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WO2007040511A1 - Stable combinations of amlodipine besylate and benazepril hydrochloride - Google Patents

Stable combinations of amlodipine besylate and benazepril hydrochloride Download PDF

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Publication number
WO2007040511A1
WO2007040511A1 PCT/US2005/034930 US2005034930W WO2007040511A1 WO 2007040511 A1 WO2007040511 A1 WO 2007040511A1 US 2005034930 W US2005034930 W US 2005034930W WO 2007040511 A1 WO2007040511 A1 WO 2007040511A1
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WO
WIPO (PCT)
Prior art keywords
amlodipine
benazepril
composition
crospovidone
pharmaceutical
Prior art date
Application number
PCT/US2005/034930
Other languages
French (fr)
Inventor
Mali Kadosh
Fanny Leska
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to PCT/US2005/034930 priority Critical patent/WO2007040511A1/en
Priority to CA002620018A priority patent/CA2620018A1/en
Priority to JP2008532202A priority patent/JP2009508948A/en
Priority to AU2005336956A priority patent/AU2005336956A1/en
Priority to DE602005005706T priority patent/DE602005005706T2/en
Priority to EP05256202A priority patent/EP1797885B1/en
Priority to DK05256202T priority patent/DK1797885T3/en
Priority to ES05256202T priority patent/ES2303198T3/en
Priority to AT05256202T priority patent/ATE390139T1/en
Priority to EP08002996A priority patent/EP1930008A1/en
Priority to PT05256202T priority patent/PT1797885E/en
Priority to EP08002835A priority patent/EP1932528A1/en
Publication of WO2007040511A1 publication Critical patent/WO2007040511A1/en
Priority to HK07112316A priority patent/HK1103658A1/en
Priority to IL189613A priority patent/IL189613A0/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61P25/06—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
    • 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
    • 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
    • A61P9/10—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 the field of combination therapy of amlodipine with benazepril.
  • ACEI angiotensin converting enzyme inhibitors
  • CCB calcium channel blockers
  • Benazepril can be administered as benazepril hydrochloride, which is chemically identified as 3 - [ [ 1 -(ethoxycarbonyl)-3 -phenyl-( 1 S)-propyl] amino] -2,3 ,4,5 -tetrahydro-2- oxo-li7-l-(3S)-benzazepine-l-acetic acid monohydrochloride (C 24 H 28 N 2 O 5 -HCl).
  • Amlodipine can be administered as amlodipine besylate, which is chemically identified as (R.S.) 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6- methyl-3,5-pyridinedicarboxylate benzenesulphonate (C 2O H 25 ClN 2 Os-AC 6 H 6 O 3 S).
  • a combination of benazepril hydrochloride and amlodipine besylate is marketed in the United States by Novartis under the trade name LOTREL® as capsules for oral administration.
  • the capsules are formulated in four different strengths with an amount of amlodipine besylate equivalent to 2.5 mg, 5 mg, or 10 mg of amlodipine free base, and 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg.
  • LOTREL® is indicated for the treatment of hypertension.
  • the present inventors have surprisingly discovered a method for making a pharmaceutical composition containing both amlodipine and benazepril wherein physical separation of the two drug components is not required.
  • Such a pharmaceutical composition and methods for making it are provided herein.
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising benazepril, solvates, esters, or pharmaceutically acceptable salts thereof, and amlodipine or solvates, esters,, or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition is stable, that is, after storage for about 3 months at about 4O 0 C at about 75% relative humidity, it contains no more than 2.5% of (s,s)-diacid by weight relative to the benazepril and/or no more than 0.3% of impurity D by weight relative to the amlodipine.
  • the benazepril is benazepril hydrochloride
  • the amlodipine is amlodipine besylate.
  • the benazepril and the amlodipine are in physical contact with one another.
  • the benazepril hydrochloride is prepared by wet granulation, and the amlodipine besylate is prepared by dry processing.
  • the present invention provides a method including the steps of: preparing a benazepril composition by wet granulation; preparing an amlodipine composition by dry processing; and contacting the benazepril composition and the amlodipine composition to obtain a combination pharmaceutical composition.
  • Wet granulation preferably includes the steps of combining benazepril hydrochloride with one or more pharmaceutical excipients preferably selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose; adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water and optionally, polysorbate 80, povidone, or both; drying the wet granulate to obtain a dry granulate; and milling the dry granulate.
  • Dry processing preferably includes the steps of sieving a mixture. of amlodipine besylate with one or more pharmaceutical excipients preferably selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide; and blending the mixture.
  • one or more pharmaceutical excipients preferably selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide
  • dry processing further includes sieving one or more additional pharmaceutical excipients, preferably crospovidone and/or magnesium stearate, and blending the additional pharmaceutical excipient with the mixture.
  • the method includes a step of encapsulating the combination pharmaceutical composition.
