This invention relates to a combination of beta blocker and an ACE inhibitor or their pharmaceuticalty acceptable salts thereof; and pharmaceutical compositions comprising said combination; a process of preparation thereof; and methods of using such compositions to treat subjects suffering from cardiovascular disorders, in particular hypertension and heart failure.
Combination therapy affords the physician and the patient the opportunity to more effectively treat diseases that may stem from more than one cause. When used correctly and appropriately, combination therapy leads to better outcomes than monotherapy by treating more than one cause of the disease and/or by synergistically enhancing the action of one of the component drugs. Combination therapy also leads to better outcome by reducing noncompliance by the patient to a particular regimen.
Compliance is highly important for treating hypertension. However, there are several reasons associated with the noncompliance in case of hypertensives, namely lack of motivation to comply with prescribed medication due to asymptomatic nature of the disease at initial stages, multiple medications and adverse effects associated with the same, and chronic therapy associated with these medications. This noncompliance to a particular regimen in case of hypertension, may lead to serious complications including sudden cardiac death, cardiac failure, and renal failure; hypertension is the strongest risk factor for atherosclerotic progression, ischaemic heart disease and stroke. Thus, a combination of two anti-hypertensive drugs would make disease management easier for the physician and make the dosage regimen more patient compliant.
A single drug acts mainly on a single pathophysiological mechanism, whereas it is widely known that hypertension is a multifactorial pathology, in which many mechanisms interact. It is also known that when a particular system is blocked, other systems are activated that reduce the initial therapeutic effect. Hence, two classes of medications, which can act on different physiological systems, could be combined into a single dosage unit, would have an additive effect.
The US application US 2005/0032879 describes a combination of metoprolol tartarate and enalapril maleate. According to the applicants, the invention reduces the number of pills a patient is required to ingest on daily basis from 7-8 pills per day to 2-3 pills per day.
The inventors have developed a process for preparing a once a day pharmaceutical composition for use in the treatment of cardiovascular disorders which comprises combining together:
a) a first active ingredient which is a beta blocker, or a pharmaceutically acceptable salt
thereof;
b) a second active ingredient which is an ACE inhibitor, or a pharmaceutically acceptable
salt thereof;
and optionally with pharmaceutically acceptable excipients wherein beta blocker is present as an extended release form and ACE inhibitor as an immediate release form.
According to another aspect, there is provided a once a day pharmaceutical composition for use in the treatment of cardiovascular disorders which comprises combining together:
a) a first active ingredient which is a beta blocker, or a pharmaceutically acceptable salt
thereof,
b) a second active ingredient which is an ACE inhibitor, or a pharmaceutically acceptable
salt thereof;
and optionally with pharmaceutically acceptable excipients wherein beta blocker is present as an extended release form and ACE inhibitor as an immediate release form.
The beta blocker is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol and pharmaceutically acceptable salts thereof. In particular, the beta blocker is metoprolol or pharmaceutically acceptable salts thereof.
Metoprolol, which is a beta adrenoreceptor antagonist, is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. It is also indicated in the long-term treatment of angina pectoris and stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin.
Metoprolol is rapidly and completely absorbed, however the plasma levels achieved are highly variable after oral administration. Besides, it also has a relatively short elimination half-life of about 3-7 hours in adults. Frequent dosing is thus necessary to maintain reasonably stable plasma concentrations. However, it results in inconvenience to the patient, leading to poor compliance. Moreover, widely fluctuating plasma concentrations of the drug also result in availability of erratic therapeutic response. Hence metoprolol is present in the composition as an extended release form.
ACE inhibitor is selected from group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril and pharmaceutically acceptable salts thereof. In particular, ACE inhibitor is ramipril or pharmaceutically acceptable salts thereof.
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl angiotensin converting enzyme inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group. Ramipril and ramiprilat are angiotensin-converting enzyme (ACE) inhibitors. Ramipril is indicated for the treatment of hypertension and in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. The preparation and pharmaceutical use of ramipril, and its salts are described in EP 79,022 B1.
According to one of the aspect, there is provided a process for preparing a pharmaceutical composition for use in the treatment of cardiovascular disorders which comprises combining together:
a) a first active ingredient which is metoprolol, or a pharmaceutically acceptable salt
thereof;
b) a second active ingredient which is ramipril, or a pharmaceutically acceptable salt
thereof;
and optionally with pharmaceutically acceptable excipients wherein metoprolol is present as an extended release form and ramipril as an immediate release form.
