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WO2006130901A1 - Lutte contre les anomalies metaboliques - Google Patents

Lutte contre les anomalies metaboliques Download PDF

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Publication number
WO2006130901A1
WO2006130901A1 PCT/AU2006/000757 AU2006000757W WO2006130901A1 WO 2006130901 A1 WO2006130901 A1 WO 2006130901A1 AU 2006000757 W AU2006000757 W AU 2006000757W WO 2006130901 A1 WO2006130901 A1 WO 2006130901A1
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WO
WIPO (PCT)
Prior art keywords
embusartan
individual
composition
acarbose
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/AU2006/000757
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English (en)
Inventor
Anthony Rodgers
Stephen Macmahon
Gilbert Wagener
Elke Dittrich-Wengenroth
Hilmar Bischoff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DIABETREX Pty Ltd
Bayer AG
Original Assignee
DIABETREX Pty Ltd
Bayer Healthcare AG
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Publication of WO2006130901A1 publication Critical patent/WO2006130901A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the control of metabolic abnormalities in an individual.
  • Type Il diabetes mellitus is defined by increased levels of blood glucose (e.g. fasting plasma glucose concentration of 7.0 mmol/l or greater).
  • blood glucose e.g. fasting plasma glucose concentration of 7.0 mmol/l or greater.
  • individuals with diabetes typically also have other metabolic abnormalities including lipoprotein disturbances characterised by low levels of high density lipoprotein (HDL) cholesterol and high levels of triglycerides.
  • HDL high density lipoprotein
  • triglycerides Such metabolic abnormalities are important determinants of the cardiovascular complications of diabetes, including diseases of the heart and kidneys.
  • insulin sensitisers such as: glitazones (e.g. trogliazone, pioglitazone, englitazone, rosiglitazone, and the like); biguanides such as: phenformin and metformin; protein tyrosine phosphatase 1-B inhibitors; and dipeptidyl peptidase IV inhibitors; (b) insulin or insulin mimetics; and (c) sulfonylureas such as tolbutamide and glipizide, ⁇ glucosidase inhibitors, examples of which include miglitol, voglibose and acarbose, have also been used for the control of blood glucose.
  • insulin sensitisers such as: glitazones (e.g. trogliazone, pioglitazone, englitazone, rosiglitazone, and the like); biguanides such as: phenformin and metformin; protein tyrosine
  • Angiotensin Il receptor blockers such as losartan and irbesartan are typically used for the treatment of hypertension in a range of patient groups including for example, those with diabetes or a pre-diabetic condition; see for example WO2004/017896A2 to Merck & Co., Inc. According to WO2004/017896A2, an individual having any of these conditions may have one or more of hyperglycemia, dyslipidemia and hypertension.
  • a dual peroxisome proliferator activated receptor ⁇ / ⁇ (PPAR ⁇ / ⁇ ) agonist can be used for treatment of both hyperglycemia and dyslipidemia and accordingly, when combined with an ARB, the three major contributors to diabetic complications, hyperglycemia, dyslipidemia and hypertension, can be treated.
  • PPAR ⁇ / ⁇ peroxisome proliferator activated receptor ⁇ / ⁇
  • WO20Q4/017896A2 discusses a combination of a dual PPAR ⁇ / ⁇ agonist (such as cinnamates and dihydrocinnamates, L-tyrosine derivatives, phenyl propanoic acid and other propanoic acid derivatives, propionic acid derivatives, iso- oxazolidinedione and oxazolidinedione derivatives, thiazolidinedione, trycyclics, carboxylic acids, malonic acids, oxobenzylglycine derivatives, alkanoate derivatives, benzamide derivatives, glitazones, phenyalkyloxy phenyl derivatives and isoprenols) for the purpose of treating hyperglycemia and dyslipidemia, with an ARB for the purpose of treating hypertension.
  • a dual PPAR ⁇ / ⁇ agonist such as cinnamates and dihydrocinnamates, L-tyrosine derivatives, phen
  • Certain ARBs are also partial PPAR ⁇ agonists and accordingly, may be useful for treatment of disease where hyperglycemia, dyslipidemia and hypertension are major contributors to morbidity and mortality; see WO2004/014308 to Bethesda Pharmaceuticals, Inc. It is important to note that according to WO2004/014308, not all ARBs of the sartan class are capable of partial agonism of the ⁇ receptors so as to sufficiently normalise carbohydrate and lipid metabolism for treatment of hyperglycemia and dyslipidemia. Indeed, according to WO2004/014308, only certain ARBs have this potential, specifically, telmisartan and irbesartan.
  • WO2004/0143008 other ARBs such as valsartan, losartan, candesartan, olmesartan and eprosartan do not partially activate PPAR ⁇ at achievable therapeutic doses sufficient to promote adipogenesis and hence treat dyslipidemia.
  • some of these compounds are discussed in WO2004/014308 as being appropriate in combination therapy with telmisartan or irbesartan as a hypotensive agent.
  • ARBs have important structural chemical differences, any unusual or unexpected results obtained with one ARB cannot be used to predict that similar results would be obtained with another ARB.
  • embusartan for controlling blood glucose level in an individual.
  • a composition for use in controlling blood glucose level in an individual including embusartan and an ⁇ - glucosidase inhibitor, the composition being further characterised in that it does not contain a dual PPAR ⁇ / ⁇ agonist.
  • compositions for use in controlling blood glucose level in an individual consisting essentially of embusartan and an ⁇ - glucosidase inhibitor.
  • compositions for use in controlling blood glucose level in an individual consisting of embusartan and an ⁇ - glucosidase inhibitor.
