Classifications

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  • 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
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  • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • 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
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/06—Antimigraine agents
• • 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
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• • A—HUMAN NECESSITIES
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  • 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
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• • 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
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
  • A61P9/06—Antiarrhythmics
• • 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

Definitions

• CBs Calcium channel blockers
• ACEIs angiotensin converting enzyme inhibitors
• a representative of the class of CCBs is amiodipine, while a representative of the class of ACEIs is benazepril or benazeprilat.
• Amiodipine is 2-[(2-aminoethoxy)methyl]-4-(2-chIorophenyl)-1 ,4-dihydro-6-methyl-3,5- pyridinedicarboxylic acid 3-ethyl 5-methyl ester. It is sold commercially in the form of its besylate salt under the trademark NORVASC® as an antihypertensive. Amiodipine may be administered in free or pharmaceutically aceptable salt form. Where amiodipine dosages are set forth herein, it is understood that the amounts are the amounts corresponding to amiodipine free base equivalents, irrespective of the salt form used, unless otherwise indicated.
• a chronic anti-hypertensive therapy with amiodipine is often associated with side effects such as dose-limiting peripheral edema, especially ankle edema.
• the amiodipine induced ankle edema is believed to be due to a preferential dilation of the precapillary arterioles in the leg and a resultant efflux of fluid into the interstitial space.
• the upper limit of mono-therapy with amiodipine is 10 mg per day, and lower doses are preferred for chronic treatments. Higher dosage formulations than 10 mg per day are not approved by regulatory authorities or marketed, as in many susceptible individuals, side effects, such as those mentioned above, may limit efficacy and may ultimately result in discontinuation of the therapy.
• a "high dose” or a “higher dose” of amiodipine refers to daily dosage amounts greater than 5 mgs amiodipine, preferably from 6-40 mgs, more preferably 7.5-20 mgs, for example, 7.5, 10, 15, or 20 mgs, more preferably at least 10 mgs, e.g., 10, 12.5, 15, or 20 mgs, most preferably 10 or 20 mgs.
• dosages of 10-60mgs, preferably 20 to 40 mgs, for example 20, 30, or 40 mgs,, especially 40 mgs, are preferred.
• Benazepril is [S-(R * ,R * )]-3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2- oxo-1 H-1-benazepine-1 -acetic acid. It is sold commercially in the form of the hydrochloride salt under the trademarks LOTENSIN® or CIBACEN® as an antihypertensive. Benazeprilat is the diacid form of benazepril formed by cleavage of the ester group, and is the active metabolite of benazepril. Benazepril and benazeprilat may be administered in free or pharmaceutically acceptable salt form.
• ACEIs may only be moderately effective in non-Caucasian populations, especially in toe African Americans, and in patients where the renin angiotensin aldosterone system (RAAS) is already suppressed.
• a "high dose” or a “higher dose” of benazepril” refers to dosage amounts corresponding to greater than 20 mg benazepril hydrochloride, preferably from 21 to 160 mgs, preferably 40 to 80 mgs, for example, 40 mg or 80 mgs. Dosage amounts of this drug may be also be given every other day, in combination with amiodipine on the same day or on alternate days on which the amiodipine is administered. In both cases, the amount of benazepril would be preferably kept constant.
• amiodipine and benazepril Fixed dose combinations of amiodipine and benazepril are being marketed under the trade name Lotrel®. Corresponding amounts of the active ingredients are 2.5 mg of amiodipine and 10 mg of benazepril, 5 mg of amiodipine and 10 mg of benazepril, and 5 mg of amiodipine and 20 mg of benazepril, the amounts of amiodipine corresponding to the free base and the amounts of benazepril corresponding to the hydrochloride. As used herein, the term “Lotrel® combination" refers to these dosage combinations.
• the therapeutic combination of amiodipine and benazepril contemplated herein includes administration of these compounds such that the combination of amiodipine and benzapril may be administered every other day.
• benazepril alone may be administered on the alternate days.