According to another aspect, there is provided a pharmaceutical composition for use in the treatment of cardiovascular disorders which comprises combining together:
a) a first active ingredient which is metoprolol, or a pharmaceutically acceptable salt
thereof;
b) a second active ingredient which is ramipril, or a pharmaceutically acceptable salt
thereof;
and optionally with pharmaceutically acceptable excipients wherein metoprolol is present as an extended release form and ramipril as an immediate release form.
According to another aspect, it provides a pharmaceutical composition comprising metoprolol and ramipril and pharmaceutically acceptable salts thereof in a single dosage unit wherein metoprolol is present as an extended release component of the composition and ramipril as an immediate release component.
According to another aspect, there is provided a process for preparation a pharmaceutical composition comprising metoprolol and ramipril and pharmaceutically acceptable salts thereof in a single dosage unit wherein metoprolol is present as an extended release component of the composition and ramipril as an in immediate release component of the composition.
In another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof in a single dosage unit comprising the steps of
a) coating inert core with a drug layer comprising metoprolol,
b) coating the said core with a polymeric coating to provide for extended release of
the drug,
c) optionally, coating the core of step b) with a seal coat,
d) coating cores of step b) or c) with a drug layer comprising ramipril,
e) optionally, coating the cores of step d) with a seal coat,
f) filing the beads of step d) or e) into capsules or compressing into tablets.
According to another aspect, there is provided a method of treating cardiovascular disorders such as hypertension and heart failure by administering to said patient a therapeutically effective amount of metoprolol and pharmaceutically acceptable salts thereof and ramipril and pharmaceutically acceptable salts thereof in a single dosage unit, wherein metoprolol is present as extended release component in the composition and ramipril is present as an immediate release component.
Metoprolol and ramipril may be present in the same matrix or may be separated by one or more pharmaceutically inert excipients.
The term 'extended released component' as used herein includes component of pharmaceutical composition that achieves the slow release of drug over an extended period of time, and includes both prolonged and sustained release compositions.
Single dosage unit as used herein includes tablet, capsule, pills or alike. This single dosage unit is suitable for once a day administration.
The present invention incorporates extended release metoprolol and an immediate release ramipril. Metoprolol reduces blood pressure (BP) by competitive antagonism of catecholamines peripherally and through suppression of renin activity, while ramipril reduces BP by inhibition of the angiotensin converting enzyme; since they act on two different physiological systems, additive effects and enhanced BP reduction would result. The metoprolol component (extended release) and ramipril both have a duration of action of about 24 hours so that once daily dosing with this combination is rational and appropriate for each of the ingredients. Also, this combination does not have any pharmacokinetic interaction.
Acting by differing mechanisms, metoprolol and ramipril in combination would produce an additive antihypertensive effect. Although an enhanced antihypertensive effect can be obtained by using a larger dose of a single drug, this may increase the incidence of side effects. Using low doses of the two drugs in combination would achieve better BP reduction without compromising tolerability. There is no overlap of any severe or serious adverse reaction profile of the two drugs. (Table 1)
Table 1: Adverse event profile of Metoprolol and Ramipril
(Table Removed)
Metoprolol and ramipril have been shown to be capable of regressing left ventricular hypertrophy, independent of their BP lowering effects. When used in combination, therefore, an additive beneficial effect is expected.
Therapeutically effective amount of metoprolol or pharmaceutically acceptable salt thereof ranges from 20-200 mg equivalent to metoprolol. Therapeutically effective amount of ramipril or pharmaceutically acceptable salt thereof ranges from 1-15 mg equivalent to ramipril. The combination may comprise strengths such as Metoprolol (extended release) and ramipril - 25 and 2.5 mg; 50 and 2.5 mg; and 100 and 2.5 mg, respectively.
Metoprolol is available in various salt forms such as tartarate, fumarate, succinate, hydrochloride, benzoate etc. These salts differ in their solubility e.g. succinate, fumarate and benzoate salts have solubility less than 600 mg/ml in water at 25°C, whereas hydrochloride and tartarate are very soluble in water. Generally salts with less solubility are preferred for the preparation of extended release pharmaceutical composition.
