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WO2008112167A1 - Combinaison de lipoate de metformine r-(+) et d'agents hypotenseurs pour le traitement de l'hyperglycémie diabétique et des complications du diabète - Google Patents

Combinaison de lipoate de metformine r-(+) et d'agents hypotenseurs pour le traitement de l'hyperglycémie diabétique et des complications du diabète Download PDF

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Publication number
WO2008112167A1
WO2008112167A1 PCT/US2008/003095 US2008003095W WO2008112167A1 WO 2008112167 A1 WO2008112167 A1 WO 2008112167A1 US 2008003095 W US2008003095 W US 2008003095W WO 2008112167 A1 WO2008112167 A1 WO 2008112167A1
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Prior art keywords
pharmaceutical composition
enalapril
pharmaceutically acceptable
prepared
acceptable salt
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PCT/US2008/003095
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English (en)
Inventor
Banavara L. Mylari
Mary E. Vaman Rao
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Indigene Pharmaceuticals Inc.
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Publication of WO2008112167A1 publication Critical patent/WO2008112167A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • RAS renin-angiotensin system
  • 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.
  • 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.
  • the renin-angiotensin system is a known causative factor in hypertension.
  • any RAS inhibitor may be employed, such as a renin inhibitor, an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin II receptor antagonist.
  • ACE angiotensin-converting enzyme
  • 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.
  • 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.
  • angiotensin-converting enzyme (ACE) inhibitor refers to a compound having the ability to inhibit the cleavage of angiotensin I to angiotensin II.
  • ACE angiotensin-converting enzyme
  • the disclosure provides for pharmaceutical compositions comprising MR-(+) LA, and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the disclosure provides for methods of treating a diabetic complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth herein below.
  • diabetic complications as, for example, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy can be treated by the methods of the disclosure.
  • the disclosure provides for methods of treating a diabetic complication in a mammal comprising administering to said mammal MR-(+) LA, and an antihypertensive agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • 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.
  • 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.
  • 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.
  • RAS renin-angiotensin system
  • ACE inhibitors include benazepril, enalapril, lisinopril, ramipril, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • A-II antagonists include losartan, irbesartan and valsartan or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • 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.
  • 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.
  • neutral endo- peptidase inhibitors include candoxatril and candoxatrilat, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • 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.
  • a beta-adrenergic receptor blocker is carvedilol, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • alpha-adrenergic receptor blockers include doxazosin, prazosin and trimazosin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the disclosure provides for a pharmaceutical composition
  • 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.
  • ACE angiotensin-converting enzyme
  • the ACE inhibitor is enalapril or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • 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, ⁇ - hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1- sulfon
  • the ACE inhibitor is enalapril maleate.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition is formulated as a tablet.
  • 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.
  • the disclosure provides for a unit dose formulation comprising:
  • metformin R-(+) lipoate (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.
  • the ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.
  • 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, ⁇ -hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 -sulfonate
  • 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.
  • 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.
  • 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.
  • 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.
  • ACE angiotensin-converting enzyme
  • 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, ⁇ - hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1- sulfonate
  • the ACE inhibitor is enalapril maleate.
  • 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.
  • the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.
  • the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • the pharmaceutical composition is a tablet.
  • the subject is dosed on a daily basis, such as once daily or twice daily. In certain embodiments, the subject is dosed twice daily.
  • 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.
  • ACE angiotensin-converting enzyme
  • the ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.
  • 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, ⁇ - hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1- sulf
  • the ACE inhibitor is enalapril maleate.
  • 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.
  • the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • the pharmaceutical composition is a tablet.
  • the subject is dosed on a daily basis, such as once daily or twice daily.
  • 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.
  • treating refers to retarding, arresting or reversing the progress of, or alleviating or preventing either the disorder or condition to which the term “treating” applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating a disorder, symptom or condition, as the term “treating” is defined above.
  • 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 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
  • 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.
  • 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.
  • felodipine which may be prepared as disclosed in U.S. Pat. No.
  • 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.
  • 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.