  • embusartan in the manufacture of a medicament for controlling blood glucose level in an individual.
  • a combination therapy for controlling blood glucose level in an individual consisting of providing embusartan and providing an ⁇ -glucosidase inhibitor to the individual.
  • embusartan for treating an individual for diabetes mellitus.
  • compositions for use in treating an individual for diabetes mellitus including embusartan and an ⁇ - glucosidase inhibitor, the composition being further characterised in that it does not contain a dual PPAR ⁇ / ⁇ agonist.
  • compositions for use in treating an individual for diabetes mellitus consisting essentially of embusartan and an ⁇ - glucosidase inhibitor.
  • composition for use in treating an individual for diabetes mellitus the composition consisting of embusartan and an ⁇ -glucosidase inhibitor.
  • embusartan in the manufacture of a medicament for treating an individual for diabetes mellitus.
  • a combination therapy for treating an individual for diabetes mellitus consisting of providing embusartan and providing an ⁇ -glucosidase inhibitor to the individual.
  • embusartan for the prevention of new onset diabetes mellitus in an individual.
  • compositions for use in the prevention of new onset diabetes mellitus in an individual including embusartan and an ⁇ -glucosidase inhibitor, the composition being further characterised in that it does not contain a dual PPAR ⁇ / ⁇ agonist.
  • compositions for use in the prevention of new onset diabetes mellitus in an individual consisting essentially of embusartan and an ⁇ - glucosidase inhibitor.
  • compositions for use in the prevention of new onset diabetes mellitus in an individual consisting of embusartan and an ⁇ -glucosidase inhibitor.
  • embusartan in the manufacture of a medicament for the prevention of new onset diabetes mellitus in an individual.
  • a combination therapy for the prevention of new onset diabetes mellitus in an individual consisting of providing embusartan and providing an ⁇ -glucosidase inhibitor to the individual.
  • embusartan for treating an individual having a condition characterised by abnormal PPAR ⁇ function.
  • compositions for use in treating an individual having a condition characterised by abnormal PPAR ⁇ function including embusartan and an ⁇ -glucosidase inhibitor, the composition being further characterised in that it does not contain a dual PPAR ⁇ / ⁇ agonist.
  • compositions for use in treating an individual having a condition characterised by abnormal PPAR ⁇ function consisting essentially of embusartan and an ⁇ - glucosidase inhibitor.
  • compositions for use in treating an individual having a condition characterised by abnormal PPAR ⁇ function the composition consisting of embusartan and an ⁇ -glucosidase inhibitor.
  • embusartan in the manufacture of a medicament for treating an individual having a condition characterised by abnormal PPAR ⁇ function.
  • a combination therapy for treating an individual having a condition characterised by abnormal PPAR ⁇ function consisting of providing embusartan and providing an ⁇ -glucosidase inhibitor to the individual.
  • embusartan for controlling blood pressure in an individual.
  • compositions for use in controlling blood pressure in an individual including embusartan and an ⁇ -glucosidase inhibitor, the composition being further characterised in that it does not contain a dual PPAR ⁇ / ⁇ agonist.
  • composition for use in controlling blood pressure in an individual the composition consisting essentially of embusartan and an ⁇ - glucosidase inhibitor.
  • compositions for use in controlling blood pressure in an individual consisting of embusartan and an ⁇ - glucosidase inhibitor.
  • embusartan in the manufacture of a medicament for controlling blood pressure in an individual.
  • a combination therapy for controlling blood pressure in an individual consisting of providing embusartan and providing an ⁇ -glucosidase inhibitor to the individual.
  • embusartan for controlling blood triglycerides in an individual.
  • compositions for use in controlling blood including embusartan and an ⁇ - glucosidase inhibitor, the composition being further characterised in that it does not contain a dual PPAR ⁇ / ⁇ agonist.
  • compositions for use in controlling blood triglycerides in an individual consisting essentially of embusartan and an ⁇ - glucosidase inhibitor.
  • compositions for use in controlling blood triglycerides in an individual consisting of embusartan and an ⁇ - glucosidase inhibitor.
  • embusartan in the manufacture of a medicament for controlling blood triglycerides in an individual.
  • a method of preventing the development of new onset diabetes mellitus in an individual including:
  • the pre-diabetic state consists of one or more of metabolic syndrome, impaired glucose tolerance, impaired fasting glucose and insulin resistance.
  • the selected individual does not have hypertension.
  • FIG. 1 Activation of PPAR ⁇ receptor 24 hr after compound stimulation in stably transfected CHO cells (GAL4 system).
  • Embusartan (methyl 6-butyl-1- ⁇ [3-fluoro-2'-(1 H-tetrazol-5-yl)biphenyl-4-y!]methyl ⁇ -2- oxo-1 ,2-dihydropyridine-4-carboxylate) is a trisubstituted biphenyl compound, the key use of which has been in the treatment of hypertension: see US Patent number 5,596,006 to Bayer Aktiengesellschaft.
  • embusartan is also a full selective activator of PPAR ⁇ . Indeed, as discussed herein, the inventors have found that embusartan is a full PPAR ⁇ agonist with an EC50 value between 15 and 20 ⁇ M in the GAL4 system.
  • embusartan has additional new uses, not only for the control of blood glucose levels in diabetic and pre-diabetic conditions, but also for improvement in lipid metabolism, and for control of blood pressure (the latter being distinct from treatment of hypertension).
  • a further advantage of embusartan is that this compound has potential for treatment of atherosclerosis, a condition that is common to many individuals having diabetes or a pre-diabetic state and some other conditions characterised by abnormal blood glucose level.
