FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION COMPRISING AMLODIPINE AND BENAZEPRIL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 -30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides a pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 - 30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof.
Amlodipine is a dihydropyridine, long acting calcium channel blocker. It is commercially available as besylate salt under the trade name of Norvasc®. It is commercially available in fixed dose combination with benazepril under the trade name of Lotrel®. Chemically Amlodipine is (R,S) 3-ethyl-5-methyl-2-(2-aminoethoxymethyl) - 4 - (2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzenesulfonate (Formula I). It is indicated for the treatment of hypertension, chronic stable angina, vasospastic angina and angiographically documented CAD.

H,CO*C

"H"1^ CHJOCHJCHJNHJ
SO3H

FORMULA I
Benazepril is an angiotensin-converting enzyme inhibitor. It is commercially available as hydrochloride salt under the trade name of Lotensin®. Chemically benazepril 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S) propyl] amino]-2,3,4,5-
2
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tetrahydro-2-oxo-1 H-1-(3S)-benzazepine-1-acetic acid monohydrochloride (Formula II). Benazeprilat is the diacid form of benazepril formed by cleavage of the ester group, and is the active metabolite of benazepril. It is indicated for the treatment of hypertension.


•HCI

FORMULA II
U.S. Patent No. 6,162,802 describes method of treating a condition responsive to co-therapy with an angiotensin converting enzyme inhibitor (benazepril) and a calcium channel blocker (amlodipine), in a mammal in a need thereof and also describes a pharmaceutical composition of amlodipine and benazepril that are physically separated from one another.
U.S. Published Application No. 20040048905 describes a combination of benazepril and amlodipine and also describes the use of this combination in the treatment or prevention or delay of progression of various conditions.
U.S. Published Application No. 20070071811 describes pharmaceutical composition of amlodipine and benazepril that are in physical contact with one another.
International (PCT) Publication WO2006097943 describes pharmaceutical composition of amlodipine and benazepril that are not physically separated from one another and contain excipients other than alkali and alkaline earth metal carbonates and phosphates and those excipients, which increase the pH of microenvironment above 5.
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International (PCT) Publication WO2006085208 describes pharmaceutical composition comprising amlodipine as first component that is substantially free of dicalcium phosphate and second component as benazepril.
The present inventors while working on the combination formulation of amlodipine and benazepril have observed that the formulation can contain both the physically separated portions as well as physically mixed portions of amlodipine and benazepril. It was also found that the resulting formulation is stable and does not show any physical incompatibility problem.
In one of the aspects of the present invention there is provided a pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 - 30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof.
The composition of the present invention comprises Amlodipine and Benazepril as active ingredients and can be present in the composition as blend, granule, coated granule, tablet, or coated tablet.
Amlodipine is present in the form of besylate salt and Benazepril is present in the form of hydrochloride salt.
As used herein, "physically separated" means the two active agents i.e. amlodipine and benazepril are not in physical contact with one another and can be present 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
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tablet or capsule, coated tablet of one agent in capsule together with powder of the other agent, powder blend of one agent in capsule together with the powder of second agent and the like.
Another aspect of the present invention provides a pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 -30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof and wherein the composition is substantially free of alkali and alkaline earth metal carbonates and phosphates.
As used herein, "substantially free" means the formulation contains about 0- 5% of alkali and alkaline earth metal carbonates and phosphates.
Suitable Alkali and alkaline earth metal carbonates and phosphates may include one or more of sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, sodium phosphate, calcium phosphate, and calcium phosphate anhydrous and the like.
Another aspect of the present invention provides a process for the preparation of pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 - 30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof, the process comprising:
(a) blending atleast 70- 99.5% of benazepril, and one or more pharmaceutically acceptable excipients, optionally granulating, optionally compressing the blend/granules and optionally coating with nonfunctional coat; and
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(b) blending an effective amount of amlodipine, and atleast 0.5 - 30% of benazepril with one or more pharmaceutically acceptable excipients, and optionally granulating and/or compressing the blend;
(c) blending step (a) and step (b)
Suitable non-functional coat may include one or more of colloidal silicon dioxide, Opadry, polyethylene glycols, and the like.
The pharmaceutically acceptable excipients comprise one or more of diluents, binders, disintegrants, lubricants, glidants, and the like.
