FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
PROVISIONAL SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVETION
"Stable Pharmaceutical Compositions"
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:

Stable Pharmaceutical Compositions
FIELD OF THE INVENTION
The present invention relates to a novel pharmaceutical composition of amlodipine, or its pharmaceutically acceptable salt and benazepril, or its pharmaceutically acceptable salt and to a process for the preparation thereof.
BACKGROUND OF THE INVENTION
Hypertension is the most common cardiovascular disease. Elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. As a consequence, hypertension is the principal cause of stroke, leads to disease of the coronary arteries with myocardial infarction and sudden cardiac death, and is major contributor to cardiac failure, renal insufficiency, and dissecting aneurysm of the aorta. The fixed-dose combination of calcium channel blocker and angiotensin-converting enzyme (ACE) inhibitor has been shown to have a superior blood pressure lowering effect compared to its individual drug components with an excellent safety profile.
The first calcium channel blocker/angiotensin-converting enzyme (ACE) inhibitor combination marketed in the United States is a fixed dose combination of amlodipine and benazepril. The said combination is available in USA under the brand name of Lotrel® and is approved since March 03, 1995. The combination is available in six different strengths for oral administration with a combination of amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine with 10 mg, 20 mg or 40 mg of benazepril hydrochloride providing for the following combination 2.5/10 mg; 5/10 mg; 5/20 mg; 5/40 mg; 10/20 mg; and 10/40 mg.
Amlodipine, a calcium channel blocker, and it salts are disclosed in US 4,879,303, whereas the invention residing in US 4,410,520 relates to benazepril, an angiotensin converting enzyme inhibitor and its salts.
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The use of abovementior ed fixed dose combination of amlodipine and benazepril to treat various cardiovascular diseases including hypertension is described in US 6,162,802 of Papa et. al. The documer t further discloses that benazepril and amlodipine are physically incompatible substances. Hence, if incorporated into a single dosage form they must be kept physically separated. This may be accomplished in any of the myriad ways known in the art, such as bi-layere I tablet, coated pellets of one agent incorporated into a tablet of the other, separately coa ed pellets of each agent in a capsule or tablet, coated pellets of one agent in capsule together with the powder of the other agent, each agent microencapsulated separately and then blended together for use in tablet or capsule, use of dual or multiple compartment transdermal device, etc.
Further, WO 2006/097''43 of Vithalapuram et. al. also teaches a pharmaceutical composition for the fixed dose combination of amlodipine and benazepril, while overcoming prior art limitations.
In WO 2006/085208 of Dhaliwal et. al. disclosing a stable formulation of amlodipine and benazepril, it is reported that presence of dicalcium phosphate in the amlodipine formulation triggers the degradation of amlodipine, which is more pronounced at a pH below 6. Hence, a stable pharmaceutical composition of amlodipine could be prepared by making it free of dicalcium phosphate.
Similarly, in a recently published application US 2007/0071811, Kadosh et. al. describes that "Impurity D', which is main degradation product of amlodipine and (S,S)-diacid (benazeprilat), a main degradation product of benazepril could be minimized by processing benazepril b] wet granulation method and amlodipine by dry processing methods.
Thus, form the above, it would be abundantly evident that there are contrary teachings available in the prior a t leaving a person in the position of bewildered. The only approved marketed composition of amlodipine and benazepril having alkaline substances has met the stringent requirements of the Regulatory Health Authorities. However, physical separation of the two components, not only requires complicated processing, but
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also has inherent risks and complications. Further, recourse to specific non-alkaline substances limits the choice of excipients for a formulator, while designing the formulation leaving a very little room to experiment with. Therefore, there exists a need for finding suitable ways to overcome the problem of stabilization in amlodipine-benazepril composition.
OBJECTS OF THE INVENTION:
A primary object of the present invention is to prepare a novel and stable pharmaceutical composition of amlodipine or its pharmaceutically acceptable salt and benazepril or its pharmaceutically acceptable salt.
Another object of the present invention is to make a pharmaceutical composition of amlodipine or its pharmaceutically acceptable salt and benazepril or its pharmaceutically acceptable salt, characterized in that it is devoid of the limitations of the prior art formulation such as physical separation or limitation of not to use alkaline substances as excipients.
