WO2006104401A1 - Compositions antagonistes du cuivre - Google Patents

Compositions antagonistes du cuivre Download PDF

Info

Publication number
WO2006104401A1
WO2006104401A1 PCT/NZ2006/000058 NZ2006000058W WO2006104401A1 WO 2006104401 A1 WO2006104401 A1 WO 2006104401A1 NZ 2006000058 W NZ2006000058 W NZ 2006000058W WO 2006104401 A1 WO2006104401 A1 WO 2006104401A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
copper
alkyl
triethylenetetramine
antagonist
Prior art date
Application number
PCT/NZ2006/000058
Other languages
English (en)
Inventor
Garth James Smith Cooper
Original Assignee
Protemix Corporation Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Protemix Corporation Limited filed Critical Protemix Corporation Limited
Publication of WO2006104401A1 publication Critical patent/WO2006104401A1/fr

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • compositions containing a pharmaceutically acceptable copper antagonist compound or a salt or prodrug thereof and a pharmaceutically acceptable hypoglycemic compound or a salt or prodrug thereof, articles and kits and delivery devices containing such compositions, and tablets and capsules and formulations comprising such compositions.
  • the invention also relates to methods of using such compositions to treat subjects suffering from or at risk for various diseases, disorders, and conditions, including impaired glucose tolerance; impaired fasting glucose; prediabetes; diabetes and/or its complications, including type 1 and type 2 diabetes and their complications; insulin resistance; Syndrome X; obesity and other weight related disorders; cardiomyopathy, including diabetic cardiomyopathy; glucose metabolism disorders; nerve diseases, including diabetic neuropathy; kidney disease, including diabetic nephropathy; eye disease, including diabetic retinopathy and cataracts; hyperglycemia; hypercholesterolemia; hypertension; hyperinsulinemia; hyperlipidemia; atherosclerosis; tissue ischemia; diseases and disorders characterized in part by any one or more of hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and/or tissue ischemia; diseases, disorders, and conditions treated or treatable with hypoglycemic agents; diseases, disorders, and conditions treated or treatable with insulin; diseases, disorders or conditions characterized in whole or in part by
  • Diabetes mellitus is a group of metabolic disorders, associated with raised plasma glucose concentration and disturbance of glucose metabolism, which results in hyperglycemia.
  • the World Health Organization has set forth a classification scheme for diabetes mellitus that includes type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, and other specific types of diabetes mellitus.
  • Type 1 diabetes also known as insulin-dependent diabetes mellitus, usually develops in children or young adults.
  • Type 1 diabetes occurs when the pancreas produces too little insulin to regulate blood sugar levels appropriately. Although there is no set age, type 2 diabetes mellitus usually develops after 40 years of age and is much more common that type 1 diabetes. Approximately 90% of all individuals with diabetes have type 2 diabetes. Type 2 diabetes mellitus is characterized by two different conditions: a decreased ability of insulin to act on peripheral tissues, usually referred to as "insulin resistance,” and dysfunction of pancreatic ⁇ -cells, as represented by the inability to produce sufficient amounts of insulin to overcome insulin resistance in the peripheral tissues. Eventually, insulin production becomes insufficient to compensate for the insulin resistance due to ⁇ - cell dysfunction. The result is a relative or absolute deficiency of insulin.
  • the Center for Disease Control (CDC) predicts that one in three Americans born in 2000 will develop diabetes during their lifetime.
  • Center for Disease Control The Burden of Chronic Diseases and Their Risk Factors (2004).
  • the number of people with diabetes worldwide continues to increase at alarming rates. In 1985, it was estimated that 30 million people had diabetes. In 2000 the number was increased to 171 million.
  • microvascular complications are said to affect the retina, kidney and nerves
  • macrovascular complications are said to include diseases of the large vessels supplying the legs (lower extremity arterial disease), and predominantly the coronary, cerebrovascular and peripheral arterial circulation.
  • Chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels and long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction.
  • Insulin resistance is a common factor in leading to hyperglycemia in type 2 diabetes. It has also been reported that impaired glucose tolerance carries an increased cardiovascular risk despite minimal hyperglycemia. Fuller JH, et ah, Lancet 1:1373-1376 (1980). In the absence of diabetes, insulin resistance is reportedly a major risk factor for CAD. Lempiainen P, et al, Circulation 100:123-128 (1999). Insulin resistance coupled with compensatory hypei ⁇ nsulinemia leads to a number of proatherogenic abnormalities referred to as Insulin Resistance Syndrome. Insulin Resistance Syndrome (or Syndrome X) is a constellation of metabolic disturbances, which enhance cardiovascular risk.
  • Syndrome characteristics include deposition of fat around the abdominal organs, called visceral or central adiposity; changes in the lipoprotein profile, such as decrease in HDL, a rise in triglycerides; and, increased LDL.
  • An increase in blood pressure is seen in many, but not all, insulin resistant populations. Increased fibrinogen, a clotting and inflammatory marker, and PAI-I 5 are also reported.
  • hypoglycemic agents include sulfonylureas, biguanides, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, and D- phenylalanine derivatives. These drugs reduce glucose levels by a variety of different methods, including lowering sugar absorption, increasing insulin production, and increasing insulin sensitivity. Sulfonylurea agents stimulate the pancreas to release more insulin and help sensitize the body to insulin. Biguanides suppress excessive hepatic glucose production, increasing glucose utilization in peripheral tissues, and reduce intestinal glucose absorption by reducing reduce food intake.
  • Alpha-glucosidase inhibitors reduce absorption of sugars in the gut by slowing down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides.
  • Meglitinides are an ultra short acting drug that acts directly on the beta cells of the pancreas and increases the secretion of insulin, much like a super fast-acting sulfonylurea agent. These drugs also correct the problems with the pulsatile release of insulin, which is seen in Type 2 diabetes.
  • Thiazolidinediones are a new class of oral antidiabetic agents, commercially known as glitazones, which enhance insulin sensitivity in peripheral tissues.
  • TZDs peripheral, with increased insulin sensitivity and increased glucose uptake.
  • TZDs have some effect on hepatic glucose uptake and sensitivity to a lesser degree.
  • D-phenylalanine derivatives increase insulin production from the pancreas.
  • hypoglycemic agents currently in clinical development, including the recently approved pramlintide peptide, include amylin and amylin agonists (e.g., pramlintide, which is ' ' Pro-h-amylin, which has been approved by the FDA for use in combination with insulin to help lower blood sugar during the three hours after meals), GLP-I and GLP-I agonists ⁇ e.g., Arg(34)Lys(26)-(N- ⁇ -( ⁇ Glu(N- ⁇ - hexadecanoyl)) ⁇ GLP-l(7-37), sometimes referred to herein as GLP-ILA)), and exendin and exendin agonists ⁇ e.g., exendin-4).
  • Side effects associated with dosing of such compounds are primarily gastrointestinal in nature. For example, side effects associated with pramlintide dosing include nausea, vomiting, abdominal pain, headache, fatigue and dizziness.
  • Heart disease is the leading cause of death for both women and men in the United States. In 2001, 700,142 people died of heart disease (52% of them women), accounting for 29% of all U.S. deaths. The age-adjusted death rate was 246 per 100,000 population. In 2001, heart disease cost the United States $193.8 billion in total health care costs. The burden of heart disease could be ameliorated by reducing the prevalence rates of its major risk factors: high blood pressure, high blood cholesterol, tobacco use, diabetes, physical inactivity, and poor nutrition. Modest reductions in the rates of one or more of these risk factors can have a large public health impact. Center for Disease Control, The Burden of Chronic Diseases and Their Risk Factors (2004).
  • Metal ions are essential for cells, but can become toxic at higher concentrations, and free metal ions have been implicated in heart disease. Metal ions replace other essential metals in enzymes or molecules, which can disrupt their function. Metal ions such as Hg + and Cu + are reactive to thiol groups and may interfere with protein structure and function. Redox active transition metals such as Fe 2+/3+ and Cu 1+/2+ , which can take up or give off an electron, give rise to free radicals which can cause oxidative stress. Jones et al., Biochim. Biophys. Acta 286: 652-655 (1991); Li and Trush, Carcinogenes 7: 1303-1311 (1993).
  • Wilson's disease is due to a defect in copper excretion into the bile by the liver. Also known as hepatolenticular degeneration, Wilson's disease occurs in individuals who have inherited an autosomal recessive defect that leads to an accumulation of copper in excess of metabolic requirements. The excess copper is deposited in several organs and tissues, and eventually produces pathological effects primarily in the liver, where damage progresses to postnecrotic cirrhosis, and in the brain, where degeneration is widespread. Copper is also deposited as characteristic, asymptomatic, golden-brown Kayser-Fleisher rings in the corneas of all patients with cerebral symptomatology and some patients who are either asymptomatic or manifest only hepatic symptomatology. Wilson's disease generally affects patients between the ages of 10 and 40 years.
  • Wilson's disease is generally treated with an orally administered copper chelator.
  • First line therapy for treatment of Wilson's disease is penicillamine, a chelating agent.
  • Penicillamine, 3-mercapto-D-valine is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy. It is a white or practically white, crystalline powder, freely soluble in water, slightly soluble in alcohol, and insoluble in ether, acetone, benzene, and carbon tetrachloride. Although its configuration is D 1 it is levorotatory as usually measured. The empirical formula is C 5 H 11 NO 2 S, giving it a molecular weight of 149.21.
  • Cuprimine ® (Penicillamine) capsules for oral administration contain either 125 mg or 250 mg of penicillamine, as well as D & C Yellow 10, gelatin, lactose, magnesium stearate, and titanium dioxide as inactive ingredients.
  • the 125 mg capsule also contains iron oxide for capsule color.
  • Trientine a chelating compound for removal of excess copper from the body, is prescribed for Wilson's disease patients who cannot tolerate penicillamine.
  • Trientine hydrochloride is N,N'-bis(2-aminoethyl)-l,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether. The empirical formula is C 6 H 18 ⁇ 4 -2HC1 and it has a molecular weight of 219.2.
  • the structural formula is: NH 2 (CH 2 ) 2 -NH(CH 2 ) 2 - NH(CH 2 ) 2 -NH 2 -2HC1.
  • Syprine ® (trientine hydrochloride) is available as 250 mg capsules for oral administration.
  • Syprine ® capsules reportedly contain gelatin, iron oxides (for capsule color), stearic acid, and titanium dioxide as inactive ingredients.
  • Zinc acetate has not shown any long-term or major side effects in patients and can be used, long-term, in place of non-tolerable chelating agents. This is useful for patients who develop adverse reactions to chelating agents.
  • U.S. Patent Nos. 6,610,693, 6,348,465, and 6,897,243 provide copper chelators and other agents (e.g., zinc which prevents copper absorption) to decrease copper values for the benefit of subjects suffering from diabetes and its complications.
  • compositions and methods of the invention that employ hypoglycemic agents in combination with copper antagonist agents, for example, copper (II) antagonists, are disclosed and claimed. These combinations also, for example, allow the use of lower doses of each agent than previously required to achieve desired therapeutic goals.
  • the invention includes pharmaceutical compositions comprising (a) a therapeutically effect amount of a pharmaceutically acceptable copper antagonist or a pharmaceutically acceptable salt, for example, an acid addition salt, or prodrug, thereof; (b) a therapeutically effect amount of a hypoglycemic agent or a pharmaceutically acceptable salt thereof, for example, an acid addition salt; and, (c) a pharmaceutically acceptable carrier or diluent.
  • Suitable copper antagonists include pharmaceutically acceptable copper chelators.
  • Copper antagonists may be present in the compositions of the invention in an amount, for example, that is effective to (1) increase copper output in the urine of said subject, (2) decrease body and/or tissue copper levels, (3) decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (6) decrease homocysteine, (7) decrease oxidative stress and/or (8) increase copper (I).
  • Copper antagonists useful in the invention include, but are not limited to, pharmaceutically acceptable compounds of Formulae I, I(a) II herein.
  • Other suitable copper antagonists include, for example, pharmaceutically acceptable linear or branched tetramines capable of binding copper; 2,3,2 tetramine and salts thereof; 2,2,2 tetramine (also referred to as trientine) and salts thereof; 3,3,3 tetramine and salts thereof; triethylenetetramine hydrochloride salts, for example, triethylenetetramine dihydrochloride and triethylenetetramine tetrahydrochloride; triethylenetetramine succinate salts, for example, triethylenetetramine disuccinate; triethylenetetramine maleate salts, for example, triethylenetetramine tetramaleate and triethylenetetramine tetramaleate dihydrate; and triethylenetetramine fumarate salts, for example, triethylenetetramine tetrafumarate and triethylenet
  • suitable copper antagonist salts include a salt of a compound of Formula I (a) and a pharmaceutically acceptable dicarboxylic organic acid or tricarboxylic organic acid.
  • Suitable dicarboxylic organic acids include aliphatic dicarboxylic acids.
  • Such dicarboxylic acids include an aliphatic dicarboxylic acid of the formula HOOC-Q 1 -COOH wherein Q 1 is alkylene of 1 to about 8 carbon atoms or alkenylene of 2 to about 8 carbon atoms and includes both straight chain and branched chain alkylene and alkenylene groups.
  • dicarboxylic organic acids and tricarboxylic organic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, citraconic acid, mesoconic acid, itaconic acid, tricarballytic acid, 1, 2, 3-butanetricarboxylic acid, trimesic acid, hemimellitic acid, and trimellitic acid. Certain salts are described in Provisional US Patent Application No. 60/772,451 filed February 9, 2006, the disclosure of which is incorporated herein by reference.
  • Suitable copper antagonists include, for example, crystalline triethylenetetramine and salts thereof. These include crystalline triethylenetetramine maleate (e.g., triethylenetetramine tetramaleate and triethylenetetramine tetramaleate dihydrate), crystalline triethylenetetramine fumarate (e.g., triethylenetetramine tetrafumarate and triethylenetetramine tetrafumarate tetrahydrate), and crystalline triethylenetetramine succinate (e.g., triethylenetetramine disuccinate anhydrate).
  • crystalline triethylenetetramine maleate e.g., triethylenetetramine tetramaleate and triethylenetetramine tetramaleate dihydrate
  • crystalline triethylenetetramine fumarate e.g., triethylenetetramine tetrafumarate and triethylenetetramine tetrafumarate tetrahydrate
  • agents capable of reducing copper include those that decrease copper uptake, including thiomolybdates (including mono-, di-, tri- and tetrathiomolybdates); zinc salts, such as zinc acetate; zinc chloride; zinc sulphate; zinc salts of intermediates of the citric acid cycle, such as citrate, isocitrate, ketoglutarate, succinate, malate; and, zinc glucoante.
  • Copper antagonists useful in the invention also include copper antagonizing metabolites, such as copper antagonizing metabolites of trientine including, for example, N-acetyl trientine, and analogues, derivatives, and prodrugs thereof.
  • Copper antagonists useful in the invention also include modified copper antagonists, for example, modified trientines. Derivatives of copper antagonists, including trientine or trientine salts or analogues, include those modified with polyethylene glycol (PEG).
  • Copper antagonists useful in the invention also include copper antagonists, including copper chelators, which have been pre-complexed with a non-copper metal ion prior to administration for therapy, the non-copper metal ion having a binding affinity for the copper antagonist that is lower that that of copper (e.g., lower than that of Cu ). Also encompassed are metal complexes comprising copper antagonists and non- copper metals (that have lower binding affinities than copper for the copper antagonist) and one or more additional ligands than typically found in complexes of that metal. These include, for example, pentacoordinate copper complexes of triethylenetetramine and another ligand.
  • Suitable hypoglycemic agents include biguanides (for example, metformin), thiazolidinediones (for example, troglitazone, rosiglitazone, and pioglitazone), ⁇ - glucosidase inhibitors (for example, acarbose and miglitol), and sulfonylureas (for example, tolbutamide, chlorpropamide, gliclazide, glibenclamide, glipizide, and glimepiride).
  • Other hypoglycemic agents include amylin and amylin agonists (e.g.,
  • O ⁇ OS OQ pramlintide which is ' ' Pro-h-amylin
  • GLP-I and GLP-I agonists e.g., Arg(34)Lys(26)-(N- ⁇ -( ⁇ -Glu(N- ⁇ -hexadecanoyl))-GLP-l(7-37), or GLP-ILA
  • exendin and exendin agonists e.g., exendin-4.
  • Such compounds may be present in the compositions of the invention amounts described herein, and in amounts, for example, that are effective to (1) lower blood glucose, (2) lower serum glucose, (3) lower urine glucose, (4) lower glycosylated hemoglobin (HbA lc ) levels, (5) lower fructosamine, (6) lower postprandial glycemia, (7) ameliorate impaired glucose tolerance, (8) ameliorate impaired fasting glucose, and/or (9) lower the rate and/or severity of hypoglycemic events, including severe hypoglycemic events.
  • Suitable copper antagonist salts include acid addition salts such as, for example, those of suitable inorganic or organic acids. Suitable organic acids include succinic acid, maleic acid, and fumaric acid. Suitable inorganic acids include hydrochloric acid. Succinate salts are preferred. Triethylenetetramine disuccinate is most preferred.
  • the invention includes pharmaceutical compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a hypoglycemic agent and one or more compounds of Formulae I, I(a) and II herein.
  • the invention includes pharmaceutical compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable earner and therapeutically effective amounts of a hypoglycemic agent and one or more linear or branched tetramines capable of binding copper. Examples of tetramines include 2,3,2 tetramine, 2,2,2 tetramine, and 3,3,3 tetramine, and salts thereof.
  • the invention includes pharmaceutical compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a hypoglycemic agent and triethylenetetramine or a triethylenetetramine salt.
  • the invention includes pharmaceutical compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a hypoglycemic agent and one or more triethylenetetramine hydrochloride salts, for example, triethylenetetramine dihydrochloride and triethylenetetramine tetrahydrochloride.
  • the invention includes pharmaceutical compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a hypoglycemic agent and one or more triethylenetetramine succinate salts, for example, triethylenetetramine disuccinate.
  • the invention includes pharmaceutical compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a hypoglycemic agent and one or more triethylenetetramine maleate salts, for example, triethylenetetramine tetramaleate and triethylenetetramine tetramaleate dihydrate; or triethylenetetramine fumarate salts, for example, triethylenetetramine tetrafumarate and triethylenetetramine tetrafumarate tetrahydrate.
  • the invention includes pharmaceutical compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a copper antagonist and a meglitinide.
  • Meglitinides include, for example, repaglinide and nateglinide.
  • the invention includes compositions, including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a pharmaceutically acceptable copper antagonist and a biguanide, for example, metformin.
  • compositions including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a pharmaceutically acceptable copper antagonist and a thiazolidinedione.
  • Thiazolidinediones include, for example, troglitazone, rosiglitazone, and pioglitazone.
  • compositions including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a pharmaceutically acceptable copper antagonist and an ⁇ -glucosidase inhibitor, ⁇ -glucosidase inhibitors include, for example, acarbose and miglitol.
  • compositions including tablets and capsules and other oral delivery forms and formulations, comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a pharmaceutically acceptable copper antagonist and a sulfonylurea.
  • Sulfonylureas include, for example, tolbutamide, chlorpropamide, gliclazide, glibenclamide, glipizide, and glimepiride.
  • the invention includes methods for treating and/or preventing, in whole or in part, various diseases, disorders and conditions, including, for example, impaired glucose tolerance; impaired fasting glucose; diabetes and/or its complications, including type 1 and type 2 diabetes and their complications; insulin resistance; Syndrome X; obesity and other weight related disorders; cardiomyopathy, including diabetic cardiomyopathy; nerve diseases, including diabetic neuropathy; kidney disease, including diabetic nephropathy; eye disease, including diabetic retinopathy and cataracts; hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and/or tissue ischemia, and diseases and disorders characterized at least in part by any one or more of hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia; and, diseases, disorders or conditions characterized in whole or in part by (a) hypercupremia and/or copper-related tissue damage and (b) hyperglycemia, insulin resistance, impaired glucose tolerance, and/
  • the invention includes methods for treating a subject having or suspected of having or predisposed to, or at risk for, for example, any diseases, disorders and/or conditions characterized in whole or in part, for example, by (a) hypercupremia and/or copper-related tissue damage and (b) hyperglycemia, insulin resistance, impaired glucose tolerance, and/or impaired fasting glucose, comprising administering a composition comprising a pharmaceutically acceptable copper antagonist and a hypoglycemic agent.
  • diseases, disorders and/or conditions include but are not limited to those described or referenced herein.
  • Such compounds may be administered in amounts, for example, that are effective to (1) decrease body and/or tissue copper levels, (2) increase copper output in the urine of said subject, (3) decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase copper (I), (8) lower serum glucose, (9) lower blood glucose, (10) lower urine glucose, (11) lower fructosamine, (12) lower glycosylated hemoglobin (HbA 10 ) levels, (13) lower postprandial glycemia, (14) ameliorate impaired glucose tolerance, (15) ameliorate impaired fasting glucose, and/or (16) lower the rate and/or severity of hypoglycemic events, including severe hypoglycemic events.
  • compositions include, for example, tablets and capsules and other oral delivery forms and formulations.
  • the invention includes methods for regulating glycemia and diminishing copper and/or available copper in a subject having or suspected of having or predisposed to diseases, disorders and/or conditions characterized in whole or in part by (a) hypercupremia and/or copper-related tissue damage and (b) hyperglycemia, insulin resistance, impaired glucose tolerance, and/or impaired fasting glucose, comprising administering a composition comprising a pharmaceutically acceptable copper antagonist and a hypoglycemic agent.
  • diseases, disorders and/or conditions include but are not limited to those described or referenced herein.
  • Such diseases, disorders and conditions include, but are not limited to, those herein disclosed herein.
  • Such compounds may be administered in amounts, for example, that are effective to (1) decrease body and/or tissue copper levels, (2) increase copper output in the urine of said subject, (3) decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase copper (I), (8) lower serum glucose, (9) lower blood glucose, (10) lower urine glucose, (11) lower fructosamine, (12) lower glycosylated hemoglobin (HbA 10 ) levels, (13) lower postprandial glycemia, (14) ameliorate impaired glucose tolerance, (15) ameliorate impaired fasting glucose, and/or (16) lower the rate and/or severity of hypoglycemic events, including severe hypoglycemic events.
  • compositions include, for example, tablets and capsules and other oral delivery forms and formulations.
  • the invention includes methods for administering a therapeutically effective amount of a pharmaceutically acceptable copper antagonist and a hypoglycemic agent formulated in a delayed release preparation, a slow release preparation, an extended release preparation, a controlled release preparation, and/or in a repeat action preparation to a subject having or suspected of having or predisposed to diseases, disorders and/or conditions characterized in whole or in part by (a) hypercupremia and/or copper-related tissue damage and (b) hyperglycemia, insulin resistance, impaired glucose tolerance, and/or impaired fasting glucose, comprising administering a composition comprising a pharmaceutically acceptable copper antagonist and a hypoglycemic agent.
  • Such diseases, disorders and conditions include, but are not limited to, those herein disclosed herein.
  • Such compounds may be administered in amounts, for example, that are effective to (1) decrease body and/or tissue copper levels, (2) increase copper output in the urine of said subject, (3) decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase copper (I), (8) lower serum glucose, (8) lower blood glucose, (10) lower urine glucose, (11) lower fructosamine, (12) lower glycosylated hemoglobin (HbA 10 ) levels, (13) lower postprandial glycemia, (14) ameliorate impaired glucose tolerance, (15) ameliorate impaired fasting glucose, and/or (16) lower the rate and/or severity of hypoglycemic events, including severe hypoglycemic events.
  • compositions include, for example, tablets and capsules and other oral delivery forms and formulations.
  • the invention includes methods for the use of therapeutically effective amounts of a pharmaceutically acceptable copper antagonist and a pharmaceutically acceptable hypoglycemic agent in the manufacture of a medicament.
  • Such medicaments include, for example, tablets and capsules and other oral delivery forms and formulations.
  • Such medicaments include those for the treatment of a subject as disclosed herein.
  • the invention includes methods for the use of a therapeutically effective amount of a copper antagonist and a pharmaceutically acceptable hypoglycemic agent in the manufacture of a dosage form.
  • dosage forms include, for example, tablets and capsules and other oral delivery forms and formulations.
  • Such dosage forms include those for the treatment of a subject as disclosed herein.
  • the invention includes transdermal patches, pads, wraps, and bandages capable of being adhered or otherwise associated with the skin of a subject, said articles being capable of delivering a therapeutically effective amount of a pharmaceutically acceptable copper antagonist and a pharmaceutically acceptable hypoglycemic agent to a subject.
  • the invention includes an article of manufacture comprising a vessel containing a therapeutically effective amount of a pharmaceutically acceptable copper antagonist and a pharmaceutically acceptable hypoglycemic agent and instructions for use, including use for the treatment of a subject.
  • the invention includes an article of manufacture comprising packaging material containing one or more dosage forms containing a pharmaceutically acceptable copper antagonist and a pharmaceutically acceptable hypoglycemic agent, wherein the packaging material has a label that indicates that the dosage form can be used for a subject having or suspected of having or predisposed to any of the diseases, disorders and/or conditions described or referenced herein, including diseases, disorders and/or conditions characterized in whole or in part by hyperglycemia and/or hypercupremia, including but not limited to those herein disclosed herein.
  • Such dosage forms include, for example, tablets and capsules and other oral delivery forms and formulations.
  • the invention includes a formulation comprising a pharmaceutically acceptable copper antagonist and a pharmaceutically acceptable hypoglycemic agent in amounts effective to remove copper from the body of a subject and reduce glycemia (including postprandial glycemia) in said subject.
  • Such formulations include, for example, tablets and capsules and other oral delivery forms and formulations.
  • the invention includes a device containing therapeutically effective amounts of a pharmaceutically acceptable copper antagonist and a pharmaceutically acceptable hypoglycemic agent comprising a rate-controlling membrane enclosing a drug reservoir.
  • the invention also includes a device containing therapeutically effective amounts of a pharmaceutically acceptable copper antagonist and a pharmaceutically acceptable hypoglycemic agent in a monolithic matrix device. These devices may be employed for the treatment of subjects in need thereof as disclosed herein.
  • a "copper antagonist” is a pharmaceutically acceptable compound that binds or chelates copper, preferably copper (II), in vivo for removal. Copper chelators are presently preferred copper antagonists. Copper (II) chelators, and copper (II) specific chelators (i.e., those that preferentially bind copper (II) over other forms of copper such as copper (I)), are especially preferred. "Copper (II)” refers to the oxidized (or +2) form of copper, also sometimes referred to as Cu +2 .
  • a disorder is any disorder, disease, or condition that would benefit from an agent that reduces local or systemic copper, extracellular copper, bound copper, or copper concentrations, and/or an agent that reduces glycemia, for example.
  • Disorders include, but are not limited to, those described and/or referenced herein, and include diseases, disorders and conditions include that would benefit from (1) a decrease body and/or tissue copper levels, (2) an increase copper output in the urine of said subject, (3) a decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase copper (I), (8) lower serum glucose, (9) lower blood glucose, (10) lower urine glucose, (11) lower fructosamine, (12) lower glycosylated hemoglobin
  • hypoglycemic agent refers to pharmaceutically acceptable therapeutic compounds capable lowering blood glucose, lowering urine glucose, lowering fructosamine, lowering glycosylated hemoglobin (HbA 1 c ) levels, lowering postprandial glycemia, ameliorating impaired glucose tolerance, ameliorating impaired fasting glucose, and/or (12) lowering the rate and/or severity of hypoglycemic events, including severe hypoglycemic events.
  • Hypoglycemic agents include but are not limited to, for example, sulfonylureas, biguanides, alpha- glucosidase inhibitors, meglitinides, thiazolidinediones, D-phenylalanine derivatives, amylin and amylin agonists, GLP-I and GLP-I agonists, and exendin and exendin agonists.
  • mammal refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, sheep, pigs, cows, etc. The preferred mammal herein is a human.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids the like.
  • salts may be prepared from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids.
  • Organic acids include both aliphatic and aromatic carboxylic acids and include, for example, aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, aliphatic tricarboxylic acids, aromatic monocarboxylic acids, aromatic dicarboxylic acids, aromatic tricarboxylic acids and other organic acids known to those of skill in the art.
  • Aliphatic carboxylic acids may be saturated or unsaturated.
  • Suitable aliphatic carboxylic acids include those having from 2 to about 10 carbon atoms.
  • Aliphatic monocarboxylic acids include saturated aliphatic monocarboxylic acids and unsaturated aliphatic monocarboxylic acids. Examples of saturated monocarboxylic acids include acetic acid, propronic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, and caprynic acid. Examples of unsaturated aliphatic monocarboxylic acids include acrylic acid, propiolic acid, methacrylic acid, crotonic acid and isocrotonic acid.
  • Aliphatic dicarboxylic acids include saturated aliphatic dicarboxylic acids and unsaturated aliphatic dicarboxylic acids.
  • saturated aliphatic dicarboxylic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid.
  • unsaturated aliphatic dicarboxylic acids include maleic acid, fumaric acid, citraconic acid, mesaconic acid, itaconic acid and the like.
  • Aliphatic tricarboxylic acids includes saturated aliphatic tricarboxylic acids and unsaturated tricarboxylic acids.
  • saturated tricarboxylic acids include tricarballylic acid, 1, 2, 3-butanetricarboxylic acid and the like.
  • Suitable aliphatic dicarboxylic acids include those of the formula: HOOC-Q 1 -COOH, wherein Q 1 is alkylene of 1 to about 8 carbon atoms or alkenylene of 2 to about 8 atoms, and includes both straight chain and branched chain alkylene and alkenylene groups.