Suitable diluents may include one or more of microcrystalline cellulose, mannitol, starch, lactose, pregelatinized starch and the like.
Suitable binders may include those well known to a person skilled in the art, as exemplified can be celluloses such as hydroxypropyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose or mixtures thereof, acrylates, methacrylates, povidone, starch, stearic acid, gums, and other materials known to have cohesive and desirable binding properties.
Suitable disintegrants may include one or more of starch, pregelatinized starch, L-HPC, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable lubricants may include those well known to a person skilled in the art, as exemplified can be talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, hydrogenated castor oil, stearic acid, sodium stearyl fumarate and sodium benzoate, sodium lauryl sulphate, colloidal silicon dioxide, palmitic acid, carnauba wax, glyceryl monostearate, palmitic acid, carnauba wax, and the like.
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Suitable glidants may include one or more of colloidal silicon dioxide, talc or cornstarch and the like.
These pharmaceutical composition of the present invention may be in the form of coated tablets of one drug and powder blend of both the drugs, filled into capsules; coated granules of one drug and powder blend of both the drugs, filled into capsules; coated granules or powder blend of one drug filled into capsule and this capsule is placed in another capsule together with powder blend or granules of both the drugs; inert pellet coated with first drug followed by nonfunctional coat and then coated with mixture of two drugs or vice versa; coated tablets of one drug and tablet comprising both the drugs, filled into capsule; coated granules of one drug and powder blend of both the drugs, compressed to form tablet and the like.
The pharmaceutical composition of the present invention is meant for oral administration.
The pharmaceutical composition of the present invention can be prepared by wet granulation, dry granulation or direct compression.
The pharmaceutical composition of the present invention may include coated tablets of benazepril in capsule together with blend comprising amlodipine and benazepril. The tablets of benazepril can be prepared by wet granulation, dry granulation or direct compression. The benazepril tablet can be prepared by mixing Benazepril HCI with one or more pharmaceutical^ acceptable excipients followed by granulating suitable granulating agent. The obtained granules can be mixed with a glidant and lubricant. The lubricated granules can be compressed to form tablets. Compressed tablets can be coated with a coating polymer i.e. Opadry (non-functional). The blend comprising amlodipine and benazepril can be prepared by mixing Amlodipine besylate, Benazepril HCI and one or more pharmaceutical^ acceptable excipients and obtained mixture/blend can be mixed
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with a glidant and lubricant. Benazepril tablets and lubricated blend of Amlodipine and Benazepril can be filled into capsule.
The pharmaceutical composition of the present invention may include granules of benazepril in capsule together with blend comprising amlodipine and benazepril. The granules of benazepril can be prepared by wet granulation or dry granulation. The benazepril granules can be prepared by mixing Benazepril HCI with one or more pharmaceutically acceptable excipients followed by granulating with suitable granulating agent. The obtained granules can be mixed with a glidant and lubricant. The lubricated granules can be optionally coated with a coating polymer i.e. Opadry (non-functional). The blend comprising amlodipine and benazepril can be prepared by mixing Amlodipine besylate, Benazepril HCI and one or more pharmaceutically acceptable excipients and obtained mixture/blend can be mixed with a glidant and lubricant.
Benazepril granules can be filled into capsule and lubricated blend of Amlodipine and Benazepril alongwith benazepril capsule can be filled into another capsule or Benazepril granules and lubricated blend of Amlodipine and Benazepril can be filled into capsule.
Suitable granulating agent may include those well known to a person skilled in the art.
The pharmaceutical composition of the present invention may include blend of benazepril in capsule and this capsule is placed in another capsule together with blend comprising amlodipine and benazepril. The blend of benazepril includes mixing of Benazepril HCI with one or more pharmaceutically acceptable excipients. The obtained blend can be lubricated and filled into capsule. The blend comprising amlodipine and benazepril can be prepared by mixing Amlodipine besylate, Benazepril HCI and one or more pharmaceutically acceptable excipients and obtained mixture/blend can be mixed with a glidant
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and lubricant. Capsule containing Benazepril and lubricated blend of Amlodipine and Benazepril are placed into another capsule.
The pharmaceutical composition of the present invention may include inert pellets comprising two active layers wherein first layer comprises benazepril alongwith pharmaceutically acceptable excipients and the second layer comprises amlodipine and benazepril alongwith pharmaceutically acceptable excipients, wherein the two layers are separated by a non-functional coat. The first and the second layer are interchangeable.
The inert pellets as used herein include those well known to a person skilled in the art, as exemplified can be sugar spheres, glass beads, microcrystalline cellulose spheres, plastic beads and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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Examples 1 -3
Table 1: Composition of Amlodipine and Benazepril.

