WO2022180531A1

WO2022180531A1 - Fixed-dose pharmaceutical compositions

Info

Publication number: WO2022180531A1
Application number: PCT/IB2022/051582
Authority: WO
Inventors: Marc THEURER; Mario STEIGERWALD
Original assignee: Teva Pharmaceutical Industries Ltd
Priority date: 2021-02-23
Filing date: 2022-02-23
Publication date: 2022-09-01
Also published as: EP4297733A1; CA3210689A1; GB202102575D0

Abstract

The invention relates to fixed-dose pharmaceutical compositions comprising: • from 1 to 25 mg rivaroxaban or apixaban; • amlodipine, torasemide, bisoprolol or metoprolol; and • a pharmaceutically acceptable excipient. The invention also relates to their use in the treatment or prevention of stroke and systemic embolism, and the treatment and prevention of stroke and systemic embolism in patients with essential hypertension.

Description

FIXED-DOSE PHARMACEUTICAL COMPOSITIONS

This invention relates to fixed-dose pharmaceutical compositions comprising an anticoagulant compound, an antihypertensive compound and a pharmaceutically acceptable excipient, and the use of the compositions for the treatment and prevention of stroke and systemic embolism, and for the treatment and prevention of stroke and systemic embolism in patients with essential hypertension.

BACKGROUND OF THE INVENTION

In 2017, global prevalence of stroke was in excess of 100 million people. Of those, more than 80 million people suffered an ischemic stroke. The remainder suffered a hemorrhagic stroke (intracerebral or subarachnoid hemorrhage). Ischemic strokes are caused by reduced blood supply to the brain. Among other things, the reduction in blood supply reduces the amount of oxygen supplied to brain tissue, which in turn leads to cellular dysfunction and cell death.

Hemorrhagic strokes are caused by intracerebral or subarachnoid hemorrhage. An intracerebral hemorrhage occurs when an artery in the brain bursts, which causes a bleed within the brain. A subarachnoid hemorrhage occurs when a bleed occurs outside of the confines of the brain, but within those of the skull. As with ischemic stroke, these bleeding events cause reduced blood and oxygen supply to the brain tissue.

Two of the most common causes of ischemic stroke are thrombosis and systemic embolism.

A thrombosis is the formation of a blood clot (thrombus) within a blood vessel. The blood clot obstructs the artery in which it is lodged, and reduces the ability of the artery supply the normal amount of blood to surrounding tissue. Ischemic stroke occurs when a blood clot blocks a blood vessel, typically an artery, close to or in the brain.

An embolism occurs when an embolus, which is frequently a part of a thrombus (but can also be a fat globule, air or gas or any other exogenous matter), blocks a blood vessel. Similarly to a thrombus, an embolus obstructs blood flow in a blood vessel, and causes a total or partial blockage. However, unlike when a thrombus causes an ischemic stroke (by blocking a vessel close to or in the brain), an embolus causes a blockage in a systemic blood vessel that is comparatively distant from the brain, located elsewhere in the body.

It is well recognised that hypertension is a prevalent risk factor for ischemic stroke, and indeed hemorrhagic stroke.

Hypertension is a long-term medical condition where the blood pressure in the arteries is consistently elevated. Hypertension alone does not necessarily present symptoms, however long-term blood pressure is known to be a risk factor and contributor to cardiac problems, including heart failure and coronary artery disease, as well as stroke and dementia. Hypertension is categorised as either primary (essential) or secondary hypertension. The vast majority of cases (85% >) present as essential hypertension. Essential hypertension has no known secondary cause, and its prevalence is linked to genetic predisposition and environmental factors. It is defined when blood pressure is consistently 140/90 mmHg or above.

Consequently, the causative factors of ischemic and stroke and systemic embolism are the formation of blood clots and hypertension, and a causative factor of hemorrhagic stroke is hypertension.

The medical profession have focused their attention on stroke prevention by recommending people seek to implement a combination of a healthy diet and regular exercise into their daily lifestyle. The avoidance of smoking and drinking too much alcohol is also recommended. The pathological effect of adhering to this advice is that the risk of high blood pressure and high cholesterol levels are reduced, which in turn reduces the risks of ischemic and hemorrhagic stroke.

However, once a person suffers a stroke, they are prescribed medication to prevent further episodes.

Patients are typically offered anticoagulants to help reduce their risk of developing future blood clots. Anticoagulants prevent blood clots by interfering with the coagulation cascade. Such interference alters the chemical composition of the blood in a way that prevents clot formation by “thinning” the blood. The long-term use of anticoagulants, for example warfarin, apixaban, dabigatran, edoxaban and rivaroxaban for the prevention of further stroke episodes is well established in the art (see J Saraiva Cardiol Ther 2018, 7, 15-24).

Anticoagulants may also be prescribed to prevent a first stroke in patients who are particularly at risk, for example those suffering from atrial fibrillation (see Sherzai and Elkind Ann N Y Acad Sci 2015, 1- 15).

Moreover, if a patient presents with essential hypertension, an antihypertensive may be prescribed to lower blood pressure, and thus reduce the risk of a first or subsequent stroke.

The use of anticoagulants and antihypertensives has been successful for the treatment and prevention of stroke in patients with and without essential hypertension. However, these medications are independently prescribed. A major consequence of this, beyond patient compliance and convenience, is that a patient must adhere to independent dosage regimens for both the anticoagulant and the antihypertensive. Independent dosage regimens for active ingredients that work via different mechanisms to prevent or treat the same disease are undesirable and sub efficacious. Accordingly, it is an object of the present invention to provide further compositions that can prevent and treat these diseases with improved efficacy. SUMMARY OF THE INVENTION

In a first aspect, the invention provides a fixed-dose pharmaceutical composition comprising:

• from 1 to 25 mg rivaroxaban or apixaban;

• amlodipine, torasemide, bisoprolol or metoprolol; and

• a pharmaceutically acceptable excipient.

The invention also provides the fixed-dose pharmaceutical composition for use in the treatment or prevention of stroke and systemic embolism, or for use in the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

The invention also provides a method for the treatment or prevention of stroke and systemic embolism, or a method for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension comprising administering to a human the fixed-dose pharmaceutical composition.

The invention also provides the use of the fixed-dose pharmaceutical composition for the treatment or prevention of stroke and systemic embolism, or for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

Surprisingly, the applicant has found that the use of a fixed-dose pharmaceutical composition comprising an anticoagulant and an antihypertensive may treat and prevent stroke and systemic embolism in patients with and without essential hypertension with improved efficacy compared to the use of either agent alone, or the use of both agents administered according to independent dosage regimens, i.e. not a fixed-dose composition. In particular, the applicant has surprisingly found that a fixed-dose composition is a viable formulation approach for the active ingredients rivaroxaban and amlodipine. This finding was surprising because the Tmax (time to maximum plasma concentration) of rivaroxaban is 2 to 4 hours, whereas the Tmax for amlodipine is 6 to 12 hours.

Typically, active ingredients with different pharmacokinetic profiles (i.e. differing Tmax) cannot be formulated as fixed-dose compositions, this is because the difference in Tmax necessitates differing dosage regimens of each active ingredient.

