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WO2008010008A2 - Combinaisons cardiovasculaires faisant appel à des inhibiteurs de rennine-angiotensine - Google Patents

Combinaisons cardiovasculaires faisant appel à des inhibiteurs de rennine-angiotensine Download PDF

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Publication number
WO2008010008A2
WO2008010008A2 PCT/IB2006/002252 IB2006002252W WO2008010008A2 WO 2008010008 A2 WO2008010008 A2 WO 2008010008A2 IB 2006002252 W IB2006002252 W IB 2006002252W WO 2008010008 A2 WO2008010008 A2 WO 2008010008A2
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WIPO (PCT)
Prior art keywords
solvate
salt
derivative
composition
granules
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PCT/IB2006/002252
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English (en)
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WO2008010008A3 (fr
Inventor
Eswaran Krishnan Iyer
Rasendra Kumar Jayantilal Jha
Girish Kumar Jain
Parag Borde
Narayanan Murli
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Wockhardt Limited
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Priority to PCT/IB2006/002252 priority Critical patent/WO2008010008A2/fr
Publication of WO2008010008A2 publication Critical patent/WO2008010008A2/fr
Publication of WO2008010008A3 publication Critical patent/WO2008010008A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide

Definitions

  • the present invention provides pharmaceutical compositions, their method of manufacture and use of these compositions for administration for a combination therapy for the treatment of cardiovascular and related disorders, in particular a combination of angiotensin II antagonists, lipid regulators (HMG CoA inhibitors), platelet aggregation inhibitors and diuretics.
  • a combination therapy for the treatment of cardiovascular and related disorders, in particular a combination of angiotensin II antagonists, lipid regulators (HMG CoA inhibitors), platelet aggregation inhibitors and diuretics.
  • HMG CoA inhibitors lipid regulators
  • platelet aggregation inhibitors diuretics
  • Heart failure is a common cause of death and disability in industrialized countries and is a syndrome commonly encountered in clinical practice.
  • the diagnosis of heart failure carries a risk of mortality comparable to that of the major malignancies.
  • advances in understanding the pathophysiology of heart failure and new developments in pharmacotherapy have added substantially to the physician's ability to alleviate the symptoms of this disease and slow the natural progression of underlying myocardial progress.
  • a primary goal in the treatment of heart failure is the alleviation of symptoms, which, maybe a direct result of the underlying hemodynamic disorder.
  • Hypertension is a common cardiovascular disease. Elevated arterial pressure can cause pathological changes in the vasculature and hypertrophy of the left ventricle of the heart. As a consequence, hypertension, a principal cause of the stroke, can lead to disease of the coronary arteries with myocardial infarction or sudden cardiac death, and may be a major contributor to cardiac failure, or renal insufficiency. The risk of cardiovascular disease, disability and death in hypertensive patients is also increased markedly by elevated low-density lipoprotein; the coexistence of hypertension with these risk factors increases cardiovascular morbidity.
  • a chief goal of antihypertensive therapy includes preventing major cardiovascular disorders such as myocardial infarction, arrhythmia, angina and the like. Although controlling blood pressure and reducing other known cardiovascular risk factors are pivotal in achieving these goals, additional strategies or a combination therapy are needed to provide optimal protection against cardiovascular disease.
  • Angiotensin-II receptor antagonists are a newer class of antihypertensive agents. These drugs are selective for angiotensin II (type 1 receptor); unlike angiotensin-converting enzyme inhibitors, they do not inhibit bradykinin metabolism or enhance prostaglandin synthesis.
  • Rennin an enzyme produced primarily by the juxtaglomerular cells of the kidney, catalyzes the conversion of angiotensinogen into an inactive substance, angiotensin I (A-I).
  • Angiotensin-converting enzyme ACE
  • A-II physiologically active angiotensin II
  • Angiotensin-II receptor antagonists act by binding to specific membrane-bound receptors that displace A-II from its type 1- receptor subtype (AT 1 ). These drugs therefore function as selective blockers.
  • Representive examples of angiotensin-II antagonists for use in the treatment of hypertension include losartan, valsartan, irbesartan, candesartan and telmisartan.
  • the symptomatic treatment for cardiac failure is directed at improving haemodynamic function through the use of drugs that can increase cardiac output and reduce ventricular filling pressures. Therefore, the selected therapy for rapid improvement may include ⁇ -adrenergic blockers, rennin-angiotensin inhibitors, calcium channel blockers, and the like. These drugs may be administered either individually or in combination.
  • Combination therapy can involve multiple doses of multiple medications. A benefit of drug combinations may be the enhanced efficacy, which fosters widespread use. Some combinations can produce offsetting interactions that weaken side effects of therapy with a single drug.
  • combination therapy has advantages such as (1) increased efficacy i.e., additive and synergistic effects, (2) reduced adverse events i.e., low dose strategy, drugs with offsetting actions, (3) enhanced convenience and compliance, (4) prolong duration of action and the like.