  • Beta-adrenergic receptor 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 omapatr ⁇ lat, 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.
  • 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.
  • 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.
  • 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 Magnoliae 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • bamethan which may be prepared as disclosed in Co ⁇ gan et al., J. Am.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts, where appropriate.
  • 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.
  • alkali metal salts e.g., sodium and potassium
  • alkaline earth metal salts e.g., calcium and magnesium
  • aluminum salts
  • salts are, for example, inorganic acids, such as hydrohalic acid, e. g. hydrochloric, hydrobromic or the like, or sulfuric acid, nitric acid, or phosphoric acid; or suitable organic acids, for example suitable aliphatic acids, like aliphatic mono or dicarboxylic acids, hydroxyalkanoic or hydroxyalkanedioic acids, e.g.
  • 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.
  • MR-(+) LA may occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the disclosure.
  • 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.
  • 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.
  • some variation in dosage will necessarily occur depending on the condition of the subject being treated.
  • 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.
  • 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.”
  • the active compositions may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the active compositions of the disclosure may be administered intranasally, as a rectal suppository or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. In certain embodiments of the disclosure, the active compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the active compositions of the disclosure and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients 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.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • 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.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • solutions of the active compositions of the disclosure in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • 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.
  • composition for buccal administration the composition (two active agents administered together or separately) may take the form of tablets or lozenges formulated in a conventional manner.
  • the active compounds of the disclosure 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.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges 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.
  • aqueous or partially aqueous solutions are prepared.
  • 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%.
  • the composition or formulation to be administered will contain a quantity of each of the components of the composition according to the disclosure in an amount effective to treat the disease/condition of the subject being treated.
  • the disclosure provides for combining separate pharmaceutical compositions in kit form.
  • the kit comprises two separate pharmaceutical compositions: MR- (+) LA, and an 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.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . " etc.
  • a "daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of the MR(+)LA 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.
  • the disclosure provides for a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • compositions of this disclosure generally will be administered in a convenient formulation.
  • 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.
  • inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric and phosphoric acid
  • 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
  • ACE angiotensin-converting enzyme
  • 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
  • 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.
  • 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).
  • IDDM human insulin-dependent diabetes
  • spontaneous diabetes appears during adolescence, with an abrupt clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketonuria.
  • BB rats 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.
  • This example describes an isolated perfused rat heart model used in development of the disclosure. Studies are performed using an isovolumic isolated rat heart preparation. Acutely diabetic male BB/W rats and non-diabetic age-matched (3-4 months old) control are pretreated with heparin (1000 u; IP), followed by sodium pentobarbital (65 mg/kg; IP). After deep anesthesia is achieved as determined by the absence of a foot reflex, the hearts are rapidly excised and placed into iced saline. The arrested hearts are retrograde perfused in a non-recirculating model through the aorta within 2 min. following their excision.
  • LVDP Left ventricular developed pressure
  • Perfusion pressure is monitored using high pressure tubing off the perfusion line. Hemodynamic measurements are recorded on a 4-channel Gould recorder.
  • the system has two parallel perfusion lines with separate oxygenators, pumps and bubble traps, but common temperature control allowing rapid change perfusion media.
  • the hearts are perfused using an accurate roller pump.
  • the perfusate consists of 118 mM NaCl, 47 mM KCl, 12 mM CaCl 2 , 12 mM MgCl 2 , 25 mM NaHCO 3 , 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.
  • Diabetic control (DC) diabetic treated (DZ) normal ⁇ control and normal treated (CZ) hearts are subjected to 20 min. of normoxic perfusion followed by 20 min. of zero-flow ischemia where the perfusate flow is completely shut off, followed by 60 min. of reperfusion.
  • Hearts are treated with 1 ⁇ M metformin R-(+) lipoate.
  • 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 ⁇ M metformin R-(+) lipoate.
  • This example describes a procedure used for study of low-flow ischemia in diabetic controls, diabetic treated, non-diabetic treated and non-diabetic control isolated hearts.
  • Diabetic control hearts are subjected to 20 min. of normoxic perfusion at a flow rate of 12.5 mL/min. followed by 30 minutes of low-flow ischemia where the perfusate flow is slowed down to 1.25 mL/min, that is about 10% of normal perfusion, followed by 30 min. of reperfusion at a normal flow rate (12.5 mL/min).
  • metformin 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 ⁇ M 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).