Examples of salts of the ACE inhibitors include acid addition salts with organic or inorganic acids. Suitable organic carboxylic acids include salicylic acid, maleic acid, tartaric acid, citric acid, adipic acid, sorbic acid, malonic acid, 1,4-butanedioic acid, malic acid, pivalic acid, succinic acid, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, acetic acid, benzoic acid, fatty acids such as, for example, lauric acid, myristic acid or oleic acid, and suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and/or phosphoric acid.
The ACE inhibitors have a tendency to undergo decomposition reactions such as hydrolysis,
cyclization or oxidation (cf., EP 280,999 B1), which are accelerated by acids or bases. They may be stabilized using buffer substances such as sodium dihydrogen phosphate, sodium citrate, sodium carbonate, sodium hydrogen carbonate or tris(hydroxymethyl)aminomethane and/or by addition of saccharides; cf., EP 317,878 B1.
The pharmaceutical composition may be provided in the form of capsules wherein the capsule comprises beads comprising metoprolol and ramipril.
In one of the embodiment, there is provided a pharmaceutical composition comprising a beta blocker and an ACE inhibitor or pharmaceutically acceptable salts thereof comprising the steps of
a) coating inert core with a drug layer comprising beta blocker,
b) coating the said core (step a) with an extended release polymer layer,
c) coating the metoprolol extended release core of step b) with a seal coat,
d) coating cores of step c) with a drug layer comprising ACE inhibitor,
e) coating the cores of step d) with a seal coat,
f) filling the beads of step e) into capsules.
The pharmaceutical composition may be provided in the form of capsules wherein the capsule comprises two beads viz. one of metoprolol and another of ramipril.
In another embodiment, there is provided a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof comprising the steps of
a) coating inert core with a drug layer comprising ramipril and
b) coating separate inert cores with a drug layer comprising metoprolol,
c) coating cores of step b) with an extended release layer,
d) filling the beads of step a) and c) into capsules.
The inert core described here can be water insoluble, soluble or swellable.
The pharmaceutical composition may be provided in the form of capsules or tablets wherein the capsule or tablet comprises spheroids.
In another embodiment, there is a provided a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof comprising the steps of:
a) extruding metoprolol with suitable excipients,
b) breaking the extruded cylinders into appropriate length and transforming them into
spheroids,
c) coating the spheroids with extended release polymer coating
d) optionally, seal coating the spheroids of step c)
e) coating the spheroid of step c) or d) with drug layer comprising ramipril
f) filing these spheroids into capsules or compressing them into tablets.
In another embodiment, there is a provided a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof comprising the steps of:
a) extruding metoprolol, extended release polymer with suitable excipients,
b) breaking the extruded cylinders into appropriate length and transforming them into
spheroids,
c) optionally, seal coating the spheroids of step b)
d) coating the spheroid of step b) or c) with drug layer comprising ramipril
e) filing these spheroids into capsules or compressing them into tablets.
The pharmaceutical composition may be provided in the form of tablets wherein metoprolol and ramipril are separated by a layer or a membrane of a physiologically acceptable inert material.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof comprising the steps of
a) blending metoprolol with one or more pharmaceutically inert excipients;
b) optionally granulating the blend,
c) lubricating the blend or granules,
d) compressing the lubricated blend of step c) into tablet,
e) optionally coating the core with suitable inert excipients,
f) dispersing or dissolving ramipril and other inert excipients in a suitable solvent system.
g) coating the tablet of step e) with drug layer of ramipril.
The pharmaceutical composition may be provided in the form of tablets wherein metoprolol and ramipril are processed to form a bilayer/multilayer tablet or inlay tablet.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof comprising the steps of i) preparation of metoprolol granules
a) blending metoprolol, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
ii) preparation of ramipril granules
a) blending ramipril and one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
iii) compressing the granules of step i) and step ii) to form a bilayer tablet.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof comprising the steps of i) preparation of metoprolol tablets
a) blending metoprolol, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
ii) preparation of ramipril granules

a) blending ramipril and one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
d) compressing the blend of step c) into tablet
iii) compressing the granules of step i) and the tablets of step ii) to form an inlay tablet.