  • busartan includes methyl 6-butyl-1- ⁇ [3-fluoro-2'-(1 H- tetrazol-5-yl)biphenyl-4-yl]methyl ⁇ -2-oxo-1 ,2-dihydropyridine-4-carboxylate, its polymorphs, solvates, hydrates, pharmaceutically acceptable salts, and combinations thereof.
  • embusartan for controlling blood glucose in an individual.
  • An individual suitable for treatment with this method may have diabetes or a pre-diabetic state such as metabolic syndrome, impaired glucose tolerance, impaired fasting glucose, insulin resistance or syndrome X.
  • Such individuals may have elevated blood glucose levels, or in other words, an impaired fasting blood glucose of 110mg/dl_ or greater or a two-hour 75-g oral glucose tolerance test value of 140 mg/dL or greater.
  • blood glucose is lowered so as to achieve a blood glucose level characterised by an impaired fasting blood glucose of less than 110mg/dL or a two-hour 75-g oral glucose tolerance test values of less than 140 mg/dL.
  • the individual may have elevated levels of haemoglobin A1c.
  • the individual may or may not have hypertension.
  • hypertension is present when the systolic blood pressure is greater than about 140 mmHg or when the ⁇ diastolic blood pressure is greater than about 90 mmHg.
  • embusartan examples include about 50 mg to 400 mg daily.
  • Embusartan can be provided once daily or twice daily (i.e once with a morning meal and once with an evening meal), although other dosage schedules may be more appropriate in circumstances with which the skilled worker is familiar.
  • the method consists of the step of providing embusartan alone.
  • the method may consist essentially of providing embusartan with another compound for controlling blood glucose levels (or related indices), such as an ⁇ glucosidase inhibitor.
  • an ⁇ glucosidase inhibitor is acarbose.
  • acarbose can be provided in amounts as low as from about 25 to 300 mg per day, preferably 100 to 200 mg per day.
  • these amounts of acarbose are between one-third and two-thirds less than required for treatment when acarbose is the only agent used for lowering blood glucose.
  • one advantage of this embodiment is that, in providing synergy between embusartan and acarbose (discussed further herein) it permits use of acarbose for control of blood glucose in a manner that avoids the toxicity often observed when acarbose is used alone at higher doses.
  • the method includes providing embusartan, acarbose and a further compound for lowering blood glucose (such as a glitazone or a biguanide), provided that the further compound is not a dual PPAR ⁇ / ⁇ agonist.
  • a further compound for lowering blood glucose such as a glitazone or a biguanide
  • useful molecules include metformin and rosiglitazone. These are typically applied in daily amounts ranging from 850- 2550 mg and 4-8 mg, respectively.
  • embusartan or embusartan and another compound such as acarbose is provided as a tablet, pill or other formulation suitable for oral administration.
  • acarbose a compound that provides a composition or they may be provided sequentially as separate compounds.
  • embusartan for treating diabetes mellitus in an individual.
  • a hallmark of diabetes mellitus is a blood glucose concentration of 7.0 mmo/l or greater.
  • the individual may or may not have hypertension.
  • embusartan examples include about 50 mg to 400 mg daily, preferably 100 to 200 mg daily.
  • Embusartan can be provided once daily or twice daily (i.e once with a morning meal and once with an evening meal), although other dosage schedules may be more appropriate in circumstances with which the skilled worker is familiar.
  • the method consists of providing embusartan alone.
  • the method may consist of providing embusartan with another compound for the treatment of diabetes, such as an ⁇ glucosidase inhibitor.
  • an ⁇ glucosidase inhibitor is acarbose.
  • acarbose can be provided in amounts as low as from about 25 to 300 mg per day, preferably 100 to 200 mg per day.
  • Other examples of glucosidase inhibitors include miglitol and voglibose.
  • the method includes providing embusartan, acarbose and .a further compound for the treatment of diabetes glucose (such as a glitazone or a biguanide), provided that the further compound is not a dual PPAR ⁇ / ⁇ agonist.
  • a further compound for the treatment of diabetes glucose such as a glitazone or a biguanide
  • useful molecules include metformin and rosiglitazone. These are typically applied in daily amounts ranging from 850-2550 mg and 4-8 mg, respectively.
  • embusartan or embusartan and another compound such as acarbose is provided as a tablet, pill or other formulation suitable for oral administration.
  • acarbose a compound that provides a composition or they may be provided sequentially as separate compounds.
  • embusartan for preventing the new onset of diabetes (usually defined on the basis of a fasting blood glucose concentration of 7.0 mmol/l or more) in an individual.
  • the pre-diabetic state may be characterised by ; metabolic syndrome, impaired glucose tolerance, impaired fasting glucose, insulin resistance or syndrome X.
  • Useful amounts of embusartan range from 50 to 400 mg daily, preferably 100 to 200 mg daily
  • the individual may or may not have hypertension.
  • embusartan ranges from about 50 mg to 400 mg daily, preferably 100 to 200 mg daily.
  • Embusartan can be provided once daily or twice daily (i.e once with a morning meal and once with an evening meal), although other dosage schedules may be more appropriate in circumstances with which the skilled worker is familiar.
  • the method consists of providing embusartan alone.
  • the method may consist of providing embusartan with another compound for preventing diabetes, such as an ⁇ glucosidase inhibitor.
  • an ⁇ glucosidase inhibitor is acarbose.
  • acarbose may be provided in doses as low as from about 25 to 300 mg per day, preferably 10 to 100 mg per day.
  • Other examples of glucosidase inhibitors include miglitol and voglibose.
  • the method includes providing embusartan, acarbose and a further compound for preventing diabetes (such as a glitazone or a biguanide), provided that the further compound is not a dual PPAR ⁇ / ⁇ agonist.