  • the present invention provides a benazepril composition
  • a benazepril composition comprising about 5% to about 20% benazepril hydrochloride, about 15% to about 20% pregelatinized starch, about 25% to about 35% lactose monohydrate, about 10% to about 15% starch, about 5% crospovidone, about 15% to about 25% microcrystalline cellulose, about 0.1% to about 2% polysorbate 80, and about 5% povidone, by weight percent relative to the total benazepril composition.
  • the present invention provides an amlodipine composition
  • an amlodipine composition comprising about 2% to about 10% amlodipine besylate, about 25% to about 30% calcium phosphate dibasic, about 1% to about 2% sodium starch glycolate, about 50% to about 60% microcrystalline cellulose, about 1% colloidal silicon dioxide, about 5% crospovidone, and about 0.2% to about 2% magnesium stearate, by weight percent relative to the total amlodipine composition.
  • Figure 1 illustrates a flowchart for a method for making a capsule comprising a mixture of benazepril and amlodipine.
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising benazepril, solvates, esters, or pharmaceutically acceptable salts thereof, and amlodipine, solvates, esters, or pharmaceutically acceptable salts thereof.
  • amlodipine refers to the free base form.
  • the benazepril is preferably benazepril hydrochloride, and the amlodipine is preferably amlodipine besylate.
  • the pharmaceutical composition is stable, that is, the pharmaceutical composition contains low levels of degradation products. Li part, the composition slows and/or avoids the degradation of the active ingredient, thereby reducing the amounts of impurities present in the active ingredient after storage.
  • a main degradation product of benazepril is (s,s)-diacid (benazeprilat), which is the active metabolite of benazepril.
  • a main degradation product of amlodipine is impurity D (-ethyl 5-methyl 2-[(2- aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate).
  • the specifications for degradation products of benazepril and amlodipine are summarized in Table 1.
  • the pharmaceutical composition after the pharmaceutical composition is stored for about 3 months at about 40°C at about 75% relative humidity, the pharmaceutical composition contains no more than 2.5% of (s,s)-diacid by weight relative to the benazepril and/or no more than 0.3% of impurity D by weight relative to the amlodipine.
  • the benazepril and the amlodipine are in physical contact with one another.
  • Examples of physical contact include physical contact at an uncoated interface between tablet layers, physical contact within the fluid medium of a liquid oral or injectable dosage form, and physical contact throughout a blended mixture of the two active ingredients.
  • a blended mixture comprising the two active ingredients is used as a capsule filling.
  • the pharmaceutical composition preferably contains about 10 mg to about 20 mg benazepril hydrochloride, more preferably about 10 mg or about 20 mg.
  • the amount of amlodipine besylate corresponds to about 2.5 mg to about 10 mg of amlodipine free base. More preferably, the amount of amlodipine besylate corresponds to about 2.5 mg, about 5 mg, or about 10 mg of amlodipine free base.
  • the ratio of benazepril to amlodipine corresponds to a weight ratio of about 2: 1 to about 4:1, more preferably about 2:1 or about 4:1.
  • the benazepril hydrochloride is prepared by wet granulation
  • the amlodipine besylate is prepared by dry processing. Wet granulation and dry processing are described in further detail below.
  • the present invention provides a method for making a pharmaceutical composition comprising both benazepril and amlodipine.
  • the pharmaceutical composition comprising both benazepril and amlodipine is referred to as the combination pharmaceutical composition.
  • the method includes the steps of: preparing a benazepril composition by wet granulation; preparing an amlodipine composition by dry processing; and contacting the benazepril composition and the amlodipine composition to obtain a combination pharmaceutical composition.
  • Fig. 1 depicts a preferred embodiment of this method.
  • Wet granulation preferably includes the steps of combining benazepril hydrochloride with one or more pharmaceutical excipients; adding a granulation solution to obtain a wet granulate, wherein the granulation solution preferably comprises water and optionally, one or more additional excipients; drying the wet granulate to obtain a dry granulate; and milling the dry granulate.
  • Pharmaceutical excipients are described in further detail below.
  • preferred pharmaceutical excipients include pregelatinized starch, lactose monohydrate, starch, crospovidone, microcrystalline cellulose, polysorbate 80, and povidone.
  • Dry processing preferably includes the steps of sieving a mixture of amlodipine besylate with one or more pharmaceutical excipients; and blending the mixture. If necessary, the sieving step is performed to avoid the inclusion of agglomerates and extraneous matter.
  • preferred pharmaceutical excipients include calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide.
  • the mixture is sieved through a size 30 mesh.
  • dry processing further includes sieving one or more additional pharmaceutical excipients and blending the additional pharmaceutical excipient with the mixture, i.e., the amlodipine composition.
  • the additional pharmaceutical excipient(s) are blended with the amlodipine composition after it is combined with the benazepril composition.
  • Preferred additional pharmaceutical excipients include crospovidone and magnesium stearate.
  • crospovidone is sieved through a size 30 mesh.
  • magnesium stearate is sieved through a size 50 mesh.
  • the method includes a step of encapsulating the combination pharmaceutical composition.