  • Diuretic agents are also effective of antihypertensive medications. Treatment with diuretic agents can result in dose-dependent blood pressure reductions because they can inhibit of sodium reabsorption at specific sites in the renal tubules, hi long-term trials, diuretics have been shown to reduce the incidence of stroke, congestive heart failure, coronary artery disease and total mortality from cardiovascular disease. Diuretics reduce the sodium and water-retaining effects of other antihypertensive drugs, and thus, they are a commonly used medication in combination with antihypertensive agents. The most commonly prescribed of the diuretics class are thiazide diuretics. Thiazide diuretics may also relax the muscles in blood vessel walls, making blood flow more easily.
  • Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries.
  • Atherosclerotic coronary heart disease (hereinafter "CHD") accounts for major deaths attributable to a cardiovascular event.
  • CHD cardiovascular disease
  • HMG-CoA reductase 3- hydroxy-3-methylglutaryl-coenzyme A reductase
  • LDL-C low density lipoprotein cholesterol
  • Atorvastatin is a selective, competitive inhibitor of HMG-CoA, the rate-limiting enzyme that converts 3-hydroxy-3-methyl- glutaryl-CoA to mevalonate, a precursor of steroids including cholesterol. It reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. It also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-I. It reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL- C, and increases HDL-C in patients with isolated hypertriglyceridemia.
  • HMG-CoA the rate-limiting enzyme that converts 3-hydroxy-3-methyl- glutaryl-CoA to mevalonate
  • steroids including cholesterol. It reduces total-C, LDL-C, and apo B in patients with homozyg
  • Platelets initiate the formation of blood clots by sticking together (clumping), a process called platelet aggregation. Clumps of platelets can then be further bound together by a protein (fibrin) formed by clotting factors present in the blood. The clumps of platelets and fibrin make up the blood clot.
  • a blood clot that forms in a coronary artery supplying blood to the muscle of the heart can cause a heart attack, and a blood clot that forms in an artery supplying blood to the brain can cause a stroke.
  • Antiplatelet agents are medications that block the formation of blood clots by preventing the clumping of platelets. There are three types of antiplatelet agents, aspirin, the thienopyridines, and the glycoprotein Ilb/IIIa inhibitors.
  • Aspirin is believed to prevent blood from clotting by blocking the production of platelets of thromboxane A-2 by inhibiting the enzyme cyclo-oxygenase-1 (COX-I) that produces thromboxane A-2.
  • COX-I cyclo-oxygenase-1
  • platelets also produce adenosine diphosphate (ADP).
  • ADP adenosine diphosphate
  • the thienopyridines for example, ticlopidine and clopidogrel, can block the ADP receptor. Blocking the ADP receptor may prevent ADP from attaching to the receptor and the platelets from clumping.
  • the platelet aggregation inhibitors when administered in combination with HMG-CoA inhibitors may provide enhanced inhibition of platelet aggregation as compared to administration of either of the agent alone. Another benefit of the combination is that lesser dosage amounts of the platelet aggregation inhibitors may be required to achieve the desired clinical result.
  • Angina pectoris is a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the left arm. Angina pectoris is often caused by ischemia of the heart and is often caused by coronary disease.
  • the symptomatic management of angina pectoris involves the use of a number of drugs, frequently as a combination of two or more of the following classes: ⁇ -blockers, nitrates and calcium channel blockers. Many patients with angina pectoris also require therapy with a lipid lowering agents or lipid regulating agents as well.
  • Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This clustering of risk factors is believed to be due to a common mechanism. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia. It would therefore be advantageous to provide patients with a single therapy, which treats both of these conditions.
  • a fixed dose administered as a once daily tablet offers dosage convenience and can help with patient compliance.
  • combination therapy may be used to treat various conditions such as Hypertension with Dyslipidemia and for inhibition of platelet aggregation and for inhibiting the formation of thrombotic occlusions; Hypertension with Dyslipidemia and Diabetic Neuropathy; Angina Pectoris with Dyslipidemia and for inhibition of platelet aggregation and for inhibiting the formation of thrombotic occlusions; and Angina Pectoris with Dyslipidemia and Diabetic Neuropathy and various other related disorders in mammals such as humans.
  • angiotensin II antagonists ARBs
  • diuretics ARBs
  • platelet aggregation inhibitors and statins as a primary treatment may provide a greater degree of protection and control of these risk factors, improving the vascular and general health of the patient.
  • U.S. patent No. 6,677,356 discloses a method for treating hypertension comprising concurrently administering a combination of a compound selected from the group consisting of pyridoxal-5'-phosphate, pyridoxal, pyridoxamine, a 3'-acylated pyridoxal analogue, and a therapeutic cardiovascular compound selected from the group consisting of an angiotensin converting enzyme (ACE) inhibitor, a calcium channel blocker, a ⁇ -adrenergic receptor antagonist, a vasodilator, a diuretic, an ⁇ -adrenergic receptor antagonist, a 3'-acylated pyridoxal analogue, an angiotensin II receptor antagonist, an antithrombolytic agent, an antioxidant, and a mixture thereof.