  • a further compound for preventing diabetes such as a glitazone or a biguanide
  • useful molecules include metformin and rosiglitazone. These are typically applied in daily amounts ranging from 850-2550 mg and 4-8 mg, respectively.
  • embusartan or embusartan and another compound such as acarbose is provided as a tablet, pill or other formulation suitable for oral administration.
  • acarbose a compound that provides a composition or they may be provided sequentially as separate compounds.
  • embusartan for treating an individual , having a condition characterised by abnormal PPAR ⁇ function.
  • Abnormal PPAR ⁇ function is characterised by comprised, defective, or otherwise reduced PPAR ⁇ activation.
  • conditions characterised by abnormal PPAR ⁇ function include proliferative, autoimmune, immunomodulatory and inflammatory disease and certain infective disease.
  • embusartan ranges from about 50 mg to 400 mg daily, preferably 100 to 200 mg daily.
  • Embusartan can be provided once daily or twice daily (i.e once with a morning meal and once with an evening meal), although other dosage schedules may be more appropriate in circumstances with which the skilled worker is familiar.
  • the method consists of providing embusartan alone.
  • the method may consist of providing embusartan with another compound for treating an individual having a condition characterised by abnormal PPAR ⁇ function, such as an ⁇ glucosidase inhibitor.
  • an ⁇ glucosidase inhibitor is acarbose.
  • acarbose may be provided in amounts as low as from about 25 to 300 mg per day, preferably 10 to 100 mg per day.
  • Other examples of glucosidase inhibitors include miglitol and voglibose.
  • the method includes the step of providing embusartan, acarbose and a further compound for treating an individual having a condition characterised by abnormal PPAR ⁇ function (such as a glitazone or a biguanide), provided that the further compound is not a dual PPAR ⁇ / ⁇ agonist.
  • a condition characterised by abnormal PPAR ⁇ function such as a glitazone or a biguanide
  • useful molecules include metformin and rosiglitazone. These are typically applied in daily amounts ranging from 850-2550 mg and 4-8 mg, respectively.
  • embusartan or embusartan and another compound such as acarbose is provided as a tablet, pill or other formulation suitable for oral administration.
  • acarbose a compound that provides a composition or they may be provided sequentially as separate compounds.
  • embusartan for controlling blood pressure in an individual.
  • the individual may have a systolic blood pressure of less than about 140 mmHg and/or a diastolic blood pressure of less than about 90 mmHg.
  • An individual suitable for treatment with this method may have diabetes or a pre-diabetic state such as metabolic syndrome, impaired glucose tolerance, impaired fasting glucose, insulin resistance or syndrome X.
  • embusartan examples include about 50 mg to 400 mg daily, preferably 100 to 200 mg daily.
  • Embusartan can be provided once daily or twice daily (i.e once with a morning meal and once with an evening meal), although other dosage schedules may be more appropriate in circumstances with which the skilled worker is familiar.
  • the method consists of providing embusartan alone.
  • the method may consist of providing embusartan with another compound suitable for the treatment of patients with diabetes or a pre-diabetic state, such as an ⁇ glucosidase inhibitor.
  • acarbose can be provided in amounts as low as 100 or 200 mg per day. Accordingly, one advantage of this embodiment is that it permits. the use of a low dose of acarbose.
  • glucosidase inhibitors include miglitol and voglibose.
  • the method includes providing embusartan, acarbose and a further compound for lowering blood pressure (such as a diuretic, a calcium channel blocker or an angiotensin converting enzyme inhibitor), provided that the further compound is not a dual PPAR ⁇ / ⁇ agonist.
  • a further compound for lowering blood pressure such as a diuretic, a calcium channel blocker or an angiotensin converting enzyme inhibitor
  • useful molecules include hydrochlorothiazide, amlodipine, and ramipril. These are typically applied in daily amounts ranging from 25-100 mg, 2.5-10 mg and 5-10 mg, respectively.
  • embusartan or embusartan and another compound such as acarbose is provided as a tablet, pill or other formulation suitable for oral administration.
  • acarbose a compound that provides a composition or they may be provided sequentially as separate compounds.
  • Embusartan the combination of embusartan and an ⁇ glucosidase inhibitor and certain- other combinations including these compounds and others (but not including a compound that is dual PPAR ⁇ / ⁇ agonist) are useful for the prevention or treatment of diabetes and for reducing the risk of the complications of diabetes, such microvascular and macrovascular diseases, through effects on blood glucose (or related indices such as haemoglobin A1c), dyslipidaemia, PPAR ⁇ or blood pressure. These treatments should be useful for such patients, irrespective of the presence or absence of hypertension.
  • the group of individuals mentioned herein as being likely to benefit from embusartan, the combination of embusartan and acarbose or other combinations including these compounds includes but is not limited to patients with diabetes, those at risk of developing diabetes, individuals with an increased body mass index (greater than 25 kg/m 2 ), patients with a disease characterised by abnormal PPAR ⁇ function, those at risk of developing a disease characterised by abnormal PPAR ⁇ function, individuals at risk of developing hypertension, patients with a disturbance of lipid metabolism (such as for example triglycerides > 150 md/dl or low density lipoprotein > 130 mg/dl cholesterol or total cholesterol > 200 mg/dl or high density lipoprotein cholesterol ⁇ 60 mg/dl), patients with renal dysfunction (such as for example, those with a plasma creatinine level, greater than 1.5 mg/dl in men and 1.4 mg/dl in women), individuals with a pre- diabetic state (such as for example metabolic syndrome, impaired glucose tolerance, impaired fasting glucose, insulin resistance or syndrome X), and patients
  • a pre-diabetic state for example metabolic syndrome, impaired glucose tolerance, impaired fasting glucose, insulin resistance or syndrome X.