The present invention will now be described with reference to the accompanying drawings, in which: Fig. 1 shows the percentage dissolution (release) of rivaroxaban in pH 4.5 acetate buffer & 0.4% SLS 900 ml_, 75 rpm @ 37°C with paddle from Xarelto and T/061 D; Fig. 2 shows the percentage dissolution (release) of amlodipine in 0.01 N HCI, 900 ml_, 50 rpm @ 37°C with paddle from Istin, T/061 D and T/097D;

Fig. 3 shows the percentage dissolution (release) of rivaroxaban in pH 4.5 acetate buffer & 0.4% SLS 900 mL, 75 rpm @ 37°C with paddle from Xarelto and T/067D;

Fig. 4 shows the percentage dissolution (release) of amlodipine in 0.01 N HCI, 900 mL, 50 rpm @ 37°C with paddle from Istin and T/067D; Fig. 5 shows the percentage dissolution (release) of rivaroxaban in pH 4.5 acetate buffer & 0.4% SLS 900 ml_, 75 rpm @ 37°C with paddle from Xarelto, T/066D and T/073D;

Fig. 6 shows the percentage dissolution (release) of amlodipine in 0.01 N HCI, 900 ml_, 50 rpm @ 37°C with paddle from Istin, T/066D and T/099D;

Fig. 7 shows the percentage dissolution (release) of rivaroxaban in pH 4.5 acetate buffer & 0.4% SLS 900 mL, 75 rpm @ 37°C with paddle from Xarelto and T/071 D;

Fig. 8 shows the percentage dissolution (release) of amlodipine in 0.01 N HCI, 900 mL, 50 rpm @ 37°C with paddle from Istin and T/071 D;

Fig. 9 shows the percentage dissolution (release) of rivaroxaban in pH 4.5 acetate buffer & 0.4% SLS 900 mL, 75 rpm @ 37°C with paddle from Xarelto, T/080D, T/085D, T/089D, T/095D and T/096D; and

Fig. 10 shows the percentage dissolution (release) of amlodipine in 0.01 N HCI, 900 mL, 50 rpm @ 37°C with paddle from Istin and T/080D, T/089D, T/091 D, T/095D and T/096D.

DEFINITIONS

In some aspects the proportions of the various components of the compositions are defined relative to other components. The wt% (weight percent) of a particular component, based on the other components, is the weight (mass) of the particular component, divided by the weight (mass) of the other components, times by 100 i.e. wt% component X (based on component Y) =

x 100

In some aspects the amount of various components of the compositions are listed in milligrams (mg). If an amount of active ingredient is provided in mg, the amount refers to the amount of free base of the compound.

The term "treatment" as used herein in the context of treating a condition i.e. state, disorder or disease, pertains generally to treatment and therapy, whether for a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, diminishment or alleviation of at least one symptom associated or caused by the condition being treated and cure of the condition. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.

The term “prevention” (i.e. use of a compound as prophylactic measure) as used herein in the context of treating a condition i.e. state, disorder or disease, pertains generally to the prophylaxis or prevention, whether for a human or an animal (e.g. in veterinary applications), in which some desired preventative effect is achieved, for example, in preventing occurrence of a disease or guarding from a disease. Prophylaxis includes complete and total blocking of all symptoms of a disorder for an indefinite period of time, the mere slowing of the onset of one or several symptoms of the disease, or making the disease less likely to occur. The term “fixed-dose composition” as used herein means a single dosage form that contains a combination of two or more active ingredients. For example, a single tablet or capsule which contains two active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

• from 1 to 25 mg rivaroxaban or apixaban;

• amlodipine, torasemide, bisoprolol or metoprolol; and

• a pharmaceutically acceptable excipient.

Fixed-dose pharmaceutical compositions Anticoagulant

Anticoagulants

Rivaroxaban and apixaban are anticoagulants that prevent blood clots by interfering with the coagulation cascade. Such interference alters the chemical composition of the blood in a way that prevents clot formation by “thinning” the blood.

The anticoagulant is present at from 1 to 25 mg, and in particular from 2 to 20 mg e.g. 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg or 20 mg.

Rivaroxaban

Rivaroxaban is an anticoagulant which binds directly and reversibly to factor Xa. It is marketed in a number of countries as Xarelto®, as an oral anticoagulant. It is indicated for the treatment of various thromboembolic diseases, including for the prevention of venous thromboembolic events (VTE) in patients who have undergone total hip replacement or total knee replacement surgery; and for the prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation and with at least one risk factor selected from: congestive heart failure, hypertension, previous stroke or transient ischaemic attack, age > 75 years, or diabetes mellitus (also see, WO 01/47919 (the basic patent), WO 2004/060887 and WO 2007/039132).

Rivaroxaban has the chemical name 5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1 ,3- oxazolidin-5-yl]methyl}thiophene-2-carboxamide, and has the following structure:

Rivaroxaban can be synthesised according to one or more methods known in the art, see for example WO 2004/060887, WO 2015/198259 and G. Yu., et. al., Organic Preparations and Procedures International 2017, 49, 169-177.

In one embodiment the fixed-dose pharmaceutical composition includes rivaroxaban, an antihypertensive selected from amlodipine, torasemide, bisoprolol or metoprolol, and a pharmaceutically acceptable excipient.

In one embodiment, the composition includes from 5 mg to 20 mg of rivaroxaban, in particular 10 mg to 20 mg e.g. 10 mg, 15 mg or 20 mg. Apixaban

Apixaban is an anticoagulant which binds directly and reversibly to factorXa. It is marketed in a number of countries as Eliquis®, as an oral anticoagulant. It is indicated for the treatment of various thromboembolic diseases, including for the prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation and with at least one risk factor selected from: congestive heart failure, hypertension, previous stroke or transient ischaemic attack, age > 75 years, or diabetes mellitus (also see, US 6,967,208 and WO 2011/106478).

Apixaban has the chemical name (1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]- 4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, and has the following structure:

Apixaban can be synthesised according to one or more methods known in the art, see for example WO 2014/072884, US 7,371 ,761 and Y. Ji„ et. al., Synthetic Communications 2013, 43, 72-79. In one embodiment, the fixed-dose pharmaceutical composition includes apixaban, an antihypertensive selected from amlodipine, torasemide, bisoprolol or metoprolol, and a pharmaceutically acceptable excipient.

In one embodiment, the composition includes from 1 mg to 15 mg of apixaban, in particular 2.5 mg to 10 mg e.g. 2.5 mg, 5 mg or 10 mg.

Antihvpertensives

Amlodipine, torasemide, bisoprolol and metoprolol are antihypertensives that lower blood pressure.

In one embodiment, the antihypertensive is present at from 0.1 to 5000 mg, or 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 0.5 to 50 mg or 1 to 100 mg e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 50 mg or 100 mg.

Amlodipine

Amlodipine is an antihypertensive drug which acts as an angioselective calcium channel blocker. It is marketed globally by numerous pharmaceutical companies, typically in salt form. The most common salts are amlodipine besilate, amlodipine camsylate, amlodipine maleate, amlodipine mesylate and amlodipine besilate monohydrate. Amlodipine is indicated as a monotherapy for the treatment of hypertension, and as a combination therapy with other antihypertensives and antianginal agents for the treatment of coronary artery disease, chronic stable angina and vasospastic angina.

Amlodipine has the chemical name 3-O-ethyl 5-O-methyl (4 RS) 2-(2-aminoethoxymethyl)-4-(2- chlorophenyl)-6-methyl-1 ,4-dihydropyridine-3,5-dicarboxylate, and has the following structure:

Amlodipine can be synthesised according to one or more methods known in the art, see for example US 4,572,909 and WO 2004/058711 .

