WO2001097751A2 - New formulation comprising a betablocker and optionally a cholesterol-lowering agent - Google Patents

New formulation comprising a betablocker and optionally a cholesterol-lowering agent Download PDF

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Publication number
WO2001097751A2
WO2001097751A2 PCT/SE2001/001380 SE0101380W WO0197751A2 WO 2001097751 A2 WO2001097751 A2 WO 2001097751A2 SE 0101380 W SE0101380 W SE 0101380W WO 0197751 A2 WO0197751 A2 WO 0197751A2
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Prior art keywords
betablocker
pharmaceutical formulation
pharmaceutically acceptable
cholesterol
admixture
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PCT/SE2001/001380
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French (fr)
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WO2001097751A3 (en
Inventor
Göran Berglund
John Wikstrand
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Astrazeneca Ab
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Publication date
Priority to EP01941409A priority Critical patent/EP1296716B1/en
Priority to DE60124400T priority patent/DE60124400T2/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to BR0111790-4A priority patent/BR0111790A/en
Priority to EEP200200703A priority patent/EE200200703A/en
Priority to IL15324501A priority patent/IL153245A0/en
Priority to HU0302371A priority patent/HUP0302371A3/en
Priority to CA002411100A priority patent/CA2411100A1/en
Priority to PL36048401A priority patent/PL360484A1/en
Priority to MXPA02012957A priority patent/MXPA02012957A/en
Priority to JP2002503228A priority patent/JP2003535875A/en
Priority to NZ523188A priority patent/NZ523188A/en
Priority to SK1807-2002A priority patent/SK18072002A3/en
Priority to AU2001274766A priority patent/AU2001274766A1/en
Publication of WO2001097751A2 publication Critical patent/WO2001097751A2/en
Publication of WO2001097751A3 publication Critical patent/WO2001097751A3/en
Priority to BG107373A priority patent/BG107373A/en
Priority to IS6653A priority patent/IS6653A/en
Priority to NO20026177A priority patent/NO20026177D0/en
Priority to HK03106811.1A priority patent/HK1054508A1/en
Priority to US11/407,505 priority patent/US20060252814A1/en

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to pharmaceutical formulations comprising a betablocker, in a maintenance dose lower than 50 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, as well as a method of treatment and use of the formulations for the treatment of atherosclerosis and related conditions.
  • Betablockers have been shown to reduce cardiovascular events and mortality in secondary (The Norwegian Multicenter Study group, NEnglJMed, 304:801-807, 1981; Olsson et al., J Am Coll Cardiol, 5:1428- 1437, 1985; MERIT-HF Study Group, Lancet, 353:2001-2007, 1999) and primary preventive studies (Wikstrand et al., JAMA, 259:1976-1982, 1988).
  • betablockers reduce the degree of diet-induced (Ostlund-Lindqvist et al., Arteriosclerosis, 8:40-45, 1988) and stress-induced atherosclerosis (Kaplan et al., Eur Heart J, 8:928-944; Pettersson et al., Curr Op in Cardiol 3:S9-S14, 1988), but no direct evidence for an anti-atherosclerotic effect of beta-blockers, similar to the effects of statins on carotid artery intima-media thickness (IMT) have so far been shown in humans
  • WO 98/02357 discloses a carton for carrying pharmaceutically active substances or combinations thereof.
  • One such combination mentioned is the combination of a beta blocker, such as metoprolol or isosorbidmononitrate, and a lipid lowering substance, such as fluvastatin. This application does not disclose any data concerning the effects of such a combination.
  • WO 99/11260 discloses a combination of atorvastatin and an antihypertensive agent. No data are disclosed in this application.
  • WO 97/38694 discloses a combination of an HMG-CoA reductase (3-hydroxy-3- methylglutaryl coenzyme A reductase) inhibitor in combination with folic acid in combination with a drug selected from a range of other types of drug including beta blockers.
  • WO 00/38725 discloses combinations of an ileal bile transport inhibitor and a range of other types of drug including antihypertensive drugs for example beta blockers. No data are presented.
  • the present invention relates to pharmaceutical formulations comprising a betablocker in a maintenance dose lower than 50 mg, particularly in the range of 10 to 47 mg, especially in the range of 25 - 47 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, as well as a method of treatment and use of the formulations for the treatment of atherosclerosis, including diet-induced and stress-induced atherosclerosis, coronary atherosclerosis, carotid plaque, hypertension, diabetes mellitus, stroke, cardiovascular death, angina pectoris, intermittent claudification, and mycardial infarction.
  • atherosclerosis including diet-induced and stress-induced atherosclerosis, coronary atherosclerosis, carotid plaque, hypertension, diabetes mellitus, stroke, cardiovascular death, angina pectoris, intermittent claudification, and mycardial infarction.
  • a low dose of a betablocker especially metoprolol
  • metoprolol can lower the rate of increase of carotid JJV1T in clinically healthy symptom-free subjects with a carotid plaque, which also indicates a favorable effect on atherosclerosis development.
  • the present invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising a betablocker in a maintenance dose in the range of 25 - 47 mg in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the dose of the betablocker is preferably lower than 30 mg, and most preferably 25 mg.
  • betablocker refers to any pharmaceutical agent that as part of its pharmacological action blocks beta-one-receptors.
  • the term “betablocker” includes chemical modifications of betablockers such as esters, stereoisomers, prodrugs, and metabolites, whether active or inactive, and pharmaceutically acceptable salts or solvates of any of these, or solvates of such salts.
  • a maintenance dose lower than 50 mg refers to the highest dose of any betablocker that blocks beta-one receptors to a similar extent as 47 mg of metoprolol succinate.
  • the degree of beta-one-receptor blockade is defined as the reduction in exercise- induced heart rate increase over 24 hours.
  • the betablockers referred to in this application include but are not limited to the compounds selected from the group consisting of acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, buprandolol, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nado
  • the betablocker is suitably metoprolol or atenolol , and stereoisomers thereof, and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts.
  • the betablocker is metoprolol succinate (disclosed in US 5,001,161), metoprolol tartrate or metoprolol fumarate.
  • the betablocker is metoprolol or a pharmaceutically acceptable salt thereof, or a solvate of such a salt.
  • Metoprolol may be in the form of metoprolol succinate, metoprolol fumarate, or metoprolol tartrate.
  • the betablocker is formulated into a pharmaceutical formulation for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or some other mode of administration.