• patients are provided with dosage forms comprising (i) combinations of amiodipine with benazepril and (ii) dosage forms comprising benazepril as active ingredient or placebo, in which case the two dosage forms may be provided in a kit of parts as described below.
• packages will comprise daily dosage amounts of appropriate active ingredients in a dispenser, blister pack or with other suitable packaging and instructions to ensure that the appropriate tablets are taken on the alternating days and otherwise ensure proper compliance with a prescribed dosage schedule.
• a high dose amiodipine may be alternated with lower dosage amounts of this drug on a daily basis in combination with daily administration of benazepril.
• the daily dosage level of the benazepril in this regime would remain constant.
• the high dose combination of amiodipine and benazepril or benazeprilate, respectively, as disclosed herein provides some surprising beneficial effects with an overall lack of adverse effects, selected from (but are not limited to) e.g. (i) a greater blood pressure control (either or both of systolic and diastolic blood pressure), especially in patients who do not achieve blood pressure levels defined as normal or optimal according to the WHO guidelines of the management of hypertension; (ii) reduction, prevention, attenuation or delay of side effects associated with amiodipine, such as the dose- limiting formation of peripheral edema, e.g.
• ankle edema (iii) reduction of afterload; (iv) end- organ protection, especially in case of the treatment of angina; and (v) reduction, prevention, attenuation or delay of risks or incidences of morbidity and mortality, especially of morbidity and mortality associated with atherosclerosis.
• a preferred patient population for applying the combination according to the present invention is selected from (i) those patients who do not achieve blood pressure levels defined as normal or optimal according to the WHO guidelines of the management of hypertension of 1999 (cf. J Hypertens 1999, 17:151-183); (ii) those patients with angina who require greater control of angina or blood pressure or both; (iii) those patients with heart failure, especially congestive heart failure, who require greater control of blood pressure, and (iv) patients suffering from pulmonary disease or pulmonary hypertension.
• moderate hypertension being characterized by a DBP of approximately 100 mm Hg according to said WHO definitions
• Corresponding clinical trials can be carried out e.g. in a double-blind, randomized, placebo- controlled, forced-titration, parallel-group trial.
• patients are randomized to receive either a Lotrel ® combination (e.g. 5 mg of amiodipine corresponding of the free base and 20 mg of benazepril corresponding to the hydrochloride) or a combination according to the present invention (e.g. 10 mg of amiodipine corresponding of the free base and 20 mg of benazepril corresponding to the free base) for 6 weeks; patients receiving placebo remain on placebo for the entire 8 weeks.
• the efficacy e.g. the change of blood pressure from baseline to the endpoint, is to be determined as well as the safety, e.g. the incidence of potential side effects.
• the combination according to the present invention can be used for the treatment (acute and especially chronic treatment) or prevention or delay of progression of a condition selected from the group consisting of hypertension (whether of the malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), heart failure, such as congestive heart failure, angina (whether stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular dysfunction, such as left ventricular hypertrophy, cognitive dysfunction (such as Alzheimer's, etc.), blood pressure-related cerebrovasular disease, stroke, pulmonary disease or pulmonary hypertension and headache.
• hypertension whether of the malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type
• heart failure such as congestive heart failure
• angina whether stable or unstable
• myocardial infarction atherosclerosis
• diabetic nephropathy diabetic
• amiodipine can be used, likewise, for the prevention, reduction, attenuation and delay of progression of side effects associated with high dose application of amiodipine; and for the protection of end-organs, including the kidneys and the heart, for example protection against left ventricular hypertrophy, right ventricular hypertrophy, e.g. as associated with pulmonary hypertension, and the like.
• the present invention relates to the use of a combination comprising
• an ACE inhibitor selected from the group consisting of benazepril, benazeprilat, and pharmaceutically acceptable salts thereof, and
• amiodipine or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention or delay of progression of a condition selected from the group consisting of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, blood pressure-related cerebrovasular disease, stroke, pulmonary disease or pulmonary hypertension and headache; wherein
• the amount of amiodipine or a pharmaceutically acceptable salt thereof is a high dose as defined above, e.g., corresponding to 6 mg to 40 mg of the free base and
• the amount of the ACE inhibitor or a pharmaceutically acceptable salt thereof is a high dose as defined above, e.g., corresponding to 20 mg to 160 mg of benazepril hydrochloride.