  • aromatic dicarboxylic acids include phthalic acid, isophthalic acid, terephthalic acid and the like.
  • aromatic tricarboxylic acids include trimesic acid, hemimellitic acid and trimellitic acid.
  • Such acids may also include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric, maleic, fumaric, and succinic acids. Succinic acid is most preferred.
  • "preventing" means preventing in whole or in part, or ameliorating or controlling.
  • a "therapeutically effective amount” in reference to the compounds or compositions of the instant invention refers to the amount sufficient to induce a desired biological, pharmaceutical, or therapeutic " result. That result can be alleviation of the signs, symptoms, or causes of a disease or disorder or condition, or any other desired alteration of a biological system. In the present invention, the result will generally involve the prevention, decrease, or reversal of effects relating to unwanted copper or copper levels, in whole or in part, and reduced glycemia, as referenced herein.
  • Therapeutic effects include, for example, (1) decreasing body and/or tissue copper levels, (2) increasing copper output in the urine, (3) decreasing copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase copper (I), (8) lowering serum glucose, (9) lowering blood glucose, (10) lowering urine glucose, (11) lowering fructosamine, (12) lowering glycosylated hemoglobin (HbA 10 ) levels, (13) lowering postprandial glycemia, (14) ameliorating impaired glucose tolerance, (15) ameliorating impaired fasting glucose, and/or (16) lowering the rate and/or severity of hypoglycemic events, including severe hypoglycemic events.
  • the term "treating" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those prone to having the disorder or diagnosed with the disorder or those in which the disorder is to be prevented.
  • a reduction in copper, particularly extracellular copper that is generally in the its copper II form, will be advantageous in the treatment of disorders, diseases, and/or conditions, caused or exacerbated by mechanisms that may be affected by or are dependent on excess copper values and/or hyperglycemia.
  • a reduction in copper and/or glycemia will be advantageous in providing a combined reduction in and/or reversal of copper-associated and/or sugar-associated damage.
  • Copper antagonist / sulfonylurea combinations may be prepared for administration via oral delivery.
  • the preparation of various tablets and capsules are described in Examples 1-12. They include tablets (see, e.g., Example 1), tablets with a filler(s) (see, e.g., Example 2), tablets with a desiccant(s) (see, e.g., Example 3), tablets with a wet granulations .
  • binder(s) see, e.g., Example 4
  • tablets with a wet granulations binder(s) and a desiccant(s) see, e.g., Example 5
  • capsules see, e.g., Example 6
  • capsules with a desiccant(s) see, e.g., Example 7
  • capsules with a filler(s) see, e.g., Example 8
  • capsules with a filler(s) and a granulation binder(s) see, e.g., Example 9
  • capsules with a desiccant(s) and a granulation binder(s) see, e.g., Example 10
  • controlled release tablets see, e.g., Example 11
  • capsules with enteric coated beads see, e.g., Example 12).
  • the triethylenetetramine dihydrochloride is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium. Copper antagonist / thiazolidinedione combinations may also be prepared for administration via oral delivery. The preparation of various tablets and capsules are described in the Examples 13-24.
  • tablets include tablets (see, e.g., Example 13), tablets with a filler(s) (see, e.g., Example 14), tablets with a desiccant(s) (see, e.g., Example 15), tablets with a wet granulations binder(s) (see, e.g., Example 16), tablets with a wet granulations binder(s) and a desiccant(s) (see, e.g., Example 17), capsules (see, e.g., Example 18), capsules with a desiccant(s) (see, e.g., Example 19), capsules with a filler(s) (see, e.g., Example 20), capsules with a f ⁇ ller(s) and a granulation binder(s) (see, e.g., Example 21), capsules with a desiccant(s) and a granulation binder(s) (see, e.g., Example 22),
  • Copper antagonist / biguanide combinations may also be prepared for administration via oral delivery.
  • the preparation of various tablets and capsules are described in the Examples 25-36. They include tablets (see, e.g., Example 25), tablets with a filler(s) (see, e.g., Example 26), tablets with a desiccant(s) (see, e.g., Example 27), tablets with a wet granulations binder(s) (see, e.g., Example 28), tablets with a wet granulations binder(s) and a desiccant(s) (see, e.g., Example 29), capsules (see, e.g., Example 30), capsules with a desiccant(s) (see, e.g., Example 31), capsules with a filler(s) (see, e.g., Example 32), capsules with a filler(s) and a granulation binder(s) (see, e.g., Example 33),
  • copper antagonist / ⁇ -glucosidase inhibitor combinations and copper antagonist / meglitinide combinations may be prepared for administration via oral delivery, using methods and dosages disclosed herein. See, e.g., Examples 1-36.
  • ⁇ - glucosidase inhibitors e.g., acarbose and miglitol
  • Meglitinides may be included in amounts ranging from, for example, about 0.5 mg to about 5 mg (for example, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg) depending on desired dose and frequency of administration.
  • Examples 37, 41, and 45 relate to liquid formulations of peptide hypoglycemic agents for delivery by injection, for example, such as amylin agonists, exendin agonists and GLP-I agonists.
  • Examples 38, 42, and 46 relate to dry powder formulations of peptide hypoglycemic agents for pulmonary delivery, for example, such as amylin agonists, exendin agonists and GLP-I agonists.
  • Examples 39, 43, and 47 relate to liquid, powder, and gel formulations of peptide hypoglycemic agents for intranasal delivery, for example, such as amylin agonists, exendin agonists and GLP-I agonists.
  • Examples 40, 44, and 48 relate to micelle formulations of peptide hypoglycemic agents for buccal delivery, for example, such as amylin agonists, exendin agonists and GLP-I agonists.
  • Sulphonylureas may be prepared using art-known methods. See, for example, U.S. Pat. Nos. 3,454,635, 3,669,966, 2,968,158, 3,501,495, 3,708,486, 3,668,215, 3,654,357, and 3,097,242).
  • Tolbutamide may be prepared as described in U.S. Patent No. 6,565,833, or alternatively may be purchased in bulk from manufacturers (e.g., Exim-Pharm International, Mumbai, India) and is administered as known in the art (e.g., U.S. Patent Nos. 6,734,197, 6,376,549, and 6,565,833).
  • Tolbutamide is preferably prepared for administration in a dose in the range of about 1 to about 3,000 mg/day, preferably -about 500 to about 3,000mg7day, in an adult patient of about 70 kg body weight.
  • Dosage forms for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Chlorpropamide may be manufactured using methods known in the art or alternatively, may purchased in bulk from manufacturers (e.g., Euroasian Chemicals P vt. Ltd., Mumbai, India), and is administered as known in the art (see, for example, U.S. Patent Nos. 6,734,197 and 6,376,549). Chlorpropamide is preferably prepared for administration in a dose in the range of about 1 to about 500 mg/day, preferably about 100 to about 500 mg/day, in an adult patient of about 70 kg body weight. Gliclazide may be manufactured using methods known in the art or, alternatively, may purchased in bulk from manufacturers (e.g., Euroasian Chemicals Pvt.
  • Gliclazide is preferably prepared for administration in a dose in the range of about 1 to about 320 mg/day, preferably about 30 to about 120 mg/day, in an adult patient of about 70 kg body weight. Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent. Glibenclamide may be produced using methods known in the art (see, for example, U.S. Patent Nos.
  • Glibenclamide is preferably prepared for administration in a dose in the range of about 1 to about 50 mg/day, preferably 2.5 to about 15 mg/day, in an adult patient of about 70 kg body weight. Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Glipizide may be manufactured using methods known in the art or alternatively, may purchased in bulk from manufacturers (e.g., Exim-Pharm International, Mumbai, India) and is administered as known in the art (see, for example, U.S. Patent Nos. 4,612,008, 5,024,843, 5,082,668, 5,091,190, 5,545,413, 5,591,454, 6,734,197, and 6,376,549).
  • Glipizide is preferably prepared for administration in a dose in the range of about 1 to about 750 mg/day, preferably about 5 to about 50 mg/day, in an adult patient of about 70 kg body weight.
  • Dosage forms for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Glimepiride may be prepared using methods known in the art or alternatively, may purchased in bulk from manufacturers (e.g., Haorui Pharma-Chem Inc., New Jersey USA) and is administered as known in the art (see, for example, U.S. Patent Nos. 4,379,785, 6,734,197, 5,416,105, and 6,376,549).
  • Glimepiride is preferably prepared for administration in dose from about 1 to about 32 mg/day, preferably about 1 to about 4 mg/day in an adult patient of about 70 kg body weight.
  • Dosage forms for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Glyburide may be prepared using methods known in the art (see, for example, U.S. Patent Nos. 4,735,805, 4,916,163, and 6,830,760) and is administered as known in the art (see, for example, U.S. Patent Nos. 6,376,549 and 6,734,197).
  • Glyburide is preferably prepared for administration in a dose in the range of about 1 to about 500, preferably about 1 to about 20 mg/day day in an adult patient of about 70 kg body weight.
  • Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Tolazamide may be prepared using methods known in the art or alternatively, may purchased in bulk from manufacturers (e.g. Co. Farmaceutica Milanese, Milan Italy) and is administered as known in the art (see, for example, U.S. Patent Nos. 6,376,549, and 6,734,197). Tolazamide is preferably prepared for administration in a dose in the range of about 1 to about 3000 mg/day, preferably about 100 to about 1000 mg/day, in an adult patient of about 70 kg body weight. Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Dosage forms for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Thiazolidinediones may be prepared using art-known methods.
  • troglitazone may be prepared as described in U.S. Patent Nos. 4,572,912 and is administered as known in the art (see, for example, U.S. Patent Nos. 5,478,852, 5,700,820, 6,451,342, 6,296,874).
  • Troglitazone is preferably prepared for administration in a dose in the range of about 0.7 to 1400 mg/day, preferably about 0.7 to about 700 mg/day, in an adult patient of about 70 kg body weight.
  • Troglitazone may also be administered as troglitazone hydrochloride, with a daily dose ranging from 200 mg to 400 mg, in an adult patient of about 70 kg body weight. Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent. Rosiglitazone may be prepared using methods known in the art (see, for example, U.S. Patent Nos. 5,965,584 and 6,515,132) or alternatively, may purchased in bulk from manufacturers (see, for example, Exim-Pharm International, Mumbai, India) and is administered as known in the art (e.g. U.S. Patent Nos.
  • rosiglitazone is preferably prepared in a dose in the range of about 0.1 to 6000 mg/day, and more usually about 1 to 1500 mg/day, in an adult patient of about 70 kg body weight.
  • the preferred dose is about 0.3 to about 70 mg/day, preferably about 0.7 to about 7 mg/day, in an adult patient of
  • Dosage forms for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Pioglitazone may be prepared as described in U.S. Patent Nos. 4,687,777, 4,287,200 and 5,594,016 and is administered as known in the art (see, for example, U.S. Patent Nos. 5,965,584, 6,150,383, 6,150,384, 6,166,042, 6,166,043, 6,172,090, 6,211,205, 6,271,243, 6,303,640, and 6,329,404).
  • Pioglitazone is preferably prepared for administration in a dose in the range of about 1 to about 70 mg/day, and more preferably about 15 to about 30 mg/day, in an adult patient of about 70 kg body weight. Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Ciglitazone may be prepared as described in U.S. Patent No. 6,653,332 and is administered as known in the art, or as disclosed in Current Pharmaceutical Design, 1996; 2:85-101, incorporated herein by reference. Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses man those presently prescribed for this agent, ⁇ -glucosidase inhibitors may be prepared using art-known methods.
  • acarbose may be prepared as described in U.S. Patent Nos. 4,904,769, 6,849,609, 6,734,300, and 6,649,755, and is administered as known in the art (see, for example, U.S. Patent Nos.
  • Acarbose is preferably prepared for administration in a dose in the range of about 1-2800 mg/day, preferably about 75 to about 300 mg/day, in an adult patient of about 70 kg body weight.
  • Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Miglitol may be prepared as described in U.S. Patent Nos. 4,639,436 and is administered as known in the art (see, for example, U.S. Patent Nos. 6,376,549 and 6,774,112.
  • Miglitol is preferably prepared for administration in a dose in the range of about from about 1 to about 3500 mg/day, most preferably from about 10 to about 500 mg/day, or about 75 to about 300 mg/day, in an adult patient of about 70 kg body weight.
  • Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent
  • Biguanides may also be prepared using art-known methods.
  • metformin may be prepared as described in U.S. Patent Nos. 6,099,859, 6,495,162, 5,741,803, 3,174,921, and 6,031,004, and administered as know in the art (see, for example, U.S. Patent Nos. 6,559,18, 6,303,146, 6,475,521, 6,660,300, 5,741,803, 5,002,953, 5,965,584, 6,166,042, and 6,288,095).
  • Metformin is administered as known in the art, and is generally administered in a dosage in the range of about 0.1 to 6000 mg/day, preferably about 500 to about 2500 mg/day, more preferably about 750 to 2000mg.day, and most preferably about 1000 to 1500, mg/day, in an adult patient of about 70 kg body weight.
  • the active ingredient metformin can be applied in the form of metformin hydrochloride in a dosage between 700 and 3000mg/day, preferably 1500, 1700 or 2550 mg/day, in an adult patient of about 70 kg body weight.
  • the controlled release dosage form provides a mean AUC 0-24hr that is about 17,200 ng/hr/ml to about 33,900 ng/hr/ml, based on administration of a 2,000 mg once-a-day dose of metformin, preferably about 17,200 ng/hr/ml to about 26,500 ng/hr/ml, based on administration of a 2,000 mg once-a-day dose of metformin, more preferably about 19,800 ng/hr/ml to about 33,900 ng/hr/ml, based on administration of a 2,000 mg once-a-day dose of metformin, in an adult patient of about 70 kg body weight.
  • Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Phenformin may be prepared using art-known methods or alternatively, may purchased in bulk from manufacturers (see, for example, Indo Amine Ltd Thane Maharashtra, India) and is administered as known in the art. Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent. Meglitinides may be prepared using art-known methods. For example, repaglinide may be prepared as described in U.S. Patent Nos. RE37035, and 6,143,769, and is administered as known in the art (see, for example, U.S. Patent No. 6,677,358 and 6,559,188).
  • Repaglinide is preferably prepared for administration in a dose in the range of about 0.01 mg to about 8 mg, more preferably from about 0.2 mg to about 6 mg per dose unit, in an adult patient of about 70 kg body weight.
  • Dosage forms for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Nateglinide may be prepared as described in U.S. Patent Nos. 5,463, 5,488,150, 6,559,188, 6,641,841 and RE34878, and may be administered as known in the art (see, for example, U.S. Patent No. 6,559,188).
  • Nateglinide is preferably prepared for administration in a dosage in the range of about 5 to 1200 mg/day, more preferably 10 to 1000 mg/day and most preferably 25 to 800 mg/day, in an adult patient of about 70 kg body weight.
  • Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently prescribed for this agent.
  • Amylin agonists may also be prepared using art-known methods.
  • pramlintide may be prepared using methods described in U.S. Patent No. 5,998,367, and may be administered as known in the art (see, for example, U.S. Patent No. 5,998,367 and 5,686,411).
  • Pramlintide may be prepared for administration in a dose in the range of about 0.1 mg to about 5 mg per day, in an adult patient of about 70 kg body weight, for example.
  • Dosage forms, for example, tablets and capsules may be prepared accordingly, or using other doses as disclosed herein, and lower doses than those presently used for this agent.
  • Exendin agonists may be prepared using art-known methods, as well.
  • exendin-4 may be prepared using methods described in U.S. Patent No.
  • Exendin-4 may be prepared for administration in a dose in the range of about 0.1 pg/kg to about
  • GLP- l's and GLP-I agonists may be prepared using art-known methods, including peptide synthesis and recombinant production. Dosing for GLP-I 's and GLP-I agonists has been described in various publications.
  • Pharmaceutically acceptable copper antagonists preferably copper (II) antagonists, and more preferably copper (II) chleator agents, may be used in the invention. Copper antagonists include, for example, trientine active agents, which include trientines (triethylenetetramines).
  • Copper antagonists useful in the invention include, but are not limited to, pharmaceutically acceptable compounds of Formulae I, I(a) and II herein.
  • Other suitable copper antagonists include, for example, pharmaceutically acceptable linear or branched tetramines capable of binding copper; 2,3,2 tetramine and salts thereof; 2,2,2 tetramine (also referred to as trientine) and salts thereof; 3,3,3 tetramine and salts thereof; triethylenetetramine hydrochloride salts, for example, triethylenetetramine dihydrochloride and triethylenetetramine tetrahydrochloride; triethylenetetramine succinate salts, for example, triethylenetetramine disuccinate; triethylenetetramine maleate salts, for example, triethylenetetramine tetramaleate and triethylenetetramine tetramaleate dihydrate; and triethylenetetramine fumarate salts, for example, triethylenetetramine tetrafumarate and triethylene
  • Suitable copper antagonists include, for example, crystalline triethylenetetramine and salts thereof. These include crystalline triethylenetetramine maleate (e.g., triethylenetetramine tetramaleate and triethylenetetramine tetramaleate dihydrate), crystalline triethylenetetramine fumarate (e.g., triethylenetetramine tetrafumarate and triethylenetetramine tetrafumarate tetrahydrate), and crystalline triethylenetetramine succinate (e.g, triethylenetetramine disuccinate anhydrate).
  • crystalline triethylenetetramine maleate e.g., triethylenetetramine tetramaleate and triethylenetetramine tetramaleate dihydrate
  • crystalline triethylenetetramine fumarate e.g., triethylenetetramine tetrafumarate and triethylenetetramine tetrafumarate tetrahydrate
  • agents capable of reducing copper include thiomolybdates (including mono-, di-, tri- and tetrathiomolybdates); zinc salts, such as zinc acetate; zinc chloride; zinc sulphate; zinc salts of intermediates of the citric acid cycle, such as citrate, isocitrate, ketoglutarate, succinate, malate; and, zinc glucoante.
  • Copper antagonists useful in the invention also include copper antagonizing metabolites, such as copper antagonizing metabolites of trientine including, for example, N-acetyl trientine, and analogues, derivatives, and prodrugs thereof. Copper antagonists useful in the invention also include modified copper antagonists, for example, modified trientines. Derivatives of copper antagonists, including trientine or trientine salts or analogues, include those modified with polyethylene glycol (PEG).
  • the invention includes pharmaceutical compositions comprising a therapeutically effective amount of a pharmaceutically acceptable precomplexed copper antagonist or a pharmaceutically acceptable salt, for example, an acid addition salt, thereof and a pharmaceutically acceptable carrier or diluent.
  • copper antagonists useful in the invention also include copper antagonists, including copper chelators, which have been pre-complexed with a non-copper metal ion prior to administration for therapy.
  • Metal ions used for pre-complexing have a lower association constant for the copper antagonist than that of copper.
  • a metal ion for pre- complexing a copper antagonist that chelates Cu 2+ is one that has a lower binding affinity for the copper antagonist than Cu 2+ .
  • the non-copper metal ion has an association constant for triethylenetetramine that is equal to or less than about 10 ⁇ 19 , more preferably less than or equal to about 10 ⁇ 18 , still more preferably less than or equal to about 10 ⁇ 15 , even more preferably less than or equal to about 10 ⁇ 12 , 10 ⁇ 10 , or 10 "9 , and most preferably less than or equal to about 10 ⁇ 8 , 10 ⁇ 7 or 10 ⁇ 5 .
  • Preferred metal ions for precomplexing include, for example, calcium (e.g., Ca 2+ ), magnesium (e.g., Mg " ), chromium (e.g., Cr and Cr ), manganese (e.g., Mn ), zinc (e.g., Zn 2+ ), and iron (e.g., Fe 2+ and Fe 3+ ).
  • Most preferred metal ions for precomplexing are calcium, zinc, and iron.
  • Other metals include, for example, cobalt (e.g., Co 2+ ), nickel (e.g., Ni 2+ ), silver (e.g., Ag 1+ ) and selenium (e.g., Se 4+ ).
  • Non-copper metals are chosen with regard, for example, to their relative binding to the copper antagonist, the dose of the copper antagonist to be administered, and relative to potential toxicity following displacement of the non-copper metal ion.
  • active metabolites, derivatives, and prodrugs of copper antagonists can also be used for precomplexing.
  • Preferred copper antagonists for precomplexing are Cu antagonists, particularly Cu 2+ chelators.
  • Preferred Cu 2+ antagonists are linear, branched or cyclic polyamines chelators including, for example, tetramines. A preferred tetramine is triethylenetetr amine.
  • Examples of precomplexed copper antagonists include precomplexed triethylenetetramines.
  • Precomplexed triethylenetetramines include, for example, triethylenetetramine (or salts thereof, such as triethylenetetramine dihydrocholoride) precomplexed with a metal ion having a binding constant lower than copper.
  • triethylenetetramine or salts thereof, such as triethylenetetramine dihydrocholoride
  • a metal ion having a binding constant lower than copper.
  • Such compounds may be referred to, for example, as "Ca-Trientine" to refer to triethylenetetramine precomplexed with calcium (e.g., Ca 2+ ).
  • copper antagonists include D-pencillamine, sar (N-methylglycine), diamsar (l,8-diamino-3, 6, 10, 13, 16, 19-hexa-azabicyclo[6.6.6]icosane), N-acetylpenicillamine, N 5 N'- diethyldithiocarbamate, bathocuproinedisulfonic acid, bathocuprinedisulfonate, and thiomolybdates, including mono-, di-, tri- and tetrathiomolybdates. Each may be precomplexed with a metal ion.
  • Precomplexed copper antagonists for example, a precomplexed triethylenetetramine
  • a precomplexed triethylenetetramine may be prepared as the precomplexed compound or a salt thereof.
  • precomplexing is believed to assist in the preparation, stability, or bioavailability of copper antagonists, including those in to be prepared and administered in aqueous formulations, such as, for example, triethylenetetramine dihydrocholoride. This allows lower dosing as well.
  • Precomplexed copper antagonists may be present in the compositions of the invention in an amount, for example, that is effective to (1) increase copper output in the urine of said subject, (2) decrease body and/or tissue copper levels, and/or (3) decrease copper uptake, for example, in the gastrointestinal tract.
  • metal complexes comprising copper antagonists and non- copper metals (that have lower binding affinities than copper for the copper antagonist) and one or more additional ligands than typically found in complexes of that metal. These additional ligands may serve to block sites of entry into the complex for water, oxygen, hydroxide, or other species that may undesirably complex with the metal ion and can cause degradation of the copper antagonist.
  • copper complexes of triethylenetetramine have been found to form pentacoordinate complexes with a tetracoordinated triethylenetetramine and a chloride ligand when crystallized from a salt solution rather than a tetracoordinate Cu 2+ triethylenetetramine complex.
  • 219 mg of triethylenetetramine * 2 HCl were dissolved in 50 ml, and 170 mg Of CuCl 2 * 2H2O were dissolved in 25 ml ethanol (95%). After addition of the CuCl 2 solution to the triethylenetetramine solution, the color changed from light to dark blue and white crystals precipitated.
  • Crystals were dissolved by addition of a solution of 80 mg NaOH in 15 ml H2O. After the solvent was evaporated, the residue was dissolved in ethanol, and two equivalents of ammonium-hexafluorophosphate were added. Blue crystals could be obtained after reduction of the solvent. Crystals were found that were suitable for x- ray structure determination. X-ray crystallography revealed a
  • [Cu(triethylenetetramine)Cl] complex may be formed from or between copper antagonists, for example, copper chelators (such as Cu2+ chelators, spermadine, spermine, tetracyclam, etc.), particularly those subject to degradative pathways such as those noted above, by providing additional complexing agents (such as anions in solution, for example, T, Br “ , F “ , (SO 4 ) 2" , (CO 3 ) 2" , BF 4" , NO 3" , ethylene, pyridine, etc.) in solutions of such complexes.
  • copper chelators such as Cu2+ chelators, spermadine, spermine, tetracyclam, etc.
  • additional complexing agents such as anions in solution, for example, T, Br “ , F “ , (SO 4 ) 2" , (CO 3 ) 2" , BF 4" , NO 3" , ethylene, pyridine, etc.
  • complexes with more accessible metal ions such as planar complexes or complexes having- four or fewer coordinating agents, where one or more additional complexing agents could provide additional shielding to the metal from undesirable ligands that might otherwise access the metal and displace a desired complexing agent.
  • Trientine active agents may be prepared in a number of ways. Trientine is a strongly basic moiety with multiple nitrogens that can be converted into a large number of suitable associated acid addition salts using an acid, for example, by reaction of stoichiometrically equivalent amounts of trientine and of the acid in an inert solvent such as ethanol or water and subsequent evaporation if the dosage form is best formulated from a dry salt. Possible acids for this reaction are in particular those that yield physiologically acceptable salts.
  • Nitrogen-containing copper antagonists for example, trientine active agents such as, for example, trientine, that can be delivered as a salt(s) (such as acid addition salts, e.g., trientine dihydrochloride) act as copper-chelating agents or antagonists, which aids the elimination of copper from the body by forming a stable soluble complex that is readily excreted by the kidney.
  • trientine active agents such as, for example, trientine
  • inorganic acids can be used, e.g., sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid. This is not an exhaustive list.
  • organic acids can be used to prepare suitable salt forms, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-or polybasic carboxylic, sulfonic or sulfuric acids, (e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono-and-disulfonic acids, and laurylsulfuric acid).
  • Nitrogen-containing copper antagonists for example, trientine active agents such as, for example, trientine, can also be in the form of quarternary ammonium salts in which the nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • nitrogen-containing copper antagonists are in the form of a compound or buffered in solution and/or suspension to a near neutral pH much lower than the pH 14 of a solution of trientine itself.
  • trientine active agents include derivative trientines, for example, trientine in combination with picolinic acid (2-pyridinecarboxylic acid). These derivatives include, for example, trientine picolinate and salts of trientine picolinate, for example, trientine picolinate HCl. They also include, for example, trientine di- picolinate and salts of trientine di-picolinate, for example, trientine di-picolinate HCl.
  • Picolinic acid moieties may be attached to trientine, for example one or more of the CH 2 moieties, using chemical techniques known in the art. Those in the art will be able to prepare other suitable derivatives, for example, trientine-PEG derivatives, which may be useful for particular dosage forms including oral dosage forms having increased bioavailability.
  • Compounds suitable as copper antagonists include cyclic and acyclic compounds according to Formula I:
  • X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of N, S and O;
  • R 1, R 2; R 3, R 45 R 5 and R 6 are independently selected from the group consisting of H, C 1 to C 1O straight chain or branched alkyl, C3 to ClO cycloalkyl, Cl to C6 alkyl C3 to ClO cycloalkyl, anyl, anyl substituted with 1 to 5 substituents, heteroaryl, fused aryl, Cl to C6 alkyl aryl, Cl to C6 alkyl aryl substituted with 1 to 5 substituents, Cl to C5 alkyl heteroaryl, Cl to C6 alkyl fused aryl, -CH 2 COOH 5
  • nl, n2 and n3 are independently 2 or 3 and each Of R 71 Rs 1 R 91 R 1O1 Ri I and R 12 is independently selected and is selected from the group consisting of H, Cl to ClO straight chain or branched alkyl, C3 to ClO cycloalkyl, Cl to C6 alkyl, C3 to ClO cycloalkyl, aryl, aryl substituted with 1 to 5 substituents, heteroaryl fused aryl, Cl to C6 alkyl aryl, Cl to C6 alkyl aryl substituted with 1 to 5 substituents, Cl to C5 alkyl heteroaryl, Cl to C6 fused aryl, provided that when X 1 is S or O, then R 2 is absent; when X 2 is S or O, then R 3 is absent, when X 3 is S or O, then R 4 is absent and
  • R 1, R 2, R 3, R 4, R 5 and R 6 may be functionalized for attachment to groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include, but are not limited to, Cl to ClO alkyl-CO-peptide, Cl to ClO alkyl-CO-protein, Cl to ClO alkyl-CO-PEG, Cl to ClO alkyl-NH-peptide, Cl to ClO alkyl-NH-protein, Cl to ClO alkyl-NH-CO-PEG, Cl to ClO alkyl-S-peptide, and Cl to ClO alkyl- S -protein.
  • R 7 , R 8 , R 9 , R 10 , Rn and R 12 may be functionalized for attachment to groups which include, but are not limited to, peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • groups which include, but are not limited to, peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include, but are not limited to, Cl to ClO alkyl-CO-peptide, Cl to ClO alkyl-CO-protein, Cl to ClO alkyl-CO-PEG, Cl to ClO alkyl-NH-peptide, Cl to ClO alkyl-NH-protein, Cl to ClO alkyl-NH-CO-PEG, Cl to ClO alkyl-S- ⁇ e ⁇ tide and Cl to ClO alkyl- S -protein.
  • R 1, R 2, R 3; R 43 R 5 and R 6 are independently selected from H, Cl to C6 alkyl, -CH 2 COOH, -CH 2 SO 3 H, -CH 2 PO(OH) 2 and -CH 2 P(CH 3 )O(OH); and each R 7 , R 8, R 9 , R 10 , Rn and R 12 is independently selected from H and Cl to C6 alkyl.
  • suitable compounds include those wherein at least one of R 1 and R 2 and at least one of R 5 and R 6 is H or Cl to C6 alkyl.
  • R 3 and R 4 are selected from H or Cl to C6 alkyl; more particularly, R 1, R 2, R 5> and R 6 are selected from H or Cl to C6 alkyl.
  • R 1 R 6; R 7; R 8j R ⁇ R 10, R 11, and R 12 are independently selected from H and Cl to C3 alkyl.
  • all of X 1; X 2j X 3; and X 4 are suitably N or, alternatively, one of X 1 and X 4 is S and X 2 and X 3 are N or S.
  • Tetra-heteroatom acyclic compounds within Formula I are provided where X 1 , X 2 , X 3 , and X 4 are independently chosen from the atoms N, S or O, such that, (a) for a four-nitrogen series, i.e., when Xi, X 2 , X 3 , and X 4 are N then: R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 al
  • Ri, R 2 , R 3 , R 4 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO- ⁇ e ⁇ tide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO - alkyl-NH-peptide, Cl-ClO alkyl-NH-protein; Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 1O , Rn, or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO- ⁇ e ⁇ tide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO- PEG, Cl-ClO alkyl-S- ⁇ eptide, and Cl-ClO alkyl-S-protein.
  • R 6 does not exist;
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O
  • R 1 , R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , Ri 0 , Rn, or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and " other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 4 does not exist and R 1 , R 2 , R 3 , R 5 , and R 6 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )
  • R 1 , R 2 , R 3 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , Ri 0 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alky 1-CQ-protein, -CL-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO " alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide 5 and Cl-
  • R 1 and R 6 do not exist;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3- ClO cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH);
  • R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 3 and R 6 do not exist;
  • R 1 , R 2 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH);
  • R 1 , R 2 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S- ⁇ rotein.
  • R 4 and R 6 do not exist;
  • R 1 , R 2 , R 3 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched -alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O
  • one or several OfR 1 , R 2 , R 3 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alky 1-NH- CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , Rg, R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 3 and R 4 do not exist;
  • R 1 , R 2 , R 5 and R 6 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); n
  • one or several OfR 1 , R 2 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl- S -peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 1 and R 2 and one ofR 5 and R 6 are joined together to form the bridging group (CR 13 R 14 ) n4
  • X 1 , X 2 , X 3 , and X 4 are independently chosen from the atoms N, S or O such that, (a) for a four-nitrogen series, i.e., when X 1 , X 2 , X 3 , and X 4 are N then:
