WO2016207824A2 - Composition pharmaceutique stable comprenant du ramipril et/ou de l'amlodipine - Google Patents

Composition pharmaceutique stable comprenant du ramipril et/ou de l'amlodipine Download PDF

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Publication number
WO2016207824A2
WO2016207824A2 PCT/IB2016/053738 IB2016053738W WO2016207824A2 WO 2016207824 A2 WO2016207824 A2 WO 2016207824A2 IB 2016053738 W IB2016053738 W IB 2016053738W WO 2016207824 A2 WO2016207824 A2 WO 2016207824A2
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WIPO (PCT)
Prior art keywords
composition
ramipril
amlodipine
present
blending
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PCT/IB2016/053738
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English (en)
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WO2016207824A3 (fr
Inventor
Rajeev Singh Raghuvanshi
Anup Avijit Choudhury
Muzammil Tariq
Ashok Kumar SIVAPRAKASAM
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Dr. Reddy's Laboratories Ltd
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Publication of WO2016207824A2 publication Critical patent/WO2016207824A2/fr
Publication of WO2016207824A3 publication Critical patent/WO2016207824A3/fr

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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
    • A61K31/40—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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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

Definitions

  • the present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, and one or more pharmaceutically acceptable excipients. Further, the present invention relates to a process of preparing such composition comprising amlodipine and/or ramipril and method of treatment of cardiovascular disorders using the said composition.
  • the fixed-dose combinations are well known in the pharmaceutical drug development, involving process of combining two or more active agents in a single pharmaceutical dosage form in order to minimize and simplify the dosing regimen, shorten the dosing schedules, minimize the errors in dosing by patients, and also exploit the synergistic effect of two or more active agents. It is always desirable to combine multiple active ingredients in a single pharmaceutical composition. Inclusion of multiple ingredients in a single composition generally reduces costs and provides the convenience of consuming a single medication rather than multiple medications for treating individual symptoms.
  • the inherent advantage of fixed-dose combination therapy resides in its improving compliance because fewer pills are required. The therapeutic treatment becomes simplified and there is more potential for improved outcomes.
  • a fixed-dose combination comprising two or more active agents certainly involves practical difficulties and challenges due to the physiochemical nature of the active agents.
  • developing a stable pharmaceutical composition comprising a fixed-dose combination of two or more active agents involves greater challenges in stability.
  • the stability of a composition might be compromised due to incompatibility of an active with an essential excipient or even with a second active itself.
  • Ramipril is one of the active ingredients in the fixed-dose combination of the present invention.
  • Ramipril is an angiotensin converting enzyme (ACE) inhibitor, and its pharmaceutically acceptable salts are disclosed in U.S. Patent No. 5,061,722. Chemically, it is designated as (2S, 3aS, 6aS)-l ⁇ -(S)-N-([(S)-l-carboxy-3-phenylpropyl] alanyl ⁇ octahydro-cyclopenta[&]pyrrole- 2-carboxylic acid 1 -ethyl ester and is used for the treatment of hypertension, heart failure, and nephropathy.
  • ACE angiotensin converting enzyme
  • Ramipril is currently marketed in the U.S. as ALTACE® capsules, available in the strengths of 1.25 mg, 2.5 mg, 5 mg, or 10 mg.
  • Ramipril is susceptible to degradation by hydrolysis to ramipril diacid [(2S, 3aS, 6aS)-l-[(S)- 2-[[(S)-l-carboxy-3-phenylpropyl] amino] propanoyl] octahydrocyclopenta [b]pyrrole-2- carboxylic acid ("Impurity E" of Formula (II)). This is an active metabolite of ramipril and therefore may not necessarily require control in the formulation.
  • ramipril is weakly acidic in nature and is very sensitive to degradation under alkaline conditions, oxidative conditions wherein moisture is present.
  • the degradation of ramipril is believed to occur mainly via two pathways: a) hydrolysis to ramipril-diacid; and b) cyclization or condensation to ramipril-diketopiperazine (ramipril-DKP), which is profoundly formed more when the pH of the microenvironment increases.
  • Ramipril has also certain undesirable characteristics during manufacturing of the dosage forms.
  • One of such characteristics for example, is poor flow property due to its sticky nature causing adherence to surface vessels while manufacturing dosage forms.
  • WO2006050533 discloses individually coated, single ramipril particles with improved stability and bioavailability; wherein the stabilized ramipril crystalline particles are individually and sufficiently coated so that no portion of a single ramipril crystalline particle remains unprotected or exposed to the atmosphere or the environment before, during or after formulation and during storage.
  • WO2004064809 describes a process to formulate ramipril compositions that utilizes excipients with low water content and processing parameters and packaging material that prohibit water or moisture uptake.
  • Amlodipine is the second active agent in fixed-dose combination of present invention.
  • Amlodipine is a calcium channel blocker, and its pharmaceutically acceptable salts are disclosed in U.S. Patent No. 4,572,909. Further, the besilate salt of amlodipine is disclosed in U.S. Patent No. 4,879,303.
  • Amlodipine is marketed as the monobenzenesulfonate salt, amlodipine besilate under the trade name Norvasc® or Istin®. It is available as oral tablets in strengths of 2.5 mg, 5 mg and 10 mg.
  • amlodipine is hygroscopic in nature and may degrade in presence of moisture.
  • One of the major routes of degradation is known to be pH-dependent catalytic oxidative process.
  • the 3-ethyl 5methyl2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6- methylpyridine-3,5-dicarboxylate is typically a cause of stability concern in case of amlodipine formulations.
  • Amlodipine has relatively low bulk density and exhibits poor flow and low aqueous solubility. Amlodipine is also highly hygroscopic, cohesive, and sticky in nature and hence adheres to surface vessels while manufacturing dosage forms, and this leads to problems such as content uniformity or of dosage units such as tablets and capsules.
  • Amlodipine besilate is weakly basic in nature and is also prone to degradation under moist conditions and also shows photo degradation under exposure to light.