  • the method includes the steps of combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose; adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water, polysorbate 80, and povidone; drying the wet granulate to obtain a dry granulate; milling the dry granulate; sieving a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide through a 30 mesh sieve; blending the mixture with the dry granulate to form a combined pharmaceutical composition; sieving crospovidone through a 30 mesh sieve; blending the crospovidone with the combined pharmaceutical composition; sieving magnesium stearate through a 50 mesh sieve;
  • the present invention provides a benazepril composition
  • a benazepril composition comprising about 5% to about 20% benazepril hydrochloride, about 15% to about 20% pregelatinized starch, about 25% to about 35% lactose monohydrate, about 10% to about 15% starch, about 5% crospovidone, about 15% to about 25% microcrystalline cellulose, about 0.1% to about 2% polysorbate 80, and about 5% povidone, by weight percent relative to the total benazepril composition.
  • the present invention provides an amlodipine composition
  • an amlodipine composition comprising about 2% to about 10% amlodipine besylate, about 25% to about 30% calcium phosphate dibasic, about 1% to about 2% sodium starch glycolate, about 50% to about 60% microcrystalline cellulose, about 1% colloidal silicon dioxide, about 5% crospovidone, and about 0.2% to about 2% magnesium stearate, by weight percent relative to the total amlodipine composition.
  • compositions of the present invention can be prepared as medicaments to be administered e.g. orally. Suitable forms for oral administration include solid forms such as tablets, powders, granulates, capsules. hi addition to the active ingredient(s), the compositions of the present invention can contain one or more excipients or adjuvants.
  • An excipient is an inert ingredient added to a pharmaceutical composition to dilute it or to give it form or consistency.
  • An adjuvant assists the action of an active ingredient. Selection of excipients and adjuvants and the amounts to use can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel ® ), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, mannitol, powdered cellulose and sorbitol.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include carboxymethylcellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ® ), hydroxypropyl methyl cellulose (e.g. Methocel ® ), methylcellulose, povidone (e.g. Kollidon ® , Plasdone ® ), pregelatinized starch, and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition.
  • Disintegrants include carboxymethylcellulose calcium, croscarmellose sodium (e.g. Ac- Di-Sol ® ), crospovidone (e.g. Kollidon ® , Polyplasdone ® ), microcrystalline cellulose, polacrilin potassium, pregelatinized starch, sodium starch glycolate (e.g. Explotab ® ), and starch.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and talc.
  • a dosage form such as a tablet
  • the composition is subjected to pressure, e.g., from a punch and dye.
  • pressure e.g., from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • the dosage form of the present invention can be a capsule containing the composition, preferably a powdered and/or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • a composition for tableting or capsule filling can be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried, screened and/or milled to the desired particle size.
  • the granulate can then be filled into capsules optionally with other ingredients. This process is the preferred process for the Benazepril component of the present invention.
  • a granular composition can be prepared conventionally by dry granulation.
  • the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules.
  • the compacted granules can subsequently be compressed into a tablet or filled into capsules.
  • This technique is more suitable for the amlodipine component of the instant invention but even more preferred is the use of a blended powder composition of the amlodipine and excipients.
  • a capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described above, however, most preferred is a capsule containing a benazepril granulate prepared by wet granulation, mixed with a dry blended powder composition of the amlodipine and excipients.
  • Capsules containing both benazepril hydrochloride and amlodipine besylate were made by the following process.
  • the granulation solution was prepared by adding purified water USP to a mixture of polysorbate 80 NF and PVP K-30 (povidone.USP) while mixing and continuing to mix until dissolved. The granulation solution was then added to the granulator mixer and mixed until a granulate was obtained. The granulate was then dried in a fluid bed drier. The dried granulate was then milled in an oscillating granulator and placed in a container.
  • amlodipine besylate calcium phosphate dibasic USP anhydrous (powder) and sodium starch glycolate NF.
  • the sieved materials were then transferred to a blender and blended.
  • Microcrystalline cellulose and colloidal silicon dioxide were sieved, added to the mixture in the blender, and mixed. The mixture was then removed to a container.
  • the granulate from part I and the dry mixture from part II were placed in a blender and blended.
  • Crospovidone was sieved and added to the blender and the mixture blended.
  • Magnesium stearate was then sieved and added to the blender and the mixture was blended.
  • amlodipine besylate correspond to 2.5 mg, 5 mg, and 10 mg of amlodipine free base, respectively.

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Abstract

The present invention provides a pharmaceutical composition comprising benazepril and amlodipine wherein the benazepril and the amlodipine are in physical contact with one another, and methods for making the same.

Description

STABLE COMBINATIONS OF AMLODIPINE BESYLATE AND BENAZEPRIL
HYDROCHLORIDE
FIELD OF INVENTION
The present invention relates to the field of combination therapy of amlodipine with benazepril.
BACKGROUND OF THE INVENTION
In the fight against cardiovascular disease, our current arsenal of weapons includes angiotensin converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB). Combination therapy of an ACEI with a CCB can achieve synergistic results effective in treating a variety of conditions including hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache. The combination of the ACEI benazepril and the CCB amlodipine is described by U.S. Patent No. 6,162,802 ("the '802 patent").