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl
  • Ro and R 14 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S- ⁇ e ⁇ tide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 5 does not exist;
  • R 2 , R 3 , and R 4 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH 5 CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl,
  • R 2 , R 3 or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S -protein.
  • R 7 , R 8 , R 9 , Rio, Rn, Rn, Ro or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 2 and R 5 do not exist;
  • R 3 and R 4 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl, n2, n3,
  • R 3 , or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 3 and R 5 do not exist;
  • R 2 and R 4 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl , n2, n
  • R 2 , or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 3 , R 4 and R 5 do not exist;
  • R 2 is independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl, n2, n
  • R 2 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , Ri 3 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Suitable copper antagonist compounds of Formula I include, for example:
  • Suitable compounds of Formula I include, for example, one or more of triethylenetetramine, salts of triethylenetetramine, prodrugs of triethylenetetramine and salts of such prodrugs; analogs of triethylenetetramine and salts and prodrugs of such analogs; and/or active metabolites of triethylenetetramine and salts and prodrugs of such metabolites, including but not limited to N-acetyl triethylenetetramine and salts and prodrugs of N-acetyl triethylenetetramine.
  • Triethylenetetramine is a strongly basic moiety with multiple nitrogens that can be converted into a large number of suitable associated acid addition salts using an acid, for example, by reaction of triethylenetetramine and of the acid, for example, stoichiometrieally equivalent -.amounts, in a solvent, for example, " an Inert solvent such as, for example, ethanol or water and subsequent evaporation if the dosage form is best formulated from a dry salt. Possible acids for this reaction are in particular those that yield physiologically acceptable salts.
  • trientine active agents such as, for example, triethylenetetramine, that can be delivered as a salt(s) (such as acid addition salts, e.g., triethylenetetramine dihydrochloride or triethylenetetramine disuccinate or other acceptable hydrochloride or succinate salts)
  • act as copper- chelating or binding agents act as copper- chelating or binding agents, which aids the elimination of copper from the body by forming a stable
  • inorganic acids can be used, e.g., sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, and sulfamic acid. This is not an exhaustive list.
  • organic acids can be used to prepare suitable salt forms, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-or polybasic carboxylic, sulfonic or sulfuric acids, (e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane-or ethanesulfonic acid, ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono-and-disulfonic acids, and laurylsulfuric acid).
  • sulfonic or sulfuric acids
  • Organic acids include both aliphatic and aromatic carboxylic acids and include, for example, aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, aliphatic tricarboxylic acids, aromatic monocarboxylic acids, aromatic dicarboxylic acids, aromatic tricarboxylic acids and other organic acids known to those of skill in the art.
  • Aliphatic carboxylic acids may be saturated or unsaturated. Suitable aliphatic carboxylic acids include those having from 2 to about 10 carbon atoms.
  • Aliphatic monocarboxylic acids include saturated aliphatic monocarboxylic acids and unsaturated aliphatic monocarboxylic acids.
  • saturated monocarboxylic acids include acetic acid, propronic acid, butyric acid, valeric acid, caproic acid, enantliic acid, caprylic acid, pelargonic acid, and caprynic acid.
  • unsaturated aliphatic monocarboxylic acids include acrylic acid, propiolic acid, methacrylic acid, crotonic acid and isocrotonic acid.
  • Aliphatic dicarboxylic acids include saturated aliphatic dicarboxylic acids and unsaturated aliphatic dicarboxylic acids.
  • saturated aliphatic dicarboxylic acids examples include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid.
  • unsaturated aliphatic dicarboxylic acids include maleic acid, fumaric acid, citraconic acid, mesaconic acid, itaconic acid and the like.
  • Aliphatic tricarboxylic acids includes saturated aliphatic tricarboxylic acids and unsaturated tricarboxylic acids. Examples of saturated tricarboxylic acids include tricarballylic acid, 1, 2, 3-butanetricarboxylic acid and the like.
  • Suitable aliphatic dicarboxylic acids include those of the formula: HOOC-Q 1 -COOH, wherein Q 1 is alkylene of 1 to about 8 carbon atoms or alkenylene of 2 to about 8 atoms, and includes both straight chain and branched chain alkylene and alkenylene groups.
  • aromatic dicarboxylic acids include phthalic acid, isophthalic acid, terephthalic acid and the like.
  • aromatic tricarboxylic acids include trimesic acid, hemimellitic acid and trimellitic acid.
  • Nitrogen- containing copper chelator(s) or binding compound(s), for example, trientine active agents such as, for example, triethylenetetramine, can also be in the form of quarternary ammonium salts in which the nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • such nitrogen-containing copper chelator(s) are in the form of a compound or buffered in solution and/or suspension nearer to a neutral pH, lower than the pH 14 of a solution of triethylenetetramine itself.
  • trientine active agents include derivative trientine active agents, for example, triethylenetetramine in combination with picolinic acid (2-pyridinecarboxylic acid). These derivatives include, for example, triethylenetetramine picolinate and salts of triethylenetetramine picolinate, for example, triethylenetetramine picolinate HCl. These also include, for example, triethylenetetramine di-picolinate and salts of triethylenetetramine di-picolinate, for example, triethylenetetramine di-picolinate HCl.
  • Picolinic acid moieties may be attached to triethylenetetramine, for example, one or more of the CH 2 moieties, using chemical techniques known in the art.
  • compounds suitable as copper antagonists include compounds of Formula I(a):
  • X 1 , X 2 , X 3 and X 4 are N or one of Xj, X 2 , X 3 and X 4 is O or S and the remainder are N; n l5 n 2 , and ⁇ .
  • R 3 are 2 or 3; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H or absent; and R 7 , R 8 , R 9 , Rj 0 , Rn, and R 12 , are independently selected from the group consisting of H, CH 3 and CH 2 CH 3 and wherein; if X 1 is S or O, then R 2 is absent; if X 2 is S or O, the R 3 is absent; if X 3 is S or O, then R 4 is absent; and if X 4 is S or O, then R 6 is absent.
  • Additional compounds suitable as copper antagonists include cyclic and acyclic compounds according to Formula II:
  • X 1 , X 2 and X 3 are independently selected from the group consisting of N 5 S and O;
  • R 1, R 2, R 3> R 5 and R 6 may be functionalized for attachment to groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include, but are not limited to, Cl to ClO alkyl-CO-peptide, Cl to ClO alkyl-CO-protein, Cl to ClO alkyl-CO-PEG, Cl to ClO alkyl-NH-peptide, Cl to ClO alkyl-NH-protein, Cl to ClO alkyl-NH-CO-PEG, Cl to ClO alkyl-S-peptide, and Cl to ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , and R 10 may be functionalized for attachment to groups which include, but are not limited to, peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • groups which include, but are not limited to, peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • PEGs polyethylene glycols
  • Examples of such functionalization include, but are not limited to, Cl to ClO alkyl-CO- ⁇ e ⁇ tide, Cl to ClO alkyl-CO-protein, Cl to ClO alkyl-CO-PEG, Cl to ClO alkyl-NH-peptide, Cl to ClO alkyl-NH-protein, Cl to ClO alkyl-NH-CO-PEG,
  • suitable compounds of Formula I include those wherein R 1 , R 2 , R 3 , R 5 and R 6 are independently selected from H, Cl to C6 alkyl, -CH 2 COOH, -CH 2 SO 3 H, -CH 2 PO(OH) 2 and -CH 2 P(CH 3 )O(OH); and each R 7j R 81 R 9 and R 10 is independently selected from H and Cl to C6 alkyl.
  • suitable compounds include those wherein at least one Of R 1 and R 2 and at least one of R 5 and R 6 is H or Cl to C6 alkyl.
  • R 3 is selected from H or Cl to C6 alkyl; more particularly, R 1; R 2> R 5 and R 6 are selected from H or Cl to C6 alkyl.
  • R 1; R 2> R 5 and R 6 are selected from H or Cl to C6 alkyl.
  • R 1; R 2> R 5 and R 6 are selected from H or Cl to C6 alkyl.
  • suitable compounds include those wherein R 1, R 6, R 7j R 8, R 9 and R 10, are independently selected from H and Cl to C3 alkyl.
  • all of X 1, X 2 and X 3 are suitably N or, alternatively, one of X 1 and X 3 is S and X 2 are N or S.
  • Tri-heteroatom compounds within Formula II are provided where X 1 , X 2 , and X 3 are independently chosen from the atoms N, S or O such that,
  • R 1 , R 2 , R 3 , R 5 or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-
  • R 7 , Rg, R 9 , or R 1O may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S- ⁇ rotein.
  • R 3 does not exist;
  • R 1 , R 2 , R 5 or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, - Cl-ClO alkyl-S-peptide, and Cl-ClO " alkyl-S-protein.
  • R 7 , R 8 , R 9 , or R 1O may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO- ⁇ e ⁇ tide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl- S -protein, (c) for a second, two-nitrogen series, when X 1 and X 2 are N and X 3 is O or S then: R 5 does not exist; R 1 , R 2 , R 3 , and R 6 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and pen
  • R 1 , R 2 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , or R J0 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl- S -peptide, and Cl-ClO alkyl-S-protein.
  • a series of tri-heteroatom cyclic analogues according to the above Formula II are provided in which R 1 and R 6 are joined together to form the bridging group (CRnRi 2 ) n3 , and X 1 , X 2 and X 3 are independently chosen from the atoms N, S or O such that:
  • R 2 , R 3 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl- ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl- ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , Rg, R 9 , Rio, Rn, or Ri 2 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 5 does not exist;
  • R 2 or R 3 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl- ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl- ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 1O , Ri b or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 3 and R 5 do not exist;
  • R 2 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO- peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH- peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S- peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl- S -peptide, and Cl- ClO alkyl-S-protein.
  • Copper antagonists useful in the invention also include copper chelators that have been pre-complexed with a non-copper metal ion prior to administration for therapy.
  • Metal ions used for pre-complexing have a lower association constant for the copper antagonist than that of copper.
  • a metal ion for pre-complexing a copper antagonist that chelates Cu 2+ is one that has a lower binding affinity for the copper antagonist than Cu 2+ .
  • Preferred metal ions for precomplexing include calcium (e.g., Ca 2+ ), magnesium (e.g., Mg 2+ ), chromium (e.g., Cr 2+ and Cr 3+ ), manganese (e.g., Mn 2+ ), zinc (e.g., Zn 2+ ), selenium (e.g., Se 4+ ), and iron (e.g., Fe 2+ and Fe 3+ ).
  • Most preferred metal ions for precomplexing are calcium, zinc, and iron.
  • metals include, for example, cobalt (e.g., Co 2+ ), nickel (e.g., Ni 2+ ), silver (e.g., Ag 1+ ), and bismuth (e.g., Bi 3+ ).
  • Metals are chosen with regard, for example, to their relative binding to the copper antagonist, and relative to toxicity and the dose of the copper antagonist to be administered.
  • metal complexes comprising copper antagonists and non- copper metals (that have lower binding affinities than copper for the copper antagonist) and one or more additional ligands than typically found in complexes of that metal.
  • additional ligands may serve to block sites of entry into the complex for water, oxygen, hydroxide, or other species that may undesirably complex with the metal ion and can cause degradation of the copper antagonist.
  • copper complexes of triethylenetetramine have been found to form pentacoordinate complexes with a tetracoordinated triethylenetetramine and a chloride ligand when crystallized from a salt solution rather than a tetracoordinate Cu 2+ triethylenetetramine complex.
  • 219 mg of triethylenetetramine • 2 HCl were dissolved in 50 ml, and 170 mg of CuCl 2 • 2H2O were dissolved in 25 ml ethanol (95%).
  • [Cu(triethylenetetramine)Cl] complex may be formed from or between copper antagonists, for example, copper chelators (such as Cu2+ chelators, spermidine, spermine, tetracyclam, etc), particularly those subject to degradative pathways such as those noted above, by providing additional complexing agents (such as anions in solution, for example, I “ , Br “ , F “ , (SO 4 ) “ , (CO 3 ) 2" , BF 4" , NO 3” , ethylene, pyridine, etc) in solutions of such complexes.
  • copper chelators such as Cu2+ chelators, spermidine, spermine, tetracyclam, etc
  • additional complexing agents such as anions in solution, for example, I “ , Br “ , F “ , (SO 4 ) “ , (CO 3 ) 2" , BF 4" , NO 3” , ethylene, pyridine, etc
  • the compounds for use according to the present invention may be made using any of a variety of chemical synthesis, isolation, and purification methods known in the art.
  • trientine active agents may be made using any of a variety of chemical synthesis, isolation, and purification methods known in the art.
  • Published United States Patent Application No. 2006/0041170 describes the synthesis of certain triethylenetetramine salts. Exemplary synthetic routes are described below. General synthetic chemistry protocols are somewhat different for these classes of molecules due to their propensity to chelate with metallic cations, including copper.
  • Glassware should be cleaned and silanized prior to use.
  • Plasticware should be chosen specifically to have minimal presence of metal ions.
  • Metal implements such as spatulas should be excluded from any chemistry protocol involving chelators.
  • Water used should be purified by sequential carbon filtering, ion exchange and reverse osmosis to the highest level of purity possible, not by distillation. All organic solvents used should be rigorously purified to exclude any possible traces of metal ion contamination. Care must also be take with purification of such derivatives due to their propensity to chelate with a variety of cations, including copper, which may be present in trace amounts in water, on the surface of glass or plastic vessels. Once again, glassware should be cleaned and silanized prior to use.
  • Plasticware should be chosen specifically to have minimal presence of metal ions.
  • Metal implements such as spatulas should be avoided, and water used should be purified by sequential carbon filtering, ion exchange and reverse osmosis to the highest level of purity possible, and not by distillation. All organic solvents used should be rigorously purified to exclude any possible traces of metal ion contamination. Ion exchange chromatography followed by lyophilization is typically the best way to obtain pure solid materials of these classes of molecules. Ion exchange resins should be washed clean of any possible metal contamination.
  • Acyclic and cyclic compounds of the invention and exemplary synthetic methods and existing syntheses from the art include the following: For tetra-heteroatom acyclic examples of Formula I:
  • X 1 , X 2 , X 3 , and X 4 are independently chosen from the atoms N, S or O such that:
  • R 1 , R 2 , R 3 , R 4 , R 5 , or Rg may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein. Also provided are embodiments wherein one, two, three or four of R 1 through R 12 are other than hydrogen. In some embodiments, the compounds of Formulae I, I(a) or II are selective for a particular oxidation state of copper.
  • the compounds may be selected so that they preferentially bind oxidized copper, or copper (II). Copper selectivity can be assayed using methods known in the art. Competition assays can be done using isotopes of copper (I) and copper (II) to determine the ability of the compounds to selectively bind one form of copper.
  • the compounds of Formulae I, I(a) or II may be chosen to avoid excessive lipophilicity, for example by avoiding large or numerous alkyl substituents. Excessive lipophilicity can cause the compounds to bind to and/or pass through cellular membranes, thereby decreasing the amount of compound available for chelating copper, particularly for extracellular copper, which may be predominantly in the oxidized form of copper (II).
  • R 1 , R 2 , R 5 and R 6 can be accomplished with this chemistry by standard procedures.
  • the oxalamide approach also can lead to successful syntheses of this class of compounds, although the central substituents are always going to be hydrogen or its isotopes with this kind of chemistry.
  • This particular variant makes use of the trichloroethyl ester group to protect one of the carboxylic acid functions of oxalic acid but other protecting groups are also envisaged.
  • Reaction of an amino acid amide derived from a natural or unnatural amino acid with a differentially protected oxalyl mono chloride gives the mono-oxalamide shown which can be reacted under standard peptide coupling condition to give the un-symmetrical bis- oxalamide which can then be reduced with diborane to give the desired tetra-aza derivative.
  • 3NX series 1 when X 1 , X 2 , X 3 , are N and X 4 is S or O then: R 6 does not exist R 1 , R 2 , R 3 , R 4 and R 5 are independently chosen from H, CH 3 , C2-
  • nl, n2, and n3 are independently chosen to be 2 or 3, and each repeat of any of nl, n2, and n3 may be the same as or different than any other repeat; and R 7 , Rg, R 9 , R 10 , R 11 , and R 12 are independently chosen from H,
  • R 1 , R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , Rio, Rn, or Ri 2 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • Synthesis of examples of the open chain 3NX series 1 of Formula I Variations of the syntheses used for the 4N series provide examples of the 3N series 1 class of compounds. The chemistry described by Meares et al. can be modified to give examples of the 3NX series of compounds.
  • X 4 is O
  • the incorporation Of R 1 , R 2 , R 5 and R 6 can be accomplished with this chemistry by standard procedures.
  • R 1 , R 2 , R 5 and R 6 can be accomplished with this chemistry by standard procedures.
  • R 7 , R 8 , R 9 , R 1O , R 11 , and R 12 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 1 , R 2 , R 3 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • Synthesis of examples of the open chain 3NX series 2 of Formula I A different approach can be used for the synthesis of the 3N series 2 class of compounds. The key component is the incorporation in the synthesis of an appropriately substituted and protected ethanolamine or ethanethiolamine derivative, which is readily available from both natural and un-natural amino acids, as shown below.
  • X 3 O or S
  • R 1 , R 2 , R 5 and R 6 can be accomplished with this chemistry by standard procedures.
  • 2N2X series 1 when X 2 and X 3 are N and Xi and X 4 are O or S then: R 1 and R 6 do not exist;
  • R 2 , R 3 , R 4 , and R5 are independently chosen from H, CH 3 , C2- ClO straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl.
  • aryl C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H 5 CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nlj n2, and n3 are independently chosen to be 2 or 3, and each repeat of any of nl, n2, and n3 may be the same as or different than any other repeat; and
  • R 7 , R 8 , R 9 , R 1O , Ri b and R 12 are independently chosen from H,
  • R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO- PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl- S -protein.
  • R 7 , R 8 , R 9 , R 10 , R] 1 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl- S -protein.
  • the oxalamide approach can lead to successful syntheses of this class of compounds.
  • This particular variant makes use of the trichloroethyl ester group to protect one of the carboxylic acid functions of oxalic acid but other protecting groups are also envisaged.
  • Reaction of an aminoalcohol or aminothiol derivative readily available from a natural or unnatural amino acid with a differentially protected oxalyl mono chloride gives the mono-oxalamide shown which can be reacted under standard peptide coupling condition to give the un- symmetrical bis- oxalamide which can then be reduced with diborane to give the desired tetra-aza derivative.
  • R 1 , R 2 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-
  • R 7 , R 8 , R 9 , R 1O , R 11 , and R 12 are independently chosen from H,
  • one or several OfR 1 , R 2 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO- ⁇ e ⁇ tide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-
  • R 7 , R 8 , R 9 , R 10 , Rn, or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • 2N2X series 3 when X 1 and X 2 are N and X 3 and X 4 are O. or S. then: - - R 4 and R 6 do not exist;
  • R 1 , R 2 , R 3 , and R 5 are independently chosen from H, CH 3 , C2-
  • R 7 , R 8 , R 9 , R 1O , R 11 , and R 12 are independently chosen from H,
  • one or several OfR 1 , R 2 , R 3 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO- PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S -protein.
  • R 7 , R 8 , R 9 , R 10 , Rn, or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to C 1 -C 10 ⁇ alkyl-CO-peptide, Cl -C 10 " alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S- ⁇ e ⁇ tide, and Cl-ClO alkyl-S-protein.
  • R 3 and R 4 do not exist
  • R 1 , R 2 , R 5 and R 6 are independently chosen from H, CH 3 , C2-
  • R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 1 , R 2 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO- PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl- S -protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl- S -protein.
  • R 1 and R 2 are joined together to form the bridging group
  • X 1 , X 2 , X 3 , and X 4 are independently chosen from the atoms N, S or O such that:
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-
  • R 7 , R 8 , R 9 , R 10 , R 11 , Ri 2 , R 13 and R 14 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-
  • R 7 , R 8 , R 9 , R 10 , Rn, R ⁇ 5 R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco- kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl- NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S- protein.
  • Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give triethylenetetramine directly.
  • Possible side products from this synthesis include the 12N4 macrocycle shown below, which could also be synthesized directly from Triethylenetetramine by reaction with a further equivalent of 1,2-dichloro ethane under appropriately dilute concentrations to provide the 12N4 macrocycle shown. Modification of this procedure by using starting materials with appropriate R a and R b (where R a> R b correspond to R 7 , R 8 or R 11 , R 12 ) groups would lead to symmetrically substituted 12N4 macrocycle examples as shown below:
  • R 1 , R 2 , R 5 and R 6 can be accomplished with this chemistry by standard procedures.
  • the oxalamide approach also can lead to successful syntheses of this class of compounds.
  • This particular variant makes use of the trichloroethyl ester group to protect one of the carboxylic acid functions of oxalic acid but other protecting groups are also envisaged.
  • Reaction of an amino acid amide derived from a natural or unnatural amino acid with a differentially protected oxalyl mono chloride gives the mono-oxalamide shown which can be reacted under standard peptide coupling condition to give the un-symmetrical bis-oxalamide which can then be reduced with diborane to give the desired tetra-aza derivative.
  • Further reaction with oxalic acid gives the cyclic derivative, which can then be reduced once again with diborane to give the 12N4 series of compounds.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 , R 3 or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-
  • R 7 , Rg, R 9 , R 10 , R 11 , R 12 , R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl- NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S- protein.
  • Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give triethylenetetramine directly.
  • Possible side products from this synthesis include the 12N4 macrocycle shown below, which could also be synthesized directly from Triethylenetetramine by reaction with a further equivalent of 1,2-dichloro ethane under appropriately dilute concentrations to provide the 12N4 macrocycle shown. Modification of this procedure by using starting materials with appropriate R groups leads to symmetrically substituted 12N4 macrocycle examples as shown below:
  • R 1 , R 2 , R 5 and R 6 can be accomplished with this chemistry by standard procedures.
  • R 2N2X series 1 when X 2 and X 3 are N and X 1 and X 4 are O or S then: R 2 and R 5 do not exist
  • R 3 and R 4 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl,
  • nl, n2, n3, and n4 are independently chosen to be 2 or 3, and each repeat of any of nl, n2, n3 and n4 may be the same as or different than any other repeat; and
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl
  • R 3 , or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 1O , R 11 , R 12 , R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco- kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NET-peptide, Cl-ClO alkyl- NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S- protein.
  • a variant of the dichloroethane approach, shown above, can also lead to successful syntheses of this class of compounds.
  • Reaction of an aminoalcohol or aminothiol derivative readily available from a natural or unnatural amino acid with an O- protected 1-chloro, 2-hydroxy ethane derivative followed by deprotection and substitution with chloride gives the mono-chloro compound shown which can be further reacted with an appropriate aminoalcohol or aminothiol derivative readily available from a natural or unnatural amino acid to give the un-symmetrical product shown.
  • Deprotection followed by cyclization with a dichloroethane derivative would give a mixture of the the two position isomers shown.
  • R 3 and R 5 do not exist
  • R 7 , R 8 , R 9 , R 1O , R 11 , R 12 , R 13 and R 14 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 , or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R ⁇ or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl- NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give triethylenetetramine directly.
  • Possible side products from this synthesis include the 12N4 macrocycle shown below, which could also be synthesized directly from Triethylenetetramine by reaction with a further equivalent of 1,2-dichloro ethane under appropriately dilute concentrations to provide the 12N4 macrocycle shown. Modification of this procedure by using starting materials with appropriate R groups would lead to symmetrically substituted 12N4 macrocycle examples as shown below:
  • protecting group chemistry such as the widely used BOC (t- butyloxycarbonyl) group and an appropriate O or S protecting group allows the chemistry to be directed specifically towards the substitution pattern shown.
  • Other approaches such as via the chemistry of ethyleneimine may also lead to a subset of the di-aza 2X series.
  • a variant of this approach using substituted dichloroethane derivatives could be used to access more complex substitution patterns. This would lead to mixtures of position isomers, which can be separated by HPLC.
  • R 2 is independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, Cl- C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl, n2, n3, and n4 are independently chosen to be 2 or 3, and each repeat of any of nl, n2, n3 and n4 may be the same as or different than any other repeat; and
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO- peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH- peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S- peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in ⁇ order to modify the overall pharmaco- kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl- NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • protecting group chemistry such as the widely used BOC (t- butyloxycarbonyl) group and an appropriate .O ⁇ or S -protecting group allows ⁇ the " chemistry to be directed specifically towards the substitution pattern shown.
  • Other approaches such as via the chemistry of ethyleneimine may also lead to a subset of the mono-aza 3X series.
  • a variant of this approach using substituted dichloroethane derivatives could be used to access more complex substitution patterns. This would lead to mixtures of position isomers, which can be separated by HPLC.
  • X 1 , X 2 , and X 3 are independently chosen from the atoms N, S or
  • R 1 , R 2 , R 3 , R 5 , and R 6 are independently chosen from H, CH 3 ,
  • nl and n2 are independently chosen to be 2 or 3, and each repeat of any of nl and n2 may be the same as or different than any other repeat;
  • R 7 , Rg, R 9 , and R 10 are independently chosen from H, CH 3 , C2-
  • R 1 , R 2 , R 3 , R 5 or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH- peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , or R 10 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give Triethylenetetramine directly.
  • a variant of this procedure by using starting materials with appropriate R groups and l-amino,2-chloro ethane would lead to some open chain 3N examples as shown below:
  • R 1 , R 2 , R 5 , and R 6 are independently chosen from H, CH 3 , C2- ClO straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl and n2 are independently chosen to be 2 or 3, and each repeat of any of nl and n2 may be the same as or different than any other repeat; and
  • R 7 , R 8 , R 9 , and R 10 are independently chosen from H, CH 3 , C2- ClO straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl
  • R 1 , R 2 , R 5 or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG 5 Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO- PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , or R 10 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 5 does not exist
  • R 1 , R 2 , R 3 and R 6 are independently chosen from H, CH 3 , C2-
  • R 7 , R 8 , R 9 , and R 10 are independently chosen from H, CH 3 , C2- ClO straight chain or branched alkyl, C3-C10 cycloalkyl, ⁇ €l-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • Ri, R 2 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO- PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , Rg, R 9 , or R 1O may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 1 , R 2 , R 5 and R 6 can be accomplished with this chemistry by standard procedures.
  • Tri-heteroatom cyclic series of Formula II Tri-heteroatom cyclic series of Formula II:
  • R 1 and R 6 form a bridging group (CRnRi 2 )n3;
  • X 1 , X 2 , and X 3 are independently chosen from the atoms N, S or
  • R 7 , R 8 , R 9 , R 1O , R 11J and R 12 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 , R 3 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • Synthesis of examples of the macrocyclic 3N series of Formula II As mentioned above Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give Triethylenetetramine directly. A variant of this procedure by using starting materials with appropriate R groups and l-amino,2-chloro ethane would lead to open chain 3N examples which could then be cyclized by reaction with an appropriate 1,2 dichloroethane derivative as shown below:
  • R 1 , R 2 , and R 5 can be accomplished with this chemistry by standard procedures.
  • R 2 and R 3 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl
  • R 7 , R 8 , R 9 , R 10 , Rn, and R 12 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 or R 3 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 1O , Rn, or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the ' overall " pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S -protein.
  • Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give Triethylenetetramine directly.
  • a variant of this procedure by using starting materials with appropriate R groups and l-amino,2-chloro ethane would lead to open chain 2NX examples which could then be cyclized by reaction with an appropriate 1,2 dichloroethane derivative as shown below:
  • R 1 , and R 2 can be accomplished with this chemistry by standard procedures.
  • R 3 and R 5 do not exist
  • R 2 is independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, Cl-
  • nl, n2, and n3 are independently chosen to be 2 or 3, and each repeat of any of nl, n2 and n3 may be the same as or different than any other repeat;
  • R 7 , R 8 , R 9 , R 10 , Rn, and R 12 are independently chosen from H,
  • R 2 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO- peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH- peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S- peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl- S -peptide, and Cl-ClO alkyl-S-protein.
  • Synthesis of examples of the macrocyclic 1N2X series of Formula II As mentioned above Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give Triethylenetetramine directly.
  • Copper antagonists and pharmaceutically acceptable salts for use according to the present invention may also be synthesized using methods described in U.S. Published Patent Application No. 2006/0041170, the contents of which are hereby incorporated by reference in its entirety.
  • Any of the methods of treating a subject having or suspected of having or predisposed to a glucose metabolism disease, disorder, and/or condition, or other diseases, disorders, and/or conditions referenced or described herein may utilize the administration of any of the doses, dosage forms, formulations, compositions and/or devices herein described.