A further object of the present invention is to provide a process for preparation of novel and stable pharmaceutical compositions of amlodipine or its pharmaceutically acceptable salt and benazepril or its pharmaceutically acceptable salt.
SUMMARY OF THE INVENTION
The present invention relates to a novel and stable pharmaceutical composition of amlodipine or its pharmaceutically acceptable salt and benazepril or its pharmaceutically acceptable salt.
In one aspect the present invention provides a stable pharmaceutical composition comprising therapeutically effective amounts of amlodipine or its pharmaceutically acceptable salt and benazepril or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier wherein the stability of the composition is achieved
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by an effective stabilizing amount of a buffering agent. Preferably the amlodipine is amlodipine besylate and benazepril is benazepril hydrochloride.
In another preferred aspect of the present invention, there is no requirement of the physical separation of amlodipine and benazepril. The two drugs could be placed in such a manner so that they are in physical contact with each other. The stability of the present invention is not affected by the criteria of physical separation. The two drugs could be placed in a physically separate manner or could be in physical contact with each other depending on the manufacturer's feasibility. In general, it is preferred that the two drugs are in physical contact with each other to avoid the complicated formulation procedures.
In still another aspect, there is provided a process for preparing such novel and stable pharmaceutical compositions comprising amlodipine or its pharmaceutically acceptable salt and benazepril or its pharmaceutically acceptable salt.
These objects of the present invention will become more fully apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Stability is an important aspect of a pharmaceutical composition. Regulatory Health Authorities all over the world has stringent norms for the impurities, which are present in a pharmaceutical composition. A main degradation product of benazepril is (S,S)-diacid (benazeprilat), which is the active metabolite of benazepril. A main degradation product of amlodipine is 'Impurity D', also known as 'Amlo-Pyridine', which is chemically 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate. Further, it has been reported that a pH of about 5.5 or less is favorable for the formation of impurity D in amlodipine composition.
Thus, the present invention relates to a stable amlodipine benazepril formulation, comprising a therapeutically effective amount of amlodipine and benazepril, an effective stabilizing amount of a buffering agent and a pharmaceutically acceptable carrier.
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As used herein the term "amlodipine" is not particularly limited and includes anhydrates, solvates, hydrates and partial hydrates as well as crystalline and amorphous forms of amlodipine or pharmaceutically acceptable salt thereof. Similarly, the term benazepril is also not particularly limited and includes anhydrates, solvates, hydrates and partial hydrates as well as crystalline and amorphous forms of benazepril or pharmaceutically acceptable salt thereof. In the stable pharmaceutical compositions of the present invention, the amlodipine is preferably amlodipine besylate and benazepril is benazepril hydrochloride.
The term buffering agent as used herein means any acidic or basic agent which is capable of stabilizing pharmaceutical compositions comprising amlodipine and benazepril combination and thereby preventing or retarding the formation of unwanted impurities such as impurity D. Buffering agents are selected from the group comprising of citric acid, maleic acid, tartaric acid, fumaric acid, ascorbic acid or alkali metal salts (e.g., lithium, sodium, potassium and the like) of these carboxylic acid and the like or mixtures thereof. The term buffering agents also include various pharmaceutically acceptable amino acids such as glycine, aspartic acid, glutamic acid. The buffering agent is preferably selected from citric acid and ascorbic acid or sodium salts of these acids and most preferably is citric acid.
The buffering agent is present in the formulations of the present invention in an effective stabilizing amount. The buffering agent is conveniently present in an amount of up to 10 percent by weight of amlodipine composition. Typically, the buffering agent is present in the range of from about 0.1 percent by weight of composition to 5 percent by weight of the composition, and preferably it is up to 1 weight percent.
The term pharmaceutically acceptable carrier as used herein refers to the various excipients which can be combined with the pharmaceutical composition of amlodipine and benazepril. The various excipients used in a given pharmaceutical composition are well known in the pharmaceutical art. Excipients used are selected from those which do not exhibit a destabilizing effect on either the amlodipine part and/or benazepril part. Examples of excipients that can be employed include diluents/fillers, binders,
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disintegrant, lubricant, glidants, antiadherants, surfactants, water soluble polymers and water insoluble polymers etc.
