WO2016207824A2

WO2016207824A2 - A stable pharmaceutical composition comprising ramipril and/or amlodipine

Info

Publication number: WO2016207824A2
Application number: PCT/IB2016/053738
Authority: WO
Inventors: Rajeev Singh Raghuvanshi; Anup Avijit Choudhury; Muzammil Tariq; Ashok Kumar SIVAPRAKASAM
Original assignee: Dr Reddys Laboratories Ltd
Current assignee: Dr Reddys Laboratories Ltd
Priority date: 2015-06-23
Filing date: 2016-06-23
Publication date: 2016-12-29
Anticipated expiration: 2017-12-23
Also published as: WO2016207824A3

Abstract

The present invention relates to a stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, and a pharmaceutically acceptable excipient. Further, the present invention relates to a process of preparing such compositions and method of using in the treatment of cardiovascular disorders.

Description

A STABLE PHARMACEUTICAL COMPOSITION COMPRISING RAMIPRIL

AND/OR AMLODIPINE

FIELD OF THE INVENTION

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.

BACKGROUND

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. Certain physical/chemical properties of the active agents, specifically photo and chemical stability, impart a great challenge in developing formulations involving fixed-dose combination and having reduced levels of total impurities during their shelf life. Hence, developing a stable pharmaceutical composition comprising a fixed-dose combination of two or more active agents involves greater challenges in stability. In addition, 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.

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. It is also susceptible to cyclization to ramipril diketopiperazide [ethyl (2S)-2-[(3S, 5aS, 8aS, 9aS)-3-methyl-l,4- dioxodecahydro-2H-cyclopenta[4,5] pyrrolo [1,2-a] pyrazin- 2-yl]-4-phenylbutanoate ("Impurity D" of Formula (III)). These impurities are defined in European Pharmacopoeia.

Also, 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.

Furthermore, stability of ramipril is also influenced by formulation excipients. It is generally very difficult to be formulated into dosage forms because many of the excipients commonly used in pharmaceutical products accelerate the rate of degradation of ramipril and hence the product is not sufficiently stable to enable long shelf-life. It is thus difficult to select the excipients that enable dosage forms with adequate stability. Various attempts have been made to stabilize ramipril in pharmaceutical formulations. For example, U.S. Patent Nos. 5,442,008 and 5, 151,433 describe an attempt to overcome instability by reporting the use of a polymeric protective coating of ramipril granules. 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.

It is known that 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 ("Impurity D" of Formula (I)) 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.

In addition to above, 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. Also, as 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.

In addition to stability, when formulating a fixed-dose combination, 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. As a result of these complex biopharmaceutical properties, 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.

US patent No. 6,162,802 claims a pharmaceutical composition consisting of amlodipine and benazepril such that the two drugs are physically separated from each other. The patent specification discloses that physical separation of amlodipine and benazepril is necessary as they are incompatible substances. 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.

International patent applications WO2008065485, WO2011104588 and WO2014076632 disclose compositions comprising a fixed-dose combination of ramipril and amlodipine.

Further, it was noted that most of the available literature related to the fixed-dose combination of amlodipine and ramipril have disclosed 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.

Another challenge faced in the manufacture of solid dosage forms is achieving the homogeneity or content uniformity of active agents when their quantity is very low compared to total weight of the dosage form. It is even more challenging when these active agents are sticky in nature which add to degradation and content uniformity problems and also lead to loss of the drug.

Thus, there is a need for a new stable solid dosage form comprising the specific combination of ramipril and amlodipine with a solution to the above mentioned problems.

There is also a need to formulate a simplified stable composition comprising a fixed-dose combination of amlodipine and ramipril, using a reproducible process which has industrial scale manufacturing feasibility and at the same time also exhibits better stability compared to the individual products.

SUMMARY OF THE INVENTION

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 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 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 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 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 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.

In another aspect, the present invention relates to 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.

In another aspect, the present invention relates to 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.

In a specific aspect, the present invention relates to 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.

In an aspect, the present invention relates to 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.

In an aspect, 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%. In an aspect, 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.

In an aspect, 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%, and content uniformity with an acceptance value of not more than 10.

In an aspect, the present invention relates to 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.