  • aspects of the invention include controlled or other doses, dosage forms, formulations, compositions and/or devices containing one or more hypoglycemic agents and one or more copper antagonists, for example, one or more compounds of Formulae I, I(a) or II, or trientine active agents, including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trientine tetrafumarate, or other pharmaceutically acceptable salts thereof, trientine analogues of Formulae I, I(a) and II and salts thereof.
  • trientine active agents including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trientine tetrafumarate, or other pharmaceutically acceptable salts thereof, trientine analogues of Formulae I, I(a) and II and salts thereof.
  • the present invention includes, for example, doses and dosage forms for at least oral administration, transdermal delivery, topical application, suppository delivery, transmucosal delivery, injection (including subcutaneous administration, subdermal administration, intramuscular administration, depot administration, and intravenous administration (including delivery via bolus, slow intravenous injection, and intravenous drip), infusion devices (including implantable infusion devices, both active and passive), administration by inhalation or insufflation, buccal administration, sublingual administration, and ophthalmic administration.
  • injection including subcutaneous administration, subdermal administration, intramuscular administration, depot administration, and intravenous administration (including delivery via bolus, slow intravenous injection, and intravenous drip)
  • infusion devices including implantable infusion devices, both active and passive
  • administration by inhalation or insufflation buccal administration, sublingual administration, and ophthalmic administration.
  • the invention includes methods for treating a subject having or suspected of having or predisposed to, or at risk for, any diseases, disorders and/or conditions
  • ⁇ characterized in whole or in part by (a) hypercupremia and/or copper-related tissue damage and (b) hyperglycemia, insulin resistance, impaired glucose tolerance, and/or impaired fasting glucose, comprising administering a composition comprising a pharmaceutically acceptable copper antagonist and a hypoglycemic agent.
  • Such compounds may be administered in amounts, for example, that are effective to (1) decrease body and/or tissue copper levels, (2) increase copper output in the urine of a subject, (3) decrease copper uptake, for example, in the gastrointestinal tract, , (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase copper (I), (8) lower serum glucose, (9) lower blood glucose, (10) lower urine glucose, (11) lower fructosamine, (12) lower glycosylated hemoglobin (HbAi c ) levels, (13) lower postprandial glycemia, (14) ameliorate impaired glucose tolerance, (15) ameliorate impaired fasting glucose, and/or (16) lower the rate and/or severity of hypoglycemic events, including severe hypoglycemic events.
  • the invention includes methods for treating and/or preventing, in whole or in part, various diseases, disorders and conditions, including, for example, impaired glucose tolerance; impaired fasting glucose; diabetes and/or its complications, including type 1 and type 2 diabetes and their complications; insulin resistance; Syndrome X; obesity and other weight related disorders; cardiomyopathy, including diabetic cardiomyopathy; nerve diseases, including diabetic neuropathy; kidney disease, including diabetic nephropathy; eye disease, including diabetic retinopathy and cataracts; hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and/or tissue ischemia, and diseases and disorders characterized at least in part by any one or more of hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia; and, diseases, disorders or conditions characterized in whole or in part by (a) hypercupremia and/or copper-related tissue damage and (b) hyperglycemia, insulin resistance, impaired glucose tolerance, and/
  • disorders to .be treated using the compositions and ' methods of the invention include disorders of the heart muscle, including heart failure; myocardial infarction; cardiomyopathy, including idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy. Still other disorders that may be treated using the compositions and methods of the invention are hypertension and stroke.
  • diabetic acute coronary syndrome e.g., myocardial infarction, diabetic hypertensive cardiomyopathy, acute coronary syndrome associated with impaired glucose tolerance (IGT), acute coronary syndrome associated with impaired fasting glucose (IFG), hypertensive cardiomyopathy associated with IGT, hypertensive cardiomyopathy associated with IFG, ischemic cardiomyopathy associated with IGT, ischemic cardiomyopathy associated with IFG, ischemic cardiomyopathy associated with coronary heart disease (CHD), acute coronary syndrome not associated with any abnormality of the glucose metabolism, hypertensive cardiomyopathy not associated with any apparent abnormality of glucose metabolism, ischemic cardiomyopathy not associated with any apparent abnormality of glucose metabolism (irrespective of whether or not such ischemic cardiomyopathy is associated with coronary heart disease or not), and any disease of the vascular tree including disease states of the aorta, carotid, cerebrovascular, coronary, renal, retinal, vasa nervorum, iliac,
  • Atheromatous disorders of the major blood vessels including the aorta, the coronary arteries, the carotid arteries, the cerebrovascular arteries, the renal arteries, the iliac arteries, the femoral arteries, and the popliteal arteries), toxic, drug-induced, and metabolic disorders of small blood vessels, and, non- fatal plaque rupture of atheromatous lesions of major blood vessels, all may be treated using the compositions and methods of the invention.
  • a therapeutically effective amount of a copper antagonist for example a copper chelator, including but not limited to trientine, trientine salts, trientine analogues of Formulae I, I(a) and II, and so on, is-from about r ⁇ mg/kg to about 1 g/kg.
  • Other therapeutically effective dose ranges include, for example, from about 1.5 mg/kg to about 950 mg/kg, about 2 mg/kg to about 900 mg/kg, about 3 mg/kg to about 850 mg/kg, about 4 mg/kg to about 800 mg/kg, about 5 mg/kg to about 750 mg/kg, about 5 mg/kg to about 700 mg/kg, about 5 mg/kg to about 600 mg/kg, about 5 mg/kg to about 500 mg/kg, about 10 mg/kg to about 400 mg/kg, about 10 mg/kg to about 300 mg/kg, about 10 mg/kg to about 200 mg/kg, about 10 mg/kg to about 250 mg/kg, about 10 mg/kg to about 200 mg/kg, about 10 mg/kg to about 200 mg/kg, about 10 mg/kg to about 150 mg/kg, about 10 mg/kg to about 100 mg/kg, about 10 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg/kg, or about 15 mg/kg to about 35 mg/kg.
  • a therapeutically effective amount of a copper antagonist including for example, trientine, trientine salts, trientine analogues of Formulae I, I(a) and II, and so on, is from about 10 mg to about 4 g per day.
  • Other therapeutically effective dose ranges include, for example, from about 20 mg to about 3.9 g, from about 30 mg to about 3.7 g, from about 40 mg to about 3.5 g, from about 50 mg to about 3 g, from about 60 mg to about 2.8 g, from about 70 mg to about 2.5 g, about 80 mg to about 2.3 g, about 100 mg to about 2 g, about 100 mg to about 1.5 g, about 200 mg to about 1400 mg, about 200 mg to about 1300 mg, about 200 mg to about 1200 mg, about 200 mg to about 1100 mg, about 200 mg to about 1000 mg, about 300 mg to about 900 mg, about 300 mg to about 800 mg, about 300 mg to about 700 mg or about 300 mg to about 600 mg per day.
  • Copper antagonists including, for example, trientine, trientine salts, trientine analogues of Formulae I, I(a) and II, and so on, will also be effective at doses in the order of 1/10, 1/50, 1/100, 1/200, 1/300, 1/400, 1/500 and even 1/1000 of those described herein.
  • low dose copper antagonists may include compounds, including copper chelators, particularly Cu+2 chelators, including but not limited to trientine active agents and compounds of Formulae I, I(a) and II, and the like, in an amount sufficient to provide, for example, dosages from about 0.001 mg/kg to about 5 mg/kg, about 0.01 mg/kg to about 4.5 mg/kg, about 0.02 mg/kg to about 4 mg/kg, about 0.02 to about 3.5 mg/kg, about 0.02 mg/kg to about 3 mg/kg, about 0.05 mg/kg to about 2.5 mg/kg, about 0.05 mg/kg to about 2 mg/kg, about 0.05-0.1 mg/kg to about 5 mg/kg, about 0.05- 0.1 mg/kg to about 4 mg/kg, about 0.05-0.1 mg/kg to about 3 mg/kg, about 0.05-0.1 mg/kg to about 2 mg/kg, about 0.05-0.1 mg/kg to about 0.05-0.1 mg/kg to about 3 mg/kg, about 0.05-0.1 mg/kg to about 2 mg/kg
  • a therapeutically effective amount is an amount effective to elicit a plasma concentration of a copper antagonist, for example, a copper chelator, including for example, trientine active agents, including but not limited to trientine, trientine salts, and compounds of Formulae I, I(a) and II, and so on, from about 0.01 mg/L to about 20 mg/L, about 0.01 mg/L to about 15 mg/L, about 0.1 mg/L to about 10 mg/L, about 0.5 mg/L to about 9 mg/L, about 1 mg/L to about 8 mg/L, about 2 mg/L to about 7mg/L or about 3 mg/L to about 6 mg/L.
  • a copper antagonist for example, a copper chelator
  • trientine active agents including but not limited to trientine, trientine salts, and compounds of Formulae I, I(a) and II, and so on, from about 0.01 mg/L to about 20 mg/L, about 0.01 mg/L to about 15 mg/L, about 0.1 mg/
  • dose ranges for hypoglycemic agents are discussed herein and additionally are known to those skilled in the art.
  • the doses described herein may be administered in a single dose or multiple doses. For example, doses may be administered, once, twice, three, four or more times a day.
  • any such dose may be administered by any of the routes or in any of the forms herein described. It will be appreciated that any of the dosage forms, compositions, formulations or devices described herein particularly for oral administration may be utilized, where applicable or desirable, in a dosage form, composition, formulation or device for administration by any of the other routes herein contemplated or commonly employed. For example, a dose or doses could be given parenterally using a dosage form suitable for parenteral administration which may incorporate features or compositions described in respect of dosage forms suitable for oral administration, or be delivered in an oral dosage form such as a modified release, extended release, delayed release, slow release or repeat action oral dosage form.
  • the invention also is directed to doses, dosage forms, formulations, compositions and/or devices comprising one or more hypoglycemic agents and one or more copper antagonists, for example, one or more compounds of Formulae I, I(a) and II and salts thereof, and one or more trientine active agents, including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trientine tetrafumarate or other pharmaceutically acceptable salts thereof, trientine analogues and salts thereof, useful for therapy of glucose metabolism diseases, disorders, and/or conditions in humans and other mammals and other disorders as disclosed herein.
  • one or more hypoglycemic agents and one or more copper antagonists for example, one or more compounds of Formulae I, I(a) and II and salts thereof, and one or more trientine active agents, including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate,
  • the use of these dosage forms, formulations compositions and/or devices of copper antagonism enables effective treatment of these conditions, through novel and improved formulations suitable for administration to humans and other mammals.
  • the invention provides, for example, dosage forms, formulations, devices and/or compositions containing one or more hypoglycemic agents and one or more copper antagonists, for example, copper chelators, such as copper (II) chelators, including one or more compounds of Formulae I, I(a) and II and salts thereof, and trientine active agents, including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trientine tetrafumarate or other pharmaceutically acceptable salts thereof, and salts thereof.
  • copper chelators such as copper (II) chelators, including one or more compounds of Formulae I, I(a) and II and salts thereof
  • trientine active agents including but not limited to, trientine, trientine dihydrochloride,
  • the dosage forms, formulations, devices and/or compositions of the invention may be formulated to optimize bioavailability and to maintain plasma concentrations within therapeutic range, including for extended periods, and results in increases in the time that plasma concentrations of the hypoglycemic agent(s) / copper antagonist(s) remain within a desired therapeutic range at the site or sites of action.
  • Controlled delivery preparations also optimize the drug concentration at the site of action and minimize periods of under and over medication, for example.
  • the dosage forms, formulated, devices and/or compositions of the invention may be formulated for periodic administration, including once daily administration, to provide low dose controlled and/or low dose long-lasting in vivo release of a hypoglycemic agent and a copper antagonist, for example, a copper chelator for chelation of copper and excretion of chelated copper via the urine and/or to provide enhanced bioavailability of a hypoglycemic agent / copper antagonist, for example, a copper chelator for chelation of copper and excretion of chelated copper via the urine.
  • a hypoglycemic agent and a copper antagonist for example, a copper chelator for chelation of copper and excretion of chelated copper via the urine.
  • dosage forms suitable for oral administration include, but are not limited to tablets, capsules, lozenges, or like forms, or any liquid forms such as syrups, aqueous solutions, emulsions and the like, capable of providing a therapeutically effective amount of a hypoglycemic agent / copper antagonist.
  • dosage forms suitable for transdermal administration include, but are not limited, to transdermal patches, transdermal bandages, and the like.
  • dosage forms suitable for topical administration of the compounds and formulations of the invention are any lotion, stick, spray, ointment, paste, cream, gel, etc. whether applied directly to the skin or via an intermediary such as a pad, patch or the like.
  • Examples of dosage forms suitable for suppository administration of the compounds and formulations of the invention include any solid dosage form inserted into a bodily orifice particularly those inserted rectally, vaginally and urethrally.
  • Examples of dosage forms suitable for transmucosal delivery of the compounds and formulations of the invention include depositories solutions for enemas, pessaries, tampons, creams, gels, pastes, foams, nebulised solutions, powders and similar formulations containing in addition to the active ingredients such carriers as are known in the art to be appropriate.
  • dosage forms suitable for injection of the compounds and formulations of the invention include delivery via bolus such as single or multiple administrations by intravenous injection, subcutaneous, subdermal, and intramuscular administration or oral administration.
  • dosage forms suitable for depot administration of the compounds and formulations of the invention include pellets or small cylinders of active agent or solid forms wherein the active agent is entrapped in a matrix of biodegradable polymers, microemulsions, liposomes or is microencapsulated.
  • infusion devices for compounds and formulations of the invention include infusion pumps containing one or more hypoglycemic agents and one or more copper antagonists, for example one or more copper chelators, such as for example, one or more compounds of Formulae I, I(a) and II and salts thereof, or trientine active agents, including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trientine tetrafumarate or other pharmaceutically acceptable salts thereof, at a desired amount for a desired number of doses or steady state administration, and include implantable drug pumps.
  • copper antagonists for example one or more copper chelators, such as for example, one or more compounds of Formulae I, I(a) and II and salts thereof, or trientine active agents, including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trientine tetrafumarate or other pharmaceutically acceptable
  • implantable infusion devices for compounds, and formulations of the invention include any solid form in which the active agent is encapsulated within or dispersed throughout a biodegradable polymer or synthetic, polymer such as silicone, silicone rubber, silastic or similar polymer.
  • dosage forms suitable for inhalation or insufflation of the compounds and formulations of the invention include compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixture thereof and/or powders.
  • dosage forms suitable for buccal administration of the compounds and formulations of the invention include lozenges, tablets and the like, compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof and/or powders.
  • Examples of dosage forms suitable for sublingual administration of the compounds and formulations of the invention include lozenges, tablets and the like, compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof and/or powders.
  • Examples of dosage forms suitable for opthalmic administration of the compounds and formulations of the invention include inserts and/or compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents.
  • controlled drug formulations useful for delivery of the compounds and formulations of the invention are found in, for example, Sweetman, S. C. (Ed.). Martindale. The Complete Drug Reference, 33rd Edition, Pharmaceutical Press, Chicago, 2002, 2483 pp.; Aulton, M.E. (Ed.) Pharmaceutics. The Science of Dosage Form Design. Churchill Livingstone, Edinburgh, 2000, 734 pp.; and, Ansel, H.C., Allen, L.V. and Popovich, N.G. Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, 676 pp. Excipients employed in the manufacture of drug delivery systems are described in various publications known to those skilled in the art including, for example, Kibbe, E.H.
  • the USP also provides examples of modified-release oral dosage forms, including those formulated as tablets or capsules. See, for example, The United States Pharmacopeia 23/National Formulary 18, The United States Pharmacopeial Convention, Inc., Rockville MD, 1995 (hereinafter "the USP"), which also describes specific tests to determine the drug release capabilities of extended-release and delayed-release tablets and capsules.
  • the USP test for drug release for extended-release and delayed-release articles is based on drug dissolution from the dosage unit against elapsed test time. Descriptions of various test apparatus and procedures may be found in the USP.
  • the individual monographs contain specific criteria for compliance with the test and the apparatus and test procedures to be used. Examples have been given, for example for the release of aspirin from Aspirin Extended-release Tablets (for example, see: Ansel, H.C., Allen, L.V. and Popovich, N.G., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, p. 237). Modified-release tablets and capsules must meet the USP standard for uniformity as described for conventional dosage units. Uniformity of dosage units may be demonstrated by either of two methods, weight variation or content uniformity, as described in the USP. Further guidance concerning the analysis of extended release dosage forms has been provided by the F.D.A. (see Guidance for Industry.
  • Extended release oral dosage forms development, evaluation, and application of in vitro/in vivo correlations. Rockville, MD: Center for Drug Evaluation and Research, Food and Drug Administration, 1997).
  • Further examples of dosage forms of the invention include, but are not limited to modified-release (MR) dosage forms including delayed-release (DR) forms; prolonged-action (PA) forms; controlled-release (CR) forms; extended-release (ER) forms; timed-release (TR) forms; and long-acting (LA) forms.
  • MR modified-release
  • DR delayed-release
  • PA prolonged-action
  • CR controlled-release
  • ER extended-release
  • TR timed-release
  • LA long-acting
  • Modified-release dosage forms of the invention include dosage forms having drug release features based on time, course, and/or location which are designed to accomplish therapeutic or convenience objectives not offered by conventional or immediate-release forms. See, for example, Bogner, R.H. Bioavailability and bioequivalence of extended-release oral dosage forms. U.S.
  • Extended-release dosage forms of the invention include, for example, as defined by The United States Food and Drug Administration (FDA), a dosage form that allows a reduction in dosing frequency to that presented by a conventional dosage form, e.g., a solution or an immediate-release dosage form. See, for example, Bogner, R.H. Bioavailability and bioequivalence of extended-release oral dosage forms. US Pharmacist 22 (Suppl.):3-12 (1997); Guidance for industry.
  • FDA United States Food and Drug Administration
  • Extended release oral dosage forms development, evaluation, and application of the in vitro/in vivo correlations.
  • Rockville, MD Center for Drug Evaluation and Research, Food and Drug Administration (1997).
  • Repeat action dosage forms of the invention include, for example, forms that contain two single doses of medication, one for immediate release and the second for delayed release.
  • Bi-layered tablets for example, may be prepared with one layer of drug for immediate release with the second layer designed to release drug later as either a second dose or in an extended-release manner.
  • Targeted-release dosage forms of the invention include, for example, formulations that facilitate drug release and which are directed towards isolating or concentrating a drug in a body region, tissue, or site for absorption or for drug action.
  • the invention in part provides dosage forms, formulations, devices and/or compositions and/or methods utilizing administration of dosage forms, formulations, devices and/or compositions incorporating one or more hypoglycemic agents and one or more copper antagonists, for example one or more copper chelators, such as for example, one or more compounds of Formulae I, I(a) or II and salts thereof, and trientine active agents, including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trientine tetrafumarate or other pharmaceutically acceptable salts thereof, complexed with one or more suitable anions to yield complexes that are only slowly soluble in body fluids.
  • copper chelators such as for example, one or more compounds of Formulae I, I(a) or II and salts thereof
  • trientine active agents including but not limited to, trientine, trientine dihydrochloride, trientine disuccinate, trientine tetramaleate, trien
  • modified release forms of one or more hypoglycemic agents and one or more copper antagonists is produced by the incorporation of the active agent or agents into certain complexes such as those formed with the anions of various forms of tannic acid (for example, see: Merck Index 12th Ed., 9221). Dissolution of such complexes may depend,- for example, on the pH of the environment. This slow dissolution rate provides for the extended release of the hypoglycemic agent / copper antagonist. For example, salts of tannic acid, and/or tannates, provide for this quality, and are expected to possess utility for the treatment of conditions in which increased copper plays a role.
  • Rynatan Wallace: see, for example, Madan, P. L., "Sustained release dosage forms," U.S. Pharmacist 15:39-50 (1990); Ryna-12 S, which contains a mixture of mepyramine tannate with phenylephrine tannate, Martindale 33rd Ed., 2080.4).
  • coated beads, granules or microspheres containing one or more hypoglycemic agents and one or more copper antagonists.
  • the invention also provides a method to achieve modified release of one or more hypoglycemic agents and one or more copper antagonists by incorporation of the drug into coated beads, granules, or microspheres.
  • Such formulations of one or more hypoglycemic agent and/or one or more copper antagonists have utility for the treatment of diseases in humans and other mammals in which a hypoglycemic agent and/or copper antagonist, for example, a copper chelator, is indicated.
  • a hypoglycemic agent and/or copper antagonist for example, a copper chelator
  • the hypoglycemic agent and/or copper antagonist is distributed onto beads, pellets, granules or other particulate systems.
  • a solution of the hypoglycemic agent / copper antagonist substance is placed onto small inert nonpareil seeds or beads made of sugar and starch or onto microcrystalline cellulose spheres.
  • the nonpareil seeds are most often in the 425 to 850 micrometer range whereas the microcrystalline cellulose spheres are available ranging from 170 to 600 micrometers (see Ansel, H.C., Allen, L.V. and Popovich, N.G., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, p. 232).
  • the microcrystalline spheres are considered more durable during production than sugar-based cores (see:
  • microspheres suitable for drug delivery have been described (see, for example, Arshady, R: Microspheres and microcapsules: a survey of manufacturing techniques. 1 : suspension and cross-linking. Polymer Eng Sci
  • the starting granules of material may be composed of the hypoglycemic agent and/or copper antagonist itself. Some of these granules may remain uncoated to provide immediate hypoglycemic agent / copper antagonist release.
  • granules receive varying coats of a lipid material such as beeswax, carnauba wax, glycerylmonostearate, cetyl alcohol, or a cellulose material such as ethylcellulose (infra). Subsequently, granules of different coating thickness are blended to achieve a mixture having the desired release characteristics.
  • the coating material may be coloured with one or more dyes to distinguish granules or beads of different coating thickness (by depth of colour) and to provide distinctiveness to the product. When properly blended, the granules may be placed in capsules or tablets.
  • Various coating systems are commercially available which are aqueous-based and which use ethylcellulose and plasticizer as the coating material (e.g., AquacoatTM [FMC Corporation, Philadelphia] and SurereleaseTM [Colorcon]; Aquacoat aqueous polymeric dispersion. Philadelphia: FMC Corporation, 1991; Surerelease aqueous controlled release coating system. West Point, PA: Colorcon, 1990; Butler, J., Gumming, I 5 Brown, J. et al., A novel multiunit controlled-release system, Pharm Tech 22:122-138 (1998); Yazici, E., Oner, L., Kas, H.S.
  • Aqueous-based coating systems eliminate the hazards and environmental concerns associated with organic solvent-based systems. Aqueous and organic solvent-based coating methods have been compared (see, for example, Hogan, J. E. Aqueous versus organic solvent coating, lnt J Pharm Tech Prod Manufacture 3:17-20 (1982)). The variation in the thickness of the coats and in the type of coating materials used affects the rate at which the body fluids are capable of penetrating the coating to dissolve the hypoglycemic agent / copper antagonist.
  • the coated beads are about 1 mm in diameter. They are usually combined to have three or four release groups among the more than 100 beads contained in the dosing unit (see Madan, P. L. Sustained release dosage forms. U.S. Pharmacist 15:39-50 (1990)). This provides the different desired sustained or extended release rates and the targeting of the coated beads to the desired segments of the gastrointestinal tract.
  • This type of dosage form is the SpansuleTM (SmithKline Beecham Corporation, U.K.).
  • Examples of film-forming polymers which can be used in water-insoluble release-slowing intermediate layer(s) (to be applied to a pellet, spheroid or tablet core) include ethylcellulose, polyvinyl acetate, Eudragit® RS, Eudragit® RL, etc. Each of Eudragit® RS and Eudragit® RL is an ammonio methacrylate copolymer.
  • the release rate can be controlled not only by incorporating therein suitable water-soluble pore formers, such as lactose, mannitol, sorbitol, etc., but also by the thickness of the coating layer applied.
  • Multi tablets may be formulated which include small spheroid-shaped compressed minitablets that may have a diameter of between 3 to 4 mm and can be placed in gelatin capsule shell to provide the desired pattern of hypoglycemic agent / copper chelator release.
  • Each capsule may contain 8-10 minitablets, some uncoated for immediate release and others coated for extended release of the hypoglycemic agent / copper chelator of the invention.
  • a number of methods may be employed to generate modified-release dosage forms of one or more hypoglycemic agents and one or more copper antagonists suitable for oral administration to humans and other mammals. Two basic mechanisms are available to achieve modified release drug delivery. These are altered dissolution or diffusion of drugs and excipients. Within this context, for example, four processes may be employed, either simultaneously or consecutively.
  • extended hypoglycemic agent and/or copper antagonist action for example, copper chelator action
  • copper chelator action may be achieved by affecting the rate at which the hypoglycemic agent and/or copper antagonist is released from the dosage form and/or by slowing the transit time of the dosage form through the gastrointestinal tract (see Bogner, R.H., Bioavailability and bioequivalence of extended-release oral dosage forms. US Pharmacist 22 (Suppl.):3-12 (1997)).
  • the rate of drug release from solid dosage forms may be modified by the technologies described below which, in general, are based on the following: 1) modifying drug dissolution by controlling access of biologic fluids to the drug through the use of barrier coatings; 2) controlling drug diffusion rates from dosage forms; and 3) chemically reacting or interacting between the drug substance or its pharmaceutical barrier and site-specific biological fluids. Systems by which these objectives are achieved are also provided herein.
  • the hypoglycemic agent / copper antagonist employing digestion as the release mechanism, the hypoglycemic agent / copper antagonist is either coated or entrapped in a substance that is slowly digested or dispersed into the intestinal tract.
  • the rate of availability of the hypoglycemic agent / copper antagonist is a function of the rate of digestion of the dispersible material. Therefore, the release rate, and thus the effectiveness of the hypoglycemic agent / copper antagonist, varies from subject to subject depending upon the ability of the subject to digest the material.
  • a further form of slow release dosage form of the compounds and formulations of the invention is any suitable osmotic system where semipermeable membranes of for example cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, is used to control the release of " hypoglycemic agent / copper chelator. These can be coated with aqueous dispersions of enteric lacquers without changing release rate.
  • An example of such an osmotic system is an osmotic pump device, an example of which is the OrosTM device developed by Alza Inc. (U.S.A.). This system comprises a core tablet surrounded by a semi-permeable membrane coating having a 0.4 mm diameter hole produced by a laser beam.
  • the core tablet has two layers, one containing the drug (the "active” layer) and the other containing a polymeric osmotic agent (the “push” layer).
  • the core layer consists of active drug, filler, a viscosity modulator, and a solubilizer.
  • the system operates on the principle of osmotic pressure. This system is suitable for delivery of a wide range of hypoglycemic agents and copper antagonists, including the compounds of Formulae I, I(a) and II, and trientine active agents, or salts of any of them.
  • the coating technology is straightforward, and release is zero-order.
  • the semi-permeable membrane When the tablet is swallowed, the semi-permeable membrane permits aqueous fluid to enter from the stomach into the core tablet, dissolving or suspending the hypoglycemic agent / copper antagonist. As pressure increases in the osmotic layer, it forces or pumps the hypoglycemic agent / copper antagonist solution out of the delivery orifice on the side of the tablet. Only the hypoglycemic agent / copper antagonist solution (not the undissolved hypoglycemic agent / copper antagonist) is capable of passing through the hole in the tablet. The system is designed such that only a few drops of water are drawn into the tablet each hour.
  • the rate of inflow of aqueous fluid and the function of the tablet depends on the existence of an osmotic gradient between the contents of the bi-layer and the fluid in the gastrointestinal tract. Delivery is essentially constant as long as the osmotic gradient remains unchanged.
  • the hypoglycemic agent / copper antagonist release rate may be altered by changing the surface area, the thickness or composition of the membrane, and/or by changing the diameter of the hypoglycemic agent / copper antagonist release orifice.
  • the hypoglycemic agent / copper antagonist release rate is not affected by gastrointestinal acidity, alkalinity, fed conditions, or gut motility.
  • the biologically inert components of the tablet remain intact during gut Transit and are eliminated in the feces as an insoluble shell.
  • the invention also provides devices for compounds and formulations of the invention that utilize monolithic matrices including, for example, slowly eroding or hydrophilic polymer matrices, in which one or more hypoglycemic agents / copper antagonists is/are compressed or embedded.