The pharmaceutical composition may be provided in the form of capsules wherein metoprolol composition in the form of tablets, minitablets, granules or pellets and ramipril in the form of the powder, granules, minitablets or pellets.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising metoprolol and ramipril or pharmaceutically acceptable salts thereof comprising the steps of
a) blending metoprolol, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a,
c) lubricating the blend or granules of step b,
d) compressing the lubricated blend of step c into suitable size tablet,
e) blending ramipril and one or more pharmaceutically inert excipients;
f) filling the tablet and ramipril powder blend into a capsule.
The beads or tablets as described above may have an additional non-functional coating such as polyethylene glycol for protection or to improve the aesthetic appeal of the product. Non functional coating may also help in overcoming a common problem of the rupturing or cracking
of release controlling layers/membrane or fragmentation of the core due to mechanical stress generated during compression of cores to tablet or filling into capsule/sachet.
The term "pharmaceutically inert excipient" as used herein includes substances known in the art as diluents, binders, disintegrants, coloring agents, flavoring agents, stabilizers, extended release polymers, surfactants, lubricants/glidants, plasticizers and preservatives for pharmaceutical compositions.
Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, copolvidone and the like.
Examples of diluents include powdered cellulose, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, dicalcium phosphate and the like.
Examples of lubricants and glidants include magnesium stearate, sodium stearyl fumarate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, zinc stearate, silicon dioxide, sodium chloride and the like.
Water insoluble core includes silicon dioxide, small particles of glass, or plastic resin particles such as polypropylene or polyethylene. Water-soluble core includes sugar spheres such as glucose, mannitol, lactose, xylitol, dextrose, sucrose and salt cores such as sodium chloride, potassium chloride. Water swellable core may be made up of hydroxypropyl methylcellulose, microcrystalline cellulose or starch. Inert core may have a diameter ranging from about 150-600 urn, preferably about 250-425 urn.
Examples of extended release polymer include water soluble polymers or water insoluble polymers. Specific example of water-soluble polymers includes polyvinylpyrrolidone, hydroxy propylcellulose, hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides (such as alginate, xanthum gurn), polyethylene oxide, maleic anhydride , methyl vinyl ether copolymers and derivatives and mixtures thereof. Specific example of water-insoluble polymers include acrylates such as methacrylates, methacrylic acid copolymers,
acrylic acid copolymers; cellulose derivatives such ethylcellulose or cellulose acetate; polyethylene, and high molecular weight polyvinylalcohols.
Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/dispersion in a suitable solvent system using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
Examples of plasticizers include polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl phthalate, dibutyl sebacate and the like.
EXAMPLES Example 1

(Table Removed)
Procedure:
1. A dispersion of Metoprolol succinate and Opadry was prepared in purified water.
2. Dispersion of step-1 was used to coat the sugar spheres to a desired weight gain.
3. A dispersion of Opadry and ethylcellulose was prepared in IPA/ purified water mix.
4. Drug layered beads of step 2 were coated with dispersion of step 3.
5. Coated beads of step-4 ere then seal coated with a solution of HPMC in IPA/water
mixture.
6. A dispersion of Ramipril was prepared with HPMC & HPC in purified water
7. Beads obtained in step 5 were coated with the ramipril dispersion of step 6.
8. Ramipril coated beads of step-7 were coated with an overcoat as indicated in table
above.
9. Beads obtained in step 8 were lubricated and filled into suitable size capsules.

WE CLAIM:
1. A once a day pharmaceutical composition for use in the treatment of cardiovascular
disorders which comprises combining together:
a) a first active ingredient, which is a beta blocker;
b) a second active ingredient, which is an ACE inhibitor;
and optionally with pharmaceutically acceptable excipients of kind such as herein described wherein beta blocker is present as an extended release form and ACE inhibitor as an immediate release form.
2. The pharmaceutical composition according to claim 1 wherein cardiovascular disorders
include heart failure or hypertension.
3. The pharmaceutical composition according to claim 1 wherein beta blocker is selected from
the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol,
esmolol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol and
pharmaceutically acceptable salts thereof.
4. The pharmaceutical composition according to claim 1 wherein ACE inhibitor is selected
from group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril,
perindopril, quinapril, ramipril, trandolapril and pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition for preparing a pharmaceutical composition for use in the
treatment of cardiovascular disorders which comprises combining together:
a) a first active ingredient which is metoprolol, or a pharmaceutically acceptable salt thereof;
b) a second active ingredient which is ramipril, or a pharmaceutically acceptable salt
thereof;
and optionally with pharmaceutically acceptable excipients of kind such as herein described wherein metoprolol is present as an extended release form and ramipril as an immediate release form.
