Stable pharmaceutical compositions of calcium channel blocker and an ACE inhibitor

Abstract

The present invention relates to a stable pharmaceutical composition of a combination of amlodipine and an ACE inhibitor; wherein the two active ingredients are not physically separated and the composition has a pH of more than 6.0. It also relates to a process for preparation, and a method for using such a composition.

Description

DETAILED DESCRIPTION OF THE INVENTION

The term “stable pharmaceutical composition” as used herein refers to the composition of amlodipine and an ACE inhibitor wherein the impurities do not exceed the regulatory requirement of country of interest. For example, stable pharmaceutical composition refers to compositions comprising amlodipine impurity D less than 0.2% w/w and ramipril impurity D less than 0.2% w/w when stored at 30° C. and 65% relative humidity (RH) for a period of one month.

The term “amlodipine” as used herein includes amlodipine free base, or pharmaceutically acceptable acid addition salts thereof or mixtures thereof. It also covers anhydrous form, hydrous form, different crystalline forms, amorphous form, enantiomers of amlodipine or pharmaceutically acceptable acid addition salts thereof or mixtures thereof. Amlodipine may be present in an amount ranging from 1% to 15% by weight of the composition.

The term “ACE inhibitor” as used herein includes angiotensin converting enzyme inhibitor selected from ramipril, benazepril, captopril, enalapril, quinapril, perindopril, lisinopril, fosinopril, trandolapril, moexipril or pharmaceutically acceptable salts thereof. ACE inhibitor may be present in an amount ranging from 1% to 15% by weight of the composition.

The term “ramipril” as used herein includes ramipril free base, ramiprilat, or pharmaceutically acceptable salts of ramipril or mixtures thereof.

The term “benazepril” as used herein includes benazepril free base, benazeprilat or pharmaceutically acceptable salts of benazepril or mixtures thereof.

Calcium channel blockers are compounds which work by blocking voltage-sensitive calcium channels in the heart and in the blood vessels. This prevents calcium levels from increasing as much in the cells when stimulated, leading to less contraction. This decreases total peripheral resistance by dilating the blood vessels, and decreases cardiac output by lowering the force of contraction. Because resistance and output drop, so does blood pressure.

With low blood pressure, the heart does not have to work as hard; this can ease problems with cardiomyopathy and coronary disease. Unlike with beta-blockers, the heart is still responsive to sympathetic nervous system stimulation, so blood pressure can be maintained more effectively.

The term “calcium channel blockers” as used herein includes (1) Dihydropyridine calcium channel blockers including (a) Amlodipine (Norvasc), (b) Felodipine (Plendil), (c) Nicardipine (Cardene, Carden SR), (d) Nifedipine (Procardia, Adalat), (e) Nimodipine (Nimotop), (f) Nisoldipine (Sular), (g) Nitrendipine (Cardif, Nitrepin), (h) Lacidipine (Motens), and (i) Lercanidipine (Zanidip); (2) Phenylalkylamine calcium channel blockers including (a) Verapamil (Calan, Isoptin), and (b) Gallopamil (D600); (3) Benzothiazepine calcium channel blockers including Diltiazem (Cardizem); and (4) other calcium channel blocker such as Menthol (mint oil). The calcium channel blocker(s) may be present in an amount ranging from 1% to 15% by weight of the composition.

The term “basifying agent” as used herein refers to compounds which has pH of more than 6.0 and are capable of increasing the pH of the formulation to more than 6.0. Preferably, the basifying agent comprises 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 ranging from 0.1% to 10% by weight of the composition. It would be apparent to a person skilled in the art that some basifying agents may be used as diluents in higher concentration.

The term “core” as used herein includes sugar globules, inert non-pareil seeds, inert beads, inert pellets, granules, flakes, tablets and such like.

The term “not physically separated” is intended to mean that calcium channel blocker and the ACE inhibitor are present together in a single unit or a single phase in the composition. Physical separation is described in U.S. Pat. No. 6,162,802 [column 3, line 50 to 58]. 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. Due to the incompatibility, combination products of the two agents in an injectable solution are not really acceptable. For example, amlodipine and ACE inhibitor as disclosed in the compositions of U.S. Pat. No. 6,162,802 and Brazilian patent application No. 00/03282 are physically separated.

The pharmaceutical compositions as described herein may comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, film forming agent, lubricant, and such like.

Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dextrose; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; or mixtures thereof. The diluent may be present in an amount ranging from 1% to 90% by weight of the composition.

Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone or mixtures thereof. The disintegrant may be present in an amount ranging from 1% to 10% by weight of the composition.

Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins, and such like. The binder may be present in an amount ranging from 0.1% to 10% by weight of the composition.

Film forming agent may be selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, hydroxypropyl cellulose, polyethylene oxide, hydroxyethyl cellulose, sodium alginate and such like. The film forming agent may be used in seal coat, drug coat, separating coat, film coat and such like.

Lubricant/glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, starch, sodium stearyl fumarate, mineral oil, magnesium trisilicate; or mixtures thereof. The lubricant/glidant may be present in an amount ranging from 0.1% to 10% by weight of the composition.

One embodiment discloses a stable pharmaceutical composition comprising

• • (a) a calcium channel blocker;
  • (b) an ACE inhibitor;
  • (c) one or more basifying agents; and
  • (d) optionally one or more pharmaceutically acceptable excipients,wherein amlodipine and ramipril are not physically separated from each other and the composition has a pH of more than 6.0.

Another embodiment discloses a stable pharmaceutical composition comprising

• • (a) amlodipine;
  • (b) ramipril/benazepril;
  • (c) one or more basifying agents; and
  • (d) optionally one or more pharmaceutically acceptable excipients,wherein amlodipine and ramipril are not physically separated from each other and the composition has a pH of more than 6.0.

Another embodiment discloses stable pharmaceutical composition comprising:

• • (i) 1-30% by weight amlodipine,
  • (ii) 1-30% by weight ramipril/benazepril,
  • (iii) 1-20% by weight hydroxypropyl methylcellulose,
  • (iv) 10-90% by weight microcrystalline cellulose, and
  • (v) 0.1-10% by weight magnesium carbonate;wherein amlodipine and ramipril are not physically separated and the composition has a pH of more than 6.0.

Another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises the steps of:

• • mixing a calcium channel blocker, an ACE inhibitor, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients;
  • granulating the mixture;
  • drying the granules;
  • optionally mixing the granules with one or more pharmaceutically acceptable excipients, and
  • filling the granules into capsules.

Another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises the steps of:

• • mixing a calcium channel blocker, an ACE inhibitor, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients,
  • granulating the mixture to obtain wet mass,
  • extruding the wet mass to obtain the pellets,
  • optionally mixing the pellets with one or more pharmaceutically acceptable excipients, and
  • filling the pellets into capsules.

Still another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises the steps of:

• • mixing a calcium channel blocker, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients,
  • granulating the mixture to obtain wet mass,
  • extruding the wet mass to obtain the pellets,
  • coating the pellets with an ACE inhibitor, and
  • filling the coated pellets into capsules.

Still another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises the steps of:

• • mixing an ACE inhibitor, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients,
  • granulating the mixture to obtain wet mass,
  • extruding the wet mass to obtain the pellets,
  • coating the pellets with a calcium channel blocker,
  • optionally mixing the pellets with one or more pharmaceutically acceptable excipients, and
  • filling the coated pellets into capsules.

Further embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises the steps of:

• • mixing a calcium channel blocker and an ACE inhibitor with one or more basifying agents and optionally one or more pharmaceutically acceptable excipients,
  • coating the mixture on a core,
  • optionally mixing the coated core with one or more pharmaceutically acceptable excipients, and
  • filling the coated cores into capsules.

The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:

COMPARATIVE EXAMPLE

Ingredients                      Qty. in mg
Seal-coating of sugar globules
Sugar Globules                   65.00
Hydroxypropyl methylcellulose (HPMC) 5.00
Talc                             2.00
Purified Water                   q.s.
Total                            72.00
Drug coating of seal-coated globules
Seal-coated sugar globules       72.00
Ramipril                         5.00
Amlodipine besylate              6.93
Hydroxypropyl methylcellulose (HPMC) 10.17
Sodium Phosphate                 1.00
Purified Water                   q.s.
Total                            95.10
Film coating of drug coated pellets
Drug Coated Pellets              95.10
Hydroxypropyl methylcellulose (HPMC) 8.00
Talc                             2.90
Purified Water                   q.s.
Total                            106.00

PROCEDURE: HPMC and talc were dispersed in water and the suspension was coated on sugar globules to provide a seal coat. Ramipril, amlodipine besylate, HPMC and sodium phosphate were mixed and dispersed in water and the suspension was coated on seal-coated sugar globules to obtain pellets. The pellets were coated with a suspension of HPMC and talc in water, dried and filled into the capsule of appropriate size. The pH of the pellets was 5.20.