  • Monolithic matrix devices comprising compounds and formulations of the invention include those formed using either of the following systems, for example: (I), hypoglycemic agent / copper antagonist dispersed in a soluble matrix, which become increasingly available as the matrix dissolves or swells; examples include hydrophilic colloid matrices, such as hydroxypropylcellulose (BP) or hydroxypropyl cellulose (USP); hydroxypropyl methylcellulose (HPMC; BP, USP); methylcellulose (MC; BP, USP); calcium carboxymethylcellulose (Calcium CMC; BP, USP); acrylic acid polymer or carboxy polymethylene (Carbopol) or Carbomer (BP, USP); or linear glycuronan polymers such as alginic acid (BP, USP), for example those formulated into microparticles from alginic acid (alginate)-gelatin hydrocolloid coacervate systems, or those in which liposomes have been encapsulated by coatings of alginic
  • Hypoglycemic agent / copper antagonist release occurs as the polymer swells, forming a matrix layer that controls the diffusion of aqueous fluid into the core and thus the rate of diffusion of hypoglycemic agent / copper antagonist from the system.
  • the rate of hypoglycemic agent / copper antagonist release depends upon the tortuous nature of the channels within the gel, and the viscosity of the entrapped fluid, such that different release kinetics can be achieved, for example, zero-order, or first-order combined with pulsatile release.
  • gels are not cross-linked, there is a weaker, non-permanent association between the polymer chains, which relies on secondary bonding. With such devices, high loading of the hypoglycemic agent / copper antagonist is achievable, and effective blending is frequent.
  • Devices may contain 20 - 80% of hypoglycemic agent / copper antagonist
  • gel modifiers that can enhance hypoglycemic agent / copper antagonist diffusion
  • examples of such modifiers include sugars that can enhance the rate of hydration, ions that can influence the content of cross-links, and pH buffers that affect the level of polymer ionization.
  • Hydrophilic matrix devices of the invention may also contain one or more of pH buffers, surfactants, counter-ions, lubricants such as magnesium stearate (BP, USP) and a glidant such as colloidal silicon dioxide (USP; colloidal anhydrous silica, BP) in addition to hypoglycemic agent / copper chelator and hydrophilic matrix;
  • lubricants such as magnesium stearate (BP, USP) and a glidant such as colloidal silicon dioxide (USP; colloidal anhydrous silica, BP) in addition to hypoglycemic agent / copper chelator and hydrophilic matrix
  • USP colloidal silicon dioxide
  • hypoglycemic agent / copper antagonist particles are dissolved in an insoluble matrix, from which hypoglycemic agent / copper antagonist becomes available as solvent enters the matrix, often through channels, and dissolves the hypoglycemic agent / copper antagonist particles.
  • Examples include systems formed with a lipid matrix, or insoluble polymer matrix, including preparations formed from Carnauba wax (BP; USP); medium-chain triglyceride such as fractionated coconut oil (BP) or triglycerida saturata media (PhEur); or cellulose ethyl ether or ethylcellulose (BP, USP).
  • BP Carnauba wax
  • medium-chain triglyceride such as fractionated coconut oil (BP) or triglycerida saturata media (PhEur)
  • cellulose ethyl ether or ethylcellulose cellulose ethyl ether or ethylcellulose
  • Lipid matrices are simple and easy to manufacture, and incorporate the following blend of powdered components: lipids (20-40% hydrophobic solids w/w) which remain intact during the release process; hypoglycemic agent / copper antagonist, e.g., copper chelator; channeling agent, such as sodium chloride or sugars, which leaches from the formulation, forming aqueous micro-channels (capillaries) through which solvent enters, and through which hypoglycemic agent / copper antagonist is released.
  • hypoglycemic agent / copper antagonist e.g., copper chelator
  • channeling agent such as sodium chloride or sugars
  • the hypoglycemic agent / copper antagonist is embedded in an inert insoluble polymer and is released by leaching of aqueous fluid, which diffuses into the core of the device through capillaries formed between particles, and from which hypoglycemic agent / copper antagonist diffuses out of the device.
  • the rate of release is controlled by the degree of compression, particle size, and the nature and relative content (w/w) of excipients.
  • An example of such a " device Is that of Ferrous Gradumet (Martindale 33rd Ed., 1360.3).
  • a further example of a suitable insoluble matrix is an inert plastic matrix.
  • hypoglycemic agent / copper antagonist is granulated with an inert plastic material such as polyethylene, polyvinyl acetate, or polymethacrylate, and the granulated mixture is then compressed into tablets. Once ingested, the hypoglycemic agent / copper antagonist is slowly released from the inert plastic matrix by diffusion (see, for example, Bodmeier, R.
  • hypoglycemic agent / copper antagonist may be compressed onto the surface of the tablet.
  • the inert tablet matrix, expended of hypoglycemic agent / copper antagonist is excreted with the feces.
  • An example of a successful dosage form of this type is Gradumet (Abbott; see, for example, Ferro-Gradumet, Martindale 33rd Ed., p. 1860.4).
  • Further examples of monolithic matrix devices of the invention have compositions and formulations of the invention incorporated in pendent attachments to a polymer matrix (see, for example, Scholsky, K.M. and Fitch, R.M., Controlled release of pendant bioactive materials from acrylic polymer colloids. J Controlled Release 3:87-108 (1986)).
  • hypoglycemic agent / copper antagonists e.g., copper chelators, are attached by means of an ester linkage to poly(acrylate) ester latex particles prepared by aqueous emulsion polymerization.
  • monolithic matrix devices of the invention incorporate dosage forms of the compositions and formulations of the invention in which the hypoglycemic agent / copper antagonist is/are bound to a biocompatible polymer by a labile chemical bond, e.g., polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug: methacryloyl chloride and the sodium salt of methoxy benzoic acid) have been used to form a matrix with a second polymer (Eudragit RL) which releases drug on hydrolysis in gastric fluid (see: Chafi, N., Montheard, J. P. & Vergnaud, J. M. Release of 2-aminothiazole from polymeric carriers. Int J Pharm 67:265-274 (1992)).
  • a labile chemical bond e.g., polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug: methacryloyl chloride and the sodium salt
  • the polymer selected for use must form a gelatinous layer rapidly enough to protect the inner core of the tablet from disintegrating too rapidly after ingestion.
  • the proportion of polymer is increased in a formulation so is the viscosity of the gel formed with a resulting decrease in the rate of hypoglycemic agent / copper antagonist diffusion and release (see Formulating for controlled release with Methocel Premium cellulose ethers. Midland, MI: Dow Chemical Company, 1995).
  • 20% (w/w) of HPMC results in satisfactory rates of drug release for an extended-release tablet formulation.
  • consideration must be given to the possible effects of other formulation ingredients such as fillers, tablet binders, and disintegrants.
  • Two-layered tablets can be manufactured containing one or more of the compositions and formulations of the invention, with one layer containing the uncombined hypoglycemic agent and/or copper antagonist for immediate release and the other layer having the hypoglycemic agent and/or copper antagonist imbedded in a hydrophilic matrix for extended-release.
  • Three-layered tablets may also be similarly prepared, with both outer layers containing the hypoglycemic agent and/or copper antagonist for immediate release.
  • Some commercial tablets are prepared with an inner core containing the extended-release portion of drug and an outer shell enclosing the core and containing drug for immediate release.
  • the invention also provides forming a complex between the compositions and formulations of the invention and an ion exchange resin, whereupon the complex may be tableted, encapsulated or suspended in an aqueous vehicle. Release of the hypoglycemic agent / copper antagonist is dependent on the local pH and electrolyte concentration such that the choice of ion exchange resin may be made so as to preferentially release the hypoglycemic agent / copper antagonist in a given region of the alimentary canal. Delivery devices incorporating such a complex are also provided.
  • a modified release dosage form of hypoglycemic agent / copper antagonist can be produced by the incorporation of hypoglycemic agent / copper antagonist into complexes with an anion-exchange resin. Solutions of hypoglycemic agent / copper antagonist may be passed through columns containing an ion-exchange resin to form a complex by the replacement of H 3 O + ions. The resin-hypoglycemic agent and/or copper antagonist complex is then washed and may be tableted, encapsulated, or suspended in an aqueous vehicle. The release of the hypoglycemic agent / copper antagonist is dependent on the pH and the electrolyte concentration in the gastrointestinal fluid. Release is greater in the acidity of the stomach than in the less acidic environment of the small intestine.
  • hypoglycemic agent and/or copper antagonist containing particles are minute, and may also be suspended to produce a liquid with extended- release characteristics, as well as solid dosage forms. Such preparations may also be suitable for administration, for example in depot preparations suitable for intramuscular injection.
  • the invention also provides a method to produce modified release preparations of one or more hypoglycemic agent / copper antagonists, for example, one or more copper chelators, by microencapsulation.
  • Microencapsulation is a process by which solids, liquids, or even gasses may be encapsulated into microscopic size particles through the formation of thin coatings of "wall" material around the substance being encapsulated such as disclosed in U.S. Patent Nos. 3,488,418; 3,391,416 and 3,155,590.
  • Gelatin is commonly employed as a wall-forming material in microencapsulated preparations, but synthetic polymers such as polyvinyl alcohol (USP), ethylcellulose (BP, USP), polyvinyl chloride, and other materials may also be used (see, for example, Zentner, G.M., Rork, G.S., and Himmelstein, KJ., Osmotic flow through controlled porosity films: an approach to delivery of water- soluble compounds, J Controlled Release 2:217-229 (1985); Fites, A.L., Banker, G.S., and Smolen, V.F., Controlled drug release through polymeric films, J Pharm Sci 59:610-613 (1970); Samuelov, Y., Donbrow, M., and Friedman, M., Sustained release of drugs from ethylcellulose-polyethylene glycol films and kinetics of drug release, J Pharm Sci 68:325-329 (1979)).
  • synthetic polymers such as polyvinyl alcohol (
  • Encapsulation begins with the dissolving of the prospective wall material, say gelatin, in water.
  • One or more hypoglycemic agents / copper antagonists for example, one or more copper chelators, is then added and the two-phase mixture is thoroughly stirred.
  • a solution of a second material is added.
  • This additive material for example, acacia, is chosen to have the ability to concentrate the gelatin (polymer) into tiny liquid droplets.
  • the coated particles are then admixed with tableting excipients and formed into dosage- sized tablets.
  • Different rates of hypoglycemic agent / copper antagonist release may be obtained by changing the core-to-wall ratio, the polymer used for the coating, or the method of microencapsulation (for example, see: Yazici, E., Oner, L., Kas, H.S. & Hincal, A. A. Phenytoin sodium microspheres: bench scale formulation, process characterization and release kinetics. Pharmaceut Dev Technol 1996; 1:175-183).
  • microencapsulation the administered dose of one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators, is subdivided into small units that are spread over a large area of the gastrointestinal tract, which may enhance absorption by diminishing localized hypoglycemic agent / copper chelator concentrations (see Yazici et al., supra).
  • An example of a drug that is commercially available in a microencapsulated extended- release dosage form is potassium chloride (Micro-K Exten-caps, Wyeth-Ayerst, Martindale 33rd Ed., pi 968.1).
  • hypoglycemic agent / copper antagonist is incorporated into polymeric colloidal particles or microencapsulates (microparticles, microspheres or nanoparticles) in the form or reservoir and matrix devices (see: Douglas, S. J., et ah, "Nanoparticles in drug delivery," CR. C.
  • the invention also includes repeat action tablets containing one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators. These are prepared so that an initial dose of the hypoglycemic agent /
  • the tablets may be prepared with the immediate-release dose in the tablet's outer shell or coating with the second dose in the tablet's inner core, separated by a slowly permeable barrier coating.
  • the hypoglycemic agent / copper antagonist from the inner core is exposed to body fluids and released 4 to 6 hours after administration.
  • An example of this type of product is proved by Repetabs (Schering Inc.).
  • Repeat action dosage forms are suitable for the administration of one or more hypoglycemic agents / copper antagonists for the indications noted herein.
  • the invention also includes delayed-release oral dosage forms containing one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators.
  • hypoglycemic agents / copper antagonist for example, one or more copper chelators
  • enteric coatings by themselves are not an efficient method for the delivery of hypoglycemic agents / copper antagonists because of the inability of such coating systems to provide or achieve a sustained therapeutic effect after release onset.
  • Enteric coats are designed to dissolve or break down in an alkaline environment. The presence of food may increase the pH of the stomach. Therefore, the concurrent administration of enteric-coated hypoglycemic agent / copper antagonists with food or the presence of food in the stomach may lead to dose dumping and unwanted secondary effects.
  • hypoglycemic agent / copper antagonist form that is capable of providing the controlled delivery of hypoglycemic agents / copper antagonists in a predictable manner over a long period of time. See, e.g., Examples, 11, 12, 23, 24, 35, and 36 herein.
  • Enteric coatings have application in the present invention when combined or incorporated with one or more of the other dose delivery formulations or devices described herein. This form of delivery conveys the advantage of minimizing the gastric irritation that may be caused in some subjects by hypoglycemic agent / copper antagonist such as,- for example, trientine.
  • the enteric coating may be time- dependent, pH-dependent where it breaks down in the less acidic environment of the intestine and erodes by moisture over time during gastrointestinal transit, or enzyme-dependent where it deteriorates due to the hydrolysis-catalyzing action of intestinal enzymes (see, for example, Bengal, N.A., et ah, "Modifying the release properties of Eudragit L30D,” DrugDev IndPharm., 17:2497-2509 (1991)).
  • agents used to enteric coat tablets and capsules known to those skilled in the art are fats including triglycerides, fatty acids, waxes, shellac, and cellulose acetate phthalate although further examples of enteric coated preparations can be found in the USP.
  • the invention also provides devices incorporating one or more hypoglycemic agent / copper antagonists, for example, one or more copper chelators, in a membrane- control system.
  • Such devices comprise a rate-controlling membrane enclosing a hypoglycemic agent / copper antagonist reservoir. Following oral administration the membrane gradually becomes permeable to aqueous fluids, but does not erode or swell.
  • the hypoglycemic agent / copper antagonist reservoir may be composed of a conventional tablet, or a microparticle pellet containing multiple units that do not swell following contact with aqueous fluids.
  • the cores dissolve without modifying their internal osmotic pressure, thereby avoiding the risk of membrane rupture, and typically comprise 60:40 mixtures of lactulose: microcrystalline cellulose (w/w).
  • Active drug(s) is/are released through a two-phase process, comprising diffusion of aqueous fluids into the matrix, followed by diffusion of the hypoglycemic agent / copper antagonist out of the matrix.
  • Multiple-unit membrane-controlled systems typically comprise more than one discrete unit.
  • spherical beads can contain discrete spherical beads individually coated with rate-controlling membrane and may be encapsulated in a hard gelatin shell (examples of such preparations include Contac 400; Martindale 33rd Ed., 1790.1 and Feospan; Martindale 33rd Ed., p.1859.4).
  • multiple-unit membrane-controlled systems may be compressed into a tablet (for example, Suscard; Martindale 33rd Ed., p.2115.1).
  • Alternative implementations of this technology include devices in which the hypoglycemic agent / copper antagonist is coated around inert sugar spheres, and devices prepared by extrusion spheronization employing a conventional matrix system. Advantages of such systems include the more consistent gastro-intestinal transit rate achieved by multiple-unit systems, and the fact that such systems infrequently suffer from catastrophic dose dumping. They are also ideal for the delivery of more than one drug at a time, as disclosed herein.
  • An example of a sustained release dosage form of one or more compounds and formulations of the invention is a matrix formation, such a matrix formation taking the form of film coated spheroids containing as active ingredient one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators and a non water-soluble spheronising agent.
  • the term "spheroid" is known in the pharmaceutical art and means spherical granules having a diameter usually of between 0.01 mm and 4 mm.
  • the spheronising agent may be any pharmaceutically acceptable material that, together with the hypoglycemic agent / copper antagonist, can be spheronised to form spheroids. Microcrystalline cellulose is preferred.
  • Suitable microcrystalline cellulose includes, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
  • the film-coated spheroids may contain between 70% and 99% (by wt), especially between 80% and 95% (by wt), of the spheronising agent, especially microcrystalline cellulose.
  • the spheroids may also contain a binder. Suitable binders, such as low viscosity, water-soluble polymers, will be well known to those skilled in the pharmaceutical art.
  • a suitable binder is, in particular polyvinylpyrrolidone in various degrees of polymerization.
  • the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid- ethyl acrylate copolymer, or ethyl cellulose.
  • thickening agents or binders include: the lipid type, among which are vegetable oils (cotton seed, sesame and groundnut oils) and derivatives of these oils (hydrogenated oils such as hydrogenated castor oil, glycerol behenate, the waxy type such as natural carnauba wax or natural beeswax, synthetic waxes such as cetyl ester waxes, the amphiphilic type such as polymers of ethylene oxide (polyoxyethylene glycol of high molecular weight between 4000 and 100000) or propylene and ethylene oxide copolymers (poloxamers), the cellulosic type (semisynthetic derivatives of cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, of high molecular weight and high viscosity, gum) or any other polysaccharide such as alginic acid, the polymeric type such as acrylic acid polymers (such as carbomers), and the mineral type such as colloidal silica and bentonite.
  • Suitable diluents for the hypoglycemic agent(s) / copper antagonist(s) in the pellets, spheroids or core are, e.g., macrocrystalline cellulose, lactose, dicalcium phosphate, calcium carbonate, calcium sulphate, sucrose, dextrates, dextrin, dextrose, dicalcium phosphate dihydrate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, cellulose, microcrystalline cellulose, sorbitol, starches, pregelatinized starch, talc, tricalcium phosphate and lactose.
  • Suitable lubricants are e.g., magnesium stearate and sodium stearyl fumarate.
  • Suitable binding agents include, e.g., hydroxypropyl methylcellulose, polyvidone, and methylcellulose.
  • Suitable binders that may be included are: gum arabic, gum tragacanth, guar gum, alginic acid, sodium alginate, sodium carboxymethylcellulose, dextrin, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, liquid glucose, magnesium and aluminum.
  • Suitable disintegrating agents are starch, sodium starch glycolate, crospovidone and croscarmalose sodium.
  • Suitable surface active are Poloxamer 188®, polysorbate 80 and sodium lauryl sulfate.
  • Suitable flow aids are talc colloidal anhydrous silica.
  • Suitable lubricants that may be used are glidants (such as anhydrous silicate, magnesium trisilicate, magnesium silicate, cellulose, starch, talc or tricalcium phosphate) or alternatively antifriction agents (such as calcium stearate, hydrogenated vegetable oils, paraffin, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, fumaric acid, stearic acid or zinc stearate and talc).
  • Suitable water-soluble polymers are PEG with molecular weights in the range 1000 to 6000.
  • Delayed release of the composition or formulation of the invention may be achieved through the use of a tablet, pellet, spheroid or core itself, which besides having a filler and binder, other ancillary substances, in particular lubricants and nonstick agents, and disintegrants.
  • lubricants and nonstick agents are higher fatty acids and their alkali metal and alkaline-earth-metal salts, such as calcium stearate.
  • Suitable disintegrants are, in particular, chemically inert agents, for example, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcelluloses, and sodium starch glycolate.
  • Yet further embodiments of the invention include formulations of one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators, incorporated into transdermal drug delivery systems, such as those described in: Transdermal Drug Delivery Systems, Chapter 10. In: Ansel, H. C, Allen, L. V. and Popovich, N. G. Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, pp. 263 - 278). Transdermal drug delivery systems facilitate the passage of therapeutic quantities of drug substances through the skin and into the systemic circulation to exert systemic effects, as originally described (see Stoughton, R. D. Percutaneous absorption, Toxicol Appl Pharmacol 7:1-8 (1965)).
  • Methods known to enhance the delivery of drugs by the percutaneous route include chemical skin penetration enhancers, which increase " skin permeability by reversibly damaging or otherwise altering the physicochemical nature of the stratum corneum to decrease its resistance to drug diffusion (see Shah, V., Peck, CC, and Williams, R.L., Skin penetration enhancement: clinical pharmacological and regulatory considerations, In: Walters, K.A. and Hadgraft, J. (Eds.) Pharmaceutical skin penetration enhancement. New York: Dekker, 1993).
  • Skin penetration enhancers suitable for formulation with hypoglycemic agent / copper antagonist in transdermal drug delivery systems may be chosen from the following list: acetone, laurocapram, dimethylacetamide, dimethylformamide, dimethylsulphoxide, ethanol, oleic acid, polyethylene glycol, propylene glycol and sodium lauryl sulphate.
  • another embodiment of the invention comprises one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators, formulated in such a manner suitable for administration by iontophoresis or sonophoresis.
  • Formulations suitable for administration by iontophoresis or sonophoresis may be in the form of gels, creams, or lotions.
  • Transdermal delivery, methods or formulations of the invention, n ⁇ ay utilize, among others, monolithic delivery systems, drug-impregnated adhesive delivery systems (e.g., the LatitudeTM drug-in-adhesive system from 3M), active transport devices and membrane- controlled systems.
  • Monolithic systems of the invention incorporate a hypoglycemic agent / copper antagonist matrix, comprising a polymeric material in which the hypoglycemic agent / copper antagonist is dispersed between backing and frontal layers.
  • Drug impregnated adhesive delivery systems comprise an adhesive polymer in which one or more compositions and formulations of the invention and any excipients are incorporated into the adhesive polymer.
  • Active transport devices incorporate a hypoglycemic agent / copper antagonist reservoir, often in liquid or gel form, a membrane that may be rate controlling, and a driving force to propel the hypoglycemic agent / copper chelator across the membrane.
  • Membrane-controlled transdermal systems of the invention comprise a hypoglycemic agent / copper antagonist reservoir(s), often in liquid or gel form, a membrane that may be rate controlling and backing, adhesive and/or protecting layers.
  • Transdermal delivery dosage forms of the invention include those which substitute the hypoglycemic agent / copper antagonist, for the diclofenic or other pharmaceutically acceptable salt thereof referred to in the transdermal delivery systems disclosed in, by way of example, U.S. Patent Nos. 6,193,996, and 6,262,121.
  • Formulations and/or compositions for topical administration of one or more compositions and formulations of the invention ingredient can be prepared as an admixture or other pharmaceutical formulation to be applied in a wide variety of ways including, but are not limited to, lotions, creams gels, sticks, sprays, ointments and pastes. These product types may comprise several types of formulations including, but not limited to solutions, emulsions, gels, solids, and liposomes. If the topical composition of the invention is formulated as an aerosol and applied to the skin as a spray-on, a propellant may be added to a solution composition. Suitable propellants as used in the art can be utilized.
  • topical administration of an active agent reference is made to U.S. Patent Nos.
  • compositions in accordance with the present invention are any variants of the oral dosage forms that are adapted for suppository or other parenteral use.
  • these compositions may be prepared by mixing one or more compounds and formulations of the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the hypoglycemic agent / copper chelator.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the hypoglycemic agent / copper chelator.
  • Suppositories are generally solid dosage forms intended for insertion into body orifices including rectal, vaginal and occasionally urethrally and can be long acting or slow release.
  • Suppositories include a base that can include, but is not limited to, materials such as alginic acid, which will prolong the release of the pharmaceutically acceptable active ingredient over several hours (5-7).
  • bases can be characterized into two main categories and a third miscellaneous group: 1) fatty or oleaginous bases, 2) water-soluble or water-miscible bases and 3) miscellaneous bases, generally combinations of lipophilic and hydrophilic substances.
  • Fatty or oleaginous bases include hydrogenated fatty acids of vegetable oils such as palm kernel oil and cottonseed oil, fat-based compound containing compounds of glycerin with the higher molecular weight fatty acids such as palmitic and stearic acids, cocoa butter is also used where phenol and chloral hydrate lower the melting point of cocoa butter when incorporated, solidifying agents like cetyl esters wax (about 20%) or beeswax (about 4%) may be added to maintain a solid suppository.
  • Other bases include other commercial products such as Fattibase (triglycerides from palm, palm kernel and coconut oils with self-emulsifying glycerol monostearate and poloxyl stearate), Wecobee and Witepsol bases.
  • Water-soluble bases are generally glycerinated gelatin and water-miscible bases are generally polyethylene glycols.
  • the miscellaneous bases include mixtures of the oleaginous and water-soluble or water- miscible materials.
  • An example of such a base in this group is polyoxyl 40 stearate and poly oxyethylene diols and the free glycols: " Transmucosal administration of the compounds and formulations of the invention may utilize any mucosal membrane but commonly utilizes the nasal, buccal, vaginal and rectal tissues.
  • Formulations suitable for nasal administration of the compounds and formulations of the invention may be administered in a liquid form, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, including aqueous or oily solutions of the hypoglycemic agent / copper chelator.
  • Formulations for nasal administration, wherein the earner is a solid include a coarse powder having a particle size, for example, of less than about 100 microns, preferably less, most preferably one or two times per day than about 50 microns, which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • compositions in solution may be nebulized by the use of inert gases and such nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a facemask, tent or intermittent positive-pressure breathing machine.
  • Solutions, suspensions or powder compositions of the hypoglycemic agent / copper antagonist may be administered orally or nasally from devices that deliver the formulation in an appropriate manner.
  • Formulations of the invention may be prepared as aqueous solutions for example in saline, solutions employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
  • the invention provides extended-release formulations containing one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators, for parenteral administration.
  • Extended rates of hypoglycemic agent / copper antagonist action following injection may be achieved in a number of ways, including the following: crystal or amorphous hypoglycemic agent / copper antagonist forms having prolonged dissolution characteristics; slowly dissolving chemical complexes of the hypoglycemic agent / copper antagonist formulation; solutions or suspensions of hypoglycemic agent / copper antagonist in slowly absorbed carriers or vehicles (as oleaginous); increased particle size of hypoglycemic agent / copper antagonist in suspension; or, by injection of slowly eroding microspheres of hypoglycemic agent / copper antagonist (for example, see: Friess, W., Lee, G.
  • compositions of the invention can be formulated into a pharmaceutical composition suitable for administration to a patient. See, e.g., Examples 1-36 herein, regarding oral tablets and capsules.
  • An acetate, phosphate, citrate or glutamate buffer may be added allowing a pH of the final composition to be from about 5.0 to about 9.5; optionally a carbohydrate or polyhydric alcohol tonicifier and, a preservative selected from the group consisting of m-cresol, benzyl alcohol, methyl, ethyl, propyl and butyl parabens and phenol may also be added.
  • Water for injection, tonicifying agents such as sodium chloride, as well as other excipients, may also be present, if desired.
  • formulations are isotonic or substantially isotonic to avoid irritation and pain at the site of administration.
  • buffer when used with reference to hydrogen-ion concentration or pH, refer to the ability of a system, particularly an aqueous solution, to resist a change of pH on adding acid or alkali, or on dilution with a solvent.
  • An example of the former system is acetic acid and sodium acetate.
  • the change of pH is slight as long as the amount of hydroxyl ion added does not exceed the capacity of the buffer system to
  • the buffer used in the practice of the present invention is selected from any of the following, for example, an acetate buffer, a phosphate buffer or glutamate buffer, the most preferred buffer being a phosphate buffer.
  • Carriers or excipients can also be used to facilitate administration of the compositions and formulations of the invention.
  • carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, polyethylene glycols and physiologically compatible solvents.
  • a stabilizer may be included in the formulations of the invention, but will generally not be needed. If included, however, a stabilizer useful in the practice of the invention is a carbohydrate or a polyhydric alcohol.
  • the polyhydric alcohols include such compounds as sorbitol, mannitol, glycerol, xylitol, and polypropylene/ethylene glycol copolymer, as well as various polyethylene glycols (PEG) of molecular weight 200, 400, 1450, 3350, 4000, 6000, and 8000).
  • the carbohydrates include, for example, mannose, ribose, trehalose, maltose, inositol, lactose, galactose, arabinose, or lactose.
  • USP United States Pharmacopeia states that anti-microbial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple dose containers.
  • Antimicrobial agents should be evaluated to ensure compatibility with all other components of the formula, and their activity should be evaluated in the total formula to ensure that a particular agent that is effective in one formulation is not ineffective in another. It is not uncommon to find that a particular agent will be effective in one formulation but not effective in another formulation.
  • a preservative is, in the common pharmaceutical sense, a substance that prevents or inhibits microbial growth and may be added to a pharmaceutical formulation for this purpose to avoid consequent spoilage of the formulation by microorganisms. While the amount of the preservative is not great, it may nevertheless affect the overall stability of the hypoglycemic agent / copper antagonist.
  • the preservative for use in the practice of the invention can range from 0.005 to 1.0% (w/v), the preferred range for each preservative, alone or in combination with others, is: benzyl alcohol (0.1-1.0%), or m-cresol (0.1-0.6%), or phenol (0.1- 0.8%) or combination of methyl (0.05-0.25%) and ethyl or propyl or butyl (0.005%- 0.03%) parabens.
  • the parabens are lower alkyl esters of para-hydroxybenzoic acid.
  • hypoglycemic agent / copper antagonist may be administered parenterally (including subcutaneous injections, intravenous, intramuscular, intradermal injection or infusion techniques) or by inhalation spray in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral formulation may be thickened with a thickening agent such as a methylcellulose.
  • the formulation may be prepared in an emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed including, for example, acacia powder, a non- ionic surfactant or an ionic surfactant.