  • ACE angiotensin converting enzyme
  • U.S. patent No. 6,669,955 discloses an orally administrable pharmaceutical composition comprising combination of cholesterol-lowering agent, an inhibitor of rennin-angiotensin system, aspirin and optionally at least one of vitamin B 6 , B 12 and folic acid.
  • the active agents are in a unit dose preparation for once daily dosing.
  • the patent states that the composition provides a simple and convenient therapy to reduce the risk of cardiovascular events in individuals who are at elevated cardiovascular risk.
  • the patent also states that the composition is therapeutic for individuals during or immediately following an occurrence of myocardial infarction.
  • U.S. Patent No. 6,235,311 discloses pharmaceutical compositions that contain a statin plus aspirin, and optionally containing vitamins B 6 , B 12 or folic acid, as anti- oxidants, and methods of use for lowering serum cholesterol, preventing, inhibiting, or treating atherosclerosis or reducing the risk of or treating a cardiovascular event or disease, coronary artery disease or cerebrovascular disease, fr
  • U.S. Patent Application No. 2003/0175344 discloses a formulation comprising blood pressure lowering agents, each selected from a diuretic, a beta blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, and a calcium channel blocker with an active agent from at least two of the three categories (i) a lipid regulating agent (ii) one platelet function altering agent and (iii) one serum homocysteine lowering agent.
  • ACE angiotensin converting enzyme
  • the application also discloses the use and method of treatment for reducing the risk of cardiovascular disease of the active principals by simultaneous, separate or sequential administration of the combination therapy.
  • U.S. Patent No. 6,251,852 discloses a combination therapy and pharmaceutical compositions comprised of a therapeutically effective amount of a cholesterol reducing agent such as an HMG-CoA reductase inhibitor in combination with a platelet aggregation inhibitor which said to be useful for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.
  • a cholesterol reducing agent such as an HMG-CoA reductase inhibitor
  • a platelet aggregation inhibitor which said to be useful for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.
  • U.S. Patent No. 6,403,571 is a from the same patent family as the '852 patent described above and also discloses a combination therapy and pharmaceutical compositions comprised of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with a platelet aggregation inhibitor which is useful for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.
  • the patent specifically discloses a pharmaceutical composition
  • a platelet aggregation inhibitor selected from the group consisting of ticlopidine, clopidogrel, and dipyridamole, an HMG-CoA reductase inhibitor and a pharmaceutically acceptable carrier.
  • U.S. Patent No. 6,576,256 discloses methods and compositions said to be useful for reducing the risk of cardiovascular events, in individuals who are at elevated cardiovascular risk, including individuals who have systemic lupus erythematosus.
  • the methods include administering a combination of a cholesterol-lowering agent, such as an HMG CoA reductase inhibitor; an inhibitor of the rennin-angiotensin system, such as an ACE inhibitor or Angiotensin II antagonists; aspirin; and optionally one or more of vitamin B 6 , vitamin B 12 , and folic acid.
  • a cholesterol-lowering agent such as an HMG CoA reductase inhibitor
  • an inhibitor of the rennin-angiotensin system such as an ACE inhibitor or Angiotensin II antagonists
  • aspirin and optionally one or more of vitamin B 6 , vitamin B 12 , and folic acid.
  • the patent discloses pharmaceutical formulations combining all the active agents in unit-dose form for once-da
  • U.S. Patent No. 6,248,729 disclose a method for preventing a cerebral infarction by administering to a patient a combination of an ADP-receptor blocking antiplatelet drug, an antihypertensive agent (such as an angiotensin II antagonist, an ACE inhibitor, or an ACE/NEP inhibitor), and optionally aspirin.
  • an antihypertensive agent such as an angiotensin II antagonist, an ACE inhibitor, or an ACE/NEP inhibitor
  • Pharmaceutical compositions comprising combinations of these agents are also disclosed. The disclosed methods and compositions, however, require an ADP-receptor blocking antiplatelet drug (which does not include aspirin).
  • U.S. Patent No. 5,994,348 discloses a pharmaceutical composition comprising a combination of irbesartan and hydrocholorothiazide (a diuretic agent) with starch or pregelatinized starch as a binder wherein the formulation is free of povidone and poloxamer.
  • the '348 patent specifically discloses the combination of irbesartan and hydrochlorothiazide.
  • U.S. Patent No. 6,294,197 discloses a compressed combination dosage form comprising valsartan and hydrochlorothiazide with at least one suitable excipient.
  • the ' 197 patent specifically discloses the combination composition of valsartan and hydrochlorothiazide.
  • U.S. Patent Application No. 2005/0101658 discloses the use of an inhibitor of the rennin-angiotensin system (RAS), optionally together with another antihypertensive drug, a cholesterol-lowering drug, a diuretic, or aspirin, in the prevention of cardiovascular events.