6. The pharmaceutical composition according to claim 5 wherein cardiovascular disorders
include heart failure or hypertension.
7. The pharmaceutical composition according to claim 5 wherein pharmaceutically acceptable
salts of metoprolol include succinate, fumarate, benzoate, hydrochloride and tartarate.
8. The pharmaceutical composition according to claim 5 wherein metoprolol is present in
dosage range of 20- 200 mg and ramipril is present in dosage range of 1-15 mg.
9. The pharmaceutical composition according to claim 5 wherein composition is for once a day
administration.
10. The pharmaceutical composition according to claim 5 wherein extended release form
comprises extended release polymer selected from water soluble and water insoluble
polymer.
11. The pharmaceutical composition according to claim 10 wherein water-soluble polymers is
selected from the group consisting of polyvinylpyrrolidine, hydroxypropylcellulose,
hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides,
polyethylene oxide, maleic anhydride/methyl vinyl ether copolymers and derivatives and
mixtures thereof.
12. The pharmaceutical composition according to claim 10 wherein water-insoluble polymers is
selected from the group consisting of acrylates such as methacrylates, methacrylic acid
copolymers, acrylic acid copolymers; cellulose derivatives such ethylcellulose or cellulose
acetate; polyethylene, and high molecular weight polyvinylalcohols.
13. The pharmaceutical composition according to any of the preceding claims wherein the
composition further comprises pharmaceutically inert excipient selected from group
consisting of diluents, binders, desiccants, disintegrants, coloring agents, flavoring agents,
stabilizers, surfactants, lubricants/glidants, plasticizers and preservatives.
14. The pharmaceutical composition according to claim 5 wherein composition is capsule.
15. The pharmaceutical composition according to claim 5 wherein composition is tablet.
16. The pharmaceutical composition according to claim 15 wherein tablet is inlay tablet.
17. The pharmaceutical composition according to claim 15 wherein tablet is compression
coated tablet.
18. The pharmaceutical composition according to claim 15 wherein tablet is bilayer tablet.
19. The pharmaceutical composition according to claim 14 wherein capsule comprises
metoprolol composition in the form of tablet, granules, minitablet or pellets and ramipril in
the form of the powder, minitablets, pellets, granules or beads.
20. A process for the preparation of pharmaceutical composition of claim 5 comprising the steps
of

a) coating inert core with a drug layer comprising metoprolol,
b) coating the said core with an extended release polymer layer,
c) coating cores of step b) with a drug layer comprising ramipril,
d) filing the beads of step b) or c) into capsules.

21. The process according to claim 19 wherein core of step b) or c) are coated with a seal coat.
22. The process according to claim 19 wherein coating is applied using techniques such as
spray coating or fluidized bed processor or dip coating.
23. The process according to claim 19 wherein inert core is selected from water insoluble,
soluble and swellable cores.
24. A process for preparation of a pharmaceutical composition of claim 5 comprising the steps
of:

a) extruding metoprolol with suitable excipients,
b) breaking the extruded cylinders into appropriate length and transforming them into
spheroids,
c) coating the spheroids with extended release polymer coating
d) optionally, seal coating the spheroids of step c)
e) coating the spheroid of step c) or d) with drug layer comprising ramipril
f) filing these spheroids into capsules or compressing them into tablets.
25. A process for preparation of a pharmaceutical composition of claim 5 comprising the steps
of:
a) extruding metoprolol, extended release polymer with suitable excipients,
b) breaking the extruded cylinders into appropriate length and transforming them into
spheroids,
c) optionally, seal coating the spheroids of step c)
d) coating the spheroid of step c) or d) with drug layer comprising ramipril
e) filing these spheroids into capsules or compressing them into tablets.
26. A process for the preparation of pharmaceutical composition of claim 5 comprising the steps
of:
i) preparation of metoprolol granules
a) blending metoprolol, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
ii) preparation of ramipril granules

a) blending ramipril and one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
iii) compressing the granules of step i) and step ii) to form a bilayer tablet.
26. Use of pharmaceutical composition as defined in any of the preceding claims in treatment of
cardiovascular disorders.
27. A pharmaceutical composition for use in the treatment of cardiovascular disorders as
herein described with reference to the relevant examples.