in the form of its free base, R-(+) lipoic acid (1.25 g dissolved in 15 mL acetone) was added dropwise with constant stirring resulting in the precipitation of a pale yellow solid. The mixture was stirred for an additional 20 min and filtered. The light yellow solid was washed with acetone (30 mL), filtered, and dried to yield metformin R-(+)-lipoate; m.p. 148-150° C; [α]D20 = + 67.7° (c=l, water); 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 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. BBAV rats were chosen for the current study because the BBAV 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 BBAV rats received daily insulin, which was discontinued 24 h prior to performing the isolated heart perfusion studies, leading to a hyperglycemic state. The rats were acutely diabetic, receiving 2.02 ± 0.04 units of insulin daily, and had been diabetic for at least 12 ± 3 days. The mean blood glucose levels in these diabetic rats were 386 ± 24 mg/dL. The age- matched non-diabetic controls had mean blood glucose levels of 92 ± 12 mg/dL.

Isolated Perfused Heart Model

This example describes an isolated perfused rat heart model used in development of the disclosure. Studies are performed using an isovolumic isolated rat heart preparation. Acutely diabetic male BB/W rats and non-diabetic age-matched (3-4 months old) control are pretreated with heparin (1000 u; IP), followed by sodium pentobarbital (65 mg/kg; IP). After deep anesthesia is achieved as determined by the absence of a foot reflex, the hearts are rapidly excised and placed into iced saline. The arrested hearts are retrograde perfused in a non-recirculating model through the aorta within 2 min. following their excision. Left ventricular developed pressure (LVDP) is determined using a latex balloon in the left ventricle with high pressure tubing connected to a pressure transducer. Perfusion pressure is monitored using high pressure tubing off the perfusion line. Hemodynamic measurements are recorded on a 4-channel Gould recorder. The system has two parallel perfusion lines with separate oxygenators, pumps and bubble traps, but common temperature control allowing rapid change perfusion media. The hearts are perfused using an accurate roller pump. The perfusate consists of 118 mM NaCl, 47 mM KCl, 12 mM CaCl₂, 12 mM MgCl₂, 25 mM NaHCO₃, and the substrate 1 1 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 © 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 R-(+) lipoate. In the metformin R-(+) 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 R-(+) 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 R-(+) 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 R-(+) lipoate. The hearts are subjected to 30 min. of low-flow ischemia (flow rate 1.25 mL/min) and 30 minutes of reperfusion at normal flow rate (12.5 mL/min).

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

It should be understood that the disclosure is not limited to the particular embodiments described herein, but that various changes and modifications may be made without departing from the spirit and scope of the disclosure as defined by the following claims. The journal articles, scientific references, and patent publications cited above are wholly incorporated herein by reference.

Claims

What is claimed is:

1. A pharmaceutical composition comprising metformin R-(+) lipoate, and an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

2. A pharmaceutical composition of claim 1 , wherein the ACE inhibitor is selected from the group consisting of benazepril, enalapril, lisinopril and ramipril, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

3. A pharmaceutical composition of claim 2, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

4. A pharmaceutical composition of claim 3, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition of claim 4, wherein 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-1,6- 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.

6. A pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of a fumarate, maleate, or tartrate.

7. A pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable salt is a maleate.

8. A pharmaceutical composition of claim 4, wherein the ACE inhibitor is enalapril maleate.

9. A pharmaceutical composition of claim 8, wherein 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.

10. A pharmaceutical composition of claim 9, wherein the enalapril 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.

11. A pharmaceutical composition of claim 10, comprising metformin R-(+) lipoate in the amount of 250 mg and enalapril in the amount of 5 mg.

12. A pharmaceutical composition of claim 10, comprising metformin R-(+) lipoate in the amount of 250 mg and enalapril in the amount of 10 mg.

13. A pharmaceutical composition of claim 12, comprising metformin R-(+) lipoate in the amount of 500 mg and enalapril in the amount of 10 mg.

14. A pharmaceutical composition of claim 9, formulated as a tablet.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered once, twice, or three times daily.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is administered once daily.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.

18. The pharmaceutical composition of claim 17, wherein the mode of administration is oral.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is a tablet.