DETAILED DESCRIPTION OF THE INVENTION

The terms "fixed-dose combination" or "FDC" as used herein refer 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. In the context of the present invention, the fixed-dose combination refers to the combination of amlodipine and ramipril.

The term "free combination" as used herein refers to a combination of at least two active ingredients taken in separate tablets or medicines - so the proportions can, if required, be varied. In the context of present invention, free combination refers to the dose units comprising amlodipine and ramipril separately administered simultaneously to a subject.

The term "subject" as used herein refers to a mammal, especially human, rat, mouse, and the like. The terms "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.

The term "amlodipine" as used herein 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. In a specific aspect, the term 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.

The term "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.

The term "pre-blending" used herein refers to mixing of one or more excipients and/or active substances prior to sifting. In another aspect, 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.

The term "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. The terms "composition", "formulation" or "preparation" as used herein 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. In an aspect, the said composition is a capsule, or a hard gelatin capsule containing fixed-dose combination of amlodipine and ramipril.

The term "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.

The term "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). As described, 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. In an aspect, the lubricant is present in the composition not more than about 1% w/w of the total weight of the composition. In another aspect, 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.

The term "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.

The term "dry process" used herein 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.

The term "basifying agents" as used herein 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. In an aspect, the said composition is substantially free of basifying agent. In a specific aspect, the said composition comprises basifying agent from about 0%w/w to about 0.5% w/w.

The term "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.

Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances, and those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given technique used to measure a value. The term "about" with reference to quantity of excipient in the composition can be plus or minus 10%.

The term "stable" as used herein denotes both chemical stability and physical and/or polymorphic stability. The term "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.

The terms "related substances" or "impurities" as used herein mean degradation substances in the composition occurring in the manufacturing process of composition, or other substances from the excipients, or intermediates or by-products occurring in the process of preparing active substance. The term "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 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 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 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.

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 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 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.

In another aspect, the present invention relates to 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.

In another aspect, the present invention relates to 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.

In a specific aspect, the present invention relates to 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.

In an aspect, the present invention relates to 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. In an aspect, 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%.

In an aspect, the present invention relates to 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.

In an aspect, 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%, and content uniformity with an acceptance value of not more than 10.

In an aspect, the present invention relates to 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. In an aspect, 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.

In an aspect, 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. In another aspect, the present invention relates to a stable pharmaceutical composition in the form of granules prepared by a dry granulation method.

In an aspect, the stable pharmaceutical composition comprising a fixed-dose combination of amlodipine and ramipril, is optionally film coated.

In an aspect, the present application relates to 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.

In another aspect, 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.

In a specific aspect, 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.

In an aspect, 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). In an aspect, 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).

In an aspect, the present invention relates to 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 an aspect, the present invention relates to 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.

In an aspect, the present invention relates to 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.

In a specific aspect, 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 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.

In a specific aspect, the present invention relates to 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.

In another aspect, the present invention relates to 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.

In an aspect, the present invention relates to 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.

In another aspect, the present invention relates to 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.

In a specific aspect, the present invention relates to 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.

In an aspect, the present invention relates to 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.

In an aspect, the present invention provides 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.

In an aspect, the present invention relates to 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.

In an aspect, 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. In another embodiment, the application includes the use of oxygen absorbers and/or desiccants with packaging material.

In an aspect, 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.

In an aspect, 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.

In an aspect, 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.

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: One or more diluent(s) is 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, Flowlac™, Pharmatose™ 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, CEOLUS™ KG801, Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, silicified microcrystalline cellulose and microcrystalline cellulose 112. Other useful 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: One or more binder(s) is 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: One or more disintegrants is 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, Kollidon™ CL, Polyplasdone™ 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.

In an aspect, 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.

In an aspect, 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 descriptions of excipients are illustrative and are not intended to be exhaustive or limiting. Those skilled in the art will be aware of many other substances that are useful in the practice of the invention, and the use of such substances is also encompassed by the present application.

In an aspect, 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.

In an aspect, 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.

In an aspect, 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.

In a specific aspect of the present invention, 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.

In an aspect, 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.

In an aspect, the present invention relates to 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.

In an aspect, 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:

(i) initially coating the surfaces of the blending equipment by blending a first part of the diluent alone in a blender,

(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),

(iii) blending from about 20 to about 30% of diluent of total diluent with the blend of step (ii), and

(iv) blending from about 20 to about 40% of diluent of total diluent with the blend of step (iii);

b) sifting the total blend obtained in step a)(iv) through a suitable sifter; and

c) sifting the remaining quantity of diluent and adding to the blend of step b).