Benazepril can be administered as benazepril hydrochloride, which is chemically identified as 3 - [ [ 1 -(ethoxycarbonyl)-3 -phenyl-( 1 S)-propyl] amino] -2,3 ,4,5 -tetrahydro-2- oxo-li7-l-(3S)-benzazepine-l-acetic acid monohydrochloride (C24H28N2O5 -HCl). Amlodipine can be administered as amlodipine besylate, which is chemically identified as (R.S.) 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6- methyl-3,5-pyridinedicarboxylate benzenesulphonate (C2OH25ClN2Os-AC6H6O3S). A combination of benazepril hydrochloride and amlodipine besylate is marketed in the United States by Novartis under the trade name LOTREL® as capsules for oral administration. The capsules are formulated in four different strengths with an amount of amlodipine besylate equivalent to 2.5 mg, 5 mg, or 10 mg of amlodipine free base, and 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg. LOTREL® is indicated for the treatment of hypertension.
The '802 patent teaches that "[bjenazepril and amlodipine are physically incompatible substances. Hence, if incorporated into a single dosage form they must be kept physically separated." Col. 3, lines 48-50.
The present inventors have surprisingly discovered a method for making a pharmaceutical composition containing both amlodipine and benazepril wherein physical separation of the two drug components is not required. Such a pharmaceutical composition and methods for making it are provided herein.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a stable pharmaceutical composition comprising benazepril, solvates, esters, or pharmaceutically acceptable salts thereof, and amlodipine or solvates, esters,, or pharmaceutically acceptable salts thereof. The pharmaceutical composition is stable, that is, after storage for about 3 months at about 4O0C at about 75% relative humidity, it contains no more than 2.5% of (s,s)-diacid by weight relative to the benazepril and/or no more than 0.3% of impurity D by weight relative to the amlodipine. Preferably, the benazepril is benazepril hydrochloride, and the amlodipine is amlodipine besylate.
In a preferred embodiment, the benazepril and the amlodipine are in physical contact with one another.
In another embodiment, the benazepril hydrochloride is prepared by wet granulation, and the amlodipine besylate is prepared by dry processing.
In another embodiment, the present invention provides a method including the steps of: preparing a benazepril composition by wet granulation; preparing an amlodipine composition by dry processing; and contacting the benazepril composition and the amlodipine composition to obtain a combination pharmaceutical composition.
Wet granulation preferably includes the steps of combining benazepril hydrochloride with one or more pharmaceutical excipients preferably selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose; adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water and optionally, polysorbate 80, povidone, or both; drying the wet granulate to obtain a dry granulate; and milling the dry granulate.
Dry processing preferably includes the steps of sieving a mixture. of amlodipine besylate with one or more pharmaceutical excipients preferably selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide; and blending the mixture.
In one embodiment, dry processing further includes sieving one or more additional pharmaceutical excipients, preferably crospovidone and/or magnesium stearate, and blending the additional pharmaceutical excipient with the mixture. In another embodiment, the method includes a step of encapsulating the combination pharmaceutical composition.
In one embodiment, the present invention provides a benazepril composition comprising about 5% to about 20% benazepril hydrochloride, about 15% to about 20% pregelatinized starch, about 25% to about 35% lactose monohydrate, about 10% to about 15% starch, about 5% crospovidone, about 15% to about 25% microcrystalline cellulose, about 0.1% to about 2% polysorbate 80, and about 5% povidone, by weight percent relative to the total benazepril composition.
In another embodiment, the present invention provides an amlodipine composition comprising about 2% to about 10% amlodipine besylate, about 25% to about 30% calcium phosphate dibasic, about 1% to about 2% sodium starch glycolate, about 50% to about 60% microcrystalline cellulose, about 1% colloidal silicon dioxide, about 5% crospovidone, and about 0.2% to about 2% magnesium stearate, by weight percent relative to the total amlodipine composition.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates a flowchart for a method for making a capsule comprising a mixture of benazepril and amlodipine.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a stable pharmaceutical composition comprising benazepril, solvates, esters, or pharmaceutically acceptable salts thereof, and amlodipine, solvates, esters, or pharmaceutically acceptable salts thereof. The general term amlodipine as used herein refers to the free base form. In the stable pharmaceutical compositions of the present invention, the benazepril is preferably benazepril hydrochloride, and the amlodipine is preferably amlodipine besylate.
The pharmaceutical composition is stable, that is, the pharmaceutical composition contains low levels of degradation products. Li part, the composition slows and/or avoids the degradation of the active ingredient, thereby reducing the amounts of impurities present in the active ingredient after storage. A main degradation product of benazepril is (s,s)-diacid (benazeprilat), which is the active metabolite of benazepril. A main degradation product of amlodipine is impurity D (-ethyl 5-methyl 2-[(2- aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate). The specifications for degradation products of benazepril and amlodipine are summarized in Table 1.