  • Metabolic syndrome or syndrome X is defined here on the basis of NCEP ATP III criteria, which are the presence of three or more of the following factors: 1) increased waist circumference (>102 cm [>40 in] for men, >88 cm [>35 in] for women); 2) elevated triglycerides (>150 mg/dl); 3) low HDL cholesterol ( ⁇ 40 mg/dl in men, ⁇ 50 mg/dl in women); 4) non-optimal blood pressure (>130 mmHg systolic or ⁇ 85 mmHg diastolic); and 5) impaired fasting glucose (>110 mg/dl).
  • Impaired glucose tolerance and impaired fasting glucose is defined here on the basis of American Diabetes Association criteria. Impaired glucose tolerance is two-hour 75-g oral glucose tolerance test values of 140 to 199 mg per dl_ (7.8 to 11.0 mmol/l). Impaired fasting glucose is defined as fasting plasma glucose values of 100 to 125 mg per dL (5.6 to 6.9 mmol/l).
  • Insulin resistance is defined here as a fasting blood insulin level greater than 20 mcU/mL.
  • a synergistic effect on blood pressure is achieved by administering the combination according to an embodiment of the invention compared with the administration of embusartan alone, i.e. blood pressure control is improved by the combination beyond that which can be achieved by embusartan alone.
  • a synergistic effect on blood glucose level is achieved by administering the combination according to an embodiment of the invention compared with administering acarbose alone, i.e. blood glucose control is improved by the combination beyond that which can be achieved by acarbose alone.
  • synergistic effects it is possible to reduce the employed amounts of acarbose used in the combination compared with the amounts required for monotherapy. Additionally, as a consequence of these synergistic effects, it is possible to reduce the frequency of the administration of acarbose to two times per day compared the three times daily requirement for acarbose when used alone.
  • HMG CoA reductase inhibitors i.e. statins
  • platelet aggregation inhibitors for example, aspirin
  • the combination therapy is further distinguished by a surprisingly good tolerability.
  • the reduction in dose and frequency of acarbose administration improves tolerability and reduces the incidence of side effects associated with higher dose, higher frequency acarbose administration
  • the synergistic effect of the combination therapy of embusartan and acarbose is preferably observed when the combination therapy contains 0.01 to 30 mg/kg, in particular 0.1 to 5 mg/kg, of acarbose and 0.01 to 30 mg/kg, in particular 0.1 to 10 mg/kg, of embusartan, in each case based on kg of the individual's bodyweight on oral administration.
  • the synergistic effect of the combination therapy of embusartan and acarbose is furthermore also observed when the combination comprises acarbose in a dosage of 5 to 500 mg, preferably in a dosage of 30 to 350 mg, particularly preferably in a dosage of 50 to 100 mg and embusartan in a dosage of 1 to 1000 mg, preferably in a dosage of 5 to 500 mg, particularly preferably in a dosage of 25 to 500 mg.
  • the synergistic effect of the combination therapy of embusartan and acarbose is also observed when the active ingredients of the combination are present in a ratio of 1 : 10 to 10 : 1 , preferably 1 : 5 to 5 : 1 , particularly preferably 1 : 2 to 2 : 1 , in relation to acarbose and embusartan.
  • Ratio means the ratio by weight of the individual components.
  • compositions for use in preventing the development of new onset diabetes mellitus in an individual including embusartan and an ⁇ -glucosidase inhibitor, the composition being further characterised in that it does not contain a dual PPAR ⁇ / ⁇ agonist.
  • the composition may however include other components for controlling blood glucose level, so long as such additional components do not comprise a dual PPAR ⁇ / ⁇ agonist.
  • compositions for use in preventing the development of new onset diabetes mellitus in an individual consisting essentially of embusartan and an ⁇ - glucosidase inhibitor.
  • the composition essentially does not have further components for control of blood glucose level in an individual. It may however, have other components including a pharmaceutically acceptable carrier, excipient, diluent, lubricant or like component for assisting in the manufacture, stability and half life of the composition.
  • compositions for use in preventing the development of new onset diabetes mellitus in an individual consisting of embusartan and an ⁇ -glucosidase inhibitor.
  • Embusartan is typically provided in the above identified compositions between about 50-400 mg daily. Typically the amount is about 100-200 mg daily. Typically the amount is about 100 mg.
  • the tablet may contain embusartan in a range between 50-100 mg. This may be taken twice a day.
  • the ⁇ -glucosidase inhibitor is acarbose, although other inhibitors are contemplated.
  • Other examples of glucosidase inhibitors include miglitol and voglibose.
  • Acarbose is typically provided in an amount of about from 25-300 mg daily Typically the amount is about 100-200 mg daily.
  • these amounts of acarbose are one third to two thirds less than that required when acarbose is the only agent used for lowering blood glucose. Accordingly, one advantage of this embodiment is that it permits use of a low dose of acarbose for control of blood glucose. Typically the amount is about 100-200mg.
  • the tablet may contain acarbose in a range between 50-100 mg. This may be taken twice a day.
  • a particularly useful composition is one in which embusartan is combined with acarbose.
  • embusartan is provided in an amount of about 50 to 400 mg daily, preferably 100 to 200 mg daily and acarbose is provided in an amount of about from 25-300 mg daily, preferably 100 to 200 mg per day.