  • the pharmaceutical formulation contains the betablocker in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the total amount of active ingredient suitably is in the range of from about 0.1 % (w/w) to about 95 % (w/w) of the formulation, suitably from 0.5 % to 50 % (w/w) and particularly from 1 % to 25 % (w/w).
  • the present invention provides a pharmaceutical formulation comprising a betablocker in a maintanance dose of less than 50mg and a cholesterol- lowering agent such as an HMG-CoA reductase inhibitor.
  • the HMG-CoA reductase inhibitor may be a statin selected from atorvastatin, cerivastatin, fluvastatin, itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin or a pharmaceutically acceptable salt, especially sodium or calcium, or a solvate thereof, or a solvate of such a salt.
  • statin is a compound with the chemical name (E)-7[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]- pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, and its calcium and sodium salts (disclosed in European Patent Application, Publication No. EP-A-0521471, and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444).
  • the preferred beta blockers and the preferred doses of these beta blockers are as defined above.
  • cholesterol-lowering agent includes chemical modifications of the HMG-CoA reductase inhibitors such as esters, stereoisomers, prodrugs and metabolites, whether active or inactive.
  • HMG-CoA reductase inhibitors such as esters, stereoisomers, prodrugs and metabolites, whether active or inactive.
  • any dose used in clinical practice may be used in the formulations of the present invention.
  • the molar ratio between the betablocker and the cholesterol-lowering agent may be in the range of from about 1000:1 to 1:1000.
  • the molar ratio between the betablocker and the cholesterol-lowering agent lies suitably in the range from 300:1 to 1:300, and particularly from 50: 1 to 1:50.
  • the active ingredients may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the active ingredients may be separately premixed with the other non-active ingredients, before mixed into a formulation.
  • the active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
  • Soft gelatine capsules may be prepared with capsules containing the active ingredient of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain granules of active ingredient.
  • Hard gelatine capsules may also contain the active ingredient with combination with solid powdrered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and poyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering agents. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent before use.
  • the dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician.
  • the dosage will particularly be in the range of from 0.01 mg kg to 10 mg/kg, but the total daily dose will not exceed 50 mg.
  • a pharmaceutical formulation comprising a betablocker, in a maintenance dose lower than 50 mg, particularly lower than 30mg and preferably in the range of 25 - 47 mg and particularly a dose of 25mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, in medical therapy and particularly for use in the prophylatic and therapeutic treatment of atherosclerosis; the use of such a formulation in the manufacture of medicaments for use in the prophylactic or therapeutic treatment of atherosclerosis, and methods of medical treatment or prophylaxis comprising the administration of a therapeutically effective amount of a betablocker, in maintenance doses described immediately above, to a patient suffering from, or susceptible to, atherosclerosis.
  • medical therapy as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
  • the formulations of the invention are expected to be useful in prophylactic or therapeutic treatment of atherosclerosis, particularly patients suffering from, or susceptible to coronary atherosclerosis, or carotid plaque.
  • the formulations of the invention are furthermore expected to be useful in prophylactic or therapeutic treatment of cardiovascular complications in general, including, but not limited to atherosclerosis including diet-induced and stress-induced atherosclerosis, cardiovascular death, hypertension, diabetes mellitus, angina pectoris, intermittent claudification, myocardial infarction, including acute myocardial infarction, and stroke.
  • atherosclerosis including diet-induced and stress-induced atherosclerosis
  • cardiovascular death cardiovascular death
  • hypertension diabetes mellitus
  • angina pectoris angina pectoris
  • intermittent claudification myocardial infarction, including acute myocardial infarction, and stroke.
  • formulations of the invention are expected to be useful in prevention of clinical events associated with the progression of atherosclerosis and/or acute vascular accidents related to atherosclerotic disease and plaque including but not limited to stroke, myocardial infarction (MI), cognitive decline, peripheral vascular disease, and renal dysfunction.
  • MI myocardial infarction
  • the present invention provides a pharmaceutical formulation comprising a betablocker in a maintenance dose in the range of 25 - 47 mg in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the manufacture of a medicament for use in the treatment or prevention of congestive heart failure (CHF) or cardiovascular death in a susceptible patient.
  • the dose of the betablocker is preferably lower than 30 mg, and most preferably 25 mg.
  • the formulation contains a cholesterol-lowering agent as described above.
  • kits of parts comprising:
  • a vessel containing a HMG-CoA reductase inhibitor which is (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)- 3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt, especially sodium or calcium, or solvate thereof, or a solvate of such a salt and instructions for the sequential, separate or simultaneous administration of the betablocker and a HMG-CoA reductase inhibitor to a patient for which such administration is necessary or advantageous.
  • a HMG-CoA reductase inhibitor which is (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)- 3,5-dihydroxyhept-6-enoic acid or
  • kits of parts comprising:
  • ком ⁇ онент comprising a betablocker and a cholesterol-lowering agent are administered, simultaneously, separately or sequentially, over the course of treatment of the relevant condition, which condition may be acute or chronic.
  • the term includes that the two formulations are administered (optionally repeatedly) sufficiently closely in time for there to be a beneficial effect for the patient, that is greater, over the course of the treat-ment of the relevant condition, than if either of the two formulations are administered (optionally repeatedly) alone, in the absence of the other formulation, over the same course of treatment.
  • betablockers have never been used previously to give an anti-atherosclerotic effect e.g. in patients suffering from hyper-cholesterolemia or hyperlipoproteinemia. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition, will depend upon the condition to be treated or prevented, but may be achieved routinely by the person skilled in the art.
  • the term "in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, or at the same time as, administration with the other component.
  • the terms “administered simultaneously” and “administered at the same time as” include that individual doses of a betablocker and a cholesterol-lowering agent are administered within 48 hours, e.g. 24 hours, of each other.
  • EXAMPLE A large scale clinical trial was designed to investigate the effect of low dose betablocker metoprolol on the progression of carotid EVIT versus placebo and clinical outcome measures during 36 months double-blind treatment in asymptomatic subjects with a carotid plaque.
  • the study was a randomized, double blind, parallel group, placebo-controlled, single-center study.