Table 1: Limits for Degradation Products of Benazepril and Amlodipine
Figure imgf000005_0001
In one embodiment, after the pharmaceutical composition is stored for about 3 months at about 40°C at about 75% relative humidity, the pharmaceutical composition contains no more than 2.5% of (s,s)-diacid by weight relative to the benazepril and/or no more than 0.3% of impurity D by weight relative to the amlodipine.
In a preferred embodiment, the benazepril and the amlodipine are in physical contact with one another. Examples of physical contact include physical contact at an uncoated interface between tablet layers, physical contact within the fluid medium of a liquid oral or injectable dosage form, and physical contact throughout a blended mixture of the two active ingredients. In a preferred embodiment, a blended mixture comprising the two active ingredients is used as a capsule filling.
The pharmaceutical composition preferably contains about 10 mg to about 20 mg benazepril hydrochloride, more preferably about 10 mg or about 20 mg. Preferably, the amount of amlodipine besylate corresponds to about 2.5 mg to about 10 mg of amlodipine free base. More preferably, the amount of amlodipine besylate corresponds to about 2.5 mg, about 5 mg, or about 10 mg of amlodipine free base. Preferably, the ratio of benazepril to amlodipine corresponds to a weight ratio of about 2: 1 to about 4:1, more preferably about 2:1 or about 4:1.
In one embodiment, the benazepril hydrochloride is prepared by wet granulation, and the amlodipine besylate is prepared by dry processing. Wet granulation and dry processing are described in further detail below. In one embodiment, the present invention provides a method for making a pharmaceutical composition comprising both benazepril and amlodipine. The pharmaceutical composition comprising both benazepril and amlodipine is referred to as the combination pharmaceutical composition. The method includes the steps of: preparing a benazepril composition by wet granulation; preparing an amlodipine composition by dry processing; and contacting the benazepril composition and the amlodipine composition to obtain a combination pharmaceutical composition. Fig. 1 depicts a preferred embodiment of this method.
Wet granulation preferably includes the steps of combining benazepril hydrochloride with one or more pharmaceutical excipients; adding a granulation solution to obtain a wet granulate, wherein the granulation solution preferably comprises water and optionally, one or more additional excipients; drying the wet granulate to obtain a dry granulate; and milling the dry granulate. Pharmaceutical excipients are described in further detail below. For the benazepril composition, preferred pharmaceutical excipients include pregelatinized starch, lactose monohydrate, starch, crospovidone, microcrystalline cellulose, polysorbate 80, and povidone.
Dry processing preferably includes the steps of sieving a mixture of amlodipine besylate with one or more pharmaceutical excipients; and blending the mixture. If necessary, the sieving step is performed to avoid the inclusion of agglomerates and extraneous matter. For the amlodipine composition, preferred pharmaceutical excipients include calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide. Preferably, the mixture is sieved through a size 30 mesh.
In one embodiment, dry processing further includes sieving one or more additional pharmaceutical excipients and blending the additional pharmaceutical excipient with the mixture, i.e., the amlodipine composition. In a preferred embodiment, the additional pharmaceutical excipient(s) are blended with the amlodipine composition after it is combined with the benazepril composition. Preferred additional pharmaceutical excipients include crospovidone and magnesium stearate. Preferably, crospovidone is sieved through a size 30 mesh. Preferably, magnesium stearate is sieved through a size 50 mesh.
In one embodiment, the method includes a step of encapsulating the combination pharmaceutical composition.
In a preferred embodiment, the method includes the steps of combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose; adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water, polysorbate 80, and povidone; drying the wet granulate to obtain a dry granulate; milling the dry granulate; sieving a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide through a 30 mesh sieve; blending the mixture with the dry granulate to form a combined pharmaceutical composition; sieving crospovidone through a 30 mesh sieve; blending the crospovidone with the combined pharmaceutical composition; sieving magnesium stearate through a 50 mesh sieve; blending the magnesium stearate with the combined pharmaceutical composition; and encapsulating the combined pharmaceutical composition.
In one embodiment, the present invention provides a benazepril composition comprising about 5% to about 20% benazepril hydrochloride, about 15% to about 20% pregelatinized starch, about 25% to about 35% lactose monohydrate, about 10% to about 15% starch, about 5% crospovidone, about 15% to about 25% microcrystalline cellulose, about 0.1% to about 2% polysorbate 80, and about 5% povidone, by weight percent relative to the total benazepril composition.
In another embodiment, the present invention provides an amlodipine composition comprising about 2% to about 10% amlodipine besylate, about 25% to about 30% calcium phosphate dibasic, about 1% to about 2% sodium starch glycolate, about 50% to about 60% microcrystalline cellulose, about 1% colloidal silicon dioxide, about 5% crospovidone, and about 0.2% to about 2% magnesium stearate, by weight percent relative to the total amlodipine composition.