  • compositions are provided in a form that permits the potential of the composition for control of blood glucose levels, particularly after eating, to be realised. Accordingly, typically the composition is provided in a form for oral administration, such as a pill, tablet, caplet, capsule or the like.
  • composition an ingredient for facilitating the potential of embusartan and acarbose to stimulate metabolism of blood glucose immediately after eating.
  • Other useful ingredients include those for facilitating slow release of embusartan and acarbose, so as to permit normalisation of blood glucose levels during fasting. These are discussed below.
  • embusartan in the manufacture of a medicament for controlling blood glucose level in an individual.
  • embusartan in the manufacture of a medicament for treating an individual for diabetes mellitus.
  • embusartan in the manufacture of a medicament for preventing the new onset of diabetes in a individual.
  • embusartan in the manufacture of a medicament for treating an individual having a condition characterised by abnormal PPAR ⁇ function.
  • embusartan in the manufacture of a medicament for controlling blood pressure in an individual.
  • embusartan is provided with one or more of metformin, a blood pressure lowering drug, such as a diuretic, calcium channel blocker or an angiotensin converting enzyme inhibitor (provided that said drug is not a dual PPAR ⁇ / ⁇ agonist) and an CoA reductase inhibitor such as simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin and lovastatin).
  • a blood pressure lowering drug such as a diuretic, calcium channel blocker or an angiotensin converting enzyme inhibitor (provided that said drug is not a dual PPAR ⁇ / ⁇ agonist)
  • an CoA reductase inhibitor such as simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin and lovastatin.
  • Embusartan may be synthesised for use in the above embodiments according to the processes discussed in US Patent number 5,596,006 to Bayer Aktiengesellschaft, the contents of which are incorporated herein by reference in its entirety.
  • embusartan is provided in an amount to manufacture a medicament having a concentration of embusartan of between about 0.5 to 90% by weight.
  • embusartan is provided in the medicament in an amount of about 50 to 200 mg per tablet.
  • the medicament consists of embusartan as the only active ingredient.
  • the medicament may include other components including a pharmaceutically acceptable carrier, excipient, diluent, lubricant or like component for assisting in the manufacture, stability and half life of the composition. These are discussed further below.
  • the medicament consists essentially of embusartan and one or more further active ingredients, provided that the further active ingredient is not a dual PPAR ⁇ / ⁇ agonist.
  • An example of a further active ingredient is an ⁇ glucosidase inhibitor, such as acarbose.
  • Other examples of glucosidase inhibitors include miglitol and voglibose.
  • the medicament may include other components including a pharmaceutically acceptable carrier, excipient, diluent, lubricant or like component for assisting in the manufacture, stability and half life of the composition. These are discussed further below.
  • Acarbose may be synthesised for use in the above embodiments according to the processes discussed in US 4,904,769 to Bayer Aktiengesellschaft the contents of which are incorporated herein by reference in its entirety.
  • Embusartan and acarbose are particularly suitable for formulation in a fixed combination in the form of a solid oral dosage form.
  • the factors on which the patients' reliability of intake (compliance) crucially depend are the number of dosage forms per time of intake and the size and weight of the (solid oral) pharmaceutical form.
  • both the number of the different medicaments to be taken separately should be as small as possible (advantage of a fixed combination), and the size and weight of a solid oral dosage form should be as small as possible while having full therapeutic potency, in order to make intake as pleasant as possible for the patient. It is thus possible to attain fixed combinations in the form of solid oral pharmaceutical formulations of minimal size and minimal weight.
  • the fixed combinations of embusartan and acarbose accordingly provide maximum patient compliance and thus crucially improve the safety and reliability of therapy.
  • the release of active ingredient can be controlled by combining them and modifying the composition or the functionality. For example, the abovementioned temporal uncoupling of the onset of action is possible even in fixed combinations through delayed release of active ingredient (slowing of release) of one component.
  • ingredients are those which are pharmaceutically accepted and physiologically unobjectionable, for example: as fillers cellulose derivatives (e.g. micro- crystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders (e.g. polyvinylpyrrolidone, gelatin, starch derivatives and cellulose derivatives), and all other excipients required to produce pharmaceutical formulations of the desired properties, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g.
  • lubricants magnesium stearate
  • disintegrants e.g.
  • crosslinked polyvinylpyrrolidone, sodium carboxymethylcellulose e.g. wetting agents (e.g. sodium lauryl sulphate), e.g. release- slowing agents (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g. stabilizers, e.g. flavourings, e.g. coloured pigments.
  • wetting agents e.g. sodium lauryl sulphate
  • release- slowing agents e.g. cellulose derivatives, polyacrylic acid derivatives
  • stabilizers e.g. flavourings, e.g. coloured pigments.
  • Liquid formulations are likewise produced by a standard method using pharmaceutically usual excipients and contain the active ingredients either dissolved or suspended. Typical administration volumes of these pharmaceutical preparations are 1 to 10 ml.
  • excipients in these liquid formulations are: solvents (e.g. water, alcohol, natural and synthetic oils, e.g. medium chain-link triglycerides), solubilizers (e.g. glycerol, glycol derivatives), wetting agents (e.g. polysorbate, sodium lauryl sulphate), and further excipients required to produce pharmaceutical formulations of the desired properties, e.g. viscosity-increasing agents, e.g. pH-correcting agents, e.g. sweeteners and flavourings, e.g. antioxidants, e.g. stabilizers, e.g. preservatives.
  • solvents e.g. water, alcohol, natural and synthetic oils, e.g. medium chain-link triglycer
  • the main ingredients of the shells of capsule formulations are, for example, gelatin or hydroxypropylmethylcellulose.