  • the major photo- degradant of amlodipine formed under light exposure is Impurity-D and this impurity is also formed in oxidative conditions. The formation of photo-degradant is more, when the pH of the microenvironment decreases.
  • ramipril and amlodipine are incompatible to each other, due to which it is difficult to manufacture a dosage form comprising the combination of these two actives.
  • both the actives are potent low dose-drugs, their sticky nature leading to adherence to vessel walls during manufacturing process, not only causes problems related to assay and content uniformity in the blend and dosage forms, but also results in considerable loss of the drugs, especially when processed on an industrial scale. This will ultimately have a negative impact on the release of these drugs from the final product and their efficacy.
  • the objective is to provide a patient-convenient combination dosage form of active ingredients that is bioequivalent to the corresponding free-combination of the same active ingredients.
  • development of a fixed-dose combination of amlodipine and ramipril that is bioequivalent to a free-combination thereof is challenging without compromising stability of these two active agents.
  • Physical separation of the two active agents has been shown to be achieved in a number of ways as follows: a) coating pellets of one active before incorporating into a tablet/capsule of the other; b) individually coating pellets of each active agents and then filling in a capsule or compressing as tablets; c) coating the pellets of one active and filling in a capsule with powder of the other active; d) microencapsulating each active separately in order to ensure that the two drugs do not come in contact and then blending together for use in a tablet or capsule; e) use of a dual or multiple compartment transdermal device, etc.
  • the BR 00/03282 patent application assigned to Libbs Pharmaceuticals Ltd. discloses the pharmaceutical combination of amlodipine and ramipril for the treatment of arterial hypertension and prevention of other cardiovascular diseases such as myocardial infarction, cerebrovascular disorders and cardiac and renal insufficiency.
  • the patent specification discloses the composition in which amlodipine and ramipril are physically isolated.
  • the patent specification discloses the capsule dosage form in three types: 1) the capsule dosage form with two kinds of coated granules (amlodipine granules and ramipril granules), 2) the capsule dosage form with two coated tablets (one coated tablet of amlodipine and one coated tablet of ramipril) and 3) the coated tablet containing amlodipine and ramipril separated by an inert layer.
  • compositions comprising a fixed-dose combination of ramipril and amlodipine.
  • compositions which are prepared using at least one solvent in the process of preparing the dosage form. Also all the cited references disclose the presence of lubricant to avoid sticking and facilitate the flow.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is prepared by a dry process.
  • Another aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is prepared by a dry process; wherein the said dry process is selected from one or more steps of dry mixing, dry granulation such as roller compaction, sifting, blending, compression, encapsulation and coating.
  • An aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is prepared by a process comprising a pre -blending step.
  • An aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is prepared by a process comprising a pre -blending step; wherein the said pre -blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • An aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is prepared by a process comprising a pre -blending step; wherein the said pre -blending step comprises initially coating the surfaces of the blending equipment with a part quantity of pregelatinised starch, and mixing of one or more excipients and/or active substances prior to sifting.
  • An aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is prepared by a dry process comprising a pre -blending step.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, and pharmaceutically acceptable excipients; wherein the said composition is devoid of lubricant.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, and pharmaceutically acceptable excipients; wherein the said fixed-dose combination is not physically separated in the composition and the said composition prevents degradation of the both amlodipine and ramipril.
  • An aspect of the present invention relates to a stable pharmaceutical composition in the form of capsule, comprising a fixed-dose combination of amlodipine and ramipril, and one or more pharmaceutical acceptable excipients; wherein the said composition is manufactured by a dry process comprising a pre -blending step, the said composition is devoid of lubricant, said amlodipine and ramipril are not physically separated in the composition, and the said composition prevents degradation of both amlodipine and ramipril during the shelf life; wherein the said dry process is selected from one or more steps of dry mixing, dry granulation, sifting, blending, compression, encapsulation and coating, and the said pre-blending comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said process is a dry process.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said process is a dry process; and wherein the said dry process is selected from one or more steps of dry mixing, dry granulation, sifting, blending, compression, encapsulation and coating.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said process comprises a pre-blending step.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said process comprises a pre -blending step; and wherein the said pre-blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said process comprises a pre-blending step; and wherein the said pre-blending step comprises initially coating the surfaces of the blending equipment with a part quantity of pregelatinised starch, and mixing of one or more excipients and/or active substances prior to sifting.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said process is a dry process comprising a pre-blending step; wherein the said dry process is selected from one or more steps of dry mixing, dry granulation, sifting, blending, compression, encapsulation and coating, and the said pre-blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent and mixing of one or more excipients and/or active substances prior to sifting.
  • An aspect of the present invention relates to a method of treating a cardiovascular disorder using a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril by orally administering the said composition to a subject.
  • a specific aspect of the present invention relates to a method of treating hypertension using a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril by orally administering the said composition to a subject.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; and b) the said ramipril or its pharmaceutically acceptable salts are present from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; and wherein the total weight of the said composition is about 250 mg to about 400 mg.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition; and wherein the total weight of the said composition is about 300 mg.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; and wherein the total weight of the said composition is not less than about 250 mg.
  • the present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%.
  • the present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition has content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; wherein the total weight of the said composition is not less than about 250 mg; and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and content uniformity with an acceptance value of not more than 10.
  • fixed-dose combination refers to a combination of at least two active agents present in a single dosage form such as a tablet or capsule or any suitable oral dosage form.
  • the fixed-dose combination refers to the combination of amlodipine and ramipril.
  • free combination refers to a combination of at least two active ingredients taken in separate tablets or medicines - so the proportions can, if required, be varied.
  • free combination refers to the dose units comprising amlodipine and ramipril separately administered simultaneously to a subject.
  • subject refers to a mammal, especially human, rat, mouse, and the like.
  • active(s) or “active agent(s)” or “active substance(s)” as used herein refer to either amlodipine or ramipril or a fixed-dose combination of amlodipine and ramipril, and their pharmaceutically acceptable salts thereof and forms known in the art. These terms are interchangeably used in the present application.