EXAMPLE 1

Ingredients                Qty. in mg
Ramipril                   5.00
Amlodipine besylate        6.93
Microcrystalline cellulose 62.49
Magnesium carbonate        0.55
Color                      0.03
Purified water             q.s.
Total                      75.00

PROCEDURE: Ramipril, amlodipine besylate, microcrystalline cellulose, magnesium carbonate and color were sifted and mixed in a rapid mixer granulator. The mixture was granulated with purified water to obtain a wet mass. The wet mass was passed through an extruder and the extrudates obtained were spheronized to obtain pellets of required size. The pellets were dried and filled into the capsule of appropriate size. The pH of the pellets was 8.40.

EXAMPLE 2

Ingredients                      Qty. in mg
Ramipril                         5.00
Amlodipine besylate              6.93
Microcrystalline cellulose       56.72
Magnesium carbonate              1.35
Purified water                   q.s.
Hydroxypropyl methylcellulose (HPMC) 5.20
Talc                             1.29
Color                            0.01
Purified water                   q.s.
Total                            76.50

PROCEDURE: Ramipril, amlodipine besylate, microcrystalline cellulose and magnesium carbonate were sifted and mixed in rapid mixer granulator. The mixture was granulated with purified water and the granules obtained were dried and sized. A coating suspension was prepared by dispersing HPMC, talc and color in purified water and the granules were coated by spraying the suspension over the granules. Coated granules were filled into the capsules of appropriate size. The pH of the granules of was 8.40.

EXAMPLE 3

Ingredients                      Qty. in mg
Ramipril                         5.00
Amlodipine besylate              6.93
Microcrystalline cellulose       57.25
Magnesium carbonate              0.82
Purified water                   q.s.
Hydroxypropyl methylcellulose (HPMC) 20.00
Talc                             5.00
Purified water                   q.s.
Total                            95.00

PROCEDURE: Ramipril, amlodipine besylate, microcrystalline cellulose and magnesium carbonate were sifted and mixed in rapid mixer granulator. The mixture was granulated with purified water and the granules obtained were dried and sized. A coating suspension was prepared by dispersing HPMC and talc in purified water and the granules were coated by spraying the suspension over the granules. Coated granules were filled into the capsules of appropriate size.

EXAMPLE 4

Ingredients                      Qty/Cap(mg)
Amlodipine spheres
Amlodipine besylate              6.93
Dibasic calcium phosphate        5.00
Microcrystalline cellulose       60.57
Magnesium carbonate              2.50
Purified water                   q.s.
Total                            75.00
Ramipril coating of Amlodipine spheres
Ramipril                         5
Magnesium oxide                  2.5
Hydroxypropyl methylcellulose (HPMC) 10
Talc                             7.50
Purified Water                   q.s.
Total                            25.00
Coating of Drug coated spheres
Hydroxypropyl methylcellulose (HPMC) 20.00
Talc                             10.00
Purified Water                   q.s.
Total                            130.00

PROCEDURE: Amlodipine besylate, dibasic calcium phosphate, microcrystalline cellulose and magnesium carbonate were sifted and mixed in a rapid mixer granulator. The mixture was granulated with purified water to obtain a wet mass. The wet mass was passed through an extruder and the extrudates obtained were spheronized to obtain spheres of required size. Ramipril, HPMC and talc were mixed and dispersed in water and the suspension was coated on amlodipine spheres to obtain pellets. The pellets were dried and filled into the capsule of appropriate size. The pH of the pellets was 9.80.

EXAMPLE 5

Ingredients                      Qty. in mg
Benazepril                       5.00
Amlodipine besylate              6.93
Microcrystalline cellulose       56.72
Magnesium carbonate              1.35
Purified water                   q.s.
Hydroxypropyl methylcellulose (HPMC) 5.20
Talc                             1.30
Purified water                   q.s.
Total                            76.50

PROCEDURE: Benazepril, amlodipine besylate, microcrystalline cellulose and magnesium carbonate are sifted and mixed in rapid mixer granulator. The mixture is granulated with purified water and the granules obtained are dried and sized. A coating suspension is prepared by dispersing HPMC and talc in purified water and the granules are coated by spraying the suspension on the granules. Coated granules are filled into the capsule of appropriate size.