  • a combination may be not only a dosage form which contains all the components (otherwise known as fixed combinations), and combination packs containing the components separate from one another, but also components which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease.
  • the active ingredients of a combination can be converted in a known manner into the usual formulations, which may be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, solutions.
  • a combination is well tolerated and in some cases is effective even in low dosages, a wide range of formulation variants is possible.
  • one possibility is to formulate the individual active ingredients of a combination separately. In this case, it is not absolutely necessary for the individual active ingredients to be taken at the same time; on the contrary, sequential intake may be advantageous to achieve optimal effects.
  • the active ingredients are present in the primary packaging in each case in separate containers which may be, for example, tubes, bottles or blister packs.
  • Such separate packaging of the components in the joint primary packaging is also referred to as a kit.
  • Further formulation variants which are suitable may be fixed combinations; these are pharmaceutical forms in which the components are present together in a fixed ratio of amounts.
  • Such fixed combinations may be, for example, in the form of oral solutions, and they are typically solid oral pharmaceutical preparations, e.g. capsules or tablets.
  • Example 1 Manufacture of a tablet composition:
  • the mixture is granulated with a 5% strength solution (m/m) of PVP in water.
  • the granules are dried and then mixed with the magnesium stearate for 5 min.
  • This mixture is compressed using a conventional tablet press.
  • a guideline force used for the compression is 15 kN.
  • Randomized crossover trial in which participants receive embusartan 100 mg bd plus either acarbose 100 mg bd or matching placebos. Treatment will be administered twice daily before breakfast (morning) and before dinner (evening). There are two 5-day active treatment phases separated by a one week washout period.
  • Plasma embusartan levels and its main metabolite BAY 10-6734 (M1) would be measured at 0, 2, and 8 hours after each dose on each day of the two active treatment phases.
  • AUC Area Under the Curve
  • JNC-7 pre-hypertension/ESH-ESC high normal blood pressure systolic 130-139 mmHg or diastolic 80-89 mmHg
  • JNC-7 stage 1/ESH-ESC grade 1 hypertension systolic 140-159 mmHg or diastolic 90-99 mmHg
  • eligible patients will randomized in a 3 x 3 factorial design, with 100 patients assigned to each of 9 treatment combinations.
  • treatment will be begin with 25 mg once daily and will be increased in a stepwise manner over two weeks until the full dose is reached. Treatment and follow-up is scheduled to continue for 12 weeks after randomization, with a further 2 week assessment following withdrawal of all study treatments.
  • Treatment will be administered twice daily before breakfast (or the first meal of the day) 1 and before dinner (evening).
  • Efficacy Difference in systolic and diastolic blood pressures (office) from randomization to 12 weeks (embusartan 100 mg vs 200 mg vs placebo; acarbose 100 mg vs 200 mg vs placebo)
  • JNC-7 pre-hypertension/ESH-ESC high normal blood pressure systolic 130-139 mmHg or diastolic 80-89 mmHg
  • JNC-7 stage 1/ESH-ESC grade 1 hypertension systolic 140-159 mmHg or diastolic 90-99 mmHg
  • Patients may be managed without antihypertensive treatment or with one or more of the following: a diuretic, a calcium antagonist or an ACE inhibitor.
  • All potentially eligible patients will enter a two-week run-in period during which active treatment with acarbose will be increased in a stepwise manner from 25 mg once a day to the full twice daily dose used in the combination treatment.
  • Patients that meet the entry criteria and tolerate run-in treatment will be randomized in a parallel group design with 200 patients assigned to each of three treatment conditions.
  • the daily dose of embusartan will be equal in the two active treatment groups.
  • Treatment assignment will be stratified background use of metformin, sulfonylurea and thiazolidenedione. Randomized treatment and follow-up is scheduled to continue initially for 12 weeks after randomization.
  • Treatment will be administered twice daily with the first mouthful of breakfast (morning) and the first mouthful of dinner (evening). Patients assigned embusartan alone will receive active treatment in the evening and placebo in the morning.
  • Tolerability Proportion of patients experiencing suspected side-effects including, but not limited to, flatulence, diarrhoea, abdominal pain, dizziness and headache (each active treatment vs placebo) Interactions; Tests of homogeneity of treatment effects (on efficacy and tolerability) comparing each study treatment vs placebo, stratified by oral glucose control treatment at baseline.
  • JNC-7 pre-hypertension/ESH-ESC high normal blood pressure systolic 130-139 mmHg or diastolic 80-89 mmHg
  • JNC-7 stage 1/ESH-ESC grade 1 hypertension systolic 140-159 mmHg or diastolic 90-99 mmHg
  • Patients may be managed without antihypertensive treatment or with one or more of the following: a diuretic, a calcium antagonist or an ACE inhibitor.
  • All potentially eligible patients will enter a two-week run-in period during which active treatment with acarbose will be increased in a stepwise manner from 25 mg once a day to the full twice daily dose used in the combination treatment.
  • Patients that meet the entry criteria and tolerate run-in treatment will be randomized in a parallel group design with 200 patients assigned to each of three treatment conditions.
  • the daily dose of embusartan will be equal in the two active treatment groups. Randomized treatment and follow-up is scheduled to continue initially for 12 weeks after randomization. Treatment will be administered twice daily with the first mouthful of breakfast (morning) and the first mouthful of dinner (evening). Patients assigned embusartan alone will receive active treatment in the evening and placebo in the morning.
  • Patients assigned embusartan alone or embusartan plus acarbose in the first 12-week phase will continue on allocated treatment (blind to acarbose assignment and embusartan dose frequency) for a further 40 weeks.
  • Patients assigned placebo in the first 12-week phase will be re-randomized to embusartan alone or embusartan plus acarbose for a further 52 weeks.