  • amlodipine refers to its free base, pharmaceutically acceptable salts, acid addition salts, all polymorphic forms (amorphous or crystalline), hydrates, anhydrous forms, enantiomers, prodrugs of amlodipine and/or mixtures thereof.
  • amlodipine refers to amlodipine besilate or amlodipine maleate.
  • Amlodipine may be present in an amount from about 0.5 % w/w to about 10 % w/w, based on total weight of the composition.
  • the dose of amlodipine is mentioned to denote the dose of the base form, for example 7 mg of amlodipine besilate will cover 5 mg of amlodipine free base.
  • ramipril as used herein includes its free base, pharmaceutically acceptable salts, acid addition salts, polymorphic forms, hydrates, anhydrous, enantiomers, prodrugs of ramipril and/or mixtures thereof. Ramipril may be present in an amount from about 0.5 % w/w to about 10 % w/w based on total weight of the composition.
  • pre-blending refers to mixing of one or more excipients and/or active substances prior to sifting.
  • the "pre-blending" step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • not physically separated as used herein to mean a fixed-dose combination of amlodipine and ramipril are present together in a single unit or as intimate mixture or in a single phase in the composition.
  • the physical separation is described in US Patent No. 6,162,802 [column 3, line 50 to 58], however this may be accomplished in any of the myriad ways known in the art, such as bi-layered tablets, coated pellets of one agent incorporated into a tablet of the other, separately coated pellets of each agent in a capsule or tablet, coated pellets of one agent in capsule together with powder of the other agent, each agent microencapsulated separately and then blended together for use in a tablet or capsule, use of a dual or multiple compartment transdermal device, etc.
  • compositions refer to the solid pharmaceutical preparations intended to be administered orally to a subject in need thereof.
  • compositions of the present application are made into suitable pharmaceutical dosage forms.
  • the different pharmaceutical dosage forms include solid oral dosage forms such as, but not limited to, tablets, capsules, granules or powders, and sachets containing granules or powders.
  • the said composition is a capsule, or a hard gelatin capsule containing fixed-dose combination of amlodipine and ramipril.
  • stable pharmaceutical composition in the context of present invention should be understood as a pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril intimately mixed in the composition; wherein total impurities related to the amlodipine and ramipril in the said composition upon storage during the shelf life, do not exceed the limits specified in the embodiments of the present application.
  • the pharmaceutical composition is said to be stable, when, upon storage under accelerated storage conditions (i.e., temperature of about 40°C and relative humidity of about 75%), the total amlodipine-related impurities in the said composition do not exceed about 2%w/w (of label drug content of amlodipine) and ramipril-related impurities in the said composition do not exceed about 4%w/w (of label drug content of ramipril) for at least one month, and amlodipine-related impurities do not exceed about 5%w/w (of amlodipine) and ramipril-related impurities do not exceed about 6%w/w (of ramipril), for at least 3 months.
  • lubricant is used to denote a pharmaceutically acceptable excipient used in the oral pharmaceutical compositions.
  • the lubricants help to provide substantial fluid property by reducing frictional forces between powder particles.
  • the lubricants as excipients are used in common in both tablet and capsule formulations.
  • Lubricants are known to ease the ejection of plugs, reduce filming on pistons and reduce adhesion of powder to other metal surfaces, and reduce friction between sliding surfaces in contact with powder.
  • the lubricants are generally added during last step in the manufacturing process, because they exert their function on particle surfaces. Lubricants are important excipients specifically for capsule composition ⁇ Larry L. Augsburg; Modern Pharmaceutics, Volume 1, Basic Principles and Systems).
  • the lubricants are important, especially for the solid oral dosage forms of sticky active agents such as amlodipine and ramipril, however the stable composition comprising a fixed-dose combination of amlodipine and ramipril, can also be prepared without the use of lubricant i.e., substantially free of lubricant.
  • the lubricant is present in the composition not more than about 1% w/w of the total weight of the composition.
  • the lubricant is not more than 0.01% w/w or 0.001% w/w of the total weight of the composition.
  • the term "devoid of lubricant" is interchangeably used with "substantially free of lubricant”.
  • the terms “devoid” or “substantially free” will comprise any percentage of the said substance which is not added for functional requirement in the composition, however may be present by the way of impurity or related substance from other excipients or from actives in the composition.
  • the term “substantially free” refers herein that the said substance is present in the composition not more than about 1% w/w based on the total weight of the composition, or not more than about 0.9%w/w or not more than about 0.8% w/w or not more than about 0.7% w/w or not more than about 0.6% w/w or not more than about 0.5% w/w or not more than about 0.4% w/w or not more than about 0.3% w/w or not more than about 0.2% w/w or not more than about 0.1% w/w or not more than about 0% w/w or 0%w/w based total weight of the composition.
  • film coating herein used to denote polymer based coating applied on the composition to improve its aesthetic property such as improving visual appeal, or protect from moisture, light, or for the purpose of taste masking and the like.
  • dry process refers to a process of preparing a composition without use of any solvent, and the said process may be selected from, but not limited to, dry mixing, and dry granulation such as compaction, slugging etc.
  • the dry process will comprise at least one step selected from dry mixing, dry granulation such as roller compaction, direct compression or combinations thereof.
  • basic agents refer to the compounds which exhibit the character of bases and provide alkaline pH conditions to the compositions, and are selected from, but not limited to, alkali or alkaline earth metal carbonates, phosphates, oxides or hydroxides.
  • the alkali or alkaline earth metal carbonate comprises sodium carbonate, sodium bicarbonate, calcium carbonate or magnesium carbonate.
  • the alkali or alkaline earth metal phosphate comprises sodium phosphate, disodium phosphate, trisodium phosphate, dibasic calcium phosphate or calcium phosphate anhydrous.
  • the alkali or alkaline earth metal oxide comprises magnesium oxide or aluminium oxide.
  • the basifying agent may be present in an amount from about 0 % w/w to about 1 % w/w, based on total weight of the composition.