The compositions of the present invention can be prepared as medicaments to be administered e.g. orally. Suitable forms for oral administration include solid forms such as tablets, powders, granulates, capsules. hi addition to the active ingredient(s), the compositions of the present invention can contain one or more excipients or adjuvants. An excipient is an inert ingredient added to a pharmaceutical composition to dilute it or to give it form or consistency. An adjuvant assists the action of an active ingredient. Selection of excipients and adjuvants and the amounts to use can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field. Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, mannitol, powdered cellulose and sorbitol.
Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include carboxymethylcellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), methylcellulose, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include carboxymethylcellulose calcium, croscarmellose sodium (e.g. Ac- Di-Sol®), crospovidone (e.g. Kollidon®, Polyplasdone®), microcrystalline cellulose, polacrilin potassium, pregelatinized starch, sodium starch glycolate (e.g. Explotab®), and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and talc.
When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure, e.g., from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
The dosage form of the present invention can be a capsule containing the composition, preferably a powdered and/or granulated solid composition of the invention, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and/or milled, dried, screened and/or milled to the desired particle size. The granulate can then be filled into capsules optionally with other ingredients. This process is the preferred process for the Benazepril component of the present invention.
A granular composition can be prepared conventionally by dry granulation. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet or filled into capsules. This technique is more suitable for the amlodipine component of the instant invention but even more preferred is the use of a blended powder composition of the amlodipine and excipients.
A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described above, however, most preferred is a capsule containing a benazepril granulate prepared by wet granulation, mixed with a dry blended powder composition of the amlodipine and excipients.
Having thus described the present invention with reference to certain preferred embodiments, the invention will now be further illustrated by the following non-limiting examples.
EXAMPLES
Example 1 : Amlodipine Besylate/Benazepril Hydrochloride Capsules
Capsules containing both benazepril hydrochloride and amlodipine besylate were made by the following process.
Preparation of Benazepril Hydrochloride granulate — Part I:
The following materials were mixed in a granulator mixer: pregelatinized starch
(Starch STA-RX-1500), lactose monohydrate NF (100 mesh), benazepril hydrochloride, starch NF, crospovidone NF, and microcrystalline cellulose NF (Avicel PH 101). The granulation solution was prepared by adding purified water USP to a mixture of polysorbate 80 NF and PVP K-30 (povidone.USP) while mixing and continuing to mix until dissolved. The granulation solution was then added to the granulator mixer and mixed until a granulate was obtained. The granulate was then dried in a fluid bed drier. The dried granulate was then milled in an oscillating granulator and placed in a container.
Dry Mix (Amlodipine) - Part II:
The following materials were sieved: amlodipine besylate, calcium phosphate dibasic USP anhydrous (powder) and sodium starch glycolate NF. The sieved materials were then transferred to a blender and blended. Microcrystalline cellulose and colloidal silicon dioxide were sieved, added to the mixture in the blender, and mixed. The mixture was then removed to a container.
Combination of Amlodipine and Benazepril Hydrochloride - Part III:
The granulate from part I and the dry mixture from part II were placed in a blender and blended. Crospovidone was sieved and added to the blender and the mixture blended. Magnesium stearate was then sieved and added to the blender and the mixture was blended.
Encapsulation - Part IV:
The final blend of part III was filled into capsules. Specific compositions are described in Table 2.
Table 2: Amlodipine Besylate/Benazepril Hydrochloride Capsules
Figure imgf000010_0001
Figure imgf000011_0001
For granulation processing only.
** 3.465 mg, 6.93 mg, and 13.86 mg of amlodipine besylate correspond to 2.5 mg, 5 mg, and 10 mg of amlodipine free base, respectively.
Example 2: Stability Study
Over the course of 3 months at 4O0C and 75% relative humidity, the degradation products of the amlodipine besylate/benazepril hydrochloride capsules were measured by HPLC. Results are summarized in Table 3 below.