In one embodiment the fixed-dose pharmaceutical composition includes an anticoagulant selected from rivaroxaban or apixaban, amlodipine and a pharmaceutically acceptable excipient. The composition may include a pharmaceutically acceptable salt of amlodipine, for example, amlodipine besilate, amlodipine camsylate, amlodipine maleate, amlodipine mesylate or amlodipine besilate monohydrate. Most preferably the composition includes amlodipine besilate. In one embodiment, the composition includes from 1 mg to 15 mg of amlodipine, in particular 5 mg to 10 mg e.g. 5 mg or 10 mg.

Torasemide

Torasemide is a loop diuretic. Loop diuretics act on the Na-K-CI cotransporter to inhibit sodium, potassium and chloride reabsorption in the kidney, they also inhibit magnesium and calcium reabsorption in the kidney. A downstream effect of this inhibitory action is diuresis, which reduces the amount of water that can be reabsorbed into the blood, which in turn causes a decrease in blood volume. Loop diuretics also increase prostaglandin production, which in turn causes vasodilation and increases blood supply to the kidney. As a result of decreased blood volume and vasodilation, loop diuretics are able to reduce blood pressure and manage edema. Torasemide is marketed globally by numerous pharmaceutical companies. It is indicated for the treatment of edema associated with congestive heart failure, renal or hepatic diseases, and for the treatment of hypertension.

Torasemide has the chemical name 1-[4-(3-methylanilino)pyridin-3-yl]sulfonyl-3-propan-2-ylurea, and has the following structure:

Torasemide can be synthesised according to one or more methods known in the art, see for example Delarge et. al„ Ann Pharm Fr 1973, 31 , 467-474, US 2,516,025 and WO 01/70226.

In one embodiment the fixed-dose pharmaceutical composition includes an anticoagulant selected from rivaroxaban or apixaban, torasemide and a pharmaceutically acceptable excipient. In one embodiment, the composition includes from 1 mg to 25 mg of torasemide, in particular 5 mg to 20 mg e.g. 5 mg, 10 mg or 20 mg.

Bisoprolol

Bisoprolol is a beta blocker. Beta blockers act on the sympathetic nervous system by blocking the receptor sites of epinephrine and norepinephrine on adrenergic beta receptors. Bisoprolol is selective for bi-adrenergic receptors which are abundant in the heart and kidneys. Thus, bisoprolol prevents adrenaline and noradrenaline stimulation of the bi-adrenergic receptor by blocking them. This inhibitory action slows the rate and force at which the heart beats, which reduces blood pressure. Bisoprolol is marketed globally by numerous pharmaceutical companies, typically in salt form. The most common salt is bisoprolol fumarate. Bisoprolol is indicated for the treatment of hypertension, angina and as an adjunct for heart failure.

Bisoprolol has the chemical name (±)-1-(propan-2-ylamino)-3-[4-(2-propan-2- yloxyethoxymethyl)phenoxy]propan-2-ol, and has the following structure:

Bisoprolol can be synthesised according to one or more methods known in the art, see for example US 4,258,062 and WO 2007/069266.

In one embodiment the fixed-dose pharmaceutical composition includes an anticoagulant selected from rivaroxaban or apixaban, bisoprolol and a pharmaceutically acceptable excipient. The composition may include a pharmaceutically acceptable salt of bisoprolol, for example bisoprolol fumarate.

In one embodiment, the composition includes from 1 mg to 25 mg of bisoprolol, in particular 2.5 mg to 10 mg e.g. 2.5 mg, 5 mg or 10 mg.

Metoprolol

Like bisoprolol, metoprolol is a beta blocker which is selective for bi-adrenergic receptors. Metoprolol therefore has a similar mechanism of action and also provides an antihypertensive effect. Metoprolol is marketed globally by numerous pharmaceutical companies, typically in salt form. The most common salts are metoprolol succinate, metoprolol tartrate and metoprolol fumarate. Metoprolol is indicated for the treatment of hypertension, angina, cardiac arrhythmia, for migraine prophylaxis and as an adjunct for hyperthyroidism. Metoprolol has the chemical name (±)-1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2- ol, and has the following structure:

Metoprolol can be synthesised according to one or more methods known in the art, see for example EP 0 050 885, US 5,082,969 and WO 2007/141593.

In one embodiment the fixed-dose pharmaceutical composition includes an anticoagulant selected from rivaroxaban or apixaban, metoprolol and a pharmaceutically acceptable excipient. The composition may include a pharmaceutically acceptable salt of metoprolol, for example metoprolol succinate, metoprolol tartrate or metoprolol fumarate. Preferably the composition includes metoprolol succinate.

In one embodiment, the composition includes from 25 mg to 125 mg of metoprolol, in particular 50 mg to 100 mg e.g. 50 mg or 100 mg.

Particular compositions

In a second aspect, the invention provides a fixed-dose pharmaceutical composition comprising:

• rivaroxaban and amlodipine;

• rivaroxaban and torasemide;

• rivaroxaban and bisoprolol; · apixaban and torasemide; or

• apixaban and metoprolol; and a pharmaceutically acceptable excipient.

In one embodiment, the composition comprises rivaroxaban or apixaban and amlodipine, and the wt ratio of rivaroxaban or apixaban to amlodipine is selected from:

• 10:1 to 1 :10;

• 8:1 to 1 :8;

• 6:1 to 1 :6;

• 5:1 to 1 :5;

• 4:1 to 1 :4; · 3:1 to 1 :3;

• 2:1 to 1 :2; and

• 1.5:1 to 1 :1.5.

In particular, the composition comprises rivaroxaban and amlodipine, and the wt ratio of rivaroxaban to amlodipine is selected from:

• 5:1 to 1 :1 ;

• 4:1 to 1 :1 ;

• 3:1 to 1 :1 ;

• 2:1 to 1 :1 ; and

• 1.5:1 to 1 :1. In one embodiment, the composition comprises rivaroxaban or apixaban and torasemide, and the wt ratio of rivaroxaban or apixaban to amlodipine is selected from:

20:1 to 1 :20; 15:1 to 1 :15; • 10:1 to 1:10;

• 8:1 to 1:8;

• 6:1 to 1 :6;

• 5:1 to 1 :5;

• 4:1 to 1 :4;

• 3:1 to 1:3;

• 2:1 to 1 :2; and

• 1.5:1 to 1:1.5.

In one embodiment, the composition comprises rivaroxaban or apixaban and torasemide and the wt ratio of rivaroxaban or apixaban to amlodipine is selected from:

• 15:1 to 1:1;

• 10:1 to 1:1;

• 8:1 to 1:1;

• 6:1 to 1:1;

• 5:1 to 1:1;

• 4:1 to 1:1;

• 3:1 to 1:1;

• 2:1 to 1:1; and

• 1.5:1 to 1:1. In particular, the composition comprises apixaban and torasemide, and the wt ratio of apixaban to torasemide is selected from:

• 5:1 to 1 :5;

• 4:1 to 1 :4;

• 3:1 to 1:3;

• 2:1 to 1:1; and

• 1:1 to 1:2.