  • RAS rennin-angiotensin system
  • the application only discloses a combination product containing an renin-angiotensin inhibitor and a cholesterol-lowering agent or with an antihypertensive agent.
  • antihypertensive agents such as calcium channel blockers, ⁇ -adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors or angiotensin II antagonists and diuretics together with lipid-regulators and platelet aggregation inhibitors have generally been found to be independent of each other in reducing the risk of cardiovascular disease.
  • ACE angiotensin converting enzyme
  • angiotensin II antagonists and diuretics together with lipid-regulators and platelet aggregation inhibitors.
  • the use of these agents can provide a reduction in cardiovascular disease.
  • the present invention provides a composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor in a single dosage form.
  • the composition is suitable for a combination therapy for prophylactic or therapeutic treatment of cardiovascular and related disorders and disorders associated with hypertension, dyslipidemia, diabetic neuropathy, and angina pectoris.
  • the composition is also useful for inhibiting platelet aggregation, inhibiting the formation of thrombotic occlusions, and treating, preventing or reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.
  • the present invention provides a pharmaceutical composition and a process for manufacturing a composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form.
  • the present invention provides a method for treating cardiovascular and related disorders, comprising administering to a mammal ⁇ e.g., a human) in need of such treatment, a pharmaceutical composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form.
  • the present invention provides a delivery system for oral administration constituting the release in the body of a mammal (e.g., a human), a composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form.
  • a mammal e.g., a human
  • a composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form.
  • the present invention provides an oral delivery system kit comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, together with suitable excipients thereof.
  • the present invention provides a method for using a composition for combination therapy for the treatment of cardiovascular and related disorders and disorders associated with hypertension, dyslipidemia, diabetic neuropathy, angina pectoris, or for inhibiting platelet aggregation, inhibiting the formation of thrombotic occlusions, and treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.
  • the composition of the invention is formulated such that the components of the tablet, capsule or kit are consumed, in any order, within 24 hours after administration of the drugs of the composition.
  • the present invention provides a method for preparing a pharmaceutical dosage form for oral administration comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor wherein the process comprises blending and granulating, using suitable binders, which may be dissolved (in case of wet granulation) in aqueous or organic solvents or hydro- alcoholic solvents, dried and lubricated. The resultant granules are then compressed using suitable double or triple layer compressing machines. Alternatively, the granules of the composition can also be prepared using roll compaction, direct compression or fluidized bed granulation technique. The granules of the instant invention can also be prepared containing each drug separately and finally mixing to provide a granular mixture and compressing the granular mixture to provide multilayer tablets or filling capsules with the granular mixture.
  • an "instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition of the invention for its designated use.
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains the composition or be shipped together with a container which contains the composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the composition be used cooperatively by the recipient.
  • the present invention provides a combination therapy comprising therapeutically effective amount of an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor in a single dosage form for prophylactic and therapeutic treatment of cardiovascular and related disorders and disorders associated with hypertension, dyslipidemia, diabetic neuropathy, angina pectoris, for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form, along with suitable pharmaceutically acceptable excipients thereof.
  • angiotensin II antagonists include losartan, valsartan, irbesartan, telmisartan, candesartan and the like.
  • Non-limiting examples of thiazide diuretics include chlorthalidone, hydrochlorothiazide and the like.
  • Non-limiting examples of HMG CoA inhibitors include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, velostatin and the like.
  • Non-limiting examples of platelet aggregation inhibitors include aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like.
  • the invention comprises an angiotensin II antagonist selected from losartan, valsartan, irbesartan, telmisartan, candesartan and the like, the thiazide diuretic selected from chlorthalidone, hydrochlorothiazide and the like, the HMG CoA inhibitor selected from lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, velostatin and the like, the platelet aggregation inhibitor selected from aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like preferably in a single dosage form, with suitable pharmaceutically acceptable excipients thereof.
  • an angiotensin II antagonist selected from losartan, valsartan, irbesartan, telmisartan, candesartan and the like
  • the thiazide diuretic selected from chlorthalidone, hydro
  • compositions of the invention having a combination of angiotensin II antagonists, diuretics, HMG CoA inhibitors and platelet aggregation inhibitors are suitable for treating cardiovascular and related disorders and disorders associated with hypertension, dyslipidemia, diabetic neuropathy, and angina pectoris.
  • the compositions are also useful for inhibiting platelet aggregation, inhibiting the formation of thrombotic occlusions, and treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.
  • the invention provides a method for preventing, ameliorating or eliminating these disorders by administration of a composition of the invention, wherein the method includes administering to a patient (e.g., human) suffering from or susceptible to such a disorder, a therapeutically effectively amount of a composition of the present invention.
  • a patient e.g., human
  • composition includes but is not limited to solutions, suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, and pellets, comprising a therapeutically effective amount of the active agents of the composition of the invention in a core with suitable excipients thereof.
  • terapéuticaally effective amount means an amount of the drug, which is capable of eliciting a physiological response in a mammal, e.g., a human patient. More specifically, the term “therapeutically effective amount” means the amount of drug, which is capable of treating cardiovascular and related disorders.