  • the study population consisted of asymptomatic men and women, aged 49 to 70 years, with a plaque in the right carotid artery. A random 50% of those who entered the study were invited to take part in a study on the epidemiology of carotid artery disease. 1548 subjects came to the enrolment examination (visit one) including medical history, physical examination, laboratory measurements and a two-dimensional B-mode ultrasound of the right carotid artery. Subjects with a qualifying lesion in the right carotid artery, and who had no contraindications to the study protocol were invited to take part. In all, 793 subjects were eligible for randomization. All participants provided written informed consent.
  • Major exclusion criteria were history of myocardial infarction, angina pectoris or stroke within the preceding three months, history of surgical intervention in the right carotid artery, regular use of beta-blockers or statins, blood pressure above 160 systolic or 95 mm Hg diastolic, hypercholesterolemia (>8.0 mmol/L) , hyperglycemia requiring or suspected to require insulin treatment, and conditions which in the opinion of the investigator rendered the subject unsuitable for the trial.
  • the randomization procedure was performed by using a computer generated randomization scheme. Participants were, according to a factorial design, randomly assigned to one of four drug combination groups: placebo/placebo, metoprolol (25 mg o.d)/placebo, fluvastatin (40 mg o.d.)/placebo or metoprolol (25 mg o.d.)/ fluvastatin (40 mg o.d.).
  • the placebo was manufactured to exactly resemble the metoprolol CR/XL tablets (AstraZeneca AB, Molndal, Sweden), and fluvastatin (Novartis Ltd, Basel, Switzerland) capsules, respectively.
  • the primary outcome measures were the change in mean intima-media thickness (IMTmean) in the common carotid artery (10 mm long section), and the change in maximum intima-media thickness (IMTmax) in the carotid bulb.
  • IMTmean mean intima-media thickness
  • IMTmax maximum intima-media thickness
  • Subjects with high serum cholesterol or triglycerides were advised to a low-fat diet and if evidence of persistent high cholesterol values such subjects were referred to an independent specialist of lipid disorders without knowledge of the subjects randomization assignment.
  • Other conditions such as high blood pressure, congestive heart failure or abnormal laboratory values during the trial were dealt with in accordance with existing guidelines.
  • At every visit each participant was asked about any hospitalization, acute myocardial infarction and stroke, since last visit. Vital status was obtained for all subjects at termination of the study.
  • the right carotid bifurcation was scanned within a pre-defined window comprising three centimeters of the distal common carotid artery, the bifurcation and one centimeter of the internal and external carotid arteries, respectively, for the presence of plaques, defined as focal intima-media thickenings above 1.2 mm. Thickness of the intima-media complex was measured in the far wall according to the leading edge principle, using a specially designed computer-assisted image analyzing system based on automated detection of the echo structures, but with the option to make manual corrections by the operator. Each image was analyzed without knowledge of the subjects' randomization group.
  • Metoprolol increased serum triglycerides by 0.14 mmol/L compared to the placebo group but no effect was observed on other metabolic variables.
  • mean heart rate decreased in the metoprolol group by 2.5 beats per min, while blood pressure and lumen diameter were not significantly changed.
  • CVD cardiovascular
  • Heart rate (beats/min) 69.5 ⁇ 9.0 68.9 ⁇ 8.4 70.2 ⁇ 9.0
  • Triglycerides (mmol /L) 1.21 (0.48-3.57) 1.18 (0.46-4.57) 1.12 (0.41 - 4.61)
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • NIDDM non-insulin dependent diabetes mellitus
  • CVD cardiovascular disease
  • IMT intima- media thickness

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Abstract

The present invention relates to pharmaceutical formulations comprising a betablocker, in a maintenance dose lower than 50 mg, particularly in the range of 25 to 47 mg, optionally containing a cholesterol lowering agent, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, as well as a method of treatment and use of the formulations for the treatment of atherosclerosis and related diseases.

Description

NEW FORMULATION
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations comprising a betablocker, in a maintenance dose lower than 50 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, as well as a method of treatment and use of the formulations for the treatment of atherosclerosis and related conditions.
BACKGROUND OF THE INVENTION
There is a constant need for new medications to further reduce the risk of atherosclerotic disease, since this is one of the industrial world's most common health problems.
Various pharmaceuticals, such as the group known as betablockers, are known to have a positive influence on various cardiovascular diseases, whereas the effect upon atherosclerotic disease is little known. Betablockers have been shown to reduce cardiovascular events and mortality in secondary (The Norwegian Multicenter Study group, NEnglJMed, 304:801-807, 1981; Olsson et al., J Am Coll Cardiol, 5:1428- 1437, 1985; MERIT-HF Study Group, Lancet, 353:2001-2007, 1999) and primary preventive studies (Wikstrand et al., JAMA, 259:1976-1982, 1988). In animal studies betablockers reduce the degree of diet-induced (Ostlund-Lindqvist et al., Arteriosclerosis, 8:40-45, 1988) and stress-induced atherosclerosis (Kaplan et al., Eur Heart J, 8:928-944; Pettersson et al., Curr Op in Cardiol 3:S9-S14, 1988), but no direct evidence for an anti-atherosclerotic effect of beta-blockers, similar to the effects of statins on carotid artery intima-media thickness (IMT) have so far been shown in humans
The administration of combinations of βi selective blockers and lipid-lowering drugs to healthy volunteers in order to observe the effects on fat metabolism, ammonia levels and the perception of effort during exercise, was disclosed in Br. J. Clin Pharmacol 1997 vol 43, no 3 pages 291-300. The combinations studied were 1) metoprolol (controlled release) and fluvastatin 2) metoprolol (controlled release) and bezafibrate 3) atenolol (normal release) and fluvastatin and 4) atenolol (normal release) and bezafibrate. The paper concluded that that these four combinations each caused significant reductions in fat metabolism increased plasma ammonia concentrations and raised the perception of exercise. Combination 1) had the least adverse effect but the formulation difference was thought to be a significant factor in explaining the differences observed with respect to combination 3).
The effects of a combination of pravastatin and atenolol on hypertensive and hypercholesterolaemic patients were reported in Scand. J. Print Health Care 1999, vol 17 122-127. The conclusion was that the effect of atenolol was not influenced by the concurrent administration of pravastatin and vice versa. However, lifestyle intervention was also a feature of this study and therefore the conclusions which can be drawn from this study are not clear.
A post hoc analysis of patients who had been treated with lovastatin and who were also receiving antihypertensive medication including βi adrenergic receptor blockers was reported in Hypertension, 1992,Nol.19,3 242. The paper concluded that, subject to a number of limitations, there was no evidence for an attenuation of the lovastsatin- induced changes in lipids and lipoproteins or an alteration in the safety profile of lovastatin when administered concurrently with commonly used antihypertensive agents.