  • the said composition is substantially free of basifying agent.
  • the said composition comprises basifying agent from about 0%w/w to about 0.5% w/w.
  • excipient or "pharmaceutically acceptable excipient” as used herein is a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc.
  • the excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use.
  • An “excipient” or a “pharmaceutically acceptable excipient” as used in the specification includes one or more than one such excipient.
  • stable denotes both chemical stability and physical and/or polymorphic stability.
  • stable or “stability” is defined as the capacity of a drug substance or drug product to remain within the established specifications to maintain its identity, strength, quality and purity throughout the retest or expiry.
  • shelf life' as used herein is used to denote the time that finished products can be stored after manufacturing, during which the defined quality of a specified proportion of the product remains acceptable under expected (or specified) conditions of distribution, storage, and display. The shelf life is established by the manufacturer of a product.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition is prepared by a dry process.
  • An aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition is prepared by a dry process; and wherein the said dry process is selected from one or more steps of dry mixing, dry granulation such as roller compaction, sifting, blending, compression, encapsulation and coating.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition is prepared by a process comprising a pre-blending step.
  • An aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition is prepared by a process comprising a pre-blending step; and wherein the said pre-blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition is prepared by a dry process comprising a pre-blending step.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising amlodipine and/or ramipril and pharmaceutically acceptable excipients; wherein the said composition is devoid of lubricant.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising amlodipine and/or ramipril, and pharmaceutically acceptable excipients; wherein the said fixed- dose combination is not physically separated in the composition and the said composition prevents degradation of the both amlodipine and ramipril.
  • An aspect of the present invention relates to a stable pharmaceutical composition in the form of capsule, comprising amlodipine and/or ramipril, and one or more pharmaceutical acceptable excipients; wherein the said composition is manufactured by a dry process comprising a pre- blending step, the said composition is devoid of lubricant and; said amlodipine and ramipril are not physically separated in the composition comprising their fixed-dose combination; and the said composition prevents degradation of both amlodipine and ramipril during the shelf life; and wherein the said dry process is selected from one or more steps of dry mixing, dry granulation such as compaction and slugging, sifting, blending, compression, encapsulation and coating, and the said pre -blending comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • the said composition is manufactured by a dry process comprising a pre- blending
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising amlodipine and/or ramipril.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said process is a dry process.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said process is a dry process; and wherein the said dry process is selected from one or more steps of dry mixing, dry granulation, sifting, blending, compression, encapsulation and coating.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said process comprises a pre- blending step.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said process comprises a pre- blending step; wherein the said pre-blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • Another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said process is a dry process and comprises a pre-blending step, the said dry process is selected from one or more steps of dry mixing, dry granulation, sifting, blending, compression, encapsulation and coating; and wherein the said pre-blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • An aspect of the present invention relates to a method of treating a cardiovascular disorder using a stable pharmaceutical composition comprising amlodipine and/or ramipril by orally administering the said composition to a subject.
  • a specific aspect of the present invention relates to a method of treating hypertension using a stable pharmaceutical composition comprising amlodipine and/or ramipril by orally administering the said composition to a subject.
  • An aspect of the present invention relates to a stable pharmaceutical composition comprising amlodipine and/or ramipril, having the in- vitro dissolution profile of: a) not less than 50% of amlodipine released in 30 minutes; and b) not less than 50% of ramipril released in 30 minutes.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amlodipine and/or ramipril; wherein amlodipine or its pharmaceutically acceptable salts is present in an amount of from about 1 mg to about 15 mg, and ramipril or its pharmaceutically acceptable salts is present in an amount of from about 1 mg to about 15 mg.
  • Another aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein amlodipine or its pharmaceutically acceptable salts is present in an amount 0.5 % w/w to about 10 % w/w based on total weight of the composition, and ramipril or its pharmaceutically acceptable salts is present in an amount of from about 0.5 % w/w to about 10 % w/w based on total weight of the composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, and/or b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition, and/or b) the said ramipril or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; and wherein the total weight of the said composition is about 250 mg to about 400 mg.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition, and/or b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition; and wherein the total weight of the said composition is about 300 mg.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, and/or b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; and wherein the total weight of the said composition is not less than about 250 mg.
  • the present invention relates to a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition has content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and/or ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, and/or b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; wherein the total weight of the said composition is not less than about 250 mg; and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and content uniformity with an acceptance value of not more than 10.
  • the stable pharmaceutical composition of the present invention comprises: a) a fixed-dose combination of amlodipine and ramipril, b) a basifying agent, and c) a pharmaceutically acceptable excipient; wherein the said fixed-dose combination is not physically separated in the composition; the said composition is prepared by a dry process comprising a pre -blending step, the said composition is substantially free of lubricant, the said composition has content uniformity or blend uniformity; wherein the composition is selected from tablet, capsule, solid powder, granules, and/or tablet, powder, granules or combinations thereof filled in a capsule.
  • the said dry process is selected from one or more steps of dry mixing, dry granulation, sifting, blending, compression, encapsulation and coating, and the said pre- blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • the present invention relates to a stable pharmaceutical composition in the form of a solid powder; wherein the said composition is prepared by dry mixing and/or dry blending.
  • the present invention relates to a stable pharmaceutical composition in the form of granules prepared by a dry granulation method.
  • the stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, is optionally film coated.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a fixed- dose combination of amlodipine and ramipril, and one or more pharmaceutically acceptable excipients; wherein amlodipine and ramipril of the fixed-dose combination are in immediate release form.
  • the stable pharmaceutical composition is in the form of a tablet, comprising a fixed-dose combination of amlodipine and ramipril, and a pharmaceutically acceptable excipient; wherein the said tablet is prepared by a dry process such as direct compression or dry granulation or a combination thereof.
  • the stable pharmaceutical composition is in the form of a capsule, comprising a fixed-dose combination of amlodipine and ramipril, and a pharmaceutically acceptable excipient; wherein the said composition comprising the fixed-dose combination is prepared by a dry process and filled into the capsule.