Table 3: 5 Stability Results for Amlodipine Besylate/Benazepnl Hydrochloride Capsules
Time zero 1 M 2M 3M
40c/75%RH 40c/75%RH 40c/75%RH PP CAP PP CAP -
100 1000 100 100 1000
2.5/1 Omg *s,s-diacid Tabs 100 Tabs Tabs 100 Tabs Tabs 1000 Tabs Tabs 100 Tabs Tabs Total(excl *) CRC1 PP CAP2 PP CAP CRC PP CAP PP CAP CRC PP CAP PP CAP
"Impurity D <0.05 0.08 - - 0.06 - - 0.1 - - Total(excl *) <0.05 <0.05 <0.05 <0.05
5/1 Omg *s,s-diacid <0.05 0.3 0.4 0.4 0.6 1.1 0.8 1.0 1.2 1.2 Total(excl *) 0.07 0.1 0.1 0.1 0.2 0.2 0.2 0.2 0.2 0.2
"Impurity D <0.05 0.1 0.1 0.1 0.08 0.1 0.08 0.1 0.1 0.1 Total(excl *) <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05
5/20mg *s,s-diacid <0.05 0.2 0.3 0.2 0.4 0.6 0.4 0.8 1.0 0.8 Total(excl *) 0.06 0.05 0.06 0.05 0.1 0.1 0.1 0.1 0.1 0.1
"Impurity D <0.05 0.1 0.1 0.1 0.06 0.08 0.07 0.1 0.09 0.1 TotaKexcl *) <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.06 0.07 0.08
10/20mg *s,s-diacid <0.05 0.2 0.3 0.6 - Total(excl *) 0.07 0.1 - - 0.1 - - 0.2 -
"Impurity D <0.05 0.06 - - 0.06 - - 0.1 - - TotaKexcl *) <0.05 <0.05 <0.05 <0.05
*s,s-diacid results from degradation of Benazepril "Impurity D results from degradation of Amlodipine 1CRC = Child resistant Cap i 2PP CAP = Polypropylene Cap '

Claims

:LAIMS/hat is claimed is:. A pharmaceutical composition comprising: a) Benazepril or its solvates, or a pharmaceutically acceptable salt thereof, and b) Amlodipine or its solvates, or a pharmaceutically acceptable salt thereof, such that the benazepril and the amlodipine are not physically separated from one another, and wherein after about 3 months at about 40°C at about 75% relative humidity, the pharmaceutical composition contains: i) no more than 2.5% of (s,s)-diacid by weight relative to the benazepril; and/or ii) no more than 0.3% of impurity D by weight relative to the amlodipine.. The pharmaceutical composition of claim 1, wherein the benazepril and the amlodipine re in physical contact with one another.. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is ncapsulated.. The pharmaceutical composition of claim 1, wherein the benazepril is benazepril ydrochloride.. The pharmaceutical composition of claim 1, wherein the amlodipine is amlodipine esylate.. The pharmaceutical composition of claim 1, wherein the benazepril is prepared by wet ranulation, and the amlodipine is prepared by dry processing.. A method comprising: a) preparing a benazepril composition by wet granulation; b) preparing an amlodipine composition by dry processing; and c) contacting the benazepril composition and the amlodipine composition, and optionally adding excipients, to obtain a combination pharmaceutical composition.. The method of claim 7, wherein the benazepril composition comprises benazepril ydrochloride and one or more pharmaceutical excipients. . The method of claim 8, wherein benazepril composition comprises one or more harmaceutical excipients selected from the group consisting of pregelatinized starch, lactose ionohydrate, starch, crospovidone, microcrystalline cellulose, polysorbate 80, and povidone.0. The method of claim 9, wherein the benazepril composition comprises: a) about 5% to about 20% benazepril hydrochloride; b) about 15% to about 20% pregelatinized starch; c) about 25% to about 35% lactose monohydrate; d) about 10% to about 15% starch; e) about 5% crospovidone; f) about 15% to about 25% microcrystalline cellulose; g) about 0.1% to about 2% polysorbate 80; and h) about 5% povidone, y weight percent relative to the total benazepril composition.
1. The method of claim 7, wherein preparing the benazepril composition by wet granulation omprises: a) combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose; b) adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water and optionally, polysorbate 80, povidone, or both; c) drying the wet granulate to obtain a dry granulate; and d) milling the dry granulate.
2. The method of claim 7, wherein the amlodipine composition comprises amlodipine esylate and one or more pharmaceutical excipients.
3. The method of claim 7, wherein the amlodipine composition comprises one or more harmaceutical excipients selected from the group consisting of calcium phosphate dibasic, odium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide.
4. The method of claim 13, wherein the amlodipine composition comprises: a) about 2% to about 10% amlodipine besylate; b) about 25% to about 30% calcium phosphate dibasic; c) about 1% to about 2% sodium starch glycolate; d) about 50% to about 60% microcrystalline cellulose; e) about 1% colloidal silicon dioxide, y weight percent relative to the total amlodipine composition.
5. The method of claim 7, wherein the optionally added excipients comprise crospovidone nd magnesium stearate.
6. The method of claim 7, wherein the optionally added excipients comprise about 1% to bout 5% crospovidone and about 0.2% to about 2% magnesium stearate by weight percent slative to the total amlodipine composition.
7. The method of claim 7, wherein preparing the amlodipine composition by dry processing omprises: a) sieving a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide; and b) blending the mixture.
8. The method of claim 7, further comprising: a) sieving one or more additional pharmaceutical excipients selected from the group consisting of crospovidone and magnesium stearate; and b) blending the additional pharmaceutical excipient with the mixture.
9. The method of claim 7, further comprising encapsulating the combined pharmaceutical omposition.
0. The method of claim 7, comprising: a) combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose; b) adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water, polysorbate 80, and povidone; c) drying the wet granulate to obtain a dry granulate; d) milling the dry granulate; e) sieving a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide, through a 30 mesh sieve; f) blending the mixture with the dry granulate to form a combined pharmaceutical composition; g) sieving crospovidone through a 30 mesh sieve; h) blending the crospovidone with the combined pharmaceutical composition; i) sieving magnesium stearate through a 50 mesh sieve; j) blending the magnesium stearate with the combined pharmaceutical composition; and k) encapsulating the combined pharmaceutical composition.