No. Ingredients Quantity / Tablet (mg)
Example 1 Example 2 Example 3
Part I
1. Benazepril HCI 36.00 18.00 9.00
2. Lactose monohydrate 24.72 12.36 6.18
3. Microcrystalline Cellulose 3.50 1.75 0.88
4. Pregelatinized starch 3.50 1.75 0.88
5. Crospovidone 1.40 0.70 0.35
6. Aerosil 0.35 0.18 0.09
7. Magnesium Stearate 0.53 0.26 0.13
8. Opadry coating (optional) q.s q.s q.s
Part II
1. Amlodipine besylate *13.89 *6.94 *3.47
2. Benazepril HCI 4.00 2.00 1.00
3. Microcrystalline Cellulose 81.86 40.93 20.47
4. Mannitol 35 17.5 8.75
5. Sodium starch glycolate 2.8 1.4 0.7
6. Aerosil 1.4 0.7 0.35
7. Magnesium stearate 1.05 0.53 0.26
*3.472 Amlodipine besylate equivalent to 2.5 mg Amlodipine
* 6.944 Amlodipine besylate equivalent to 5.0 mg Amlodipine
* 13.889 Amlodipine besylate equivalent to 10.0 Amlodipine
Procedure: The pharmaceutical compositions mentioned in examples 1, 2 and 3 includes 2 parts i.e. Part I and Part II. The Part I include benazepril as active ingredient and was prepared by mixing Benazepril HCI, lactose monohydrate, microcrystalline cellulose, pregelatinized starch and crospovidone and the mixture was granulated with water in rapid mixer granulator. The obtained granules were mixed with Aerosil and magnesium stearate in double cone blender. The lubricated granules can be optionally coated with a coating polymer
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i.e. Opadry or can be compressed to form tablets. Compressed tablets can be coated with a coating polymer i.e. Opadry.
The Part II include blend of amlodipine and benazepril that was prepared by mixing Amlodipine besylate, Benazepril HCI, microcrystalline cellulose, Mannitol and sodium starch glycolate in double cone blender and was then mixed with Aerosil and lubricated with magnesium stearate in double cone blender.
Benazepril tablets (Part I) and Lubricated blend of Amlodipine and Benazepril (Part II) were filled into capsule.
Examples 4- 6
Table 1: Composition of Amlodipine and Benazepril.