In one embodiment, the composition comprises rivaroxaban or apixaban and bisoprolol, and the wt ratio of rivaroxaban or apixaban to bisoprolol is selected from:

• 10:1 to 1:10; · 8:1 to 1:8;

• 6:1 to 1 :6;

• 5:1 to 1 :5;

• 4:1 to 1 :4;

• 3:1 to 1:3;

• 2:1 to 1 :2; and

• 1.5:1 to 1:1.5. In one embodiment, the composition comprises rivaroxaban and bisoprolol, and the wt ratio of rivaroxaban to bisoprolol is selected from:

• 10:1 to 1 :1 ;

• 8:1 to 1 :1 ;

• 6:1 to 1 :1 ;

• 3:1 to 1 :1 ; and

• 2:1 to 1 :1.

In one embodiment, the composition comprises rivaroxaban or apixaban and metoprolol, and the wt ratio of rivaroxaban or apixaban to metoprolol is selected from:

40:1 to 1 :40 30:1 to 1 :30 20:1 to 1 :20 15:1 to 1 :15

10:1 to 1 :10 and

5:1 to 1 :5.

In particular, the composition comprises apixaban and metoprolol, and the wt ratio of apixaban to metoprolol is selected from:

• 1 :1 to 1 :40;

• 1 :1 to 1 :30; · 1 :1 to 1 :20;

• 1 :1 to 1 :15; and

• 1 :1 to 1 :10.

In one embodiment the fixed-dose pharmaceutical composition includes:

• from 10 mg to 20 mg rivaroxaban and from 5 mg to 10 mg amlodipine;

• from 10 mg to 20 mg rivaroxaban and from 5 mg to 20 mg torasemide;

• from 10 mg to 20 mg rivaroxaban and from 2.5 mg to 10 mg bisoprolol;

• from 5 mg to 10 mg apixaban and from 5 mg to 10 mg torasemide; or

• from 2.5 mg to 5 mg apixaban and from 50 mg to 100 mg metoprolol; and a pharmaceutically acceptable excipient. In one embodiment the fixed-dose pharmaceutical composition includes from 10 mg to 20 mg rivaroxaban, from 5 mg to 10 mg amlodipine and a pharmaceutically acceptable excipient.

Preferably the composition includes from 10 mg to 20 mg rivaroxaban, from 5 mg to 10 mg amlodipine and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form selected from a monolayer or bilayer tablet, or a capsule. In one embodiment the fixed-dose pharmaceutical the composition includes:

• 10 mg rivaroxaban and 5 mg amlodipine,

• 10 mg rivaroxaban and 10 mg amlodipine;

• 15 mg rivaroxaban and 5 mg amlodipine;

• 15 mg rivaroxaban and 10 mg amlodipine;

• 20 mg rivaroxaban and 5 mg amlodipine; or

• 20 mg rivaroxaban and 10 mg amlodipine; and a pharmaceutically acceptable excipient, wherein amlodipine is included in the composition as a free base or as a pharmaceutically acceptable salt of amlodipine, for example amlodipine besilate. Preferably the composition includes:

• 10 mg rivaroxaban and 5 mg amlodipine,

• 10 mg rivaroxaban and 10 mg amlodipine;

• 15 mg rivaroxaban and 5 mg amlodipine;

• 15 mg rivaroxaban and 10 mg amlodipine;

• 20 mg rivaroxaban and 5 mg amlodipine; or

• 20 mg rivaroxaban and 10 mg amlodipine; and a pharmaceutically acceptable excipient, wherein amlodipine is included in the composition as a free base or as a pharmaceutically acceptable salt of amlodipine, for example amlodipine besilate, and wherein the composition is an oral dosage form. Preferably the oral dosage form is a tablet, for example a monolayer or bilayer tablet or a capsule.

Most preferably, the composition includes 20 mg rivaroxaban and 10 mg amlodipine wherein the oral dosage form is a monolayer or bilayer tablet, or the composition includes 20 mg rivaroxaban and 5 mg amlodipine wherein the oral dosage form is a monolayer or bilayer tablet.

In one embodiment the fixed-dose pharmaceutical composition includes from 10 mg to 20 mg rivaroxaban, from 5 mg to 20 mg torasemide and a pharmaceutically acceptable excipient.

Preferably the composition includes from 10 mg to 20 mg rivaroxaban, from 5 mg to 20 mg torasemide and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form selected from a monolayer or bilayer tablet, or a capsule.

In one embodiment the fixed-dose pharmaceutical composition includes:

• 10 mg rivaroxaban and 5 mg torasemide,

• 10 mg rivaroxaban and 10 mg torasemide;

• 15 mg rivaroxaban and 5 mg torasemide;

• 15 mg rivaroxaban and 10 mg torasemide; 20 mg rivaroxaban and 5 mg torasemide;

20 mg rivaroxaban and 10 mg torasemide; or 20 mg rivaroxaban and 20 mg torasemide; and a pharmaceutically acceptable excipient.

Preferably the composition includes:

• 10 mg rivaroxaban and 5 mg torasemide,

• 10 mg rivaroxaban and 10 mg torasemide;

• 15 mg rivaroxaban and 5 mg torasemide;

• 15 mg rivaroxaban and 10 mg torasemide; · 20 mg rivaroxaban and 5 mg torasemide;

• 20 mg rivaroxaban and 10 mg torasemide; or

• 20 mg rivaroxaban and 20 mg torasemide; and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form. Preferably the oral dosage form is a tablet, for example a monolayer or bilayer tablet or a capsule.

In one embodiment the fixed-dose pharmaceutical composition includes from 10 mg to 20 mg rivaroxaban, from 2.5 mg to 10 mg bisoprolol and a pharmaceutically acceptable excipient.

Preferably the composition includes from 10 mg to 20 mg rivaroxaban, from 2.5 mg to 10 mg bisoprolol and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form selected from a monolayer or bilayer tablet, or a capsule. In one embodiment the fixed-dose pharmaceutical composition includes:

• 10 mg rivaroxaban and 5 mg bisoprolol,

• 10 mg rivaroxaban and 10 mg bisoprolol;

• 15 mg rivaroxaban and 2.5 mg bisoprolol;

• 15 mg rivaroxaban and 5 mg bisoprolol;

• 15 mg rivaroxaban and 10 mg bisoprolol;

• 20 mg rivaroxaban and 2.5 mg bisoprolol;

• 20 mg rivaroxaban and 5 mg bisoprolol; or

• 20 mg rivaroxaban and 10 mg bisoprolol; and a pharmaceutically acceptable excipient. Preferably the composition includes:

• 10 mg rivaroxaban and 5 mg bisoprolol,

• 10 mg rivaroxaban and 10 mg bisoprolol;

• 15 mg rivaroxaban and 2.5 mg bisoprolol; • 15 mg rivaroxaban and 5 mg bisoprolol;

• 15 mg rivaroxaban and 10 mg bisoprolol;

• 20 mg rivaroxaban and 2.5 mg bisoprolol;

• 20 mg rivaroxaban and 5 mg bisoprolol; or

• 20 mg rivaroxaban and 10 mg bisoprolol; and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form. Preferably the oral dosage form is a tablet, for example a monolayer or bilayer tablet or a capsule.

In one embodiment the fixed-dose pharmaceutical composition includes from 5 mg to 10 mg apixaban, from 5 mg to 10 mg torasemide and a pharmaceutically acceptable excipient. Preferably the composition includes from 5 mg to 10 mg apixaban, from 5 mg to 10 mg torasemide and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form selected from a monolayer or bilayer tablet, or a capsule. Even more preferably, the apixaban is formulated in the aforementioned tablet or capsule oral dosage form to provide controlled release of apixaban from the oral dosage form.