  • cardiovascular and related disorders refers to coronary or cerebrovascular event(s) and disease, including but not limited to myocardial infarction, myocardial ischemia, angina pectoris, congestive heart failure, sudden cardiac death, cerebral infarction, cerebral thrombosis, cerebral ischemia, transient ischemic attacks, and the like.
  • compositions of the present invention comprise a formulation substantially as herein described, and in a deliverable form.
  • deliverable forms include tablets, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the capsules can include micro-tablets, granules or pellets in a capsule.
  • the drug delivery form may be a combination tablet, capsule or a kit, substantially as described herein.
  • the compositions of the present invention provide an oral composition comprising at least one angiotensin II antagonist, at least one thiazide diuretic, at least one HMG CoA inhibitor and at least one platelet aggregation inhibitor with suitable pharmaceutically acceptable excipients thereof.
  • the invention provides a kit comprising a composition including a therapeutically effective amount of an angiotensin-II antagonist, a therapeutically effective amount of a thiazide diuretic, a therapeutically effective amount of HMG CoA inhibitor, and a therapeutically effective amount of platelet aggregation inhibitor, along with instructional material which describes administering the composition comprising the inhibitor to an animal in need of the composition.
  • a kit comprising a (preferably sterile) solvent suitable for dissolving or suspending the composition of the invention prior to administering the compound to an animal.
  • the animal is a human.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the agents of the pharmaceutical composition of the invention.
  • the kit comprises a pharmaceutical composition including a therapeutically effective amount of an angiotensin-II antagonist, a therapeutically effective amount of a thiazide diuretic, a therapeutically effective amount of HMG CoA inhibitor, and a therapeutically effective amount of platelet aggregation inhibitor in suitable combinations of the agents.
  • the kit can include four (4) containers each having one pharmaceutical agent; three (3) containers, one container including two agents and the other two containers each including one agent; two (2) containers, one container including one agent and the other container including the three remaining agents, or two (2) containers, with each container including two agents; or one container including a mixture of all four agents.
  • the kit is provided including two containers, as dual entities (each container having two agents) or triple entities, (with one container having three agents and the remaining agent in the other container) for treating an animal subject in need of treatment of cardiovascular and related disorders.
  • the animal is a human.
  • the composition of the present invention may be prepared by blending an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor using suitable binders that may be dissolved (in case of wet granulation) in aqueous or organic solvents or hydro-alcoholic solvents thereof, and drying, granulating and lubricating the mixture to obtain a granular mixture.
  • suitable binders may be dissolved (in case of wet granulation) in aqueous or organic solvents or hydro-alcoholic solvents thereof, and drying, granulating and lubricating the mixture to obtain a granular mixture.
  • the granular mixture may be compressed using suitable double or triple layer compressing machines.
  • the granular mixture may be prepared using roll compaction, direct compression or fluidized bed granulation techniques.
  • granular compositions of the instant invention may be prepared containing each drug separately and blending the granular components to provide a mixture and compressing the granular mixture to provide multi-drug tablets or filling capsules with the granular mixture.
  • granular compositions of the instant invention may also be prepared containing a combination of an angiotensin-II antagonist with a diuretic and granules containing the other two drugs prepared separately and blending the granules to provide a granular mixture and compressing the granular mixture to provide multi-drug tablets or filling capsules with the granular mixture,
  • a combination composition comprises pharmaceutically active agents together with suitable excipients for oral administration.
  • a preferred angiotensin II antagonist suitable for practicing the invention is selected from the group consisting of losartan, valsartan, irbesartan, telmisartan, candesartan and the like.
  • a more preferred angiotensin II antagonist is losartan, irbesartan or valsartan; or a salt, solvate or derivative of these angiotensin II antagonists.
  • a preferred thiazide diuretic is selected from the group consisting of chlorthalidone, hydrochlorothiazide and the like.
  • a more preferred thiazide diuretic is hydrochlorothiazide or a salt, solvate or derivative thereof.
  • a preferred HMG CoA inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, velostatin and the like.
  • a more preferred HMG CoA inhibitor is simvastatin or ; or a salt, solvate or derivative of these HMG CoA inhibitors.
  • a preferred platelet aggregation inhibitor is selected from the group consisting of aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like.
  • a more preferred platelet aggregation inhibitor is aspirin or clopidogrel ; or a salt, solvate or derivative of these platelet aggregation inhibitors.
  • the composition may comprise a combination of these active agents where aspirin may be formulated in delayed release form, such as enteric-coated granules as described herein.
  • the present invention provides, a tablet composition
  • a tablet composition comprising a tablet core or layers provided with a delayed release or enteric-coated aspirin or a pharmaceutical acceptable salt, or solvate thereof, with at least one angiotensin II antagonist, one diuretic and one HMG CoA inhibitor, and suitable excipients.