It was concluded in Presse Med Volume 1996, vol 25, no.40, 2013-2016 that the effect of the βt adrenergic receptor blocker atenolol was not diminished in combination with pravastatin. However, the effect of pravastatin on lipid metabolism was more favourable when pravastatin was combined with the angiotensin converting enzyme inhibitor captopril rather than with atenolol. Low doses of metoprolol for the treatment of hypertension and heart disease have been reported, but these reports indicate that the use of lower doses of metoprolol has a varying degree of efficacy. Westergren et al. in Current Therapeutic Research, 1994 vol. 55, No.2, 142, describe the use of a 50 mg dose of metoprolol (half of the most commonly used daily dose of immediate-release metoprolol) in the form of a controlled release tablet to treat mild-to-moderate hypertension. They report that this dose of metoprolol is well tolerated. However, Sanderson et al. allege in the British Heart Journal, 1995, vol. 74, 502, that a low dose of metoprolol of 6.25 mg administered twice daily can be hazardous in patients with severe heart failure.
A review by Garnett in Americal Journal of Health-System Pharmacology, 1995, vol. 52, 1639, describes the pharmacokinetic profiles of HMG-CoA reductase inhibitors and explores the specific drug interactions that have been documented.
WO 98/02357 discloses a carton for carrying pharmaceutically active substances or combinations thereof. One such combination mentioned is the combination of a beta blocker, such as metoprolol or isosorbidmononitrate, and a lipid lowering substance, such as fluvastatin. This application does not disclose any data concerning the effects of such a combination.
WO 99/11260 discloses a combination of atorvastatin and an antihypertensive agent. No data are disclosed in this application.
WO 97/38694 discloses a combination of an HMG-CoA reductase (3-hydroxy-3- methylglutaryl coenzyme A reductase) inhibitor in combination with folic acid in combination with a drug selected from a range of other types of drug including beta blockers. WO 00/38725 discloses combinations of an ileal bile transport inhibitor and a range of other types of drug including antihypertensive drugs for example beta blockers. No data are presented.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical formulations comprising a betablocker in a maintenance dose lower than 50 mg, particularly in the range of 10 to 47 mg, especially in the range of 25 - 47 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, as well as a method of treatment and use of the formulations for the treatment of atherosclerosis, including diet-induced and stress-induced atherosclerosis, coronary atherosclerosis, carotid plaque, hypertension, diabetes mellitus, stroke, cardiovascular death, angina pectoris, intermittent claudification, and mycardial infarction.
DETAILED DESCRIPTION OF THE INVENTION
It has surprisingly been found that a low dose of a betablocker, especially metoprolol, can lower the rate of increase of carotid JJV1T in clinically healthy symptom-free subjects with a carotid plaque, which also indicates a favorable effect on atherosclerosis development.
In one aspect, the present invention relates to a pharmaceutical formulation comprising a betablocker in a maintenance dose in the range of 25 - 47 mg in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The dose of the betablocker is preferably lower than 30 mg, and most preferably 25 mg.
In the present application, the term "betablocker" refers to any pharmaceutical agent that as part of its pharmacological action blocks beta-one-receptors. Furthermore, in the present application, the term "betablocker" includes chemical modifications of betablockers such as esters, stereoisomers, prodrugs, and metabolites, whether active or inactive, and pharmaceutically acceptable salts or solvates of any of these, or solvates of such salts.
The phrase "in a maintenance dose lower than 50 mg" in the present application refers to the highest dose of any betablocker that blocks beta-one receptors to a similar extent as 47 mg of metoprolol succinate.
The degree of beta-one-receptor blockade is defined as the reduction in exercise- induced heart rate increase over 24 hours.
The betablockers referred to in this application include but are not limited to the compounds selected from the group consisting of acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, buprandolol, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol, perbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sufinalol, talindol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol, and stereoisomers thereof and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts.
In the present invention the betablocker is suitably metoprolol or atenolol , and stereoisomers thereof, and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts. Particularly, the betablocker is metoprolol succinate (disclosed in US 5,001,161), metoprolol tartrate or metoprolol fumarate.
Therefore, in another embodiment of this aspect of the invention, the betablocker is metoprolol or a pharmaceutically acceptable salt thereof, or a solvate of such a salt. Metoprolol may be in the form of metoprolol succinate, metoprolol fumarate, or metoprolol tartrate. For clinical use, the betablocker is formulated into a pharmaceutical formulation for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or some other mode of administration. The pharmaceutical formulation contains the betablocker in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
The total amount of active ingredient suitably is in the range of from about 0.1 % (w/w) to about 95 % (w/w) of the formulation, suitably from 0.5 % to 50 % (w/w) and particularly from 1 % to 25 % (w/w).
In another aspect the present invention provides a pharmaceutical formulation comprising a betablocker in a maintanance dose of less than 50mg and a cholesterol- lowering agent such as an HMG-CoA reductase inhibitor. The HMG-CoA reductase inhibitor may be a statin selected from atorvastatin, cerivastatin, fluvastatin, itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin or a pharmaceutically acceptable salt, especially sodium or calcium, or a solvate thereof, or a solvate of such a salt. An example of such a statin is a compound with the chemical name (E)-7[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]- pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, and its calcium and sodium salts (disclosed in European Patent Application, Publication No. EP-A-0521471, and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444). The preferred beta blockers and the preferred doses of these beta blockers are as defined above.
In the present patent application, the term "cholesterol-lowering agent" includes chemical modifications of the HMG-CoA reductase inhibitors such as esters, stereoisomers, prodrugs and metabolites, whether active or inactive. For the cholesterol-lowering agent, any dose used in clinical practice may be used in the formulations of the present invention.
The molar ratio between the betablocker and the cholesterol-lowering agent may be in the range of from about 1000:1 to 1:1000. The molar ratio between the betablocker and the cholesterol-lowering agent lies suitably in the range from 300:1 to 1:300, and particularly from 50: 1 to 1:50.
In the preparation of the pharmaceutical formulations of the present invention the active ingredients may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets.
The active ingredients may be separately premixed with the other non-active ingredients, before mixed into a formulation. The active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
Soft gelatine capsules may be prepared with capsules containing the active ingredient of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of active ingredient. Hard gelatine capsules may also contain the active ingredient with combination with solid powdrered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and poyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering agents. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent before use.
The dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. The dosage will particularly be in the range of from 0.01 mg kg to 10 mg/kg, but the total daily dose will not exceed 50 mg.
Medical and pharmaceutical use
Also provided according to the present invention is the use of a pharmaceutical formulation, comprising a betablocker, in a maintenance dose lower than 50 mg, particularly lower than 30mg and preferably in the range of 25 - 47 mg and particularly a dose of 25mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, in medical therapy and particularly for use in the prophylatic and therapeutic treatment of atherosclerosis; the use of such a formulation in the manufacture of medicaments for use in the prophylactic or therapeutic treatment of atherosclerosis, and methods of medical treatment or prophylaxis comprising the administration of a therapeutically effective amount of a betablocker, in maintenance doses described immediately above, to a patient suffering from, or susceptible to, atherosclerosis.
The term "medical therapy" as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. The formulations of the invention are expected to be useful in prophylactic or therapeutic treatment of atherosclerosis, particularly patients suffering from, or susceptible to coronary atherosclerosis, or carotid plaque.
The formulations of the invention are furthermore expected to be useful in prophylactic or therapeutic treatment of cardiovascular complications in general, including, but not limited to atherosclerosis including diet-induced and stress-induced atherosclerosis, cardiovascular death, hypertension, diabetes mellitus, angina pectoris, intermittent claudification, myocardial infarction, including acute myocardial infarction, and stroke.
More particularly the formulations of the invention are expected to be useful in prevention of clinical events associated with the progression of atherosclerosis and/or acute vascular accidents related to atherosclerotic disease and plaque including but not limited to stroke, myocardial infarction (MI), cognitive decline, peripheral vascular disease, and renal dysfunction.
In another aspect the present invention provides a pharmaceutical formulation comprising a betablocker in a maintenance dose in the range of 25 - 47 mg in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the manufacture of a medicament for use in the treatment or prevention of congestive heart failure (CHF) or cardiovascular death in a susceptible patient. The dose of the betablocker is preferably lower than 30 mg, and most preferably 25 mg. Optionally the formulation contains a cholesterol-lowering agent as described above.
A further aspect of the present invention relates to kits of parts comprising:
(i) a vessel containing a betablocker in a maintenance dose lower than 50 mg, preferably in the range of 25 - 47 mg, and
(ii) a vessel containing a HMG-CoA reductase inhibitor which is (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)- 3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt, especially sodium or calcium, or solvate thereof, or a solvate of such a salt and instructions for the sequential, separate or simultaneous administration of the betablocker and a HMG-CoA reductase inhibitor to a patient for which such administration is necessary or advantageous.
Another aspect of the invention relates to kits of parts comprising:
(i) a pharmaceutical formulation containing a betablocker in a maintenance dose in a maintenance dose lower than 50 mg, preferably in the range of 25 - 47 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and (ii) a pharmaceutical formulation containing a cholesterol-lowering agent, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; wherein the betablocker and the cholesterol-lowering agent are each provided in a form that is suitable for administration in conjunction with the other.
By "administration in conjunction with", we include that respective formulations comprising a betablocker and a cholesterol-lowering agent are administered, simultaneously, separately or sequentially, over the course of treatment of the relevant condition, which condition may be acute or chronic. Particularly, the term includes that the two formulations are administered (optionally repeatedly) sufficiently closely in time for there to be a beneficial effect for the patient, that is greater, over the course of the treat-ment of the relevant condition, than if either of the two formulations are administered (optionally repeatedly) alone, in the absence of the other formulation, over the same course of treatment. It must, however, be emphasized that betablockers have never been used previously to give an anti-atherosclerotic effect e.g. in patients suffering from hyper-cholesterolemia or hyperlipoproteinemia. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition, will depend upon the condition to be treated or prevented, but may be achieved routinely by the person skilled in the art.
Thus, the term "in conjunction with" includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, or at the same time as, administration with the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" include that individual doses of a betablocker and a cholesterol-lowering agent are administered within 48 hours, e.g. 24 hours, of each other.
The following example is intended to illustrate, but in no way limit the scope of the invention.
EXAMPLE A large scale clinical trial was designed to investigate the effect of low dose betablocker metoprolol on the progression of carotid EVIT versus placebo and clinical outcome measures during 36 months double-blind treatment in asymptomatic subjects with a carotid plaque. The study was a randomized, double blind, parallel group, placebo-controlled, single-center study.
The study population consisted of asymptomatic men and women, aged 49 to 70 years, with a plaque in the right carotid artery. A random 50% of those who entered the study were invited to take part in a study on the epidemiology of carotid artery disease. 1548 subjects came to the enrolment examination (visit one) including medical history, physical examination, laboratory measurements and a two-dimensional B-mode ultrasound of the right carotid artery. Subjects with a qualifying lesion in the right carotid artery, and who had no contraindications to the study protocol were invited to take part. In all, 793 subjects were eligible for randomization. All participants provided written informed consent. Major exclusion criteria were history of myocardial infarction, angina pectoris or stroke within the preceding three months, history of surgical intervention in the right carotid artery, regular use of beta-blockers or statins, blood pressure above 160 systolic or 95 mm Hg diastolic, hypercholesterolemia (>8.0 mmol/L) , hyperglycemia requiring or suspected to require insulin treatment, and conditions which in the opinion of the investigator rendered the subject unsuitable for the trial.
The randomization procedure was performed by using a computer generated randomization scheme. Participants were, according to a factorial design, randomly assigned to one of four drug combination groups: placebo/placebo, metoprolol (25 mg o.d)/placebo, fluvastatin (40 mg o.d.)/placebo or metoprolol (25 mg o.d.)/ fluvastatin (40 mg o.d.). The placebo was manufactured to exactly resemble the metoprolol CR/XL tablets (AstraZeneca AB, Molndal, Sweden), and fluvastatin (Novartis Ltd, Basel, Switzerland) capsules, respectively.
The primary outcome measures were the change in mean intima-media thickness (IMTmean) in the common carotid artery (10 mm long section), and the change in maximum intima-media thickness (IMTmax) in the carotid bulb. Safety and tolerability pattern during treatment with fluvastatin or metoprolol, was evaluated by comparing adverse events and laboratory findings to placebo. Death and incidence of major cardiovascular endpoints were monitored.