In one embodiment the fixed-dose pharmaceutical composition includes:

• 5 mg apixaban and 5 mg torasemide;

• 10 mg apixaban and 10 mg torasemide;

• 5 mg apixaban and 10 mg torasemide; or

• 10 mg apixaban and 5 mg torasemide; and a pharmaceutically acceptable excipient.

Preferably the composition includes:

• 5 mg apixaban and 5 mg torasemide;

• 10 mg apixaban and 10 mg torasemide;

• 5 mg apixaban and 10 mg torasemide; or

• 10 mg apixaban and 5 mg torasemide; and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form. Preferably the oral dosage form is a tablet, for example a monolayer or bilayer tablet or a capsule. Even more preferably, the apixaban is formulated in the aforementioned tablet or capsule oral dosage form to provide controlled release of apixaban from the oral dosage form. In one embodiment the fixed-dose pharmaceutical composition includes from 2.5 mg to 5 mg apixaban, from 50 mg to 100 mg metoprolol and a pharmaceutically acceptable excipient. Preferably the composition includes from 2.5 mg to 5 mg apixaban, from 50 mg to 100 mg metoprolol and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form selected from a monolayer or bilayer tablet, or a capsule.

In one embodiment the fixed-dose pharmaceutical composition includes:

• 2.5 mg apixaban and 50 mg metoprolol;

• 5 mg apixaban and 50 mg metoprolol;

• 2.5 mg apixaban and 100 mg metoprolol; or

• 5 mg apixaban and 100 mg metoprolol; and a pharmaceutically acceptable excipient, wherein metoprolol is included in the composition as a free base or as a pharmaceutically acceptable salt of metoprolol, for example metoprolol succinate.

Preferably the composition includes:

• 2.5 mg apixaban and 50 mg metoprolol;

• 5 mg apixaban and 50 mg metoprolol;

• 2.5 mg apixaban and 100 mg metoprolol; or

• 5 mg apixaban and 100 mg metoprolol; and a pharmaceutically acceptable excipient, wherein metoprolol is included in the composition as a free base or as a pharmaceutically acceptable salt of metoprolol, for example metoprolol succinate, and wherein the composition is an oral dosage form. Preferably the oral dosage form is a tablet, for example a monolayer or bilayer tablet or a capsule. Methods of treatment

The combinations of active ingredients as defined herein by the fixed-dose pharmaceutical compositions produce an increased therapeutic effect relative to the therapeutic effect of the individual components when administered alone or when administered in combination according to independent dosage regimens, i.e. not as a fixed-dose composition.

In particular, the combination of active ingredients may, relative to the individual components when administered alone, provide additivity and synergism.

A "synergistic" effect occurs when the combination of active ingredients provides an effect which is larger than the sum of the therapeutic effects of the agents administered alone.

An "additive" effect occurs when the combination of active ingredients provides an effect which is larger than the either of the components when administered alone.

The term "combination" means that the components are administered as part of the same overall treatment regimen, as the fixed-dose pharmaceutical compositions defined herein. The fixed-dose pharmaceutical compositions are generally administered to a subject in need of such administration, for example a human or animal, typically a human. The fixed-dose pharmaceutical compositions will typically be administered in amounts that are therapeutically or prophylactically useful.

The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only.

A typical daily dose of the compounds can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, typically 10 nanograms to 10 milligrams per kilogram of bodyweight, more typically 1 microgram to 10 milligrams although higher or lower doses may be administered where required. Ultimately, the quantity of compound administered will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

Particular fixed dose compositions and dosage regimens include:

The skilled person will be aware of the dosing notation qd, bid, tid and qid. However, to avoid any confusion qd means once daily, bid means twice daily, tid means three times a day and qid means four times a day.

The fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention are suitable for use in the treatment or prevention of stroke and systemic embolism.

The fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention are also suitable for use in the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

The fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention are also suitable for use in the treatment or prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one risk factor selected from: congestive heart failure, hypertension, previous stroke ortransient ischaemic attack, age > 75 years or, diabetes mellitus.

The fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention are also suitable for use in the treatment or prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one risk factor selected from: previous stroke or transient ischaemic attack, symptomatic heart failure, diabetes mellitus, hypertension or age > 75 years.

For the avoidance of doubt, the skilled person possesses the knowledge to accurately measure blood pressure and identify patients with essential hypertension. Patients with essential hypertension consistently present with a blood pressure of 140/90 mmHg or above. The invention also provides a method for the treatment or prevention of stroke and systemic embolism, or a method for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension comprising administering to a human a fixed-dose pharmaceutical composition comprising any of the fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention.

The invention also provides a method for the treatment or prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one risk factor selected from: congestive heart failure, hypertension, previous stroke or transient ischaemic attack, age > 75 years or, diabetes mellitus comprising administering to a human a fixed-dose pharmaceutical composition comprising any of the fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention.

The invention also provides a method for the treatment or prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one risk factor selected from: previous stroke or transient ischaemic attack, symptomatic heart failure, diabetes mellitus, hypertension or age > 75 years comprising administering to a human a fixed-dose pharmaceutical composition comprising any of the fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention.

The invention also provides the use of the fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism, or for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

The invention also provides the use of the fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one risk factor selected from: congestive heart failure, hypertension, previous stroke or transient ischaemic attack, age > 75 years or, diabetes mellitus.

The invention also provides the use of the fixed-dose pharmaceutical compositions as defined herein by the first and second aspects of the invention for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one risk factor selected from: previous stroke or transient ischaemic attack, symptomatic heart failure, diabetes mellitus, hypertension or age > 75 years.

In one embodiment, the fixed-dose pharmaceutical composition is administered once-daily, twice-daily or th rice-daily.

In one embodiment, the fixed-dose pharmaceutical composition is administered once-daily.

In one embodiment, the fixed-dose pharmaceutical composition is administered twice-daily. Formulations

In addition to including the active ingredients as defined herein, the compositions include one or more pharmaceutically acceptable excipients.

The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

The compositions as defined herein can be can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

The fixed-dose pharmaceutical compositions of the invention are preferably formulated as oral dosage forms.

In one embodiment, the compositions are instant release formulations. In another embodiment, the compositions are extended release compositions.

Oral dosage forms include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

Preferably, the compositions are provided as tablets, for example a monolayer or bilayer tablet or as capsules.

A monolayer tablet has a single layer, where the active ingredients and excipients are present in a single uniform structure. A bilayer tablet has two layers, where the active ingredients and excipients are present as a uniform structure in two separate layers.

Where the compositions are provided as monolayer tablets, both active ingredients are contained within said monolayer. That is, the anticoagulant and antihypertensive are contained within the same layer, along with the excipients. Where the compositions are provided as a bilayer tablets, one layer contains the anticoagulant and excipient, and the other layer contains the antihypertensive and excipient.

As described hereinabove in a preferred embodiment, the composition includes 20 mg rivaroxaban and 10 mg amlodipine wherein the composition is an oral dosage form that is a monolayer or bilayer tablet, or the composition includes 20 mg rivaroxaban and 5 mg amlodipine wherein the oral dosage form is a monolayer or bilayer tablet.

Where the composition is a bilayer tablet, the rivaroxaban part of the tablet is preferably prepared according to a wet granulation/dispersion process, and the amlodipine part is preferably prepared according to a direct compression blending process. The rivaroxaban and amlodipine parts are then preferably compressed together to form a bilayer tablet.