  • aqueous suspensions such as synthetic and natural gums, e.g., tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. It is possible that other ingredients may be present in the parenteral pharmaceutical formulation of the invention.
  • Such additional ingredients may include wetting agents, oils (e.g., a vegetable oil such as sesame, peanut or olive), analgesic agents, emulsifiers, antioxidants, bulking agents, tonicity modifiers, metal ions, oleaginous vehicles, proteins (e.g., human serum albumin, gelatin or proteins) and a zwitterion (e.g., an amino acid such as betaine, taurine, arginine, glycine, lysine and histidine).
  • oils e.g., a vegetable oil such as sesame, peanut or olive
  • analgesic agents emulsifiers, antioxidants, bulking agents, tonicity modifiers, metal ions, oleaginous vehicles
  • proteins e.g., human serum albumin, gelatin or proteins
  • a zwitterion e.g., an amino acid such as betaine, taurine, arginine, glycine, lysine and histidine.
  • Suitable routes of parenteral administration include intramuscular, intravenous, subcutaneous, intraperitoneal, subdermal, intradermal, intraarticular, intrathecal and the like. Mucosal delivery is also permissible.
  • the dose and dosage regimen will depend upon the weight and health of the subject.
  • the rate and duration of hypoglycemic agent / copper antagonist delivery may be controlled by, for example by using mechanically controlled drug infusion pumps.
  • the hypoglycemic agent(s) / copper antagonist(s), such as, for example, a copper chelator(s) can be administered in the form of a depot injection that may be formulated in such a manner as to permit a sustained release of the hypoglycemic agent / copper antagonist.
  • the hypoglycemic agent / copper antagonist can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly.
  • the pellets or cylinders may additionally be coated with a suitable biodegradable polymer chosen so as to provide a desired release profile.
  • the hypoglycemic agent / copper antagonist may alternatively be micropelleted.
  • the hypoglycemic agent / copper antagonist micropellets using bioacceptable polymers can be designed to allow release rates to be manipulated to provide a desired release profile.
  • injectable depot forms can be made by forming microencapsulated matrices of the hypoglycemic agent / copper antagonist in biodegradable polymers such as polylactide-polyglycolide.
  • hypoglycemic agent / copper antagonist can be controlled.
  • examples of other biodegradable polymers include poly(orthoesters) and ⁇ oly(anhydrides).
  • Depot injectable formulations can also be prepared by entrapping the hypoglycemic agent / copper chelator in liposomes, examples of which include unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearyl amine or phosphatidylcholines.
  • Depot injectable formulations can also be prepared by entrapping the hypoglycemic agent / copper antagonist in microemulsions that are compatible with body tissue.
  • the invention in part provides infusion dose delivery formulations and devices, including but not limited to implantable infusion devices for delivery of compositions and formulations of the invention.
  • Implantable infusion devices may employ inert material such as biodegradable polymers listed above or synthetic silicones, for example, cylastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation.
  • the polymer may be loaded with hypoglycemic agent / copper antagonist and any excipients.
  • Implantable infusion devices may also comprise a coating of, or a portion of, a medical device wherein the coating comprises the polymer loaded with hypoglycemic agent / copper antagonist and any excipient.
  • a medical device wherein the coating comprises the polymer loaded with hypoglycemic agent / copper antagonist and any excipient.
  • Such an implantable infusion device may be prepared as disclosed in U.S. Patent No. 6,309,380 by coating the device with an in vivo biocompatible and biodegradable or bioabsorbable or bioerodible liquid of gel solution containing a polymer with the solution comprising a desired dosage amount of hypoglycemic agent / copper antagonist and any excipients. The solution is converted to a film adhering to the medical device thereby forming the implantable hypoglycemic agent / copper antagonist-deliverable medical device.
  • An implantable infusion device may also be prepared by the in situ formation of a hypoglycemic agent / copper antagonist containing solid matrix as disclosed in U.S. Patent No. 6,120,789, herein incorporated in its entirety.
  • Implantable infusion devices may be passive or active.
  • An active implantable infusion device may comprise a hypoglycemic agent / copper antagonist reservoir, a means of allowing the hypoglycemic agent / copper antagonist to exit the reservoir, for example a permeable membrane, and a driving force to propel the hypoglycemic agent / copper antagonist from the reservoir.
  • Such an active implantable infusion device may additionally be activated by an extrinsic signal, such as that disclosed in WO 02/45779, wherein the implantable infusion device comprises a system configured to deliver the hypoglycemic agent / copper antagonist comprising an external activation unit operable by a user to request activation of the implantable infusion device, including a controller to reject such a request prior to the expiration of a lockout interval.
  • an active implantable infusion device include implantable drug pumps.
  • Implantable drug pumps include, for example, miniature, computerized, programmable, refillable drug delivery systems with an attached catheter that inserts into a target organ system, usually the spinal cord or a vessel. See Medtronic Inc.
  • Implantable drug infusion pumps are indicated for long-term intrathecar infusion of morphine sulfate for the treatment of chronic intractable pain; intravascular infusion of floxuridine for treatment of primary or metastatic cancer; intrathecal injection (baclofen injection) for severe spasticity; long-term epidural infusion of morphine sulfate for treatment of chronic intractable pain; long-term intravascular infusion of doxorubicin, cisplatin, or methotrexate for the treatment or metastatic cancer; and long-term intravenous infusion of clindamycin for the treatment of osteomyelitis.
  • Such pumps may also be used for the long-term infusion of one or more hypoglycemic agent / copper antagonists, for example, one or more copper chelators, at a desired amount for a desired number of doses or steady state administration.
  • One form of a typical implantable drug infusion pump (Synchromed EL programmable pump; Medtronic) is titanium covered and roughly disk shaped, measures 85.2 mm in diameter and 22.86 mm in thickness, weighs 185 g, has a drug reservoir of 10 niL, and runs on a lithium thionyl-chloride battery with a 6- to 7-year life, depending on use.
  • the downloadable memory contains programmed drug delivery parameters and calculated amount of drug remaining, which can be compared with actual amount of drug remaining to access accuracy of pump function, but actual pump function over time is not recorded.
  • the pump is usually implanted in the right or left abdominal wall.
  • Other pumps useful in the invention include, for example, portable disposable infuser pumps (PDIPs).
  • PDIPs portable disposable infuser pumps
  • implantable infusion devices may employ liposome delivery systems, such as a small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles can be formed from a variety of phospholipids, such as cholesterol, stearyl amine or phosphatidylcholines.
  • the invention also includes delayed-release ocular preparations containing one or more hypoglycemic agents / copper antagonists, for example, one or more copper chelators.
  • One of the problems associated with the use of ophthalmic solutions is the rapid loss of administered drug due to blinking of the eye and the flushing effect of lacrimal fluids. Up to 80% of an administered dose may be lost through tears and the action of nasolacrimal drainage within 5 minutes of installation. Extended periods of therapy may be achieved by formulations of the invention that increase the contact time between the hypoglycemic agent / copper chelator and the corneal surface.
  • hypoglycemic agents / copper antagonists for example, one or more copper chelators
  • suitable for ocular administration to humans may be formulated using synthetic high molecular weight cross-linked polymers such as those of acrylic acid (e.g., Carbopol 940) or gellan gum (Gelrite; see, Merck Index 12th Ed., 4389), a compound that forms a gel upon contact with the precorneal tear film (e.g. as employed in Timoptic-XE by Merck, Inc.).
  • Further examples include delayed-release ocular preparations containing hypoglycemic agent / copper antagonist in ophthalmic inserts, such as the OCUSERT system (Alza Inc.).
  • ophthalmic inserts such as the OCUSERT system (Alza Inc.).
  • OCUSERT system Alza Inc.
  • inserts are elliptical with dimensions of about 13.4 mm by 5.4 mm by 0.3 mm (thickness).
  • the insert is flexible and has a hypoglycemic agent / copper antagonist -containing core surrounded on each side by a layer of hydrophobic ethylene/vinyl acetate copolymer membranes through which the hypoglycemic agent / copper antagonist diffuses at a constant rate.
  • the white margin around such devices contains white titanium dioxide, an inert compound that confers visibility.
  • the rate of hypoglycemic agent / copper antagonist diffusion is controlled by the polymer composition, the membrane thickness, and the hypoglycemic agent / copper antagonist solubility. During the first few hours after insertion, the hypoglycemic agent / copper antagonist release rate is greater than that which occurs thereafter in order to achieve initially therapeutic hypoglycemic agent / copper antagonist levels.
  • the hypoglycemic agent / copper antagonist -containing inserts may be placed in the conjunctival sac from which they release their medication over a treatment period.
  • Another form of an ophthalmic insert is a rod shaped, water-soluble structure composed of hydroxypropyl cellulose in -which hypoglycemic agent " / copper antagonist is embedded.
  • the insert is placed into the inferior cul-de-sac of the eye once or twice daily as required for therapeutic efficacy.
  • the inserts soften and slowly dissolve, releasing the hypoglycemic agent / copper antagonist that is then taken up by the ocular fluids.
  • a further example of such a device is that furnished by Lacrisert (Merck Inc.).
  • the invention also provides in part dose delivery formulations and devices formulated to enhance bioavailability of hypoglycemic agent / copper antagonist. This may be in addition to or in combination with any of the formulations or devices described above.
  • one or more hypoglycemic agents / copper antagonists such as a copper chelator, for example, trientine, may be poorly absorbed in the digestive tract.
  • a therapeutically effective amount of hypoglycemic agent / copper antagonist is an amount capable of providing an appropriate level of hypoglycemic agent / copper antagonist in the bloodstream.
  • An increase in bioavailability of hypoglycemic agent / copper antagonist may be achieved by complexation of hypoglycemic agent / copper antagonist with one or more bioavailability or absorption enhancing agents or in bioavailability or absorption enhancing formulations.
  • the invention in part provides for the formulation of hypoglycemic agent / copper antagonist, e.g., copper chelator, with other agents useful to enhance bioavailability or absorption.
  • bioavailability or absorption enhancing agents include, but are not limited to, various surfactants such as various triglycerides, such as from butter oil, monoglycerides, such as of stearic acid and vegetable oils, esters thereof, esters of fatty acids, propylene glycol esters, the polysorbates, sodium lauryl sulfate, sorbitan esters, sodium sulfosuccinate, among other compounds.
  • a hypoglycemic agent / copper chelator By altering the surfactant properties of the delivery vehicle it is possible to, for example, allow a hypoglycemic agent / copper chelator to have greater intestinal contact over a longer period of time that increases uptake and reduces side effects.
  • agents include carrier molecules such as cyclodextrin and derivatives thereof, well known in the art for their potential as complexation agents capable of altering the physicochemical attributes of drug molecules.
  • cyclodextrins may stabilize (both thermally and oxidatively), reduce the volatility of, and alter the solubility of, hypoglycemic agent and/or copper antagonist with which they are complexed.
  • Cyclodextrins are cyclic molecules composed of glucopyranose ring units that form toroidal structures.
  • the interior of the cyclodextrin molecule is hydrophobic and the exterior is hydrophilic, making the cyclodextrin molecule water-soluble.
  • the degree of solubility can be altered through substitution of the hydroxyl groups on the exterior of the cyclodextrin.
  • the hydrophobicity of the interior can be altered through substitution, though generally the hydrophobic nature of the interior allows accommodation of relatively hydrophobic guests within the cavity.
  • Accommodation of one molecule within another is known as complexation and the resulting product is referred to as an inclusion complex.
  • Examples of cyclodextrin derivatives include sulfobutylcyclodextrin, maltosylcyclodextrin, hydroxypropylcyclodextrin, and salts thereof.
  • a microemulsion is a fluid and stable homogeneous solution composed of four major constituents, respectively, a hydrophilic phase, a lipophilic phase, at least one surfactant (SA) and at least one cosurfactant (CoSA).
  • a surfactant is a chemical compound possessing two groups, the first polar or ionic, which has a great affinity for water, the second which " contains a longer or shorter aliphatic chain and is hydrophobic. These chemical compounds having marked hydrophilic character are intended to cause the formation of micelles in aqueous or oily solution.
  • suitable surfactants include mono-, di- and triglycerides and polyethylene glycol (PEG) mono- and diesters.
  • a cosurfactant also sometimes known as "co-surface-active agent" is a chemical compound having hydrophobic character, intended to cause the mutual solubilization of the aqueous and oily phases in a microemulsion.
  • Suitable co-surfactants include ethyl diglycol, lauric esters of propylene glycol, oleic esters of polyglycerol, and related compounds.
  • the invention in part also provides for the formulation of hypoglycemic agents / copper antagonists with various polymers to enhance bioavailability by increasing adhesion to mucosal surfaces, by decreasing the rate of degradation by hydrolysis or enzymatic degradation of the hypoglycemic agent / copper antagonist, and by increasing the surface area of the hypoglycemic agent / copper antagonist relative to the size of the particle.
  • Suitable polymers can be natural or synthetic, and can be biodegradable or non-biodegradable.
  • low molecular weight active agents such as for example hypoglycemic agent / copper antagonist, including compounds of Formulae I, I(a) and II and trientine active agents, may occur by either diffusion or degredation of the polymeric system.
  • Representative natural polymers include proteins such as zein, modified zein, casein, gelatin, gluten, serum albumin, and collagen, polysaccharides such as cellulose, dextrans, and polyhyaluronic acid. Synthetic polymers are generally preferred due to the better characterization of degradation and release profiles.
  • Representative synthetic polymers include polyphosphazenes, polyvinyl alcohols), polyamides, polycarbonates, polyacrylates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof.
  • suitable polyacrylates include pory(methyl - methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), ⁇ oly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate).
  • Synthetically modified natural polymers include cellulose derivatives such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses.
  • Suitable cellulose derivatives include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate and cellulose sulfate sodium salt.
  • polymers described above can be obtained from commercial sources such as Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich Chemical Co., Milwaukee, Wis., Fluka, Ronkonkoma, N.
  • polymers described above can be separately characterized as biodegradable, non-biodegradable, and bioadhesive polymers, as discussed in more detail below.
  • Representative synthetic degradable polymers include polyhydroxy acids such as polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), polyanhydrides, polyorthoesters and blends and copolymers thereof.
  • Representative natural biodegradable polymers include polysaccharides such as alginate, dextran, cellulose, collagen, and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), and proteins such as albumin, zein and copolymers and blends thereof, alone or in combination with synthetic polymers. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion.
  • non-biodegradable polymers examples include ethylene vinyl acetate, ⁇ oly(meth)acrylic acid, polyamides, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylphenol, and copolymers and mixtures thereof.
  • Hydrophilic polymers and hydrogels tend to have bioadhesive properties.
  • Hydrophilic polymers that contain carboxylic groups e.g., poly[acrylic acid]
  • Polymers with the highest concentrations of carboxylic groups are preferred when bioadhesiveness on soft tissues is desired.
  • cellulose derivatives such as sodium alginate, carboxymethylcellulose, hydroxymethylcellulose and methylcellulose also have bioadhesive properties. Some of these bioadhesive materials are water-soluble, while others are hydrogels.
  • Polymers such as hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP) may be utilized to enhance the bioavailability of hypoglycemic agent and/or copper antagonist with which they are complexed.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • CAT cellulose acetate trimellitate
  • CAP cellulose acetate phthalate
  • HPCAP hydroxypropylcellulose acetate phthalate
  • MCAP methylcellulose acetate phthalate
  • Rapidly bioerodible polymers such as poly(lactide-co-glycolide), polyanhydrides, and polyorthoesters, whose carboxylic groups are exposed on the external surface as their smooth surface erodes, can also be used for bioadhesive hypoglycemic agent / copper chelator delivery systems.
  • polymers containing labile bonds such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. Their hydrolytic degradation rates can generally be altered by simple changes in the polymer backbone. Upon degradation, these materials also expose carboxylic groups on their external surface, and accordingly, these can also be used for bioadhesive hypoglycemic agent / copper chelator delivery systems.
  • agents that may enhance bioavailability or absorption of one or more hypoglycemic agents / copper antagonists can act by facilitating or inhibiting transport across the intestinal mucosa.
  • agents that increase blood flow such as vasodilators, may increase the rate of absorption " of orally administered hypoglycemic agent / copper chelator by increasing the blood flow to the gastrointestinal tract.
  • Vasodilators have been used in combination with other drugs.
  • a coronary vasodilator diltiazem
  • drugs which have an absolute bioavailability of not more than 20%, such as adrenergic beta-blocking agents (e.g., propranolol), catecholamines (e.g., dopamine), benzodiazepine derivatives (e.g., diazepam), vasodilators (e.g., isosorbide dinitrate, nitroglycerin or amyl nitrite), cardiotonics or antidiabetic agents, bronchodilators (e.g., tetrahydroisoquinoline), hemostatics (e.g., carbazochrome sulfonic acid), antispasmodics (e.g., timepidium halide) and antitussives (e.g., tipepidine).
  • Vasodilators therefore constitute another class
  • compositions and formulations of the invention include the inhibition of reverse active transport mechanisms.
  • one of the active transport mechanisms present in the intestinal epithelial cells is p-glycoprotein transport mechanism which facilitates the reverse transport of substances, which have diffused or have been transported inside the epithelial cell, back into the lumen of the intestine.
  • the p-glycoprotein present in the intestinal epithelial cells may function as a protective reverse pump which prevents toxic substances which have been ingested and diffused or transported into the epithelial cell from being absorbed into the circulatory system and becoming bioavailable.
  • p-glycoprotein in the intestinal cell can also function to prevent bioavailability of substances which are beneficial, such as certain drugs which happen to be substrates for the p- glycoprotein reverse transport system. Inhibition of this p-glycoprotein mediated active transport system will cause less drug to be transported back into the lumen and will thus increase the net drug transport across the gut epithelium and will increase the amount of drug ultimately available in the blood.
  • p- glycoprotein inhibitors are well known and appreciated in the art. These include, water-soluble vitamin E; polyethylene glycol; poloxamers including Pluronic F-68;
  • Inhibition of a reverse active transport system of which, for example, a hypoglycemic agent / copper antagonist is a substrate may thereby enhance the bioavailability of said hypoglycemic agent / copper antagonist.
  • This Example describes preparation of tablets having a copper antagonist(s) such as, for example, one or more copper chelators ⁇ e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas ⁇ e.g., gliclazide), which may be prepared by compaction and direct compression.
  • a copper antagonist(s) such as, for example, one or more copper chelators ⁇ e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas ⁇ e.g., gliclazide
  • ingredients for tablets including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, are provided in the below table:
  • the following process employs compaction and direct compression.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA).
  • the compacted antagonist(s) is/are then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Quadro Comill, oscillator mill, or pin mill, for example.
  • the milled copper antagonist(s) is/are blended with a sulfonylurea (e.g., gliclazide), silicon dioxide and magnesium stearate, for example, in a suitable blender.
  • suitable blenders include v-Blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is compressed into tablets using a suitable tablet machine, such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • a suitable tablet machine such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of . triethylenetetramine- dihydroGhloride or triethylenetetramine disuccinate (or other copper antagonist) may range from about
  • 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets including fillers and having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared by blending and direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared by blending and direct compression.
  • ingredients for tablets with fillers including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, are provided in the below table.
  • the following process employs a combination of blending and direct compression techniques.
  • the copper antagonist(s) ⁇ e.g., triethylenetetramine disuccinate
  • a sulfonylurea e.g., gliclazide
  • suitable blenders include, for example, V-Blenders (Patterson-Kelly), planetary blenders (Hobart Corp).
  • the resulting blend is mixed with microcrystalline cellulose, which may also be done in a suitable blender.
  • This blend is milled and screened in a Fitz mill (Fitzpatrick Corp) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • a Fitz mill Frazier Corp
  • suitable mill such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the resulting blend is mixed with the silicon dioxide, croscarmellose sodium, and magnesium stearate, which may also be accomplished in a suitable blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine
  • ingredients for tablets with desiccant(s) including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, are provided in the below table.
  • the following process employs compaction, blending and direct compression.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • sulfonylurea(s) e.g., gliclazide
  • a desiccant e.g. anhydrous sodium phosphate
  • Suitable blenders include, for example, v-blenders (Patterson- Kelly), planetary blenders (Hobart). This blend is compacted in a suitable roller compacter, such as a Vector Mini-model
  • TF TF
  • Fitz mill or other suitable mill.
  • suitable mills include a Quadro Comill, oscillating mills, and pin mills, for example.
  • the resulting blend is blended with a sulfonylurea (e.g. gliclazide), silicon dioxide and magnesium stearate in a suitable blender.
  • a sulfonylurea e.g. gliclazide
  • the final blend is compacted into tablets on a suitable tablet machine, such as a Manesty beta press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas
  • gliclazide e.g., gliclazide
  • ingredients for tablets with wet granulation binder(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, are provided in the below table.
  • the following tablet is prepared using wet granulation methods.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • a sulfonylurea(s) e.g., gliclazide
  • lactose lactose
  • dicalcium phosphate in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol. Where triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • the blend is wet granulated with the solution of hydroxypropylcellulose in the suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in a Glatt fluid bed dryer.
  • This final granulation is mixed with the crosscarmellose sodium and magnesium stearate or other lubricant in a suitable blender, such as Patterson Kelly V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea ⁇ ), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 5 A COMBINATION TABLET EMPLOYING A WET GRANULATION AND A DESICCANT
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by wet granulation.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by wet granulation.
  • copper chelators e.g., a trientine, such
  • ingredients for tablets with a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, which may be prepared using wet granulation methods, are provided in the below table.
  • the following tablet is prepared using wet granulation methods.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • a sulfonylurea(s) e.g., gliclazide
  • lactose in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulat or/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol. Where triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non- copper metal ion as disclosed herein, e.g., calcium.
  • the blend is wet granulated with the solution of hydroxypropylcellulose in a suitable granulator/dryer. The wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in, for example, a Glatt fluid bed dryer.
  • This granulation is mixed with the disodium phosphate and magnesium stearate or other lubricant in a suitable blender, such as JPatterson- Kelly- V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 6 A COMBINATION CAPSULE EMPLOYING DIRECT FILLING This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators ⁇ e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas ⁇ e.g., gliclazide), which may be prepared by compaction and direct filling.
  • Ingredients for capsules including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, that may be prepared by direct filling, are provided in the below table.
  • the following process employs compaction.
  • the copper antagonist(s) ⁇ e.g., triethylenetetramine disuccinate
  • Suitable roller compactors include, for example, the Vector Mini- Model TF (Vector Corp., Marion, IA).
  • the milled copper antagonist is blended with the sulfonylurea ⁇ e.g., gliclazide), silicon dioxide and magnesium stearate or other lubricant in a suitable blender.
  • suitable blenders include, for example, v-Blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is filled into hard gelatin capsules with on a suitable encapsulation machine, such as a Zanasi 40 E capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 7 A COMBINATION CAPSULE EMPLOYING A DESICCANT AND DIRECT FILLING
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by compaction and direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by compaction and direct compression.
  • copper chelators e.g., a trientine, such as
  • ingredients for capsules with a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, which may be prepared by direct filling, are provided in the below table.
  • the following process employs compaction, blending and encapsulation.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • a suitable roller compacter include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the milled copper antagonist is blended with the sulfonylurea, disodium phosphate, silicon dioxide and magnesium stearate or other lubricant in a suitable blender.
  • Suitable blenders include, for example, V-blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is encapsulated into hard gelatin capsules on a suitable capsule machine, such as a Zanasi 4OE capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 8 A COMBINATION CAPSULE EMPLOYING FILLERS AND DIRECT FILLING
  • This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas
  • fillers e.g., gliclazide
  • ingredients for capsules with fillers including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, which may be prepared by direct filling, are provided in the below table.
  • the following process employs a combination of blending and direct encapsulation techniques.
  • the copper antagonist(s) is/are blended, for example, with a sulfonylurea (e.g. gliclazide) and lactose in a suitable blender.
  • suitable blenders include, for example, v-blenders (Patterson-Kelly), and planetary blenders (Hobart
  • the resulting blend is mixed with the crosscarmellose sodium in the same blender.
  • This blend may be milled and screened in a Fitz mill (Fitzpatrick Corp) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the resulting blend is mixed with the magnesium stearate, or other lubricant, which may also be accomplished in a suitable blender.
  • the final blend is filled into hard gelatin capsules on a suitable encapsulation machine, such as a Zanasi capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range ffoih " about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared by wet granulation methods.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared by wet granulation methods.
  • Ingredients for capsules including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, that may be prepared by wet granulation, are provided in the below table.
  • the following capsule is prepared using wet granulation methods.
  • the copper antagonist(s) is/are blended with a sulfonylurea (e.g. gliclazide), and lactose and in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol. Where triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • the blend is wet granulated with the solution of hydroxypropylcellulose in a suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in a Glatt fluid bed dryer.
  • This granulation is mixed with the sodium starch glycolate and magnesium stearate in a suitable blender, such as Patterson Kelly V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by wet granulation.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), together with one or more desiccants, which may be prepared by wet granulation.
  • copper chelators e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate
  • ingredients for capsules having a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, that may be prepared using wet granulation methods, are provided in the below table.
  • the following capsule is prepared using wet granulation methods.
  • the copper antagonist(s) is/are blended with a sulfonylurea (e.g. gliclazide), lactose, and a desiccant (e.g. anhydrous disodium phosphate) in a suitable fluid bed granulator/dryer.
  • a sulfonylurea e.g. gliclazide
  • lactose e.g. anhydrous disodium phosphate
  • a desiccant e.g. anhydrous disodium phosphate
  • suitable fluid bed granulator/dryer e.g. gliclazide
  • lactose e.g. lactose
  • a desiccant e.g. anhydrous disodium phosphate
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved
  • the blend is wet granulated with the solution of hydroxypropylcellulose in a suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in a Glatt fluid bed dryer.
  • This granulation is mixed with the disodium phosphate, crosscarmellose sodium and magnesium stearate in a suitable blender, such as Patterson Kelly V-blender.
  • a suitable blender such as Patterson Kelly V-blender.
  • the final blend is filled into hard gelatin capsules in a suitable encapsulation machine, such as.a Zanasi 40E-capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of matrix controlled release tablets having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared using roller compaction and direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared using roller compaction and direct compression.
  • copper chelators e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate
  • sulfonylureas e.g.,
  • a controlled release tablet having a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, which may be prepared using compaction and direct compression methods, are provided in the below table.
  • the copper antagonist(s) is/are first compacted, for example, in a suitable roller compacter.
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Comill mill, oscillator mill, or pin mill, for example.
  • the milled copper antagonist is/are blended with a sulfonylurea ⁇ ), hydroxypropyl- methylcellulose, and lactose in a suitable blender.
  • Suitable blenders include V- Blenders (Patterson-Kelly, and planetary blenders (Hobart Corp., Troy OH.). This blend is blended with the magnesium stearate or other lubricant in the same blender.