• the invention likewise relates to a composition, such as a pharmaceutical composition e.g. for the treatment or prevention or delay of progression of a condition selected from the group consisting of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, blood pressure-related cerebrovasular disease, stroke, pulmonary hypertension, and headache; comprising
• an ACEI selected from the group consisting of benazepril, benazeprilat, and pharmaceutically acceptable salts thereof, and
• the amount of amiodipine or a pharmaceutically acceptable salt thereof is a high dose as defined above, e.g., corresponding to 6 mg to about 40 mg of the free base and (ii) the amount of the ACE inhibitor or a pharmaceutically thereof is a high dose as defined above, e.g., corresponding to 20 mg to 160 mg of benazepril hydrochloride.
• Fixed combinations of amiodipine and benazepril in accordance with the present invention thus include combinations of high dose amiodipine and high dose benazepril, in ranges as described above, and also combinations at higher dosages of amiodipine than currently approved and provided in Lotrel® combinations, for example combinations containing amounts corresponding to 10-60 mg amiodipine and 20-160 mgs benazepril, e.g., combintations corresponding to (i)10-40 mgs amiodipine ree base, e.g., 10, 15 or 20 mgs, and (ii) 20-80 mgs benazepril hydrochloride, for example combinations corresponding to 10mg amolodipine free base and 20 mgs benazepril HCI, 10 mg amiodipine free base and 40 mgs benazepril HCI, 20 mgs amiodipine free base and 40 mgs benzapril HCI, and 20 mgs amiodipine free base and
• amolidpine is preferably in the form of amiodipine besylate.
• the benazepril is preferably in the form of benazepril hydrochloride.
• pharmaceutically acceptable carrier includes compounds well known to one of skill in the art and comprises excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).
• the present invention likewise relates to a method of treatment or prevention or delay of progression of a condition selected from the group consisting of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, blood pressure-related cerebrovasular disease, stroke, pulmonary disease or pulmonary hypertension and headache, comprising administering to a warm-blooded animal including man in need thereof an effective amount of a combination comprising
• an ACEI selected from the group consisting of benazepril, benazeprilat, and pharmaceutically acceptable salts thereof, and
• the amount of amiodipine or a pharmaceutically acceptable salt thereof in a high dose as defined above e.g., corresponding to 6 mg to about 40 mg free base
• the amount of the ACE inhibitor or a pharmaceutically acceptable salt thereof is a high does as defined above, e.g., corresponding to 20 mg to 160 mg benazepril hydrochloride.
• the corresponding active ingredients or a pharmaceutically acceptable salt thereof may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization according to conventional methods.
• the compounds to be combined can be present as pharmaceutically acceptable salts. As these compounds have at least one basic center, they can form acid addition salts.
• a preferred pharmaceutically acceptable salt of amiodipine is the besylate salt being the subject matter of US Patent 4,879,303; furthermore the maleate salt as set forth in US Patent 4,572,909; both patents are incorporated by reference herein in their entirety.
• the ACEI is benazepril or a salt thereof, most preferably the hydrochloride thereof.
• Suitable salts of benazepril and benazeprilat can be found in US Patent No. 4,410,520 and which is incorporated by reference herein in its entirety.
• the hydrochloride salt of the ACEI is most advantageous, with the most preferred specific ACEI compound being benazepril hydrochloride.
• the most preferred active components according to the instant invention are amiodipine besylate and benazepril hydrochloride.
• Preferred dosage ranges in combinations according to the instant invention comprise an amount of amiodipine or a pharmaceutically acceptable salt thereof from 6 mg to 40 mg and an amount of the ACEI or a pharmaceutically acceptable salt thereof from 20 mg to 160 mg, in each case, corresponding to the free base.