In terms of preparing the amlodipine-containing part of the bilayer tablet, preferably the amlodipine, diluent, disintegrant, glidant and optionally any colourants are mixed in a blender. During the mixing process, a lubricant may be added thereto, and the resulting mixture is thoroughly mixed.

It was however surprisingly found that using magnesium stearate as a lubricant was incompatible with amlodipine

To prepare the bilayer tablet, the rivaroxaban part and the amlodipine part are compressed together.

In one embodiment, the fixed-dose pharmaceutical composition is a bilayer tablet comprising a rivaroxaban part and an amlodipine part, wherein the rivaroxaban part is obtained by o dissolving at least a binding agent and a wetting agent in water to provide a dispersion solution; o suspending rivaroxaban in the dispersion solution to provide a dispersion suspension; o mixing at least a diluent, a disintegrant and optionally rivaroxaban together to form a pre-mixture; and o spraying the dispersion suspension onto the pre-mixture to form rivaroxaban granules in a wet granulation step wherein the amlodipine part is obtained by o mixing amlodipine, and at least a diluent, disintegrant and glidant; and wherein the bilayer tablet is obtained by bringing together the rivaroxaban part and the amlodipine part.

Preferably, the bilayer tablet is obtained by bringing together the rivaroxaban part and the amlodipine part in a direct compression step.

Preferably, the binding agent includes hydroxypropylmethylcellulose, and the wetting agent includes sodium lauryl sulfate. Preferably, 100% of the rivaroxaban that is required to be contained in the final dosage form is suspended in dispersion solution.

More preferably, 10 to 30% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 70-90% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture; or 15 to 25% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 75-85% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture; or 20% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 80% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture.

Preferably, the pre-mixture includes a diluent, e.g. microcrystalline cellulose or lactose monohydrate or mannitol, and disintegrant e.g. croscarmellose, and optionally rivaroxaban.

Preferably, the pre-mixture does not include sodium starch glycolate as a diluent.

The applicant surprisingly found that where sodium starch glycolate was used as a disintegrant, release of rivaroxaban was slower than release of rivaroxaban from the commercial mono-product Xarelto®, and therefore not satisfactory.

Preferably, the wet granulation step used to prepare the rivaroxaban granules is performed in a high- shear mechanical grinder (HSMG), and then the granules are dried in a fluid bed drier.

Preferably, the wet granulation step used to prepare the rivaroxaban granules is a wet fluidized-bed granulation.

In a further embodiment, after the rivaroxaban granules are prepared by wet granulation, the granules may be dried, sieved and milled, and a lubricant e.g. magnesium stearate may be added thereto.

In the amlodipine part, preferably at least croscarmellose sodium or sodium starch glycolate is used as a disintegrant.

In the amlodipine part, preferably lactose is not used as a diluent.

Where the composition is a monolayer tablet, the rivaroxaban and amlodipine parts of the tablet are preferably preferred according to the process described for the bilayer tablet. However, the rivaroxaban and amlodipine parts are brought together and compressed as a monolayer tablet.

In one embodiment, there is provided a process for preparing a fixed-dose composition, wherein the composition is an oral dosage form bilayer tablet, comprising a rivaroxaban part and an amlodipine part, comprising the steps of: o dissolving at least a binding agent and a wetting agent in water to provide a dispersion solution; o suspending rivaroxaban in the dispersion solution to provide a dispersion suspension; o mixing at least a diluent, a disintegrant and optionally rivaroxaban together to form a pre- mixture; o spraying the dispersion suspension onto the pre-mixture to form rivaroxaban granules in a wet granulation step, to provide the rivaroxaban part, and o mixing amlodipine, and at least a diluent, disintegrant and glidant, to provide the amlodipine part; and o bringing together the rivaroxaban part and the amlodipine part to form a bilayer tablet.

Preferably, the binding agent includes hydroxypropylmethylcellulose, and the wetting agent includes sodium lauryl sulfate.

Preferably, 100% of the rivaroxaban that is required to be contained in the final dosage form is suspended in dispersion solution.

Preferably, the wet granulation step used to prepare the rivaroxaban granules is performed in a high- shear mechanical grinder, and then the granules are dried in a fluid bed drier.

Preferably, the wet granulation step used to prepare the rivaroxaban granules is a wet fluidized-bed granulation. In a further embodiment, after the rivaroxaban granules are prepared by wet granulation, the granules may be dried, sieved and milled, and a lubricant e.g. magnesium stearate may be added thereto.

In the amlodipine part, preferably at least croscarmellose sodium or sodium starch glycolate is used as a disintegrant. In the amlodipine part, preferably lactose is not used as a diluent.

Where the compositions are provided in capsules, the active ingredients the anticoagulant and antihypertensive are contained within a single capsule. The anticoagulant and antihypertensive may be contained as separate powders or granulates in the capsule, or the anticoagulant and antihypertensive may be formulated together as a single granulate with excipient.

The fixed-dose pharmaceutical compositions defined herein may be formulated as tablet compositions, that may contain the active ingredients as defined herein together with an inert diluent, filler or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures.

Preferably, the compositions of the invention are formulated with a pharmaceutically acceptable filler or bulking agent.

Examples of excipients include dibasic calcium phosphate anhydrous, magnesium stearate, silicon dioxide, carboxymethylcellulose, crospovidone, and hydroxypropyl cellulose dosage forms capsule or tablet.

Tablets may be designed to release the active ingredient either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.

In embodiments of the invention where the fixed-dose composition includes apixaban, the apixaban may be formulated to provide immediate release or controlled release of apixaban from the dosage form.

In one embodiment, the composition is a monolayer tablet.

In one embodiment, the monolayer tablet comprises:

• the anticoagulant; · the antihypertensive;

• a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and

• one or more additional pharmaceutically acceptable excipients as defined herein.

In one embodiment, the monolayer tablet comprises: • rivaroxaban;

• torasemide;

In one embodiment, the monolayer tablet comprises:

• rivaroxaban;

• amlodipine (e.g. amlodipine besilate);

• one or more additional pharmaceutically acceptable excipients as defined herein. In one embodiment, the monolayer tablet comprises:

• rivaroxaban;

• amlodipine (e.g. amlodipine besilate);

• a filler, such as microcrystalline cellulose, calcium phosphate or starch, but not lactose; and

In one embodiment, the composition is a bilayer tablet.

In one embodiment, the bilayer tablet comprises:

• a first layer comprising o the anticoagulant; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o one or more additional pharmaceutically acceptable excipients as defined herein; and

• a second layer comprising o the antihypertensive; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o one or more additional pharmaceutically acceptable excipients as defined herein.

In one embodiment, the bilayer tablet comprises:

• a first layer comprising o rivaroxaban; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o one or more additional pharmaceutically acceptable excipients as defined herein; and · a second layer comprising o torasemide; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o one or more additional pharmaceutically acceptable excipients as defined herein.

In one embodiment, the bilayer tablet comprises: • a first layer comprising o rivaroxaban; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o a disintegrant, such as croscarmellose sodium, wherein the disintegrant is not sodium starch glycolate; and o one or more additional pharmaceutically acceptable excipients as defined herein; and

• a second layer comprising o amlodipine (e.g. amlodipine besilate); o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o one or more additional pharmaceutically acceptable excipients as defined herein.

In one embodiment, the bilayer tablet comprises:

• a first layer comprising o rivaroxaban; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o one or more additional pharmaceutically acceptable excipients as defined herein; and

• a second layer comprising o amlodipine (e.g. amlodipine besilate); o a filler, such as microcrystalline cellulose, calcium phosphate or starch, but not lactose; and o one or more additional pharmaceutically acceptable excipients as defined herein.