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

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

21. The unit dose formulation of claim 20, wherein the ACE inhibitor is selected the group consisting of benazepril, enalapril, lisinopril and ramipril, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

22. The unit dose formulation of claim 21, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

23. The unit dose formulation of claim 22, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

24. A unit dose of claim 23, wherein 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.

25. A unit dose of claim 24, wherein the pharmaceutically acceptable salt is selected from the group consisting of a fumarate, maleate, or tartrate.

26. A unit dose of claim 23, wherein the pharmaceutically acceptable salt is a maleate.

27. A unit dose of claim 23, wherein the ACE inhibitor is enalapril maleate.

28. The unit dose formulation of claim 27, wherein 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.

29. The unit dose formulation of claim 28, wherein the enalapril 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.

30. The unit dose formulation of claim 29, comprising metformin R-(+) lipoate in the amount of 250 mg and enalapril in the amount of 5 mg.

31. The unit dose formulation of claim 29, comprising metformin R-(+) lipoate in the amount of 250 mg and enalapril in the amount of 10 mg.

32. The unit dose formulation of claim 29, comprising metformin R-(+) lipoate in the amount of 500 mg and enalapril in the amount of 10 mg.

33. A method of treating a diabetic complication in a human or mammal subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising comprising metformin R-(+) lipoate, and an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

34. The method of claim 33, wherein the ACE inhibitor is selected from the group consisting of benazepril, enalapril, lisinopril and ramipril, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

35. The method of claim 34, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

36. The method of claim 35, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein 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.

38. A method of claim 37, wherein the pharmaceutically acceptable salt is selected from the group consisting of a fumarate, maleate, or tartrate.

39. A method of claim 36, wherein the pharmaceutically acceptable salt is a maleate.

40. A method of claim 36, wherein the ACE inhibitor is enalapril maleate.

41. A method of claim 33, wherein the pharmaceutical composition comprises 250 mg of metformin R-(+) lipoate and 5 mg of enalapril.

42. A method of claim 33, wherein the pharmaceutical composition comprises 250 mg of metformin R-(+) lipoate and 10 mg of enalapril.

43. A method of claim 33, wherein the pharmaceutical composition comprises 500 mg of metformin R-(+) lipoate and 10 mg of enalapril.

44. The method of claim 33, wherein the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.

45. The method of claim 33, wherein the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.

46. The method of claim 45, wherein the mode of administration is oral.

47. The method of claim 33, wherein the pharmaceutical composition is a tablet.

48. The method of claim 33, wherein the subject is dosed once daily.

49. The method of claim 33, wherein the subject is dosed twice daily.

50. A method of treating Type 2 diabetes in a human or mammal subject, comprising administering to the human or mammal subject a therapeutically effective amount of a unit dose comprising comprising metformin R-(+) lipoate, and an angiotensin- converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

51. The method of claim 50, wherein the ACE inhibitor is selected from the group consisting of benazepril, enalapril, lisinopril and ramipril, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

52. The method of claim 51, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

53. The method of claim 52, wherein the ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

54. The method of claim 53, wherein 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.

55. A method of claim 54, wherein the pharmaceutically acceptable salt is selected from the group consisting of a fumarate, maleate, or tartrate.

56. A method of claim 53, wherein the pharmaceutically acceptable salt is a maleate.

57. A method of claim 53, wherein the ACE inhibitor is enalapril maleate.

58. A method of claim 50, wherein the pharmaceutical composition comprises 250 mg of metformin R-(+) lipoate and 5 mg of enalapril.

59. A method of claim 50, wherein the pharmaceutical composition comprises 250 mg of metformin R-(+) lipoate and 10 mg of enalapril.

60. A method of claim 50, wherein the pharmaceutical composition comprises 500 mg of metformin R-(+) lipoate and 10 mg of enalapril.

61. The method of claim 50, wherein the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.

62. The method of claim 61, wherein the mode of administration is oral.

63. The method of claim 50, wherein the pharmaceutical composition is a tablet.

64. The method of claim 50, wherein the subject is dosed once daily.

65. The method of claim 50, wherein the subject is dosed twice daily.