• the amount of amiodipine or a pharmaceutically acceptable salt thereof is preferably from 6 mg to 20 mg, especially 10 mg, in all above cases, corresponding to the free base.
• a preferred amount of benazepril or benazeprilat, respectively, or, in each case, pharmaceutically acceptable salt thereof is from 20 mg to 80 mg, preferably 20 mg to 40 mg, e.g., 20, 30, or 40 mgs, especially 20 mgs, or from 40 mg to 160 mg, especially 40 mg to 120 mg, most preferably 40 mg to 80 mg, , e.g., 40, 50, 60 70 or 80 mgs, esp. 40 mgs; in all above cases, corresponding to benazepril hydrochloride.
• a preferred amount of amiodipine or a pharmaceutically acceptable salt thereof is 10 or 20 mg and preferred amounts of benazepril or a pharmaceutically acceptable salt thereof are 20 mg, 40 mg or 80 mg. Most preferably all said doses are daily doses.
• a "daily dose” refers to the total amount of the drug substance administered in a 24 hour period, with a single administration the preferred method of treatment.
• the active ingredients of the pharmaceutical composition according to the present invention as described herein may be used for simultaneous use or sequential use in any order, for separate use or most preferably as a fixed combination.
• the CCB and the ACEI can be administered at different times, they are most preferably administered at the same time. Most conveniently, this is via a single, fixed combination dosage form. However, the CCB can be administered at times different from the administration of the ACEI and the invention benefits still be realized. When administered at different times, the CCB and the ACEI should be given within about 16 hours of each other, preferably within about 12 hours of each other, more preferably within about 8 hours of each other, most preferably within about 4 hours of each other. Of course, these time periods can be extended if the dosage form is one that will "administer" the agents for extended periods.
• the CCB and the ACEI When the CCB and the ACEI are given substantially simultaneously, they may be given by a single fixed combination dosage form or by different dosage forms, whichever are convenient. When given by different dosage forms, it is irrelevant whether the route of administration is the same for each agent or different for each agent. Any route of administration known for the individual agents is acceptable for the practice of the present invention. Most preferably, the agents are given in a fixed combination, or at least substantially simultaneously, i.e. within about 1 hour of each other. Also, the most suitable dosage form is an oral dosage form, where an oral administration is a clinically suitable route.
• the present invention likewise relates to a "kit-of-parts", for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points.
• the parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
• the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is more beneficial than the effect that would be obtained by use of only any one of the components.
• Dosages of the two agents include all dosages at which the agents are used individually.
• Corresponding dosages for other salts of amiodipine, for free benazepril and other salts of benazepril, and benazeprilat and its salts will be readily apparent to those of ordinary skill in the art.
• the range is the acceptable range based on adult mammal of approximately 50 to about 70 kg. Modified dosage ranges for mammals of other sizes and stages of development will be apparent to those of ordinary skill in the art.
• Benazepril and amiodipine are normally physically incompatible substances. Hence, if incorporated into a single dosage form they must be kept physically separated.
• preferred mammals are rabbits, dogs, goats, hogs, sheep, horses, cattle, and primates, more preferably primates, most preferably humans.
• the invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use.
• Benazepril hydrochloride cores are prepared using the following:
• Components 1-3 are milled and blended together and water is added to granulate the blend.
• the wet granules are screened and oven dried.
• the dried granules are then milled together with components 5-7.
• Component 4 is screened and then mixed with the other ingredients. The resulting mixture is then compressed into a core.
• Component 10 is dissolved in the water and component 9 is added thereto.
• the previously made cores are then coated with this solution and the wet coated tablets are dried. The dried tablets are then dusted with component 12.
• Amiodipine besylate for incorporation into the formulation is prepared as follows:
• Components 13-16 are mixed together and the blended mixture is screened and reblended.
• Component 17 is separately screened and then blended with the reblended mixture containing the amiodipine.
• No. 1 hard gelatin capsules are used to encapsulate one benazepril hydrochloride containing coated core along with 200 mg of the amiodipine besylate containing powder per capsule.

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• 2000
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• 2001
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