Every participant was seen four times during the first year (after one, three, six and twelve months) and every 6 months thereafter. Weight was obtained every six months and a fasting lipid profile (total cholesterol, LDL-lipoprotein, HDL-lipoprotein and triglycerides) was determined every year. Liver transaminases (AST, ALT) and creatine kinase (CK) were obtained at every visit during the first year and then every year thereafter. AST or ALT values ≥3 times, and CK values ≥IO times the upper limit of normal was considered elevated during the study. Carotid ultrasound investigation was performed at baseline and after 18 and 36 months treatment. Subjects with high serum cholesterol or triglycerides were advised to a low-fat diet and if evidence of persistent high cholesterol values such subjects were referred to an independent specialist of lipid disorders without knowledge of the subjects randomization assignment. Other conditions such as high blood pressure, congestive heart failure or abnormal laboratory values during the trial were dealt with in accordance with existing guidelines. At every visit each participant was asked about any hospitalization, acute myocardial infarction and stroke, since last visit. Vital status was obtained for all subjects at termination of the study.
Throughout the trial an Acuson 128 Computed Tomography System (Acuson, Mountain View, California) with a 7 MHz transducer was used. The examination procedure and image analysis, as described elsewhere (Wendelhag et al., Clin Physiol, 11:565-577, 1991; Wendelhag et al., Stroke, 28:2195-2200, 1997) was performed by specially trained sonographers certified upon completion of an extensive educational program (Berglund, et al., J Intern Med, 236:581-586, 1994). In brief, the right carotid bifurcation was scanned within a pre-defined window comprising three centimeters of the distal common carotid artery, the bifurcation and one centimeter of the internal and external carotid arteries, respectively, for the presence of plaques, defined as focal intima-media thickenings above 1.2 mm. Thickness of the intima-media complex was measured in the far wall according to the leading edge principle, using a specially designed computer-assisted image analyzing system based on automated detection of the echo structures, but with the option to make manual corrections by the operator. Each image was analyzed without knowledge of the subjects' randomization group.
From previous experience (Furberg et al., Circulation, 90:1679-1687, 1994) it was anticipated that the annual carotid artery TMTmean progression rate in the placebo group would be approximately 15 μm per year with a standard deviation of 30 μm. A sample size of 200 subjects per group, i.e. a total of 800 individuals, was determined based on a withdrawal rate of 20 %, a significance level of 5 % (two-sided), a power of 0.90, and a treatment effect of >75% (fluvastatin) and 30 % (metoprolol), respectively. The primary effect variables, change in TMTmean CCA, and IMTmax Bulb, was analyzed in a linear model with change in EV1T as dependent variable and with treatment as a factor. Baseline IMTs and time between measurements were included in the model as covariates.
The randomization yielded well-balanced treatment groups, (see Table 1). Mean baseline LDL-cholesterol was 4.1 mmol/L. Current medication at baseline or during trial for other cardiovascular compounds (e.g. diuretics, calcium channel blockers, ACE-inbibitors, aspirin and postmenopausal hormone replacement therapy for women) were similar in the treatment groups (data not shown). The mean follow-up time was 35.9 (range 8 to 40) months. Metabolic and physiological effects of treatment
Metoprolol increased serum triglycerides by 0.14 mmol/L compared to the placebo group but no effect was observed on other metabolic variables. In comparison to the placebo group mean heart rate decreased in the metoprolol group by 2.5 beats per min, while blood pressure and lumen diameter were not significantly changed.
Treatment effect on carotid IMF
Baseline ultrasound data are given in Table 1 and 2. The observed annual TMTmean CCA progression rate in the placebo group was 13±53 μm. The annual IMTmax progression rate in the bifurcation in the placebo group was 89±154 μm. Fluvastatin, but not metoprolol, reduced the rate of progression of TMTmean CCA compared with placebo after 36 months of treatment (mean difference of yearly change between groups: -9, 95% confidence interval [CI]: -15 to -3 μm, p=0.002), Table 2-3.
Metoprolol was effective in slowing the progression rate of carotid TMTmaxBulb compared with placebo after 36 months of treatment (mean difference of yearly change between groups: -23, 95% CI: -44 to -3 μm, p=0.014), Table 2-3. This effect was evident already after 18 months' of treatment (mean difference of yearly change between groups: -58, 95% CI: -94 to -23 μm, p=0.004). Metoprolol CR/XL also reduced the progression rate of IMTmaxBulb after 36 months of treatment in the subgroup with serum cholesterol ≥6.5 mmol/L at baseline (mean difference of yearly change between groups: -53, 95% CI: -87 to -19 μm, p=0.001).
Incidence of cardiovascular events during follow-up Eighteen of the participants had a cardiovascular (CVD) event (one subject suffered a fatal and seven a non-fatal myocardial infarction, two died suddenly because of ischaemic heart disease, and eight suffered a non-fatal stroke). The CVD event rate tended to be lower in the metoprolol group compared to the placebo group (5 versus 13 cases, p=0.055), Figure 2. Corresponding numbers in the fluvastatin and placebo groups were 7 and 11 cases, respectively, p=0.350. Tolerability
Permanent withdrawal from randomized treatment was 15% in the metoprolol group, 21 % in the fluvastatin group, and 23% in the placebo group. The withdrawal rate in the group of the combination of the two drugs was 25 %. Women in the fluvastatin group had, in comparison with the placebo group, an increased frequency of transiently high liver enzymes (10.2 % versus 1.8 %). Incidence of severe adverse events or cancer did not differ between the treatment groups.
TABLE 1.