In one embodiment, the bilayer tablet comprises:

• a first layer comprising o rivaroxaban; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; o a disintegrant, such as croscarmellose sodium, wherein the disintegrant is not sodium starch glycolate; and o one or more additional pharmaceutically acceptable excipients as defined herein; and

In one embodiment, the bilayer tablet comprises:

• a second layer comprising o amlodipine (e.g. amlodipine besilate); o a filler, such as microcrystalline cellulose, calcium phosphate or starch, but not lactose; o a disintegrant, such as croscarmellose sodium or sodium starch glycolate; and o one or more additional pharmaceutically acceptable excipients as defined herein.

In one embodiment, the filler in the first layer may also be mannitol. In one embodiment, the bilayer tablet comprises:

• a first layer comprising o rivaroxaban, and one or more additional pharmaceutically acceptable excipients as defined herein, wherein the total weight of the first layer does not exceed 165 mg; and

• a second layer comprising o amlodipine (e.g. amlodipine besilate) and one or more additional pharmaceutically acceptable excipients as defined herein.

The applicant surprisingly found that if the total weight of the first layer comprising rivaroxaban exceeded 165 mg, then the direct compression process was no longer feasible for the bilayer tablet.

In one embodiment, the bilayer tablet comprises: · a first layer comprising o rivaroxaban, and one or more additional pharmaceutically acceptable excipients as defined herein, wherein the total weight of the first layer does not exceed 165 mg; and

• a second layer comprising o amlodipine (e.g. amlodipine besilate) and one or more additional pharmaceutically acceptable excipients as defined herein, wherein the total weight of the second layer does not exceed 205 mg.

Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof. Hydroxypropyl methyl cellulose (HPMC) capsules are also suitable.

In one embodiment, the composition is a capsule formulation.

In one embodiment, the capsule formulation comprises:

• the anticoagulant;

• the antihypertensive; • a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and

In one embodiment, the capsule formulation comprises:

• rivaroxaban;

• torasemide;

In one embodiment, the capsule formulation comprises:

• rivaroxaban;

• amlodipine (e.g. amlodipine besilate);

The solid dosage forms (e.g. tablets, capsules etc.) can be coated or un-coated. Coatings may act either as a protective film (e.g. a polymer, wax or varnish) or as a mechanism for controlling active ingredient release or for aesthetic or identification purposes. The coating (e.g. a Eudragit ™ type polymer) can be designed to release the active component at a desired location within the gastrointestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejenum or colon. Instead of, or in addition to, a coating, the active ingredient can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively the active ingredient can be presented in a polymer coating e.g. a polymethacrylate polymer coating, which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the gut. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (for example formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art.

The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on active ingredient dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow release tablets would in addition contain 0-99% (w/w) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w/w) release-controlling (e.g. delaying) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Other embodiments of the invention

In another aspect, the invention provides a fixed-dose pharmaceutical composition comprising:

• an anticoagulant;

• an antihypertensive; and a pharmaceutically acceptable excipient.

The invention also provides a fixed-dose pharmaceutical composition comprising: · an anticoagulant;

• an antihypertensive; and a pharmaceutically acceptable excipient, for use in the treatment or prevention of stroke and systemic embolism, or for use in the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

The invention also provides a method for the treatment or prevention of stroke and systemic embolism, or a method for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension comprising administering to a human a fixed-dose pharmaceutical composition comprising:

• an anticoagulant; · an antihypertensive; and a pharmaceutically acceptable excipient.

The invention also provides the use of a fixed-dose pharmaceutical composition comprising:

• an anticoagulant;

• an antihypertensive; and a pharmaceutically acceptable excipient, for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism, or for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

In an additional aspect, the invention provides a fixed-dose pharmaceutical composition comprising an anticoagulant which is a factor Xa inhibitor, an antihypertensive which is selected from a calcium channel blocker, a diuretic or a beta blocker, and a pharmaceutically acceptable excipient. The invention also provides a fixed-dose pharmaceutical composition comprising an anticoagulant which is a factor Xa inhibitor, an antihypertensive which is selected from a calcium channel blocker, a diuretic or a beta blocker, and a pharmaceutically acceptable excipient, for use in the treatment or prevention of stroke and systemic embolism, or for use in the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

The invention also provides a method for the treatment or prevention of stroke and systemic embolism, or a method for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension comprising administering to a human a fixed-dose pharmaceutical composition comprising an anticoagulant which is a factor Xa inhibitor, an antihypertensive which is selected from a calcium channel blocker, a diuretic or a beta blocker, and a pharmaceutically acceptable excipient.

The invention also provides the use of a fixed-dose pharmaceutical composition comprising an anticoagulant which is a factor Xa inhibitor, an antihypertensive which is selected from a calcium channel blocker, a diuretic or a beta blocker, and a pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism, or for the manufacture of a medicament for the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

EXAMPLES

Example 1: Formulations

Rivaroxaban/amlodipine monolayer tablet

A monolayer tablet composition containing rivaroxaban and amlodipine was prepared by wet granulating rivaroxaban and excipients to form a granulated mixture. Amlodipine was incorporated into the mixture by extragranular addition, and the mixture was compressed into a tablet.

Rivaroxaban/amlodipine bilaver tablet

A bilayer tablet composition containing rivaroxaban and amlodipine was prepared by wet granulating rivaroxaban and excipients to form a granulated mixture, and by wet granulating amlodipine and excipients to form a granulated mixture. The respective mixtures were provided as layers and compressed into a tablet.

Rivaroxaban/amlodipine capsules

A capsule formulation was prepared by combining rivaroxaban and amlodipine with filler and appropriate excipients (e.g. disintegrant and/or glidant) and then filling the resulting mixture into HPMC/gelatin capsules.

Rivaroxaban/torasemide monolayer tablet

A monolayer tablet composition containing rivaroxaban and torasemide was prepared by wet granulating rivaroxaban and excipients to form a granulated mixture. Torasemide was incorporated into the mixture by extragranular addition, and the mixture was compressed into a tablet.

Rivaroxaban/torasemide bilaver tablet

A bilayer tablet composition containing rivaroxaban and torasemide was prepared by wet granulating rivaroxaban and excipients to form a granulated mixture, and by wet granulating torasemide and excipients to form a granulated mixture. The respective mixtures were provided as layers and compressed into a tablet.

Rivaroxaban/torasemide capsules

A capsule formulation was prepared by combining rivaroxaban and torasemide with filler and appropriate excipients (e.g. disintegrant and/or glidant) and then filling the resulting mixture into HPMC/gelatin capsules.

Example 2: Clinical studies

A two-arm clinical assessment may be performed as follows:

Patients in the test arm may be administered a fixed-dose composition including an anticoagulant and an antihypertensive, whereas patients in the comparator arm may be administered a non-fixed combination of an anticoagulant and an antihypertensive, or patients may be administered an. anticoagulant or an antihypertensive monotherapy.

The patients in the comparator arm may receive the anticoagulant and antihypertensive according to their approved dosage regimen, whereas patients in the test arm may receive a single fixed-dose composition included the same dosage.

Alternatively, the patients in the test arm may be administered a fixed-dose composition including an anticoagulant and an antihypertensive, whereas patients in the comparator arm may be administered a different fixed-dose composition including an anticoagulant and an antihypertensive.