In an aspect, 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. In a specific aspect, 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:

(i) initially coating the surfaces of the blending equipment by blending a first part of the pregelatinised starch alone in a blender,

(ii) blending amlodipine, ramipril, magnesium oxide and about 5-20% of pregelatinised starch together with the blend of step a);

(iii) blending about 20-30% of pregelatinised starch together with the blend of step b);

(iv) 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).

In the above process, 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.

In an aspect, 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.

In an aspect, a dry process of preparing a stable pharmaceutical composition comprising a fixed- dose combination of amlodipine and ramipril comprises geometrically mixing with pregelatinised starch. In an aspect, 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.

In an aspect, 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.

In an aspect, 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.

In an aspect of the present invention, the usage of optimum thickness dosing disk eliminates the sticking problem.

In specific aspect, the capsules are filled using dosing disk having a thickness of about 18-19 mm to eliminate the sticking in the manufacturing process.

In an aspect, the present invention relates to 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).

In an aspect, the present invention relates to 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. In an aspect, the said powder has a bulk density from about 0.1 g/ml to about 1 g/ml. In another aspect, the said powder has a bulk density from about 0.48 g/ml to about 0.57 g/ml. In another aspect, the said powder has a tapped density from about 0.1 g/ml to about 1 g/ml. In another aspect, the said powder has a tapped density from about 0.80 g/ml to about 0.84 g/ml.

In an aspect, the present invention relates to 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%.

In an aspect, the present invention relates to 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.

In another aspect, the present invention relates to 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.

In yet another aspect, the present invention relates to 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.

In yet another aspect, the present invention relates to 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.

In another aspect, the present invention relates to 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.

In yet another aspect, the present invention relates to 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.

In yet another aspect, the present invention relates to 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.

In a specific aspect of the present invention relates to 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,

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, ,

c) total weight of the said composition is not less than about 250 mg,

d) the said composition has blend uniformity with a relative standard deviation of not more than 4%, and

e) the said composition has content uniformity with an acceptance value of not more than 10.

In a specific aspect of the present invention relates to 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,

c) 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,

d) total weight of the said composition is not less than about 250 mg,

e) the said composition is devoid of lubricant,

f) the said composition has blend uniformity with a relative standard deviation of not more than 4%, and

g) the said composition has content uniformity with an acceptance value of not more than 10.

In an aspect, 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.

All the above aspects and the following examples further describe certain specific aspects and embodiments of the application. These examples are provided solely for the purpose of illustration, and should not be construed as limiting the scope of the disclosure in any manner. Accordingly, 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.

Example 1:

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.

Table- 1 Blend in capsule

mg/cap mg/cap mg/cap mg/cap

S.No. Ingredient

(5/2.5) (5/5) (5/10) (10/10)

1 Amlodipine besilate 6.93 6.93 6.93 13.87

2 Ramipril 2.50 5.00 10.00 10.00

3 Pregelatinised starch 290.37 287.87 282.87 275.93

4 Magnesium oxide (light) 0.20 0.20 0.20 0.20

Total 300.00 300.00 300.00 300.00

Manufacturing Process A: a) Sifting: Ingredients 1, 2, 3 & 4 were sifted through appropriate screen

b) Blending: Materials of step a) were loaded into double cone blender, and blended for suitable time.

c) Encapsulation: The blend obtained from step 3 was filled in suitable sized hard gelatin capsule.

Manufacturing Process B: a) Dispensing:

Amlodipine, ramipril and all the excipients were dispensed as per the list

b) Pre-Blending:

(i) A part quantity of pregelatinised starch was blended alone in a blender to provide a coat to the stainless steel surface of blender. This reduces the direct contact of hygroscopic substances amlodipine besilate and/or ramipril with stainless steel surface,

(ii) Amlodipine besilate, ramipril and magnesium oxide and about 5-20% of pregelatinised starch was blended together with the blend of step (i),

(iii) About 20-30% of pregelatinised starch was blended together with the blend of step

(ii) , and

(iv) About 20-40% of pregelatinised starch was blended together with the blend of step

(iii) .

c) Sifting: (i) Pre-blended materials as obtained above were passed through a suitable screen using Quadra sifter and collected in suitable containers, and

(ii) Remaining quantity of pregelatinised starch was rinsed or passed through the screen and collected into the above container. Any residue of the actives and other materials adhered to the screen and walls of the sifter were recovered by this step. d) Blending:

The materials of step c) were loaded into blender and blended for 10 minutes at 8 RPM. e) Encapsulation:

The blend obtained from step d) was filled in suitable sized hard gelatin capsule. Example 2:

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.