  • the present invention provides a tablet composition
  • a tablet composition comprising a tablet core or layers having clopidogrel or a pharmaceutical acceptable salt, or solvate thereof, with at least one angiotensin II antagonist, one diuretic and one HMG CoA inhibitor, and suitable excipients.
  • compositions with the active agents herein are administered orally to a patient.
  • the invention further provides compositions for use in the treatment of cardiovascular and related disorders.
  • the patient is a human.
  • compositions of the present invention in tablet form can include suitable excipients selected to provide the required properties for pharmaceutical use, such as the required hardness, friability, dissolution, disintegration time and the like.
  • suitable excipients include inert diluents, disintegrating agents, binding agents, lubricating agents, and sweetening agents, flavoring agents, coloring agents and preservatives.
  • Suitable diluents that may be employed in a composition of the present invention can be selected based on desired pharmaceutical properties as disclosed herein, such as dissolution, content uniformity, hardness, friability, disintegration time and the like.
  • Non-limiting examples of diluents suitable for practicing the invention can be selected from the group consisting of sodium and calcium carbonate, sodium and calcium phosphate, lactose either present in anhydrous or hydrated form, or spray dried, and microcrystalline cellulose, starch and the like.
  • the appropriate choice of diluents would be well known to a person having ordinary skill in the art, in order to achieve the desired pharmaceutical properties of a pharmaceutical composition according to present invention.
  • Suitable binders may also be employed using known methods. Such binders should be selected to provide satisfactory compressibility.
  • binders suitable for practicing the invention include acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose and other cellulose derivatives, magnesium aluminum silicate, povidone, pregelatinized starch, sodium alginate, starch, dextrin, gelatin, hydrogenated vegetable oils, polymethacrylates, zein and the like.
  • Other binders known in the art may also be employed.
  • compositions of the present invention may also include pharmaceutically acceptable lubricants and glidants.
  • pharmaceutically acceptable lubricants and glidants A person having ordinary skill in the art can select appropriate lubricants and glidants in order to obtain good flow to aid in compression of the tablets.
  • Non-limiting examples of lubricants and glidants suitable for practicing the invention include magnesium stearate, calcium stearate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium steryl fumarate, stearic acid, talc, hydrogenated castor oil, calcium silicate, magnesium silicate and colloidal silicon dioxide and the like.
  • the present invention provides a tablet composition
  • a tablet composition comprising a tablet core or layers provided with a delayed release or enteric-coated aspirin or a pharmaceutical acceptable salt, or solvate thereof, together with at least one angiotensin II antagonist, one diuretic, and one HMG CoA inhibitor, with suitable excipients thereof.
  • the aspirin granules may be coated with conventional enteric-coated polymers in aqueous or non-aqueous systems.
  • enteric-coated polymers are known in the art and can be selected from the group consisting of methaacrylic acid derivatives (for example,
  • Plasticizers suitable for use with the enteric-coating polymers are selected from the group consisting of triethyl citrate, diethyl phthalate, tributyl citrate, triacetin, dibutyl phthalate, dibutyl sebicate, and the like. Suitable enteric-coating polymers with one or more plasticizers may be used in aqueous or non-aqueous system to form an enteric-coating on the aspirin granules.
  • the present invention includes a process for preparing a pharmaceutical product, or a pharmaceutical composition, or a medicament substantially as described herein.
  • the granular compositions of the present invention include an angiotensin II antagonist selected from valsartan, irbesartan, losartan, salts, solvates or derivatives thereof; a thiazide diuretic preferably hydrochlorothiazide, a salt, solvate or derivative thereof; an HMG CoA inhibitor selected from simvastatin, pravastatin, salts, solvates or derivatives thereof; and a platelet aggregation inhibitor selected from aspirin (e.g., enteric-coated granules), clopidogrel, salts, solvates or derivatives thereof; blended and granulated using suitable binders that may be dissolved (in case of wet granulation) in aqueous and/or organic solvents and/or hydroalcoholic solvents thereof, dried and lubricated.
  • angiotensin II antagonist selected from valsartan, irbesartan, losartan, salts, solvates or derivatives
  • the granular compositions of the invention can be prepared using roll compaction, direct compression or fluidized bed granulation technique.
  • the compositions can be prepared containing each drug separately using wet granulation or roll compaction or dry granulation or fluidized bed processor techniques and mixing and the granules to obtain granular compositions.
  • granules may be prepared containing a combination of angiotensin-II antagonist with a diuretic and granules containing the other two drugs separately using wet granulation or roll compaction or dry granulation or fluidized bed processor techniques and mixing the granules to obtain a granular composition with the four agents.
  • the present invention provides a composition comprising valsartan, or a salt, solvate or derivative thereof; hydrochlorothiazide, or a salt, solvate or derivative thereof; simvastatin, or a salt, solvate or derivative thereof; and aspirin (delayed release or enteric-release), prepared by forming granules of the valsartan and hydrochlorothiazide, and blending the valsartan and hydrochlorothiazide granules with granules of enteric-coated aspirin, and granules containing simvastatin to form a granular composition.