Characteristics Treatment group
Placebo/ Metoprolol/ Metoprolol/
Placebo Placebo Fluvastatin
Sex
Men, n ( ) 92 (46.2) 89 (44.7) 86 (43.7)
Women, n (%) 107 (53.8) 110 (55.3) 111 (56.3)
Age (years) 61.9 + 5.4 61.1 + 5.6 62.2 ± 5.2
Current smokers (%) 57 (28.6) 63 (31.7) 66 (33.5)
Body mass index (kg /m2) 25.6 + 3.7 25.6 + 3.8 25.4 ± 3.4
Systolic blood pressure (mm Hg) 139.1 ±14.6 137.9 ± 15.0 139.1 ± 13.7
Diastolic blood pressure (mm Hg) 84.5 ± 8.0 84.5 ± 6.9 84.8 ± 6.6
Heart rate (beats/min) 69.5 ± 9.0 68.9 ± 8.4 70.2 ± 9.0
History of hypertension, n (%) 22 (11.1) 21 (10.6) 24 (12.2)
Serum cholesterol (mmol L ) 6.05 ± 0.98 6.14 ± 1.03 6.14 ± 0.93
> 6.5 mmol /L, n (%) 66 (33.2) 70 (35.4) 68 (34.7)
LDL ( mmol IL) 4.1 ± 0.9 4.2 ± 1.0 4.2 ± 0.9
HDL (mmol /L) 1.40 ± 0.41 1.35 ± 0.37 1.39 ± 0.35
Triglycerides (mmol /L) 1.21 (0.48-3.57) 1.18 (0.46-4.57) 1.12 (0.41 - 4.61)
History of hyperlipidemia, n (%) 31 (15.6) 42 (21.1) 37 (18.8)
Fasting blood glucose (mmol /L) 5.1 + 0.9 5.2 ± 0.7 5.1 ± 0.6
History of NIDDM, n (%) 10 (5.0) 7 (3.5) 5 (2.5)
History of CVD, n (%) 7 (3.5) 8 (4.0) 8 (4.1)
Carotid ultrasonography
Common carotid TMTmean (μm) 898 ± 171 920 + 197 903 ± 205
Bifurcation carotid IMTmax Bulb 1875 ± 505 1936 ± 651 1970 ± 652
(μm)
Selected baseline characteristics of randomized BCAPS participants by treatment group. Abbreviations: LDL, low density lipoprotein; HDL, high density lipoprotein; NIDDM, non-insulin dependent diabetes mellitus; CVD, cardiovascular disease; IMT, intima- media thickness. TABLE 2.
Characteristics Treatment groups
Placebo Metoprolol Placebo Fluvastatin
Common carotid TMTmean (μm)
Number of subjects 390 393 394 389
Baseline (± SD) 893 ± 170 912 ± 202 910 ± 186 895 ± 188
18 months (+ SD) 896 ± 176 908 ± 205 913 ± 186 890 ± 196
36 months (± SD) 917 ± 203 934 ± 220 945 + 216 905 + 205
Δ 18 months to baseline (+ SD) 3 ± 10 -5 ± 12 3 + 11 -5 ± 11
Δ 36 months to baseline (± SD) 24 ± 13 22 ± 13 36 ± 15 11 ± 11
Δ between groups at 36 months -2 (-20 to 17) -25 (-44 to -
(95% CI) 7)
Bifurcation carotid TMTmean (μm)
Number of subjects 369 364 375 358
Baseline (± SD) 1875 ± 541 1936 ± 634 1886 ± 570 1926 ± 609
18 months (± SD) 1982 ± 572 1937 ± 572 1954 ± 589 1965 ± 554
36 months (± SD) 2133 ± 630 2003 ± 624 2097 ± 670 2095 ± 652
Δ 18 months to baseline (+ SD) 112 ± 376 23 ± 325 72 ± 373 63 ± 334
Δ 36 months to baseline (± SD) 227 ± 421 154 ± 411 211 ± 455 170 ± 374
Δ between groups at 36 months -73 (-133 to - -41 (-102 to (95% CI) 13) 19)
Mean values for and mean change in common and bifurcation carotid intima-media 5 thickness at baseline and at the 18 and 36 months follow-up according to treatment groups. TMT, intima-media thickness; SD, standard deviation; CI, confidence interval. TABLE 3.
Outcome measure Treatment β-coeffϊcient Standard error p-value
IMTmean CCA
Fluvastatin
18 months -0.0135 0.008 0.077
36 months -0.0275 0.009 0.002
Metoprolol
18 months 0.0049 0.008 0.524
36 months 0.0012 0.009 0.897
IMTmax bifurcation
Fluvastatin
18 months 0.0009 0.029 0.940
36 months -0.0132 0.013 0.329
Metoprolol
18 months -0.0367 0.013 0.004
36 months -0.0333 0.013 0.014
Treatment effects during 36 months on progression (in μm) of the common carotid artery IMTmean and the carotid artery bifurcation IMTmax, respectively. Intention-to- treat analysis. Adjusted for baseline IMTmean and IMTmax, respectively, and time between measurements

Claims

1. A pharmaceutical formulation, comprising a betablocker, in a maintenance dose in the range of 25 - 47 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
2. The pharmaceutical formulation according to claim 1, wherein the dose of the betablocker is 25 mg.
3. The pharmaceutical formulation according to either claim 1 or claim 2, wherein the betablocker is metoprolol or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a solvate of such a salt.
4. The pharmaceutical formulation according to claim 3, wherein the betablocker is metoprolol succinate, metoprolol fumarate, or metoprolol tartrate.
5. A pharmaceutical formulation, comprising a betablocker, in a maintenance dose lower than 50 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier and further comprising a cholesterol-lowering agent.
6. The pharmaceutical formulation according to any one of claims 1 to 4, further comprising a cholesterol-lowering agent.
7. The pharmaceutical formulation according to claim 6, wherein the cholesterol- lowering agent is an HMG-CoA reductase inhibitor.
8. The pharmaceutical formulation according to claim 7, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, lovastatin, nivastatin, pravastatin, and simvastatin.
9. The pharmaceutical formulation according to claim 8, wherein the HMG-CoA reductase inhibitor is fluvavastin.
10. The pharmaceutical formulation according to claim 9, wherein the HMG-CoA reductase inhibitor is of (E)-7[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
11. The pharmaceutical formulation according to any one of claims 6 to 10, wherein the molar ratio between the betablocker and the cholesterol-lowering agent lies in the range of from about 1000: 1 to about 1 : 1000, particularly from 300: 1 to 1 :300.
12. A formulation according to any one of claims 1 to 11 , for use in medical therapy.
13. A method for prophylactic or therapeutic treatment of a patient suffering from, or susceptible to, atherosclerosis which method comprises administering to the patient a formulation as defined in any one of claims 1 to 11.
14. The use of a pharmaceutical formulation, comprising a betablocker, in a maintenance dose lower than 50 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier in the manufacture of a medicament for the prophylactic or therapeutic treatment of atherosclerosis.
15. The use of a pharmaceutical formulation, comprising a betablocker, in a maintenance dose lower than 50 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier in the manufacture of a medicament for the prophylactic or therapeutic treatment of diet-induced and stress-induced atheroscerosis, hypertension, diabetes mellitus, angina pectoris, intermittent claudification, myocardial infarction, including acute myocardial infarction, and stroke.