No. Ingredients Quantity / Tablet (mg))
Example 4 Example 5 Example 6
Part I
9. Benazepril HCI 36.00 18.00 9.00
10. Lactose monohydrate 24.72 12.36 6.18
11. Microcrystalline Cellulose 3.50 1.75 0.88
12. Pregelatinized starch 3.50 1.75 0.88
13. Crospovidone 1.40 0.70 0.35
14. Aerosil 0.35 0.18 0.09
15. Magnesium Stearate 0.53 0.26 0.13
Part II
8. Amlodipine besylate *13.89 *6.94 *3.47
9. Benazepril HCI 4.00 2.00 1.00
10. Microcrystalline Cellulose 81.86 40.93 20.47
11. Mannitol 35 17.5 8.75
12. Sodium starch glycolate 2.8 1.4 0.7
13. Aerosil 1.4 0.7 0.35
14. Magnesium stearate 1.05 0.53 0.26
*3.472 Amlodipine besylate equivalent to 2.5 mg Amlodipine
* 6.944 Amlodipine besylate equivalent to 5.0 mg Amlodipine
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* 13.889 Amlodipine besylate equivalent to 10.0 Amlodipine
Procedure: The pharmaceutical compositions mentioned in examples 4, 5 and 6 includes 2 parts i.e. Part I and Part II. The Part I include benazepril as active ingredient and was prepared by mixing Benazepril HCI, lactose monohydrate, microcrystalline cellulose, pregelatinized starch and crospovidone and the mixture was granulated with water in rapid mixer granulator. The obtained granules were mixed with Aerosil and magnesium stearate in double cone blender. The lubricated granules were filled into capsule.
The Part I can also be prepared by mixing Benazepril HCI, lactose monohydrate, microcrystalline cellulose, pregelatinized starch and crospovidone. The obtained powder blend was mixed with Aerosil and magnesium stearate in double cone blender. The lubricated powder blend was filled into capsule.
The Part II include blend of amlodipine and benazepril that was prepared by mixing Amlodipine besylate, Benazepril HCI, microcrystalline cellulose, Mannitol and sodium starch glycolate in double cone blender and was then mixed with Aerosil and lubricated with magnesium stearate in double cone blender.
Benazepril granules filled into capsule (Part I) or Benazepril powder blend filled into capsule (Part I) and Lubricated blend of Amlodipine and Benazepril (Part II) were filled into another capsule.
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WE CLAIM:
1. A pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 - 30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 - 30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof and wherein the composition is substantially free of alkali and alkaline earth metal carbonates and phosphates.
3. The pharmaceutical composition of claim 1 and 2, wherein the benazepril is benazepril hydrochloride.
4. The pharmaceutical composition of claim 1 and 2, wherein the amlodipine is amlodipine besylate.
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5. The pharmaceutical composition of claim 1 and 2, wherein alkali and alkaline earth metal carbonates and phosphates comprises one or more of sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, sodium phosphate, calcium phosphate, calcium phosphate anhydrous.
6. The pharmaceutical composition of claim 1 and 2, in the form of capsule comprising within it (a) coated tablet of benazepril and (b) amlodipine and benazepril blend.
7. The pharmaceutical composition of claim 1 and 2, in the form of capsule comprising within it (a) benazepril granules or blend in a capsule and (b) amlodipine and benazepril blend.
8. A process for the preparation of pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 -30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof, the process comprising:

a) blending atleast 70- 99.5% of benazepril, and one or more pharmaceutically acceptable excipients, optionally granulating, optionally compressing the blend/granules and optionally coating with non-functional coat; and
b) blending an effective amount of amlodipine, and atleast 0.5 - 30% of benazepril with one or more pharmaceutically acceptable excipients substantially free of alkali and alkaline earth metal
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carbonates and phosphates and optionally granulating and/or compressing the blend; c) blending step (a) and step (b)
9. The process of claim 8, wherein the pharmaceutically acceptable excipients comprises one or more of diluents, binders, disintegrants, lubricants and glidants.
10. The process of claim 8, wherein the non- functional coat comprises one or more of colloidal silicon dioxide, Opadry, polyethylene glycols.
Dated this 29TH day of June, 2007

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Abstract
The present invention provides a pharmaceutical composition comprising benazepril or pharmaceutically acceptable salt thereof in combination with amlodipine or pharmaceutically acceptable salt thereof wherein atleast 0.5 - 30% of benazepril is not physically separated from amlodipine or pharmaceutically acceptable salt thereof and atleast 70- 99.5% of benazepril is physically separated from amlodipine or pharmaceutically acceptable salt thereof.
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