Table-2

Example 3: Stability Studies

The accelerated stability study of the fixed-dose combination capsules of Examples 2A, 2B, 2C and 2D, was conducted under storage conditions of 40°C /75% RH. The data was obtained for 0, 1, 2, and 3 months during the study, the results of which are shown in Table-3A and Table- SB.

Table-3

Table-3A: Accelerated Stability studies for Example 2A and Example 2B,

*ND- Not Detected

Table-3B: Accelerated Stability studies for Example 2C and Example 2D

Ramipril

ND 0.15 0.19 0.37 0.00 0.17 0.43 1.59

Impurity E

*ND- Not Detected

Based on the accelerated stability results the composition of 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.

Table-3C: Long Term Stability Studies for Example 2C

Example 4:

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-4

3 Pregelatinised starch Ph. Eur. 275.930

4 Magnesium oxide (Light) Ph. Eur. 0.200

Total Fill Weight 300.000

Example 5: Dissolution studies

The two test formulations namely capsules comprising blend (Example 2C) and capsules comprising tablets (Example 4), were subjected to dissolution study. It was observed that both the formulations have shown the immediate release profiles of ramipril and amlopidine, and were found to be similar. The data of the study results are shown in the Table-5

Table-5: Dissolution data of blend filled in capsules (Example 2C) and tablets filled in capsules (Example 4)

Example 6: Pharmacokinetic Data

An Open label, two-way randomized crossover pharmacokinetic study was conducted, involving administration of the fixed-dose combination capsules of the test formulation (example 2C of strength 10/10 mg of amlodipine and ramipril) as the test product and the commercial products Istin™ 10 mg tablets and Tritace^® 10 mg tablets as reference products, in 42 healthy human volunteers in the fasting state, and plasma concentrations of the drug compounds were determined at desired intervals after dosing. Pharmacokinetic data are shown in the Table-6A & Table-6B. Table-6A

Table-6B

Example 7: Study on the impact of manufacturing process on the blend uniformity

It is important that the active substances should be uniformly distributed in a blend before filling them into capsules, especially for hygroscopic drugs such as amlodipine which stick to metallic surfaces to a considerable extent leading to blend uniformity problems. Therefore, uniformity of the blend needs to be studied during the manufacturing process.

For this purpose, 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.

The results of average, minimum, maximum and RSD of unit samples reveal poor distribution of active agents and their cohesive nature. These results are shown in Table-7A.

Table-7A

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.

Based on this finding, scale -up batches of compositions of both lowest and highest strengths (5/2.5 mg and 10/10 mg of amlopidine and ramipril respectively) were prepared on industrial scale (batch sizes of 135,000 Capsules each) using the process B comprising a pre-blending step, to confirm the robustness and industrial applicability of the process. The blend uniformity analysis was done at 7, 10 and 13 minutes of blending times.

The results of average, minimum, maximum and RSD of unit samples reveal blend uniformity at all the blending times with uniform distribution of the active agents, especially amlodipine that sticks to metallic surfaces to a considerable extent. The results of the analysis are shown in Table-7B.