  • the final blend is compressed into tablets using a suitable tablet machine, such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • a suitable tablet machine such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). - Other amounts may also be ' used. "" Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 12 A COMBINATION CAPSULE CONTAINING ENTERIC COATED BEADS
  • This Example describes preparation of a capsule containing enteric beads having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared using granulation, spheronization, and bead coating.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more sulfonylureas (e.g., gliclazide), which may be prepared using granulation, spheronization, and bead coating.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenet
  • ingredients for a capsule containing enteric coated beads release including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a gliclazide, which may be prepared as set forth herein, are provided in the below table.
  • the copper antagonist(s), a sulfonylurea (e.g. gliclazide), and hydroxypropylcellulose are blended in a suitable granulator-spheronizer, such as a
  • Niro Roto-Processor spheronizer Water or alcohol is used to wet the granulation and the wet mass is spheronized to beads on the processor. Where triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium. The beads are dried in a fluid bed coating/drying processor, such as a Niro Precision coater.
  • a commercial aqueous or alcohol solution of cellulose acetate phthalate for example, Aquacote CPD-FMC Corporation, is used to coat the beads in the coating- drying processor.
  • the dried beads are coated with the solution and dried in fluid bed coating apparatus.
  • Talc can be added to keep the beads free flowing.
  • the beads are filled into hard gelatin capsules using an appropriate capsule-filling machine, such as a Zanasi encapsulation machine
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may sulfonylureas other than gliclazide.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and sulfonylurea(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and gliclazide set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50.mg, about 100 -mg, about 125 mg, about 150 ing, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of gliclazide may range from about 10 mg to about 320 mg (for example, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 160 mg, and about 320 mg). Other amounts may also be used. Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets having a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by compaction and direct compression.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by compaction and direct compression.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate
  • ingredients for tablets including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, are provided in the below table:
  • the following process employs compaction and direct compression.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA).
  • the compacted antagonist(s) is/are then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Quadro Comill, oscillator mill, or pin mill, for example.
  • the milled copper antagonist(s) is/are blended with a thiazolidinedione (e.g., rosiglitazone), silicon dioxide and magnesium stearate, for example, in a suitable blender.
  • Suitable blenders include v-Blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is compressed into tablets using a suitable tablet machine, such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • a suitable tablet machine such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably j)recomplexed_ with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 1 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets including fillers and having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by blending and direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by blending and direct compression.
  • Ingredients for tablets with fillers including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, are provided in the below table.
  • the following process employs a combination of blending and direct compression techniques.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • a thiazolidinedione e.g., rosiglitazone
  • suitable blenders include, for example, V-Blenders (Patterson-Kelly), planetary blenders (Hobart Corp).
  • the resulting blend is mixed with microcrystalline cellulose, which may also be done in a suitable blender.
  • This blend is milled and screened in a Fitz mill (Fitzpatrick Corp) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the resulting blend is mixed with the silicon dioxide, croscarmellose sodium, and magnesium stearate, which may also be accomplished in a suitable blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 1 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more desiccants, which may be prepared by direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more desiccants, which may be prepared by direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenete
  • ingredients for tablets with desiccant(s) including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, are provided in the below table.
  • the following process employs compaction, blending and direct compression.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • thiazolidinedione(s) e.g., rosiglitazone
  • a desiccant e.g. anhydrous sodium phosphate
  • Suitable blenders include, for example, v-blenders (Patterson- Kelly), planetary blenders (Hobart). This blend is compacted in a suitable roller compacter, such as a Vector Mini-model
  • TF TF. It is then milled and screened in a Fitz mill or other suitable mill. Suitable mills include a Quadro Comill, oscillating mills, and pin mills, for example. The resulting blend is blended with a thiazolidinedione (e.g. rosiglitazone), silicon dioxide and magnesium stearate in a suitable blender.
  • a thiazolidinedione e.g. rosiglitazone
  • silicon dioxide silicon dioxide
  • magnesium stearate magnesium stearate
  • the final blend is compacted into tablets on a suitable tablet machine, such as a Manesty beta press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 1 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by wet granulation.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by wet granulation.
  • Ingredients for tablets with wet granulation binder(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, are provided in the below table.
  • the following tablet Is prepared using wet granulation methods.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • a thiazolidinedione(s) e.g., rosiglitazone
  • lactose and dicalcium phosphate in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol. Where triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • the blend is wet granulated with the solution of hydroxypropylcellulose in the suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in a Glatt fluid bed dryer.
  • This final granulation is mixed with the crosscarmellose sodium and magnesium stearate or other lubricant in a suitable blender, such as Patterson Kelly V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 1 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • a COMBINATION TABLET EMPLOYING A WET GRANULATION AND A DESICCANT This Example describes preparation of tablets having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones ⁇ e.g., rosiglitazone), together with one or more desiccants, which may be prepared by wet granulation.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones ⁇ e.g., rosiglitazone), together with one or more desiccants, which may be prepared by wet granulation.
  • ingredients for tablets with a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, which may be prepared using wet granulation methods, are provided in the below table.
  • the following tablet is prepared using wet granulation methods.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • a thiazolidinedione(s) e.g., rosiglitazone
  • lactose in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol.
  • triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • the blend is wet granulated with the solution of hydroxypropylcellulose in a suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in, for example, a Glatt fluid bed dryer.
  • This granulation is mixed with the disodium phosphate and magnesium stearate or other lubricant in a suitable blender, such as Patterson Kelly V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 1 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, ⁇ for example one or two or more-tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 18 A COMBINATION CAPSULE EMPLOYING DIRECT FILLING This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by compaction and direct filling.
  • Ingredients for capsules including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, that may be prepared by direct filling, are provided in the below table.
  • the following process employs compaction.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • Suitable roller compactors include, for example, the Vector Mini- Model TF (Vector Corp., Marion, IA).
  • a Fitz mill Fastpatrick Company, Elmhurst, 111.
  • suitable mill such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the milled copper antagonist is blended with the thiazolidinedione (e.g., rosiglitazone), silicon dioxide and magnesium stearate or other lubricant in .
  • suitable blenders include, for example, v-Blenders (Patterson- Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is filled into hard gelatin capsules with on a suitable encapsulation machine, such as a Zanasi 40 E capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 0.5 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • a preferred capsule size is 300 mg.
  • capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day.
  • Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • a COMBINATION CAPSULE EMPLOYING A DESICCANT AND DIRECT FILLING This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more desiccants, which may be prepared by compaction and direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more desiccants, which may be prepared by compaction and direct compression.
  • copper chelators e.g., a trientine
  • ingredients for capsules with a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, which may be prepared by direct filling, are provided in the below table.
  • the following process employs compaction, blending and encapsulation.
  • the copper antagonist(s) e.g., triethylenetetramine disuccinate
  • a suitable roller compacter include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the milled copper antagonist is blended with the thiazolidinedione, disodium phosphate, silicon dioxide and magnesium stearate or other lubricant in a suitable blender.
  • suitable blenders include, for example, V-blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is encapsulated into hard gelatin capsules on a suitable capsule machine, such as a Zanasi 4OE capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 0.5 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • a preferred capsule size is 300 mg.
  • capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day.
  • Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more fillers, which may be prepared by direct filling.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more fillers, which may be prepared by direct filling.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetra
  • ingredients for capsules with fillers including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, which may be prepared by direct filling, are provided in the below table.
  • the following process employs a combination of blending and direct encapsulation techniques.
  • the copper antagonist(s) is/are blended, for example, with a thiazolidinedione (e.g. rosiglitazone) and lactose in a suitable blender.
  • suitable blenders include, for example, v-blenders (Patterson-Kelly), and planetary blenders (Hobart Corp).
  • the resulting blend is mixed with the crosscarmellose sodium in the same blender.
  • This blend may be milled and screened in a Fitz mill (Fitzpatrick Corp) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the resulting blend is mixed with the magnesium stearate, or other lubricant, which may also be accomplished in a suitable blender.
  • the final blend is filled into hard gelatin capsules on a suitable encapsulation machine, such as a Zanasi capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about
  • the amount of rosiglitazone may range from about 0.5 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day. A preferred capsule size is 300 mg. Thus, capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 21 A COMBINATION CAPSULE EMPLOYING WET GRANULATION
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared by wet granulation methods.
  • Ingredients for capsules including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, that may be prepared by wet granulation, are provided in the below table.
  • the following capsule is prepared using wet granulation methods.
  • the copper antagonist(s) is/are blended with a thiazolidinedione (e.g. rosiglitazone), and lactose and in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol. Where triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • the blend is wet granulated with the solution of hydroxypropylcellulose in a suitable granulator/dryer. The wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in a Glatt fluid bed dryer.
  • This granulation is mixed with the sodium starch glycolate and magnesium stearate in a suitable blender, such as Patterson Kelly V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 0.5 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • a preferred capsule size is 300 mg.
  • capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example " one or two or more capsules once, twice, or more per day.
  • Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of capsules having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more desiccants, which may be prepared by wet granulation.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), together with one or more desiccants, which may be prepared by wet granulation.
  • copper chelators e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate
  • ingredients for capsules having a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, that may be prepared using wet granulation methods, are provided in the below table.
  • the following capsule is prepared using wet granulation methods.
  • the copper antagonist(s) is/are blended with a thiazolidinedione (e.g. rosiglitazone), lactose, and a desiccant (e.g. anhydrous disodium phosphate) in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol. Where triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • the blend is wet granulated with the solution of hydroxypropylcellulose in a suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in a Glatt fluid bed dryer.
  • This granulation is mixed with the disodium phosphate, crosscarmellose sodium and magnesium stearate in a suitable blender, such as Patterson Kelly V-b lender.
  • the final blend is filled into hard gelatin capsules in a suitable encapsulation machine, such as a Zanasi 4OE capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about
  • the amount of rosiglitazone may range from about 1 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day. A preferred capsule size is 300 mg. Thus, capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day. Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 23 A CONTROLLED RELEASE COMBINATION TABLET This Example describes preparation of matrix controlled release tablets having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared using roller compaction and direct compression.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared using roller compaction and direct compression.
  • copper chelators e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine
  • a controlled release tablet having a desiccant(s) and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and a rosiglitazone, which may be prepared using compaction and direct compression methods, are provided in the below table.
  • the following process employs compaction and direct compression.
  • the copper antagonist(s) is/are first compacted, for example, in a suitable roller compacter.
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Comill mill, oscillator mill, or pin mill, for example.
  • the milled copper antagonist is/are blended with a thiazolidinedione(s), hydroxypropyl-methylcellulose, and lactose in a suitable blender.
  • suitable blenders include V-Blenders (Patterson-Kelly, and planetary blenders (Hobart Corp., Troy OH.).
  • This blend is blended with the magnesium stearate or other lubricant in the same blender.
  • the final blend is compressed into tablets using a suitable tablet machine, such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetrarriine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 1 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • a COMBINATION CAPSULE CONTAINING ENTERIC COATED BEADS This Example describes preparation of a capsule containing enteric beads having a copper antagonist(s), for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared using granulation, spheronization, and bead coating.
  • a copper antagonist(s) for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more thiazolidinediones (e.g., rosiglitazone), which may be prepared using granulation, spheronization, and bead coating.
  • ingredients for a capsule containing enteric coated beads release and including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disucc ⁇ nate and a rosiglitazone, which may be prepared as set forth herein, are provided in the below table.
  • the copper antagonist(s), a thiazolidinedione (e.g. rosiglitazone), and hydroxypropylcellulose are blended in a suitable granulator-spheronizer, such as a Niro Roto-Processor spheronizer.
  • a suitable granulator-spheronizer such as a Niro Roto-Processor spheronizer.
  • Water or alcohol is used to wet the granulation and the wet mass is spheronized to beads on the processor.
  • triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • the beads are dried in a fluid bed coating/drying processor, such as a Niro Precision coater.
  • a commercial aqueous or alcohol solution of cellulose acetate phthalate for example, Aquacote CPD-FMC Corporation, is used to coat the beads in the coating- drying processor.
  • the dried beads are coated with the solution and dried in fluid bed coating apparatus.
  • Talc can be added to keep the beads free flowing.
  • the beads are filled into hard gelatin capsules using an appropriate capsule-filling machine, such as a Zanasi encapsulation machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may thiazolidinediones other than rosiglitazone.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and thiazolidinedione(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and rosiglitazone set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of rosiglitazone may range from about 0.5 mg to about 8 mg (for example, about 1 mg, about 2 mg, about 4mg, about 6 mg or about 8mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • a preferred capsule size is 300 mg.
  • capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example one or two or more capsules once, twice, or more per day.
  • Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 25 COMBINATION TABLET This Example describes preparation of tablets having a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using compaction and direct compression methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using compaction and direct compression methods.
  • Ingredients for tablets including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin, are provided in the below table:
  • the process employs compaction and direct compression.
  • the copper antagonist(s) is/are first compacted, for example, in a suitable roller compacter.
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Quadro Comill, oscillator mill, or pin mill, for example.
  • the milled copper antagonist is blended with the biguanide, silicon dioxide and magnesium stearate, for example, in a suitable blender.
  • Suitable blenders include v- Blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is compressed into tablets using a suitable tablet machine, such as a Manesty beta-press (Manesty, Knowsley, Merseyside, UK).
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and biguanide(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate (or other copper antagonist) may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg)
  • the amount of metformin may range from about 100 mg to about 2500 mg (for example, about 100 mg, about 200, about 250 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg and about 2500 mg).
  • Other amounts may also be used. The amounts are not inflexible
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets including fillers and having a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using compaction and direct compression methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using compaction and direct compression methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.
  • ingredients for tablets including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin, are provided in the below table:
  • the process employs a combination of blending and direct compression techniques.
  • the copper antagonist is blended, for example, with the biguanide in a suitable blender.
  • suitable blenders include, for example, V-Blenders (Patterson-Kelly), planetary blenders (Hobatt Corp).
  • the resulting blend is mixed with microcrystalline cellulose, which may also be done in a suitable blender.
  • This blend is milled and screened in a Fitz mill (Fitzpatrick Corp) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the resulting blend is mixed with the silicon dioxide and magnesium stearate, which may also be accomplished in a suitable blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and biguanide(s) including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of metformin may range from about 100 mg to about 2500 mg (for example, about 100 mg, about 200, about 250 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg and about 2500 mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets having a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), together with one or more desiccants, which may be prepared using direct compression methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), together with one or more desiccants, which may be prepared using direct compression methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and
  • ingredients for tablets including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin, are provided in the below table:
  • the process employs compaction, blending and direct compression.
  • the copper antagonist(s), biguanide(s) and desiccant(s) are blended in a suitable blender.
  • suitable blenders include, for example, v-blenders (Patterson-Kelly), planetary blenders(Hobart).
  • This blend is compacted in a suitable roller compacter, such as a Vector Mini-model TF. It is then milled and screened in a Fitz mill or other suitable mill. Suitable mills include a Quadro Comill, oscillating mills, and pin mills, for example.
  • the resulting blend is blended with the LEAD DRUG, silicon dioxide and magnesium stearate in a suitable blender.
  • the final blend is compacted into tablets on a suitable tablet machine, such as a Manesty beta press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and biguanide(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate (or other copper antagonist) may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • This Example describes preparation of tablets having a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using wet granulation methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using wet granulation methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., met
  • ingredients for tablets including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin, are provided in the below table:
  • This tablet is prepared using wet granulation methods.
  • the copper antagonist(s) is blended with the biguanide(s), lactose and dicalcium phosphate in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or ethanol, and the blend is wet granulated with the solution of hydroxypropylcellulose in the suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • triethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in a Glatt fluid bed dryer.
  • This final granulation is mixed with the crosscarmellose sodium and magnesium stearate or other lubricant in a suitable blender, such as Patterson Kelly V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and biguanide(s) including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg), and the amount of metformin may range from about 100 mg to about 2500 mg (for example, about 100 mg, about 200, about 250 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg and about 2500 mg). Other amounts may also be used. The amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example/ one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 29 A COMBINATION TABLET EMPLOYING A WET GRANULATION AND A DESICCANT
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate) and one or more biguanides (e.g., metformin), together with one or more desiccants, which may be prepared using wet granulation methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate) and one or more biguanides (e.g., metformin), together with one or more desiccants, which may be prepared using wet granulation methods.
  • Ingredients for tablets including, for example, triethylenetetramine dihydrochloride or triethylenete
  • This tablet is prepared using wet granulation methods.
  • the copper antagonist(s) is blended with the biguanides(s), and lactose in a suitable fluid bed granulator/dryer.
  • Suitable granulator/dryers include Glatt or Niro fluid bed granulator/dryers.
  • the hydroxypropylcellulose is dissolved in water or-ethanol, and the blend is wet granulated with the solution of hydroxypropylcellulose in a suitable granulator/dryer.
  • the wet granulation is dried in the granulator dryer.
  • ti ⁇ ethylenetetramine dihydrochloride is used in this formulation it is preferably precomplexed with a non-copper metal ion as disclosed herein, e.g., calcium.
  • this granulation can be prepared by blending the copper antagonist(s) with lactose and dicalcium phosphate and wet granulating with the hydroxypropylcellulose solution in a Niro or Glatt high speed granulator and drying it in, for example, a Glatt fluid bed dryer.
  • This granulation is mixed with the disodium phosphate and magnesium stearate or other lubricant in a suitable blender, such as Patterson Kelly V-blender.
  • the final blend is compressed into tablets on a suitable tablet machine, such as a Manesty beta-press.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and biguanide(s) including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 nig, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about
  • the amount of metformin may range from about 100 mg to about 2500 mg (for example, about 100 mg, about 200, about 250 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg and about 2500 mg). Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the tablet may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more tablets once, twice, or more per day. Tablets are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 30 A COMBINATION CAPSULE EMPLOYING DIRECT FILLING This Example describes preparation of capsules having a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using compaction and direct filling methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate), and one or more biguanides (e.g., metformin), which may be prepared using compaction and direct filling methods.
  • Ingredients for capsules including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin, are provided in the below table:
  • the process employs compaction.
  • the copper antagonist(s) is/are first compacted, for example, in a suitable roller compacter.
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • a Fitz mill Fitzpatrick Company, Elmhurst, 111.
  • suitable mill such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the milled copper antagonist is blended with the biguanide, silicon dioxide and magnesium stearate or other lubricant in a suitable blender.
  • suitable blenders include, for example, v-Blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is filled into hard gelatin capsules with on a suitable encapsulation machine, such as a Zanasi 40 E capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for example, a triethylenetetramine complexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and biguanide(s) including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 tng, about 200 mg, about
  • the amount of metformin may range from about 50 mg to about 2500 mg (for example, about 100 mg, about 200, about 250 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg and about 2500 mg).
  • Other amounts may also be used.
  • the amounts are not inflexible and may be determined, in part, for example, based on the number of capsules to be taken per day.
  • a preferred capsule size is 300 mg.
  • capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more capsules once, twice, or more per day.
  • Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • a COMBINATION CAPSULE EMPLOYING A DESICCANT AND DIRECT FILLING This Example describes preparation of capsules having a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate) and one or more biguanides (e.g., metformin), together with one or more desiccants, which may be prepared using compaction and direct compression methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate) and one or more biguanides (e.g., metformin), together with one or more desiccants, which may be prepared using compaction and direct compression methods.
  • Ingredients for capsules including, for example, triethylenetetramine dihydrochloride or triethylenet
  • the process employs compaction, blending and encapsulation.
  • the copper antagonist(s) is/are first compacted, for example, in a suitable roller compacter.
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the milled copper antagonist is blended with the biguanide, disodium phosphate, silicon dioxide and magnesium stearate or other lubricant in a suitable blender.
  • suitable blenders include, for example, V-blenders (Patterson-Kelly), planetary blenders (Hobart Corp., Troy OH.).
  • the final blend is encapsulated into hard gelatin capsules on a suitable capsule machine, such as a Zanasi 4OE capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.
  • Pentacoordinate copper antagonists may also be used, including for-example, a triethyrenefetrami ⁇ e c ⁇ mplexed with calcium (or another non-copper metal ion) and another complexing agent, such as, for example, chloride, as disclosed herein.
  • Amounts of the copper antagonist(s) and biguanide(s), including the amounts of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin set forth in this Example, may be varied, as appropriate.
  • the amount of triethylenetetramine dihydrochloride or triethylenetetramine disuccinate (or other copper antagonist) may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 400 mg, about 500 mg, about 600 mg, and about 750 mg)
  • the amount of metformin may range from about 50 mg to about 2500 mg (for example, about 100 mg, about 200, about 250 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg and about 2500 mg).
  • Other amounts may also be used. The amounts are not inflexible
  • a preferred capsule size is 300 mg.
  • capsules may be prepared using appropriate doses within the ranges provided in order to yield a 300 mg size.
  • the capsule may be prepared for administration of drug, by way of example, in one or more doses, for example, one or two or more capsules once, twice, or more per day.
  • Capsules are generally prepared for administration no more than four times per day, preferably less, most preferably one or two times per day.
  • EXAMPLE 32 A COMBINATION CAPSULE EMPLOYING FILLERS AND DIRECT FILLING
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate) and one or more biguanides (e.g., metformin), together with one or more fillers, which may be prepared using direct filling methods.
  • a copper antagonist(s) such as, for example, one or more copper chelators (e.g., a trientine, such as triethylenetetramine dihydrochloride or triethylenetetramine disuccinate) and one or more biguanides (e.g., metformin)
  • fillers which may be prepared using direct filling methods.
  • Ingredients for capsules including, for example, triethylenetetramine dihydrochloride or triethylenetetramine disuccinate and metformin, are provided in the
  • the process employs a combination of blending and direct encapsulation techniques.
  • the copper antagonist is blended, for example, with the biguanide and lactose in a suitable blender.
  • suitable blenders include, for example, v-blenders (Patterson- Kelly), and planetary blenders (Hobart Corp).
  • the resulting blend is mixed with the crosscarmellose sodium in the same blender. This blend may be milled and screened in a Fitz mill (Fitzpatrick Corp) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the resulting blend is mixed with the magnesium stearate, or other lubricant, which may also be accomplished in a suitable blender.
  • the final blend is filled into hard gelatin capsules on a suitable encapsulation machine, such as a Zanasi capsule machine.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used including, for example, triethylenetetramine dihydrochloride, triethylenetetramine triethylenetetramine tetrafumarate and triethylenetetramine tetramaleate, as may biguanides other than metformin.
  • a copper antagonist compound which has already been considerably precomplexed with a non-copper metal ion as disclosed herein may also be used, for example, a triethylenetetramine precomplexed with calcium or another non-copper metal ion.