.1. A benazepril composition comprising: a) about 5% to about 20% benazepril hydrochloride; b) about 15% to about 20% pregelatinized starch; c) about 25% to about 35% lactose monohydrate; d) about 10% to about 15% starch; e) about 5% crospovidone; f) about 15% to about 25% microcrystalline cellulose; g) about 0.1% to about 2% polysorbate 80; and h) about 5% povidone, iy weight percent relative to the total benazepril composition.
'2. An amlodipine composition comprising: a) about 2% to about 10% amlodipine besylate; b) about 25% to about 30% calcium phosphate dibasic; c) about 1% to about 2% sodium starch glycolate; d) about 50% to about 60% microcrystalline cellulose; e) about 1% colloidal silicon dioxide; f) about 5% crospovidone; and g) about 0.2% to about 2% magnesium stearate,
•y weight percent relative to the total amlodipine composition.
PCT/US2005/034930 2005-09-28 2005-09-28 Stable combinations of amlodipine besylate and benazepril hydrochloride WO2007040511A1 (en)

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ES05256202T ES2303198T3 (en) 2005-09-28 2005-10-04 STABLE COMBINATIONS OF BENZEPRILO AMLODIPINE AND HYDROCLORIDE BESYLATE.
EP05256202A EP1797885B1 (en) 2005-09-28 2005-10-04 Stable combinations of amlodipine besylate and benazepril hydrochloride
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PT05256202T PT1797885E (en) 2005-09-28 2005-10-04 Stable combinations of amlodipine besylate and benazepril hydrochloride
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008065485A2 (en) * 2006-10-19 2008-06-05 Torrent Pharmaceuticals Limited Stable pharmaceutical compositions of a calcium channel blocker and an ace inhibitor
WO2011104588A3 (en) * 2010-02-24 2012-04-19 Sanofi-Aventis Deutschland Gmbh Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation
CN102440993A (en) * 2011-12-08 2012-05-09 扬子江药业集团广州海瑞药业有限公司 Amlodipine benazepril tablet and preparation method thereof
WO2014076632A1 (en) 2012-11-15 2014-05-22 Adamed Sp. Z O.O. A pharmaceutical composition containing an ace inhibitor and a calcium channel blocker
US10130624B2 (en) 2005-03-15 2018-11-20 Lupin Limited Pharmaceutical compositions of amlodipine and benazepril

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002049645A1 (en) * 2000-12-18 2002-06-27 Novartis Ag Therapeutic combination of amlodipine and benazepril
US20020176889A1 (en) * 2000-12-29 2002-11-28 Lemmens Jacobus M. Pharmaceutical compositions comprising amlodipine maleate

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2772615B1 (en) * 1997-12-23 2002-06-14 Lipha MULTILAYER TABLET FOR INSTANT RELEASE THEN PROLONGED ACTIVE SUBSTANCES

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002049645A1 (en) * 2000-12-18 2002-06-27 Novartis Ag Therapeutic combination of amlodipine and benazepril
WO2002049646A1 (en) * 2000-12-18 2002-06-27 Novartis Ag Therapeutic combination of amlodipine and benazepril/benazeprilat
US20020176889A1 (en) * 2000-12-29 2002-11-28 Lemmens Jacobus M. Pharmaceutical compositions comprising amlodipine maleate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAIDU ET AL: "Stability indicating RP-HPLC method for simultaneous determination of amlodipine and benazepril hydrochloride from their combination drug product", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, NEW YORK, NY, US, vol. 39, no. 1-2, 1 September 2005 (2005-09-01), pages 147 - 155, XP005013202, ISSN: 0731-7085 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10130624B2 (en) 2005-03-15 2018-11-20 Lupin Limited Pharmaceutical compositions of amlodipine and benazepril
WO2008065485A2 (en) * 2006-10-19 2008-06-05 Torrent Pharmaceuticals Limited Stable pharmaceutical compositions of a calcium channel blocker and an ace inhibitor
WO2008065485A3 (en) * 2006-10-19 2009-04-23 Torrent Pharmaceuticals Ltd Stable pharmaceutical compositions of a calcium channel blocker and an ace inhibitor
WO2011104588A3 (en) * 2010-02-24 2012-04-19 Sanofi-Aventis Deutschland Gmbh Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation
CN102440993A (en) * 2011-12-08 2012-05-09 扬子江药业集团广州海瑞药业有限公司 Amlodipine benazepril tablet and preparation method thereof
WO2014076632A1 (en) 2012-11-15 2014-05-22 Adamed Sp. Z O.O. A pharmaceutical composition containing an ace inhibitor and a calcium channel blocker
EA027568B1 (en) * 2012-11-15 2017-08-31 Адамед Сп. З О.О. Pharmaceutical composition containing an ace inhibitor and a calcium channel blocker
AU2013346397B2 (en) * 2012-11-15 2017-09-14 Adamed Pharma S.A A pharmaceutical composition containing an ace inhibitor and a calcium channel blocker

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