Table-7B

5 100.0 99.5 102.6 100.0 98.8 99.8 101.9 100.0 101.8 99.7 109.8 100.5

6 102.8 98.7 99.6 103.6 98.0 100.4 102.4 99.5 101.7 100.6 101.2 102.6

7 97.1 99.2 100.8 99.5 97.5 98.6 102.0 100.8 100.9 100.3 101.5 101.0

8 95.2 98.2 103.6 106.6 95.3 99.7 102.9 99.7 102.3 99.9 101.0 99.9

9 101.3 97.8 97.0 99.4 104.8 101.7 97.3 98.1 101.8 99.2 104.2 100.2

10 103.2 98.6 100.7 99.4 96.0 99.8 101.9 99.4 99.0 99.3 100.8 101.3

Avg. 99.0 98.5 99.9 101.1 99.4 100.1 101.1 99.6 101.1 99.6 102.5 101.1

Min 95.2 97.6 95.6 98.5 95.3 98.6 97.3 98.1 99.0 98.1 100.8 99.9

Max 103.2 99.5 104.4 106.6 104.8 101.7 102.9 100.8 102.3 100.6 109.8 102.6 SD 2.9 0.6 3.1 2.6 2.9 0.9 1.6 0.7 1.3 0.7 2.7 0.8

Example 8: Study of the content uniformity of the final capsule

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.

Table-8

Tl, T2, T3, T4, and T5 denote time points for about every half an hour

Rami- Ramipril

Amlo- Amlodipine

AV- Acceptance Value

From the above aspects and examples, and based on the results of the studies done, it can be observed that a unit dosage capsule formulation comprising the fixed-dose combination of ramipril and amlodipine was successfully prepared using the process of the invention (Process B of Example 1), and the process was found to be reproducible during scale up and industrially applicable on the large scale. The capsules of the invention were found to be stable with respect to all the impurities which were maintained well within the limits, and the results of accelerated and long term stability studies were found to be satisfactory. Both, the capsules filled with blend as well as capsules filled with tablets, were found to give desired immediate release profile of the active agents amlodipine and ramipril. The pharmacokinetic parameters such as AUC and Cmax values of ramipril and amlodipine were comparable to their respective innovator products Tritace® lOmg tablets and Is tin™ 10 mg tablets.

Above all, it was observed that the said process of preparation of the capsules involving a pre- blending step, as described in the examples, reduced the contact and adherence of the sticky active substances to the walls and surfaces of the blender, thus avoiding the formation of impurities and loss of these potent low dose drugs during the manufacturing process. Moreover the, blend uniformity data from the examples show that both the active substances were uniformity distributed in the blend before filling it into final capsules. This blend uniformity ensures the quality of the final product with respect to content uniformity, release profile and thus the therapeutic efficacy. The content uniformity of both ramipril and amlodipine were achieved in the final capsules, which are considerably larger in weight in spite of the absence of lubricant and the variation was found to be within the limits as observed in the study results.

Claims

We Claim:

1. 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;

(ii) coating of the blender 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.

2. The composition according to claim 1 , wherein the said pharmaceutically acceptable excipients are selected from diluents, disintegrants, binders, basifying agent and/or combinations thereof.

3. The composition according to claim 1, wherein the said composition is devoid of lubricant.

4. The composition according to claim 1 , wherein the said composition is substantially free of basifying agent.

5. The composition according to claim 1 , wherein the composition is in the form of a tablet or a capsule or a solid powder or a tablet and/or powder filled in a capsule.

6. A process of preparing a stable pharmaceutical composition comprising ramipril and/or amlodipine or pharmaceutically acceptable salts thereof; wherein the said process comprises steps of:

a) pre-blending comprising:

(ii) blending amlodipine, ramipril, magnesium oxide and about 5-20% of diluent together with the blend of step (i),

(iii) blending about 20-30% of diluent together with the blend of step (ii), and (iv)blending about 20-40% of diluent together with the blend of step (iii);

b) sifting the total blend obtained in step a)(iv) by passing through a suitable sifter; and c) sifting the remaining quantity of diluent and adding it to the blend of step b).

7. The process according to claim 6, wherein the diluent is selected from starch, lactose, or cellulose or derivatives thereof.

8. The process according to claim 7, wherein the diluent is pregelatinised starch.

9. 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,

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,

c) total weight of the said composition is not less than about 250 mg,

10. The composition according to claim 9, wherein the said amlodipine and ramipril are not physically separated.

11. The composition according to claim 9, wherein the said composition is devoid of lubricant.

12. The composition according to claim 9, wherein total weight of the said composition is not less than about 250 mg to about 400mg.

13. The composition according to claim 9, wherein total weight of the said composition is not less than about 300mg.

14. The composition according to claim 9, wherein the said amlodipine or ramipril or their pharmaceutically acceptable salts are present in an amount not exceeding about 5% w/w based on total weight of the composition.