  • Treatment will be administered twice daily with the first mouthful of breakfast (morning) and the first mouthful of dinner (evening).
  • Patients assigned embusartan alone will receive active treatment in the evening and placebo in the morning.
  • Safety Serious adverse events, including but not limited to cardiovascular mortality, acute coronary syndrome, stroke, heart failure, and total cardiovascular events.
  • Adverse events including but not limited to flatulence, diarrhoea, dizziness and headache.
  • All potentially eligible patients will enter a two-week run-in period during which active treatment with acarbose will be increased in a stepwise manner from 25 mg once a day to the full twice daily dose used in the combination treatment.
  • Patients that meet the entry criteria and tolerate run-in treatment will be randomized in a parallel group design with 400 patients assigned to each of three treatment conditions.
  • the daily dose of embusartan will be equal in the two active treatment groups. Randomized treatment and follow-up is scheduled to continue initially for 12 weeks after randomization.
  • Treatment will be administered twice daily with the first mouthful of breakfast (morning) and the first mouthful of dinner (evening). Patients assigned embusartan alone will receive active treatment in the evening and placebo in the morning.
  • Tolerability Proportion of patients experiencing suspected side-effects including, but not limited to, flatulence, diarrhoea, abdominal pain, dizziness and headache (each active treatment vs placebo)
  • Tolerability Proportion of patients experiencing suspected side-effects including but not limited to flatulence, diarrhoea, abdominal pain, dizziness and headache
  • Amount of embusartan and acarbose in a composition (such as a tablet) according to the invention.
  • Amount of embusartan and acarbose in a composition (such as a tablet) according to the invention.
  • a cell-based assay was used to identify peroxisome-proliferator-activated receptor gamma (PPAR ⁇ ) agonists.
  • PPAR ⁇ peroxisome-proliferator-activated receptor gamma
  • a chimeric system in which the ligand binding domain of the human PPAR ⁇ protein was fused to the DNA binding domain of the yeast transcription factor GAL4.
  • the human GAL4-PPAR ⁇ expression construct contains the ligand binding domain of PPAR ⁇ (aa 203-506). This part has been amplified by PCR and cloned into the pcDNA3.1 vector. This vector contains the GAL4 DNA binding domain (aa 1-147) of the pFC2-dbd vector (Stratagene).
  • the reporter construct pFRLuc (Stratagene), which contains five copies of the GAL4 binding site in front of the thymidine kinase promoter leads to the expression of the firefly luciferase (Photinus pyralis) after activation of the bound GAL4-PPAR ⁇ fusion protein.
  • Stably transfected CHO (Chinese hamster ovary) cells were seeded in DMEM/ F12 media (BioWhittaker) containing 10 % FCS and 1 % penicillin/ streptomycin (GIBCO). 2 x 10 3 cells per well were seeded on a 384 well plate format (Greiner). After cultivation for 48h at 37°C, cells were stimulated.

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Abstract

La présente invention concerne la lutte contre les anomalies métaboliques chez un individu sous embusartan.
PCT/AU2006/000757 2005-06-07 2006-06-02 Lutte contre les anomalies metaboliques Ceased WO2006130901A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008143262A1 (fr) 2007-05-21 2008-11-27 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
US9233204B2 (en) 2014-01-31 2016-01-12 Aseko, Inc. Insulin management
US9483619B2 (en) 2012-09-11 2016-11-01 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
US9486580B2 (en) 2014-01-31 2016-11-08 Aseko, Inc. Insulin management
US9886556B2 (en) 2015-08-20 2018-02-06 Aseko, Inc. Diabetes management therapy advisor
US9892234B2 (en) 2014-10-27 2018-02-13 Aseko, Inc. Subcutaneous outpatient management
US9897565B1 (en) 2012-09-11 2018-02-20 Aseko, Inc. System and method for optimizing insulin dosages for diabetic subjects
US11081226B2 (en) 2014-10-27 2021-08-03 Aseko, Inc. Method and controller for administering recommended insulin dosages to a patient

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5596006A (en) * 1992-10-23 1997-01-21 Bayer Aktiengesellschaft Trisubstituted biphenyls
WO2004017896A2 (fr) * 2002-08-21 2004-03-04 Merck & Co., Inc. Traitement combine faisant intervenir un double agoniste de ppar alpha/gamma et un recepteur de type i d'angiotensine ii

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5596006A (en) * 1992-10-23 1997-01-21 Bayer Aktiengesellschaft Trisubstituted biphenyls
WO2004017896A2 (fr) * 2002-08-21 2004-03-04 Merck & Co., Inc. Traitement combine faisant intervenir un double agoniste de ppar alpha/gamma et un recepteur de type i d'angiotensine ii

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BREITHAUPT-GRÖGLER ET AL.: "Pharmacodynamic and pharmacokinetic properties of an aniogtensin II receptor antagonists - characterization by use of Schild regression technique in man", JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 35, no. 10, 1997, pages 434 - 441, XP008073619 *
YAMAGISHI ET AL.: "Telmisartan is a promising cardiometabolic sartan due to its unique PPAR-gamma-inducing property", MEDICAL HYPOTHESES, vol. 64, 2005, pages 476 - 478, XP004691096 *
ZHANG ET AL.: "Peripheral administration of AT1 receptor blockers and pressor responses to central angiotensin II and sodium", CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, vol. 79, no. 10, 2001, pages 861 - 867, XP009073396 *

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US8501750B2 (en) 2007-05-21 2013-08-06 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US10629294B2 (en) 2012-09-11 2020-04-21 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
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