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Abstract

L'invention porte sur des compositions pharmaceutiques, procédés et kits comprenant du lipoate de metformine R-(+) et un agent hypotenseur ou un sel pharmaceutiquement acceptable, un hydrate, un solvate et un dérivé de promédicament de ces derniers. Lesdits compositions pharmaceutiques, procédés et kits sont destinés au traitement de l'hyperglycémie du diabète de type 2 et des complications du diabète.
PCT/US2008/003095 2007-03-09 2008-03-07 Combinaison de lipoate de metformine r-(+) et d'agents hypotenseurs pour le traitement de l'hyperglycémie diabétique et des complications du diabète WO2008112167A1 (fr)

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WO2011025270A3 (fr) * 2009-08-25 2011-07-21 한올바이오파마주식회사 Sel d'acide cafféique de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant
WO2011025267A3 (fr) * 2009-08-25 2011-07-21 한올바이오파마주식회사 Méthanesulfonate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant
WO2011025269A3 (fr) * 2009-08-25 2011-07-21 한올바이오파마주식회사 Taurate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant
EP2599481A1 (fr) * 2011-11-30 2013-06-05 Lunamed AG Acide 4-phénylbutyrique pour traiter ou prévenir diverses maladies
US20150231123A1 (en) * 2012-10-30 2015-08-20 Pharnext Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level
EP3062782A1 (fr) * 2013-10-30 2016-09-07 Pharnext Compositions, procédés et utilisations pour le traitements de diabète et d'états associés en régulant le niveau de glycémie
US20190307735A1 (en) * 2015-03-26 2019-10-10 Merck Sharp & Dohme Corp Composition and Methods for Treating Chronic Kidney Disease

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WO2011025270A3 (fr) * 2009-08-25 2011-07-21 한올바이오파마주식회사 Sel d'acide cafféique de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant
WO2011025267A3 (fr) * 2009-08-25 2011-07-21 한올바이오파마주식회사 Méthanesulfonate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant
WO2011025269A3 (fr) * 2009-08-25 2011-07-21 한올바이오파마주식회사 Taurate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant
EP2599481A1 (fr) * 2011-11-30 2013-06-05 Lunamed AG Acide 4-phénylbutyrique pour traiter ou prévenir diverses maladies
US20150231123A1 (en) * 2012-10-30 2015-08-20 Pharnext Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level
JP2016501841A (ja) * 2012-10-30 2016-01-21 ファーネクストＰｈａｒｎｅｘｔ 血中グルコースレベルを制御することによる糖尿病及び関連容態の処置のための組成物、方法及び使用
US10092554B2 (en) * 2012-10-30 2018-10-09 Pharnext Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level
EP2914252B1 (fr) * 2012-10-30 2019-09-04 Pharnext Compositions, traitements et utilisations pour le traitement du diabète et troubles connexes par le contrôle du taux de glycémie
US10596160B2 (en) 2012-10-30 2020-03-24 Pharnext Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level
AU2018253580B2 (en) * 2012-10-30 2020-04-30 Pharnext Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level
EP3062782A1 (fr) * 2013-10-30 2016-09-07 Pharnext Compositions, procédés et utilisations pour le traitements de diabète et d'états associés en régulant le niveau de glycémie
US20190307735A1 (en) * 2015-03-26 2019-10-10 Merck Sharp & Dohme Corp Composition and Methods for Treating Chronic Kidney Disease

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