16. The use of a pharmaceutical formulation, comprising a betablocker, in a maintenance dose lower than 50 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier in the manufacture of a medicament for the prophylactic or therapeutic treatment of stroke, myocardial infarction (MI), cognitive decline, peripheral vascular disease, and renal dysfunction.
17. A pharmaceutical formulation comprising a betablocker in a maintenance dose in the range of 25 - 47 mg in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the manufacture of a medicament for use in the treatment or prevention of congestive heart failure (CHF) or cardiovascular death in a susceptible patient.
18. A kit of parts comprising:
(i) a vessel containing a betablocker in a maintenance dose lower than 50 mg and (ii) a vessel containing a HMG-CoA reductase inhibitor which is (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)- 3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt, especially sodium or calcium, or solvate thereof, or a solvate of such a salt and instructions for the sequential, separate or simultaneous administration of the betablocker and a HMG-CoA reductase inhibitor to a patient for which such administration is necessary or advantageous.
19. A kit of parts comprising:
(i) a pharmaceutical formulation containing a betablocker in a maintenance dose in a maintenance dose lower than 50 mg, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and
(ii) a pharmaceutical formulation containing a cholesterol-lowering agent, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; wherein the betablocker and the cholesterol-lowering agent are each provided in a form that is suitable for administration in conjunction with the other.
PCT/SE2001/001380 2000-06-22 2001-06-15 New formulation comprising a betablocker and optionally a cholesterol-lowering agent WO2001097751A2 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
NZ523188A NZ523188A (en) 2000-06-22 2001-06-15 Use of a betablocker in the manufacture of a medicament to treat artherosclerosis
JP2002503228A JP2003535875A (en) 2000-06-22 2001-06-15 New formulation
SK1807-2002A SK18072002A3 (en) 2000-06-22 2001-06-15 New formulation comprising a betablocker and optionally a cholesterol-lowering agent
DE60124400T DE60124400T2 (en) 2000-06-22 2001-06-15 USE OF BETABLOCKER FOR THE TREATMENT OF ATHEROSCLEROSIS
IL15324501A IL153245A0 (en) 2000-06-22 2001-06-15 New formulation comprising a betablocker and optionally a cholesterol-lowering agent
HU0302371A HUP0302371A3 (en) 2000-06-22 2001-06-15 New pharmaceutical composition comprising a betablocker and optionally a cholesterol-lowering agent
CA002411100A CA2411100A1 (en) 2000-06-22 2001-06-15 New formulation comprising a betablocker and optionally a cholesterol-lowering agent
PL36048401A PL360484A1 (en) 2000-06-22 2001-06-15 New formulation comprising a betablocker and optionally a cholesterol-lowering agent
MXPA02012957A MXPA02012957A (en) 2000-06-22 2001-06-15 New formulation.
EP01941409A EP1296716B1 (en) 2000-06-22 2001-06-15 Use of a beta-blocker for the treatment of atherosclerosis
EEP200200703A EE200200703A (en) 2000-06-22 2001-06-15 A new formulation containing a beta-blocker and, if necessary, a cholesterol-lowering agent
BR0111790-4A BR0111790A (en) 2000-06-22 2001-06-15 Pharmaceutical formulation, method for prophylactic or therapeutic treatment of a patient suffering from or susceptible to atherosclerosis, use of a pharmaceutical formulation, and kit of parts.
AU2001274766A AU2001274766A1 (en) 2000-06-22 2001-06-15 New formulation comprising a betablocker and optionally a cholesterol-lowering agent
BG107373A BG107373A (en) 2000-06-22 2002-12-11 New formulation comprising a betablocker and optionally a cholesterol-lowering agent
IS6653A IS6653A (en) 2000-06-22 2002-12-11 A new blend containing beta-inhibitors and possibly cholesterol-lowering substances
NO20026177A NO20026177D0 (en) 2000-06-22 2002-12-20 New formulation comprising a beta blocker and optionally a cholesterol reducing agent
HK03106811.1A HK1054508A1 (en) 2000-06-22 2003-09-22 New formulation
US11/407,505 US20060252814A1 (en) 2000-06-22 2006-04-19 Formulation comprising a betablocker and optionally a cholestrol-lowering agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0002354-9 2000-06-22
SE0002354A SE0002354D0 (en) 2000-06-22 2000-06-22 New formulation

Related Child Applications (1)

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US11/407,505 Continuation US20060252814A1 (en) 2000-06-22 2006-04-19 Formulation comprising a betablocker and optionally a cholestrol-lowering agent

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DE (1) DE60124400T2 (en)
EE (1) EE200200703A (en)
ES (1) ES2274892T3 (en)
HK (1) HK1054508A1 (en)
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JP2003535875A (en) 2003-12-02
MXPA02012957A (en) 2003-05-15
ATE344675T1 (en) 2006-11-15
NO20026177L (en) 2002-12-20
AR028699A1 (en) 2003-05-21
BG107373A (en) 2003-09-30
US20060252814A1 (en) 2006-11-09
NO20026177D0 (en) 2002-12-20
CZ20024181A3 (en) 2003-04-16
RU2271802C2 (en) 2006-03-20
ES2274892T3 (en) 2007-06-01
IL153245A0 (en) 2003-07-06
ZA200209908B (en) 2004-03-05
DE60124400D1 (en) 2006-12-21
EP1296716B1 (en) 2006-11-08
AU2001274766A1 (en) 2002-01-02
PL360484A1 (en) 2004-09-06
HK1054508A1 (en) 2003-12-05
HUP0302371A3 (en) 2007-03-28
HUP0302371A2 (en) 2003-11-28
CN1437484A (en) 2003-08-20
CA2411100A1 (en) 2001-12-27
NZ523188A (en) 2006-06-30
EE200200703A (en) 2004-08-16
SE0002354D0 (en) 2000-06-22
KR20030010750A (en) 2003-02-05
US20030191177A1 (en) 2003-10-09
EP1296716A2 (en) 2003-04-02
DE60124400T2 (en) 2007-10-31
WO2001097751A3 (en) 2002-03-28
SK18072002A3 (en) 2003-08-05
BR0111790A (en) 2003-05-20
IS6653A (en) 2002-12-11

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