  • the stable pharmaceutical composition of the present invention comprises a fixed- dose combination of amlodipine and ramipril; wherein both amlodipine and ramipril remain physically and chemically stable when stored at accelerated storage conditions (i.e., temperature of about 40°C and relative humidity of about 75%), for at least one month. And wherein the total amlodipine-related impurities in the said composition upon such storage do not exceed about 2%w/w (of label drug content of amlodipine) and ramipril-related impurities in the said composition upon storage do not exceed about 4%w/w (of label drug content of ramipril).
  • the stable pharmaceutical composition of the present invention comprises a fixed- dose combination of amlodipine and ramipril; wherein both amlodipine and ramipril remain physically and chemically stable when stored at accelerated storage conditions (i.e., temperature of about 40°C and relative humidity of about 75%), for at least three months and wherein the total amlodipine-related impurities in the said composition upon such storage do not exceed about 5%w/w (of amlodipine) and ramipril-related impurities in the said composition upon storage do not exceed about 6%w/w (of ramipril).
  • accelerated storage conditions i.e., temperature of about 40°C and relative humidity of about 75%
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the percentage of amlodipine released is not less than about 50%, within about 30 minutes when subjected to an in vitro dissolution study.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the percentage of amlodipine released is not less than about 50%, within about 30 minutes when subjected to an in vitro dissolution study in the medium of 0.0 IN HC1, 50 RPM, USP II, 900 ml.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising amlodipine and ramipril; wherein amlodipine is present in an amount of from about 1 mg to about 15 mg, and ramipril is present in an amount of from about 1 mg to about 15 mg.
  • the stable pharmaceutical composition comprises a combination of amlodipine and ramipril in the fixed-dose selected from 5mg/2.5mg, 5mg/5mg, 5mg/10mg or lOmg/lOmg; or a combination of amlodipine besilate and ramipril in the fixed-dose selected from about 7mg/2.5mg or about 7mg/5mg. or about 7mg/10mg or about 14mg/10mg equivalent to free base forms of amlodipine and ramipril.
  • Another aspect of the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein amlodipine or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition, and ramipril or its pharmaceutically acceptable salts is present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts from about 5 % w/w to about 6 % w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts from about 5 % w/w to about 6 % w/w based on total weight of the composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; and wherein the total weight of the said composition is about 250 mg to about 400 mg.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition; and wherein the total weight of the said composition is about 300 mg.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; and wherein the total weight of the said composition is not less than about 250 mg.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; wherein the total weight of the said composition is about 250 mg to about 400 mg; wherein the said composition is devoid of lubricant; and wherein amlodipine and ramipril are not physically separated in the said composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition; wherein the total weight of the said composition is about 300 mg; wherein the said composition is devoid of lubricant; and wherein amlodipine and ramipril are not physically separated in the said composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; wherein the total weight of the said composition is not less than about 250 mg; wherein the said composition is devoid of lubricant; and wherein amlodipine and ramipril are not physically separated in the said composition.
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein amlodipine and ramipril are not physically separated and are physically and chemically stable during preparation of the composition and also during the shelf-life of the composition.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the dosage form of the said composition is packaged in any suitable packaging material to avoid contact with light, moisture or any such environmental exposures.
  • the said packaging is selected from, but not limited to, a strip or a blister or a HDPE container optionally together with a desiccant and/or an oxygen absorbent.
  • the present invention provides a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is dispensed in suitable packaging materials.
  • the packaging materials comprise containers including lids, composed of polyethylene, polypropylene and/or glass, and blisters or strips composed of aluminum or high-density polypropylene, or polyvinyl chloride or polyvinyl chloride coated with polyvinylidene dichloride, generally termed PVC/PVDC.
  • the application includes the use of oxygen absorbers and/or desiccants with packaging material.
  • the present invention provides a stable pharmaceutical composition in the form of a capsule comprising a fixed-dose combination of amlodipine and ramipril, and a pharmaceutically acceptable excipient; wherein both amlodipine and ramipril are in immediate release form.
  • the present invention provides a stable pharmaceutical composition in the form of a tablet, comprising a fixed-dose combination of amlodipine and ramipril, and a pharmaceutically acceptable excipient; wherein both amlodipine and ramipril are in immediate release form.
  • the present invention relates to a stable pharmaceutical composition in the form of a capsule filled with a solid powder, granules or with a tablet, comprising a) a fixed-dose combination of amlodipine and ramipril; b) a basifying agent; and c) a pharmaceutically acceptable excipient; wherein the said fixed-dose combination is intimately mixed with the basifying agent and one or more pharmaceutically acceptable excipients in the powder blend or the tablet, and filled in a hard gelatin capsule; wherein both amlodipine and ramipril remain physically and chemically stable when stored at accelerated storage conditions (i.e., temperature of about 40°C and relative humidity of about 75%), for at least one month.
  • accelerated storage conditions i.e., temperature of about 40°C and relative humidity of about 75%)
  • the stable pharmaceutical composition comprising one or more pharmaceutical acceptable excipients along with a fixed-dose combination of amlodipine and ramipril; wherein the said excipient is selected from diluents, binders, disintegrants, and the like or combination thereof.
  • Diluents are selected from, but not limited to, calcium sulfate, cellulose acetate, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, maltitol, maltodextrin, maltose, polymethacrylates, sodium chloride, sucrose and talc, starches, lactose, mannitol, cellulose derivatives and the like.
  • Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, FlowlacTM, PharmatoseTM and others.
  • Different grades of starches include, but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinised starch and Starch 1500, Starch 1500 LM grade (low moisture content grade), fully pregelatinised starch, and others.
  • Different cellulose compounds that can be used include crystalline cellulose, powdered cellulose or cellulose acetate. Examples of crystalline cellulose products include, but are not limited to, CEOLUSTM KG801, AvicelTM PH 101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, silicified microcrystalline cellulose and microcrystalline cellulose 112.
  • diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, light magnesium oxide, heavy magnesium oxide, sodium hydrogen phosphate, calcium sulfate, disodium hydrogen phosphate, dibasic calcium phosphate, and tribasic calcium phosphate.
  • Binders are selected from, but not limited to, carboxymethylcellulose, hydroxyethylcellulose, dextrin, gelatin, maltodextrin, polyethylene oxide, sodium alginate, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone or povidone (PVP-K25, PVP-K29, PVP-K30, PVP-K90D), powdered acacia, gelatin, guar gum, carbomer (e.g. carbopol), methylcellulose, polymethacrylates, and starches.
  • Disintegrants are selected from, but not limited to, carmellose calcium, carboxymefhylstarch sodium, croscarmellose sodium, crospovidone(examples of commercially available crospovidone products include, but not limited to crosslinked povidone, KollidonTM CL, PolyplasdoneTM XL, XI- 10, and INF- 10), and low-substituted hydroxypropylcellulose(examples of low-substituted hydroxypropylcellulose include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33.
  • Other useful disintegrants include sodium starch glycolate (type A or type B), colloidal silicon dioxide and starches.
  • the stable pharmaceutical composition of present invention is substantially free of lubricant.
  • An aspect of the present invention relates to a method of treating cardiovascular disorder using a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril by orally administering the said composition to a subject in need thereof.
  • the present invention relates to a method of treating cardiovascular disorders in a subject by orally administering to the subject in need thereof, a stable pharmaceutical composition, comprising a fixed-dose combination of amlodipine and ramipril; wherein the said fixed-dose combination of amlodipine and ramipril is present in the dose of about 5mg/2.5mg, or about 5mg/5mg, or about 5mg/10mg, or about lOmg/lOmg equivalent to the free base forms of said amlodipine/ramipril.
  • the cardiovascular disorders are selected from group comprising, but not limited to, hypertension, myocardial infraction, ischemic heart disease, artrial fribrillation, and congenital heart disease. In a specific aspect, the cardiovascular disorder is hypertension.
  • the stable pharmaceutical composition of the present invention is administered once-daily or twice-daily with suitable dose to the subject in need thereof.
  • the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein the said composition is prepared by multi step process comprising one or more of the steps of mixing, dry granulation/dry blending, sifting, blending and preparing the final composition.
  • the stable pharmaceutical composition of the present invention is prepared by a dry process.
  • the stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril can be prepared without the use of any solvent in the manufacturing process.
  • the solvents generally used in pharmaceutical product development are water, lower alcohols, acetone and the like. Usage of water in the preparation of oral dosage forms such as tablets, and capsules is preferred because of its compatibility, wide acceptability as solvent, also use of water in preparing a composition is preferred because it provides cohesiveness required to compress the granules to final composition.
  • the dry process of the present invention to prepare a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, comprises steps of: a) mixing amlodipine and ramipril with diluent to obtain a blend; b) sifting the blend of step a) into a blender and sifting any additional one or more excipients into the blender; c) blending the mixture of step b) or optionally processing the blend for dry granulations such as slugging, or roll compaction; and d) filling the dry blend of step c) into a capsule, or compressing the dry granules into a tablet or filling these granules into a capsule; wherein the said dry process is performed without use of lubricant.
  • the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, comprising the steps of: a) preparing a blend comprising amlodipine, ramipril, and diluent using a suitable blender; b) preparing the final blend by mixing basifying agent with the blend of step a) using a suitable bender; c) preparing a stable pharmaceutical composition in the form of capsule and/or tablet using the final blend; wherein the said process is a dry process.
  • the stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril is prepared by a process comprising "pre- blending" step.
  • This pre -blending comprises initially coating the metallic surface of blender with the diluent before initializing the process.
  • This coated diluent on metallic surface of the blender helps in reducing the contact between hygroscopic substances such as amlodipine and/or ramipril, to the metallic surface, thus avoiding the degradation of these substances, by preventing the formation of related substances during the process of preparing the composition.
  • This "pre-blending" step also ensures the uniform drug distribution in the blend during the process, and also the content uniformity in the final pharmaceutical composition, especially in the industrial scale preparation of the composition of considerably larger weight.
  • the process of preparing compositions of present invention including "pre-blending" step comprises a) initially coating the surfaces of the blending equipment by blending a first part of the diluent alone in a blender; b) adding second part of diluent and active agents amlodipine and ramipril, basifying agent, and optionally other excipients, and blending them together with the first part; and c) adding a third part of the diluent and blending together with the blend of step b). The complete blend thus obtained is again blended together in the blender.
  • This process of pre-blending is identified as an essential step in the process of preparing pharmaceutical composition containing hygroscopic substances like amlodipine and/or ramipril.
  • the amount of diluent used in the pre-blending steps depends on the size of metallic surface in the blender, and the amount can be decided and fixed by skilled technician during the process.
  • the process of preparing a stable pharmaceutical composition comprising amlodipine and/or ramipril or pharmaceutically acceptable salts thereof, is a dry process and comprises a pre-blending step; wherein the said dry process is selected from one or more steps of dry mixing, dry granulation, sifting, blending, compression, encapsulation and coating; and wherein the said pre-blending step comprises initially coating the surfaces of the blending equipment with a part quantity of diluent, and mixing of one or more excipients and/or active substances prior to sifting.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a) amlodipine and/or ramipril; and b) one or more pharmaceutically acceptable excipients; wherein the pharmaceutical composition is prepared by a process comprising one or more steps selected from (i) a dry process including pre-blending step; (ii) coating of the blending and/or other equipment with one or more pharmaceutically acceptable excipients, and (iii) reducing the contact of the amlodipine and/or ramipril with the surfaces of one or more equipment during the process of manufacturing.