EXAMPLE 6

Ingredients                      Qty. in mg
Seal-coating of sugar globules
Sugar Globules                   65.00
Hydroxypropyl methylcellulose (HPMC) 5.00
Talc                             2.00
Purified Water                   q.s.
Total                            72.00
Drug coating of seal-coated globules
Seal-coated sugar globules       72.00
Ramipril                         5.00
Amlodipine besylate              6.93
Hydroxypropyl cellulose (HPC)    10.17
Magnesium carbonate              1.00
Purified Water                   q.s.
Total                            95.10
Film coating of drug coated pellets
Drug Coated Pellets              95.10
Hydroxypropyl methylcellulose (HPMC) 8.00
Talc                             2.90
Purified Water                   q.s.
Total                            106.00

PROCEDURE: HPMC and talc are dispersed in water and the suspension is coated on sugar globules to provide a seal coat. Ramipril, amlodipine besylate, HPC and magnesium carbonate are mixed and dispersed in water and the suspension is coated on seal-coated sugar globules to obtain pellets. The pellets are coated with a suspension of HPMC and talc in water, dried and filled into the capsule of appropriate size. The pH of the pellets is expected to be more than 6.

The compositions were subjected to stability studies at 30° C. and 65% relative humidity and the level of impurities were measured at regular interval. The impurities were measured by High Performance Liquid Chromatography (HPLC) using the stationary and the mobile phase system and conditions as below:

Mobile phase     A: Buffer
                 B: Acetonitrile
Column           C18, Waters 250 mm × 4.6 mm; 5μ
Flow             1.0 ml/min
Detection        At 210 nm
Oven Temp.       50° C.
Injection Volume 20 μl
Run time         120 Minutes.
Diluent          Buffer: Acetonitrile (50:50)

The buffer may be prepared by dissolving 1.36 gm of potassium dihydrogen phosphate in 1000 ml water. 1 gm octane sulphonic acid sodium salt is added to the solution and sonicated. The pH is adjusted to 2.5±0.05 with orthophosphoric acid (10% v/v).

Gradient Program:

Time(min)	Mobile Phase A	Mobile Phase B
0.01	70	30
30.00	70	30
50.00	60	40
70.00	50	50
80.00	50	50
90.00	40	60
100.00	40	60
105.00	70	30
120.00	70	30

The standard solution was prepared by making a solution containing Ramipril Impurity D, Ramipril Impurity E and Amlodipine Impurity D at a concentration of 2.5 ppm in diluent. The test solution was prepared by dissolving the contents of the capsules in diluent to get a final concentration of 500 ppm of Ramipril and Amlodipine. The standard and the test solution were injected separately and the chromatograms were recorded. The level of impurities in the test was calculated by comparing with the standard chromatogram.

The result of the stability studies for Examples 2, 3, 4 and Comparative Example are summarized in Table 1:

TABLE 1
Stability studies for Examples 2, 3, 4 and Comparative Example
	Example 2	Example 3	Example 4
	Condition
		30° C./		30° C./		30° C./
Impurity	Ambient	65% RH	Ambient	65% RH	Ambient	65% RH
(% w/w)	Initial	1M	2M	Initial	2M	Initial	2 M
Amlodipine	0.08	0.10	0.10	0.12	0.15	ND*	0.12
Impurity D
Ramipril	0.13	0.16	0.12	ND*	ND*	0.14	ND*
Impurity D
Ramipril	0.04	0.59	0.58	0.26	0.60	—	0.81
Impurity E
[*ND = not detectable or below the level of quantification]

Claims

1) A stable pharmaceutical composition comprising (a) a calcium channel blocker;(b) an ACE inhibitor;(c) one or more basifying agents; and.(d) optionally one or more pharmaceutically acceptable excipients,wherein the calcium channel blocker and the ACE inhibitor are not physically separated.

2) The composition according to claim 1, wherein the calcium channel blocker comprises a compound selected from the group consisting of amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, verapamil, gallopamil, diltiazem, menthol, pharmaceutically acceptable salts thereof, and combinations thereof.

3) The composition according to claim 2, wherein the calcium channel blocker is amlodipine.

4) The composition according to claim 1, wherein the ACE inhibitor comprises a compound selected from the group consisting of ramipril, benazepril, captopril, enalapril, quinapril, perindopril, lisinopril, fosinopril, trandolapril, moexipril, pharmaceutically acceptable salts thereof, and combinations thereof.

5) The composition according to claim 4, wherein the ACE inhibitor is ramipril or benazepril.

6) The composition according to claim 1, wherein the composition has a pH of more than 6.0.

7) The composition according to claim 6, wherein the composition has a pH in the range of 7 to 8.5.

8) The composition according to claim 1, wherein the basifying agent comprises alkali or alkaline earth metal carbonates, phosphates, oxides or hydroxides, and combinations thereof.