  • the present invention provides a composition comprising irbesartan, or a salt, solvate or derivative thereof; hydrochlorothiazide, or a salt, solvate or derivative thereof; pravastatin, or a salt, solvate or derivative thereof; and clopidogrel, or a salt, solvate or derivative thereof; prepared by by forming granules of the irbesartan and hydrochlorothiazide, and blending the irbesartan and hydrochlorothiazide granules with granules containing clopidogrel, and granules containing pravastatin to form a granular composition.
  • the granular compositions prepared herein can be formed into suitably adapted oral dosage forms such as tablets, pills, capsules by compressing the granular compositions using suitable double or triple layer compressing machines to form tablets and pills or filling capsules with the granular compositions.
  • the granular compositions of the invention may be prepared by any granulation process known to those skilled in the art, such as direct compression processes, dry granulation processes, wet granulation processes or fluidized bed processing technology. These processes are suitable for preparing pharmaceutical oral compositions of the present invention.
  • the present invention further provides, therefore, a method of preparing a pharmaceutical composition substantially as described herein, which process may comprise wet granulation or direct compression or dry granulation techniques.
  • the tablets/capsules of the invention are orally administered in the amounts necessary to achieve a particular blood level. Representative therapeutically effective amounts of the respective therapeutic compounds when administered as sole active ingredients are known in the art and may be found in, for example, Physicians' Desk Reference (5th ed., 2002).
  • the blood level may be maintained by repeated oral administration of the tablet/capsule at a dose interval of 24 hours, Le., one tablet/capsule administered daily.
  • An optimum dosage size may be readily determined by a person skilled in the art by observing the therapeutic results achieved, the side effects encountered or by blood serum analysis.
  • Valsartan, Hydrochlorothiazide, Lactose, Croscarmellose sodium, microcrystalline cellulose (MCC), Aerosil 200 and part of magnesium stearate are mixed.
  • the blend from Step 1 is compacted using a Roll compactor at a suitable speed to ensure that the compacts of sufficient hardness are formed. These compacts are crushed into granules using a suitable granulator.
  • the granules from Step 2 are mixed with Magnesium stearate and blended.
  • Step 2 The blend of Step 1 is compacted using a Roll compactor at a suitable speed to ensure that the compacts of sufficient hardness are formed. These compacts are crushed into granules using a suitable granulator.
  • the tablets are coated with Opadry clear to provide a seal coat.
  • Eudragit L 30 D 55 is prepared by dilution with water and addition of triethyl citrate under constant stirring.
  • Simvastatin was mixed with lactose monohydrate and butylated hydroxy anisole in a suitable rapid mixer granulator.
  • lactose monohydrate is mixed with the following ingredients:
  • Example 1 & 3 The Granules obtained in Example 1 & 3 are mixed.
  • the resultant granules & Aspirin DR tablets from Example 2 are added to capsules using a suitable capsule-filling machine.
  • Aspirin DR tablets is the core tablet and granules of example 1 & 3 would be coating of the core tablet.
  • the granules are extruded and spheronized to provide beads of 300 - 500 micron.
  • Eudragit L 30 D 55 is prepared by dilution with water and addition of triethyl citrate under constant stirring.
  • the seal coated beads are coated with the Eudragit dispersion prepared in step 4.
  • the coated beads are mixed with MCC, PEG, Stearic acid & talc.
  • Combination Composition :
  • Granules prepared in Example 1, 3 & 4 are compressed as a tri-layer tablet.
  • Step 2 The mixture from Step 1 is compacted using the Roll compactor at a suitable speed to ensure that the compacts of sufficient hardness are formed.
  • the compacts are crushed into granules using suitable granulator.
  • step 3 The granules from step 2 are mixed with Magnesium stearate and blended.
  • Example 8 Granules of Clopidogrel 75 nig
  • Clopidogrel and part of the polyethylene glycol 6000 are co-sifted and mixed.
  • the mixture is transferred to a Fluidized Bed Dryer and heated at 6O 0 C (PEG 6000 melts) with fluidization and granulation.
  • the granules are sifted using a suitable sieve.
  • the remaining PEG 6000 (2.12 % or 5 mg) is mixed with the granules obtained from Step 3 to obtain a uniform mixture.
  • the mixture is transferred to a Fluidized Bed Dryer and heated at 60°C with fluidization and granulated.
  • the final granules are dried and sifted using a suitable sieve.
  • Microcrystalline cellulose, Lactose Anhydrous, Crosspovidone and mannitol are sifted and mixed with the granules obtained from Step 5.
  • Talc and colloidal silicon dioxide are sifted and mixed using a suitable blender with the granules from Step 6.
  • step 7 The granules from step 7 are blended, sifted and lubricated with hydrogenated castor oil and Glyceryl Behenate, for 2 min.
  • Pravastatin, Polacrilin potassium and Carboxymethylcellulose calcium are weighed, screened and mixed in suitable blender.