  • the present invention relates to a process of preparing a stable pharmaceutical composition comprising ramipril and/or amlodipine or pharmaceutically acceptable salts thereof; wherein the said process is a dry process and comprises the following steps: a) pre -blending comprising:
  • step (ii) blending amlodipine and/or ramipril, one or more pharmaceutically acceptable excipients, and from about 5% to about 20% of diluent of total diluent with the blend of step (i),
  • step (iii) blending from about 20 to about 30% of diluent of total diluent with the blend of step (ii), and
  • step (iv) blending from about 20 to about 40% of diluent of total diluent with the blend of step (iii);
  • step b) sifting the total blend obtained in step a)(iv) through a suitable sifter;
  • step b) sifting the remaining quantity of diluent and adding to the blend of step b).
  • the present invention relates to a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, comprising steps of: a) pre -blending comprising initially coating the surfaces of the blending equipment by blending a first part of the diluent alone in a blender, and blending amlodipine, ramipril, basifying agent, and optionally other excipients with the first part of the diluent; b) blending the obtained mixture with remaining portion of diluent; c) optionally processing the blend for dry granulations such as slugging, or roll compaction; and d) filling the dry blend of step a) or b) into a capsule or compressing the dry granules into a tablet or filling these granules into a capsule.
  • the present invention provides a process of preparing a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, the said process is a dry process and comprises the following steps: a) pre -blending comprising:
  • step a) blending amlodipine, ramipril, magnesium oxide and about 5-20% of pregelatinised starch together with the blend of step a);
  • step b) blending about 20-40% of pregelatinised starch together with the blend of step c); b) sifting the total blend obtained in step a)(iv) by passing through a suitable sifter; and c) sifting the remaining quantity of pregelatinised starch and adding it to the blend of step b).
  • the last step (iii) of sifting the remaining portion of pregelatinised starch helps in recovering any residues of the active agents adhered to the screen and walls of the sifter due to their sticky nature, thus avoiding the loss of the drug.
  • the present invention provides a process of preparing a stable pharmaceutical composition having uniform drug distribution, comprising steps of: a) pre-blending comprising initially coating the surface of the double cone blender with by blending a small quantity of diluent alone for a suitable time of at least 7 minutes; b) sifting amlodipine, ramipril and basifying agent and/or one or more pharmaceutically acceptable excipients; c) blending in double cone blender coated with diluent by pre-blending step, for a suitable time to form a pharmaceutical composition having uniform distribution of amlodipine and ramipril; and d) resultant blended composition may then be processed further into a desired unit dosage form such as capsule or tablet.
  • the present invention provides a process of preparing a stable pharmaceutical composition comprising the fixed-dose combination of amlodipine and ramipril, comprising a step of "pre-blending" as described above; wherein the said process is devoid of use of lubricant; and wherein the relative humidity of filling area is maintained in the range of from about 25% to about 45% to control sticking issue in the absence of lubricant and the said composition is capsule.
  • the capsule blend has a bulk density from about 0.1 g/ml to 1 g/ml. In a specific aspect, the capsule blend has a bulk density from about 0.48 g/ml to 0.57 g/ml.
  • the capsule blend has a tapped density from about 0.1 g/ml to 1 g/ml. In a specific aspect, the capsule blend has a tapped density from about 0.80 g/ml to 0.84 g/ml.
  • the usage of optimum thickness dosing disk eliminates the sticking problem.
  • the capsules are filled using dosing disk having a thickness of about 18-19 mm to eliminate the sticking in the manufacturing process.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a) ramipril and/or amlodipine or pharmaceutically acceptable salts thereof; and b) one or more pharmaceutically acceptable excipients; wherein the said composition is substantially free of lubricant, and prepared by a dry process comprising pre-blending; wherein total amlodipine - related impurities in the said composition upon storage do not exceed about 5%w/w (of amlodipine) and ramipril-related impurities in the said composition upon storage do not exceed about 6%w/w (of ramipril).
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a) ramipril and/or amlodipine or pharmaceutically acceptable salts thereof; and b) one or more pharmaceutically acceptable excipients; wherein the said composition is substantially free of lubricant, and prepared by a dry process comprising pre-blending, and the said composition is powder filled in capsule.
  • the said powder has a bulk density from about 0.1 g/ml to about 1 g/ml.
  • the said powder has a bulk density from about 0.48 g/ml to about 0.57 g/ml.
  • the said powder has a tapped density from about 0.1 g/ml to about 1 g/ml.
  • the said powder has a tapped density from about 0.80 g/ml to about 0.84 g/ml.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a) ramipril and/or amlodipine or pharmaceutically acceptable salts thereof; and b) one or more pharmaceutically acceptable excipients; wherein the said composition is substantially free of lubricant, and prepared by a dry process comprising pre-blending, and the said composition is a solid powder or granules, and the said composition has blend uniformity with a relative standard deviation of not more than 4%.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a) ramipril and/or amlodipine or pharmaceutically acceptable salts thereof; and b) one or more pharmaceutically acceptable excipients; wherein the said composition is substantially free of lubricant, and prepared by a dry process comprising pre-blending, and the said composition is a tablet or powder filled in a capsule, or granules filled in a capsule, and/or tablet in a capsule, and the said composition has content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; wherein the total weight of the said composition is about 250 mg to about 400 mg, and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and/or content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition; wherein the total weight of the said composition is about 300 mg; and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and/or content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; wherein the total weight of the said composition is not less than about 250 mg; and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and/or content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts from about 0.5 % w/w to about 10 % w/w based on total weight of the composition; wherein the total weight of the said composition is about 250 mg to about 400 mg; wherein the said composition is devoid of lubricant; wherein amlodipine and ramipril are not physically separated in the said composition; and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and/or content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 5% w/w based on total weight of the composition; wherein the total weight of the said composition is about 300 mg; wherein the said composition is devoid of lubricant; wherein amlodipine and ramipril are not physically separated in the said composition; and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and/or content uniformity with an acceptance value of not more than 10.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, and b) the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition; wherein the total weight of the said composition is not less than about 250 mg; wherein the said composition is devoid of lubricant; wherein amlodipine and ramipril are not physically separated in the said composition; and wherein the said composition has blend uniformity with a relative standard deviation of not more than 4%, and/or content uniformity with an acceptance value of not more than 10.