Abstract

L’invention se rapporte à des compositions pharmaceutiques ayant un ou plusieurs composé(s) antagoniste(s) du cuivre acceptable(s) du point de vue pharmaceutique, par exemple un ou plusieurs antagoniste(s) du cuivre (II) et un agent hypoglycémiant acceptable d’un point de vue pharmaceutique. L’invention se rapporte également à des articles, des kits et des dispositifs de délivrance contenant ces compositions, des comprimés, des gélules et des formulations contenant ces compositions, et des procédés d’utilisation pour le traitement de sujets, y compris d’humains, sont atteints de nombreuses maladies, troubles et états pathologiques ou sont exposés à un risque vis-à-vis de ceux-ci, caractérisés totalement ou en partie par une hypercuprémie et/ou une hyperglycémie.
PCT/NZ2006/000058 2005-03-26 2006-03-27 Compositions antagonistes du cuivre WO2006104401A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US66552105P 2005-03-26 2005-03-26
US60/665,521 2005-03-26

Publications (1)

Publication Number Publication Date
WO2006104401A1 true WO2006104401A1 (fr) 2006-10-05

Family

ID=37053610

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NZ2006/000058 WO2006104401A1 (fr) 2005-03-26 2006-03-27 Compositions antagonistes du cuivre

Country Status (1)

Country Link
WO (1) WO2006104401A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008062470A2 (fr) * 2006-10-19 2008-05-29 Torrent Pharmaceuticals Limited Forme posologique à libération contrôlée stabilisée de gliclazide
CN104208034A (zh) * 2013-12-11 2014-12-17 重庆康刻尔制药有限公司 一种格列美脲药物组合物片剂、制备方法及其应用
WO2017142424A1 (fr) * 2016-02-18 2017-08-24 Garth Cooper Traitement de troubles neurodégénératifs
US9770422B2 (en) 2012-01-06 2017-09-26 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
WO2017213524A1 (fr) * 2016-06-10 2017-12-14 Garth Cooper Traitement de troubles neurodégénératifs
US9962344B2 (en) 2011-01-07 2018-05-08 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US10028923B2 (en) 2011-01-07 2018-07-24 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10159658B2 (en) 2011-01-07 2018-12-25 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
EP3352743A4 (fr) * 2015-09-24 2019-07-03 Innolife Co., Ltd. Utilisation de trientine pour délivrer du cuivre à un tissu ischémique
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US11974971B2 (en) 2011-01-07 2024-05-07 Anji Pharmaceuticals Inc. Compositions and methods for treating metabolic disorders

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020156020A1 (en) * 1998-09-25 2002-10-24 Baker John Richard Fructosamine oxidase: antagonists and inhibitors
WO2003075910A1 (fr) * 2002-03-08 2003-09-18 Protemix Corporation Limited Prevention et/ou traitement d'une maladie vasculaire, d'une cardiomyopathie et/ou d'une defaillance cardiaque associee
WO2004017957A1 (fr) * 2002-08-20 2004-03-04 Protemix Corporation Limited Prevention et/ou traitement de maladies cardio-vasculaires et/ou insuffisance cardiaque associee
WO2005027981A1 (fr) * 2003-09-17 2005-03-31 Board Of Regents, The University Of Texas System Imagerie de cellules beta cibles du pancreas fondee sur un mecanisme, et therapie associee

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020156020A1 (en) * 1998-09-25 2002-10-24 Baker John Richard Fructosamine oxidase: antagonists and inhibitors
WO2003075910A1 (fr) * 2002-03-08 2003-09-18 Protemix Corporation Limited Prevention et/ou traitement d'une maladie vasculaire, d'une cardiomyopathie et/ou d'une defaillance cardiaque associee
WO2004017957A1 (fr) * 2002-08-20 2004-03-04 Protemix Corporation Limited Prevention et/ou traitement de maladies cardio-vasculaires et/ou insuffisance cardiaque associee
WO2005027981A1 (fr) * 2003-09-17 2005-03-31 Board Of Regents, The University Of Texas System Imagerie de cellules beta cibles du pancreas fondee sur un mecanisme, et therapie associee

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"The Merck Index", vol. 13TH ED., 2001, MERCK RESEARCH LABORATORIES NJ *
"The Merck Manual of Diagnosis and Therapy", vol. 16TH ED., 1992, MERCK RESEARCH LABORATORIES NJ, pages: 1112 - 1120 *
COOPER G. ET AL.: "Regeneration of the Heart in Diabetes by Selective Copper Chelation", DIABETES, vol. 53, 2004, pages 2501 - 2508, XP003003530, DOI: doi:10.2337/diabetes.53.9.2501 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008062470A2 (fr) * 2006-10-19 2008-05-29 Torrent Pharmaceuticals Limited Forme posologique à libération contrôlée stabilisée de gliclazide
WO2008062470A3 (fr) * 2006-10-19 2009-01-29 Torrent Pharmaceuticals Ltd Forme posologique à libération contrôlée stabilisée de gliclazide
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US10201511B2 (en) 2011-01-07 2019-02-12 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
US11974971B2 (en) 2011-01-07 2024-05-07 Anji Pharmaceuticals Inc. Compositions and methods for treating metabolic disorders
US11065215B2 (en) 2011-01-07 2021-07-20 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US10610500B2 (en) 2011-01-07 2020-04-07 Anji Pharma (Us) Llc Chemosensory receptor ligand-based therapies
US9962344B2 (en) 2011-01-07 2018-05-08 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US10028923B2 (en) 2011-01-07 2018-07-24 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10159658B2 (en) 2011-01-07 2018-12-25 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US10603291B2 (en) 2012-01-06 2020-03-31 Anji Pharma (Us) Llc Compositions and methods for treating metabolic disorders
US9770422B2 (en) 2012-01-06 2017-09-26 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
CN104208034A (zh) * 2013-12-11 2014-12-17 重庆康刻尔制药有限公司 一种格列美脲药物组合物片剂、制备方法及其应用
CN104208034B (zh) * 2013-12-11 2017-11-07 重庆康刻尔制药有限公司 一种格列美脲药物组合物片剂、制备方法及其应用
EP3352743A4 (fr) * 2015-09-24 2019-07-03 Innolife Co., Ltd. Utilisation de trientine pour délivrer du cuivre à un tissu ischémique
US11033579B2 (en) 2015-09-24 2021-06-15 Innolife Co., Ltd. Use of trientine to deliver copper to ischemic tissue
AU2016328156B2 (en) * 2015-09-24 2022-03-17 Innolife Co., Ltd. Use of trientine to deliver copper to ischemic tissue
WO2017142424A1 (fr) * 2016-02-18 2017-08-24 Garth Cooper Traitement de troubles neurodégénératifs
WO2017213524A1 (fr) * 2016-06-10 2017-12-14 Garth Cooper Traitement de troubles neurodégénératifs

Similar Documents

Publication Publication Date Title
WO2006104401A1 (fr) Compositions antagonistes du cuivre
US11419831B2 (en) Dosage forms and related therapies
JP7403259B2 (ja) 代謝障害を治療するための組成物および方法
US20050159364A1 (en) Copper antagonist compounds
JP5611275B2 (ja) 真性糖尿病の治療のためのロフルミラスト
JP2008509145A (ja) 抗糖尿病性経口インスリン−ビグアニドの組み合わせ
JP2008526733A (ja) 糖尿病治療剤の経口投与用徐放性複合製剤及びその製造方法
US20060128610A1 (en) Methods of treatment
JP2009506978A (ja) インスリン類の併用
TW202015683A (zh) Glp1r激動劑的治療用途
JP2018087214A (ja) スタチン、ビグアナイド、およびさらなる薬剤を含む心血管代謝性リスクを減少させるための組成物
WO2006104397A1 (fr) Compositions antagonistes du cuivre
EP4125896A1 (fr) Traitement du diabète de type 2 ou de l'obésité ou du surpoids avec de l'acide 2-[(4-{6-[(4-cyano-2-fluorobenzyl) oxy]pyridin-2-yl}pipéridin-1-yl)méthyl]-1-[(2s)-oxétan-2-ylméthyl]-1h-benzimidazole-6-carboxylique ou un sel pharmaceutiquement acceptable correspondant
ES2744495T3 (es) Preparación farmacéutica sólida
WO2006104400A1 (fr) Compositions antagonistes du cuivre
US20090093542A1 (en) Copper antagonist compositions
WO2006104396A1 (fr) Compositions antagonistes du cuivre pre-complexees
WO2014008374A2 (fr) Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie
WO2006104398A1 (fr) Compositions antagonistes du cuivre
US11684596B2 (en) Antidiabetic pharmaceutical compositions and preparation method thereof
US20090093506A1 (en) Copper antagonist compositions
WO2006104399A1 (fr) Compositions antagonistes du cuivre
WO2006104402A1 (fr) Compositions d'antagonistes du cuivre
US20230277465A1 (en) Antidiabetic pharmaceutical compositions
NZ539695A (en) Dosage forms and related therapies

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06733147

Country of ref document: EP

Kind code of ref document: A1