A combination of excipients may also be used. Such excipients are known to those skilled in the art, and thus, only few representative examples for each class of excipient are mentioned herein below:
Diluents for the formulations are inert substances that may be used as a vehicle for the active agent, optionally in conjunction with other excipients, as long as the resulting formulation meets the desired dissolution profile and/or is stable. Suitable diluents include, lactose-based materials such as lactose monohydrate, spray dried lactose; cellulosic materials such as microcrystalline cellulose; starches including partially pregelatinized starch, pregelatinized starch, partially hydrolyzed starch, maize starch, potato starch, rice starch, wheat starch, and tapioca starch; sugar such as sucrose, dextrose, fructose, and the like; sugar alcohols such as mannitol, sorbitol, xylitol, and the like; saccharides / polysaccharides such as maltodextrin and the like; dibasic calcium phosphate, calcium sulphate, and the combinations thereof.
Combination of two or more diluents can be used in the dosage formulations. When used, the total amount of diluents can be up to about 99 weight percent of the total weight of the imlodipine formulation; specifically about 01 to about 60 weight percent; more specifically about 05 to about 30 weight percent; and yet more specifically about 10 to about 25 weight percent.
Bine ers may be, for example, starch, sugars, gums, hydroxypropyl methyl cellulose, hydroxyl propyl cellulose or the like. Certain traditional tablet diluents may also function as disintegrant (e.g. starch), while other materials provide superior results as a disirategrant, for example, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, alginates, and the like. The disintegrant can he present in the formulations in an amount of about 0.0: to about 20 weight percent of the total weight of the formulation.
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A lubricant and/or glidant can also be used in the dosage formulations to aid in the processing of powder materials. Exemplary lubricants include calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, and combinations thereof.
Other optional additives to the dosage formulations include, for example, sweetening agent, flavoring agents, stabilizing agents, colorants, antioxidants and combinations comprising one or more of the foregoing additives.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
Examples:
Considering the feasibility of the pharmaceutical preparation, following examples were
carried out.
Example-1:
A blend of amlodipine with the excipients as given in the Table- 1 can be prepared. A
tablet formulation of Benazepril could also be prepared. Then the two formulations, then
could be provided in a suitable form such as capsule having desired concentrations of
amlodipine and Benazepril.
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Table- 1: Pharmaceutical composition of Amlodipine and Benazepril

Mg per Capsule
Sr. No. Ingredient 2.5 + 10 5 + 20 10 + 40 10 + 20 5 + 10 5 + 40
Amlodipine Blend
1 Amlodipine Besylate 3.47 6.94 13.88 13.88 6.94 6.94
2 Dicalcium phosphate 5.51 11.02 22.04 22.04 11.02 22.04
3 Microcrystalline cellulose 4.5 9.0 18.0 18 9.0 24.94
4 Citric Acid 0.15 0.3 0.6 0.6 0.3 0.6
5 Purified Water q.s. q.s. q.s. q.s. q.s. q.s.
6 Sodium starch glycolate 1.3 2.6 5.2 5.2 2.6 5.2
7 Magnesium Stearate 0.07 0.14 0.28 0.28 0.14 0.28
Mg per Capsule
Sr. No. Ingredient 2.5 + 10 5 + 20 10 + 40 10 + 20 5 + 10 5 + 40
Benazepril Hydrochloride Tablets
8 Benazepril Hydrochloride 10 20 40 20 10 40
9 Lactose monohydrate 13.2 26.4 52.8 63.1 31.55 52.7
10 Pregelatinised starch 2 4 8 4 2 8
11 Purified Water q.s. q.s. q.s. q.s. q.s. q.s.
12 Crospovidone 2.5 5 10 10 5 10
13 Microcrystalline Cellulose 12 24 48 62 31 48
14 Hydrogenated Castor oil 0.2 0.4 0.8 0.4 0.2 0.8
15 Magnesium Stearate 0.1 0.2 0.4 0.5 0.25 0.5
Total fill weight 55 110 220 220 110 220
Dated this fourth (04) day of June, 2007

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