9) The composition according to claim 8, wherein the alkali or alkaline earth metal carbonate comprises sodium carbonate, sodium bicarbonate, calcium carbonate or magnesium carbonate, and combinations thereof.

10) The composition according to claim 8, wherein the alkali or alkaline earth metal phosphate comprises sodium phosphate, disodium phosphate, trisodium phosphate, dibasic calcium phosphate or calcium phosphate anhydrous, and combinations thereof.

11) The composition according to claim 8, wherein the alkali or alkaline earth metal oxide comprises magnesium oxide or aluminum oxide, and combinations thereof.

12) The composition according to claim 1, wherein the pharmaceutically acceptable excipients comprise one or more diluents, disintegrants, binders, film forming agents or lubricants, and combinations thereof.

13) The composition according to claim 1, wherein the composition is in the form of a tablet or a capsule.

14) A process of preparing a stable pharmaceutical composition according to claim 1, wherein the process comprises: (i) mixing the calcium channel blocker, an ACE inhibitor, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients;(ii) granulating the mixture of step (i);(iii) drying the granules of step (ii);(iv) optionally mixing the granules of step (iii) with one or more pharmaceutically acceptable excipients; and(v) filling the granules of step (iii) or product of step (iv) into capsules.

15) A process of preparing a stable pharmaceutical composition according to claim 1, wherein the process comprises: (i) mixing the calcium channel blocker, an ACE inhibitor, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients;(ii) granulating the mixture of step (i) to obtain wet mass;(iii) extruding the wet mass to obtain pellets;(iv) optionally mixing the pellets of step (iii) with one or more pharmaceutically acceptable excipients; and(v) filling the granules of step (iii) or product of step (iv) into capsules.

16) A process of preparing a stable pharmaceutical composition according to claim 1, wherein the process comprises: (i) mixing the calcium channel blocker, an ACE inhibitor, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients;(ii) coating the mixture of step (i) on a core;(iii) optionally mixing the coated core of step (ii) with one or more pharmaceutically acceptable excipients; and(iv) filling the product of step (ii) into capsules.

17) A process of preparation of a stable pharmaceutical composition according to claim 1, wherein the process comprises: (i) mixing the calcium channel blocker, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients;(ii) granulating the mixture of step (i) to obtain wet mass;(iii) extruding the wet mass to obtain pellets;(iv) coating the pellets with an ACE inhibitor;(v) optionally mixing the pellets of step (iv) with one or more pharmaceutically acceptable excipients; and(vi) filling the pellets of step (iv) or product of step (v) into capsules.

18) A process of preparation of a stable pharmaceutical composition according to claim 1, wherein the process comprises: (i) mixing an ACE inhibitor, one or more basifying agents and optionally one or more pharmaceutically acceptable excipients;(ii) granulating the mixture of step (i) to obtain wet mass;(iii) extruding the wet mass to obtain pellets;(iv) coating the pellets with the calcium channel blocker;(v) optionally mixing the pellets of step (iv) with one or more pharmaceutically acceptable excipients; and(vi) filling the pellets of step (iv) or product of step (v) into capsules.

19) A stable pharmaceutical composition comprising: (i) 1-15% by weight calcium channel blocker,(ii) 1-15% by weight of an ACE inhibitor(iii) 1-10% by weight hydroxypropyl methylcellulose,(iv) 30-90% by weight microcrystalline cellulose, and(v) 0.1-10% by weight magnesium carbonate;wherein the calcium channel blocker and the ACE inhibitor are not physically separated.

20) The composition according to claim 19, wherein the calcium channel blocker comprises a compound selected from the group consisting of amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, verapamil, gallopamil, diltiazem, menthol, pharmaceutically acceptable salts thereof, and combinations thereof.

21) The composition according to claim 20, wherein the calcium channel blocker is amlodipine.

22) The composition according to claim 19, wherein the ACE inhibitor comprises a compound selected from the group consisting of ramipril, benazepril, captopril, enalapril, quinapril, perindopril, lisinopril, fosinopril, trandolapril, moexipril, pharmaceutically acceptable salts thereof, and combinations thereof.

23) The composition according to claim 22, wherein the ACE inhibitor is ramipril or benazepril.

24) The composition according to claim 19, wherein the composition has a pH of more than 6.0.

25) The composition according to claim 19, wherein the composition contains the following:

26) A method for treatment of hypertension, wherein the method comprises administering a patient in need thereof a stable pharmaceutical composition according to claim 1.