  • Anhydrous lactose, macrocrystalline cellulose and colloidal silicon dioxide (weighed, screened) are added to the mixture from Step 1.
  • the composition is mixed in a suitable blender.
  • Example 10 Tablets and Capsules [0088] Using a suitable capsule-filling machine, capsules are prepared using granules obtained in Examples 7, 8, and 9.
  • a tri-layer tablet is prepared using the granules obtained in Examples 7, 8, and 9.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouvelles compositions pharmaceutiques, leur procédé de préparation et l'utilisation de ces compositions, lesquelles sont administrées comme polythérapie pour le traitement d'affections cardiovasculaires et de troubles associés, notamment sous la forme d'une combinaison d'antagonistes de l'angiotensine II, de régulateurs lipidiques (inhibiteurs de HMG-CoA réductase), d'inhibiteurs de l'agrégation plaquettaire et de diurétiques.
PCT/IB2006/002252 2006-07-17 2006-07-17 Combinaisons cardiovasculaires faisant appel à des inhibiteurs de rennine-angiotensine WO2008010008A2 (fr)

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EP2180891A2 (fr) * 2007-08-13 2010-05-05 Hanall Pharmaceutical Co., Ltd. Préparation combinée contenant un inhibiteur de hmg-coa reductase et aspirine et son procédé d'élaboration
EP2568972A2 (fr) * 2010-05-14 2013-03-20 Hanmi Science Co., Ltd. Formulation pharmaceutique sous la forme de comprimés bicouches comprenant un inhibiteur de hmg-coa réductase et d'irbésartan
US8642083B2 (en) * 2006-10-30 2014-02-04 Hanall Biopharma Co., Ltd. Controlled release complex composition comprising angiotensin-II-receptor blockers and HMG-CoA reductase inhibitors
WO2014026261A1 (fr) * 2012-08-17 2014-02-20 Hypermarcas S.A. Préparation pharmaceutique orale solide pour la prévention de maladies cardiovasculaires et cérébrovasculaires, et comprimé
EP2890371A1 (fr) * 2012-08-31 2015-07-08 Hanmi Pharm. Co., Ltd. Formulation de capsule composite pharmaceutique comprenant de l'irbésartan et un inhibiteur de la hmg-coa réductase
CN105232484A (zh) * 2015-09-24 2016-01-13 青岛华之草医药科技有限公司 一种解热、镇痛、抗炎药物阿司匹林组合物片剂
EP3342400A1 (fr) * 2016-12-31 2018-07-04 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique comprenant de la valsartane et du chlorthalidone

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8642083B2 (en) * 2006-10-30 2014-02-04 Hanall Biopharma Co., Ltd. Controlled release complex composition comprising angiotensin-II-receptor blockers and HMG-CoA reductase inhibitors
EP2180891A2 (fr) * 2007-08-13 2010-05-05 Hanall Pharmaceutical Co., Ltd. Préparation combinée contenant un inhibiteur de hmg-coa reductase et aspirine et son procédé d'élaboration
EP2180891A4 (fr) * 2007-08-13 2010-12-29 Hanall Biopharma Co Ltd Préparation combinée contenant un inhibiteur de hmg-coa reductase et aspirine et son procédé d'élaboration
EP2568972A2 (fr) * 2010-05-14 2013-03-20 Hanmi Science Co., Ltd. Formulation pharmaceutique sous la forme de comprimés bicouches comprenant un inhibiteur de hmg-coa réductase et d'irbésartan
EP2568972A4 (fr) * 2010-05-14 2014-07-02 Hanmi Science Co Ltd Formulation pharmaceutique sous la forme de comprimés bicouches comprenant un inhibiteur de hmg-coa réductase et d'irbésartan
AU2016203739B2 (en) * 2010-05-14 2017-11-02 Hanmi Science Co., Ltd. Pharmaceutical formulation in the form of bilayered tablets comprising HMG-CoA reductase inhibitor and irbesartan
WO2014026261A1 (fr) * 2012-08-17 2014-02-20 Hypermarcas S.A. Préparation pharmaceutique orale solide pour la prévention de maladies cardiovasculaires et cérébrovasculaires, et comprimé
EP2890371A1 (fr) * 2012-08-31 2015-07-08 Hanmi Pharm. Co., Ltd. Formulation de capsule composite pharmaceutique comprenant de l'irbésartan et un inhibiteur de la hmg-coa réductase
EP2890371A4 (fr) * 2012-08-31 2016-04-06 Hanmi Pharm Ind Co Ltd Formulation de capsule composite pharmaceutique comprenant de l'irbésartan et un inhibiteur de la hmg-coa réductase
CN105232484A (zh) * 2015-09-24 2016-01-13 青岛华之草医药科技有限公司 一种解热、镇痛、抗炎药物阿司匹林组合物片剂
EP3342400A1 (fr) * 2016-12-31 2018-07-04 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique comprenant de la valsartane et du chlorthalidone

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