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein: a) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition,
  • the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition, ,
  • the said composition has blend uniformity with a relative standard deviation of not more than 4%
  • the said composition has content uniformity with an acceptance value of not more than 10.
  • a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril; wherein: a) amlodipine and ramipril that are not physically separated in the said composition, b) the said amlodipine or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition,
  • the said ramipril or its pharmaceutically acceptable salts are present in amounts not exceeding about 6% w/w based on total weight of the composition,
  • total weight of the said composition is not less than about 250 mg
  • the said composition is devoid of lubricant
  • the said composition has blend uniformity with a relative standard deviation of not more than 4%
  • the said composition has content uniformity with an acceptance value of not more than 10.
  • the said composition provides homogeneity and content uniformity of amlodipine and ramipril even though they are present in small quantities in the dosage forms such as tablets and/or capsules; wherein the dosage forms are considerably larger in weight as compared to those disclosed in the literature; and wherein the said compositions are devoid of lubricants and the two active agents are not physically separated.
  • the invention encompasses all the approaches alternate to pre-blending process, that are capable to achieve the objective of reducing the contact of the active substances to the surfaces of any equipment during the entire process till the completion of the preparation of the final product.
  • Capsule compositions comprising fixed-dose combinations of amlodipine and ramipril of 4 different strengths (5/2.5, 5/5, 5/10, and 10/10) were manufactured using two different processes, process A that does not comprise a pre-blending step, and process B that comprises a pre-blending step.
  • the compositions are shown in Table- 1.
  • Manufacturing Process A a) Sifting: Ingredients 1, 2, 3 & 4 were sifted through appropriate screen
  • step b) Blending: Materials of step a) were loaded into double cone blender, and blended for suitable time.
  • step 3 The blend obtained from step 3 was filled in suitable sized hard gelatin capsule.
  • Manufacturing Process B a) Dispensing:
  • step c) The materials of step c) were loaded into blender and blended for 10 minutes at 8 RPM. e) Encapsulation:
  • Capsule compositions comprising fixed-dose combination of amlodipine and ramipril of the strength 10/10 mg, were manufactured with varying concentrations of magnesium oxide using the manufacturing process B of Example 1. The compositions are shown in Table-2.
  • example 2C was optimized, and the long term stability study of the fixed-dose combination capsule comprising the composition example 2C, was conducted for 24 months under the conditions of 25°C / 60% RH. The data was obtained for 0, 3, 6, 9, 12, 18 and 24 months during long term stability study. The details of study results are shown under Table-3C.
  • Tablet composition comprising fixed-dose combination of amlodipine and ramipril of the strength 10/10 mg, were manufactured using the process B of example 1 ; wherein the blended materials obtained in step 4 were compressed into tablets using tablet punch of suitable dimension at suitable hardness. The compressed tablets were then filled into suitable sized empty hard gelatin capsule.
  • the composition is shown in the Table-4
  • Table-5 Dissolution data of blend filled in capsules (Example 2C) and tablets filled in capsules (Example 4)
  • a blend of the composition of lowest strength of example 1 (5/2.5 mg of amlopidine and ramipril respectively), was prepared by a process A that comprises co-sifting of active agents amlodipine and ramipril, and excipients using a suitable sifter, followed by blending the sifted materials in a suitable blender.
  • the blend uniformity analysis was done at 7, 10 and 13 minutes of blending times. This process was performed on a small scale (batch size of 5,500 capsules), and did not involve a pre -blending step.
  • Another blend of the same composition was prepared using a different process B comprising a pre-blending step; wherein initially a part quantity of pregelatinised starch was blended alone in a blender to provide a coat to the stainless steel surface of blender. This prevents the direct contact of hygroscopic substances such as amlodipine besilate and/or ramipril with stainless steel surface. Both the amlodipine and ramipril were geometrically mixed with pregelatinised starch in subdivided parts in the blender and finally sifted using a suitable sifter. A part of pregelatinised starch was kept to rinse the sifter screen to recover any active substance residue on the sifter. The sifted pre-blend was then blended in suitable blender and subjected for blend uniformity analysis.
  • the blend uniformity analysis has shown that the presence of a pre-blending step in process B has resulted in uniform mixing of the blend especially with respect to amlodipine, and the % RSD was found to be well within the prescribed limits.
  • the uniformity of the blend prepared by the process A that did not comprise a pre-blending step was found to be poor with RSD above the limits.
  • the capsules comprising fixed-dose combination of amlodipine and ramipril were prepared by filling the empty capsules with the final blend of the optimized formula (Example 2C), prepared by the process of the invention (process B of example 1) under controlled humidity conditions of not more than 45%.
  • the capsules were analysed for content uniformity intermittently at different time points during the total filling time of about 4 hours.
  • the study results of content uniformity of the capsule are presented in Table 8.
  • Tl, T2, T3, T4, and T5 denote time points for about every half an hour

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Abstract

La présente invention concerne une composition pharmaceutique stable comprenant une combinaison à dose fixe d'amlodipine et de ramipril, et un excipient pharmaceutiquement acceptable. En outre, la présente invention concerne un procédé de préparation desdites compositions et un procédé d'utilisation de celle-ci dans le traitement de troubles cardiovasculaires.
PCT/IB2016/053738 2015-06-23 2016-06-23 Composition pharmaceutique stable comprenant du ramipril et/ou de l'amlodipine WO2016207824A2 (fr)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2011104588A2 (fr) * 2010-02-24 2011-09-01 Sanofi-Aventis Deutschland Gmbh Formulations pharmaceutiques solides de ramipril et de bésylate d'amlodipine et leur préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011104588A2 (fr) * 2010-02-24 2011-09-01 Sanofi-Aventis Deutschland Gmbh Formulations pharmaceutiques solides de ramipril et de bésylate d'amlodipine et leur préparation

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