The fixed-dose composition may provide unexpected advantageous effects according to the following rationale.

Patients at highest risk of stroke and systemic embolism, for example those suffering from atrial fibrillation (AF) and or essential hypertension, typically receive greater than five separate medications to manage their condition. The use of five or more separate medications not only requires a great deal of patient compliance, it also raises long term concerns with respect to patient safety.

The use of a fixed-dose composition including an anticoagulant and antihypertensive as described herein, for example rivaroxaban orapixaban, with amlodipine, torasemide, bisoprolol ormetoprolol may provide unexpected benefits in the treatment and prevention of stroke and systemic embolism in patients with and without essential hypertension. In particular, the efficacy of rivaroxaban or apixaban to prevent coagulation may unexpectedly boost the efficacy of the antihypertensives. In this case, advantageously, but unexpectedly, patients who previously required five or more separate medications to treat, prevent and/or manage their risk of stroke and systemic embolism can now do so by taking only two medicaments in a fixed-dose composition.

Examples of potential trials include the following:

Trials 1 and 2:

A clinical trial may be performed to assess the comparative efficacy of a fixed-dose combination including 10 mg rivaroxaban and 10 mg amlodipine, and a non fixed-dose combination including 10 mg rivaroxaban and 10 mg amlodipine, for the treatment and prevention of stroke and systemic embolism in patients with essential hypertension.

In this trial, a patient in the test arm may be administered a fixed-dose combination including 10 mg rivaroxaban and 10 mg amlodipine, whereas a patient in the comparator arm may be individually administered a 10 mg dose of rivaroxaban and a 10 mg dose of amlodipine. To best represent real- world circumstances the patients in the comparator arm may receive their dose of rivaroxaban and amlodipine according to the approved dosing guidelines.

A clinical trial may be performed to assess the comparative efficacy of a fixed-dose combination including 20 mg rivaroxaban and 10 mg amlodipine, and a non fixed-dose combination including 20 mg rivaroxaban and 10 mg amlodipine, for the treatment and prevention of stroke and systemic embolism in patients with essential hypertension.

In this trial, a patient in the test arm may be administered a fixed-dose combination including 20 mg rivaroxaban and 10 mg amlodipine, whereas a patient in the comparator arm may be individually administered a 20 mg dose of rivaroxaban and a 10 mg dose of amlodipine.

An unexpected benefit of the fixed-dose composition may be enhanced efficacy for the reasons discussed hereinabove and also owing to co-administration of the active ingredients. Trial 3:

A clinical trial may be performed to assess the comparative efficacy of a fixed-dose combination including 20 mg rivaroxaban and 10 mg amlodipine, 20 mg rivaroxaban monotherapy and 10 mg amlodipine monotherapy, for the treatment and prevention of stroke and systemic embolism in patients with essential hypertension.

In this trial, a patient in the test arm may be administered a fixed-dose combination including 20 mg rivaroxaban and 10 mg amlodipine, whereas a patient in the comparator arm may be individually administered a 20 mg dose of rivaroxaban or a 10 mg dose of amlodipine.

The relative efficacy of the combinations in the test and comparator arms may be measured, and in particular the synergy of the combinations can be determined. In addition, the drug:drug interactions can be determined.

Trials 4 and 5:

A clinical trial may be performed to assess the comparative efficacy of a fixed-dose combination including 20 mg or 10 mg rivaroxaban and 10 mg amlodipine, and a non fixed-dose combination including a different fixed-dose combination, for the treatment and prevention of stroke and systemic embolism in patients with essential hypertension.

In this trial, a patient in the test arm may be administered a fixed-dose combination including 20 mg or 10 mg rivaroxaban and 10 mg amlodipine, whereas a patient in the comparator arm may be individually administered a comparative fixed-dose composition including a different drug combination.

The fixed-dose composition of rivaroxaban and amlodipine, may unexpectedly provide improved effects with respect to the comparative fixed-dose combination.

Example 3: Dissolution and stability studies

3.1 Rivaroxaban/Amlodipine bilaver tablets 20mq/10mq A bilayer tablet (047D) was prepared according to the following process. The rivaroxaban part was prepared by wet granulation and the amlodipine part by direct compression.

Part I - Granulation in high shear mechanical granulator (HSMG) - rivaroxaban part

Load material 1 , 2 & 3 in the HSMG

Prepare the binder solution by dissolving material 4 & 5 in water Granulate the blend using binder solution in HSMG Dry the material in fluid bed dryer

Mill the dried granules and blend with croscarmellose sodium Lubrication, mix the above step granules with magnesium stearate

Part II Direct compression process blending amlodipine part - Co-sift material 1 to 7 and mix in blender

Add pre sifted magnesium stearate and mix in blender

Combining step Compression of bilayer tablet of rivaroxaban/amlodipine

Compress the blend of part I and part II as bilayer tablets

The composition of the tablet is shown in Table 3.1.1 , the associated dissolution and stability data are shown in Table 3.1 .2 and Table 3.1 .3 respectively. Table 3.1.1

Table 3.1.2

Dissolution of T047D is satisfactory for rivaroxaban as well as for amlodipine.

Table 3.1 .3

Conclusion: There is no change in the impurities of rivaroxaban. For amlodipine, there was an increase in impurity D and N-Lactoside (observed at 3 months 40° C/75 RH accelerated conditions) but this is within specification.

3.2 Rivaroxaban/Amlodipine monolayer tablets 20mq/10mq

A first monolayer tablet (061 D) was prepared according to the following process. The rivaroxaban part was prepared by wet granulation and amlodipine was added during a blending stage.

Part I - Granulation in HSMG - rivaroxaban part

Load material 1 , 2, 3 & 4 in the HSMG

Prepare the binder solution by dissolving material 5 & 6 in water Granulate the blend using binder solution in HSMG Dry the material in fluid bed dryer Mill the dried granules Part II - Blending - amlodipine part

Co-sift material 8 to 12 and mix in blender with rivaroxaban granules Add pre sifted magnesium stearate and mix in blender

Combining step - Compression monolayer tablet of rivaroxaban/amlodi pine

Compress the lubricated blend as monolayer tablets

The composition of the tablet is shown in Table 3.2.1.

Table 3.2.1

A second monolayer tablet (097D) was prepared according to the following process. The rivaroxaban part was prepared by wet granulation and amlodipine was added during a blending stage.

Part I - Granulation in HSMG - rivaroxaban part

Load material 1 , 2, 3, 4 and 5 in the HSMG Prepare the dispersion of material 6, 7 & 8 in water Granulate the blend using API + binder dispersion in HSMG Dry the material in fluid bed dryer Mill the dried granules

Part II Direct compression process blending amlodipine part

Co-sift material 10 to 13 and mix in blender with rivaroxaban granules Add pre sifted magnesium stearate and mix in blender

Combining step Compression monolayer tablet of rivaroxaban/amlodi pine

Compress the blend as monolayer tablets

The composition of the tablet is shown in Table 3.2.2.

Table 3.2.2

The associated dissolution and stability data for tablets 061 D and 097D are shown in Table 3.2.3 and 3.2.4.

Table 3.2.3

Conclusion: Drug release of rivaroxaban from 061 D and 097D is faster at initial time points (5 and 10 minutes), but after 15 minutes is comparable with brand. Drug release of amlodipine from 097D is comparable with brand. These data are also illustrated in Figures 1 and 2. Table 3.2.4

Conclusion: Significant increase in N-Lactoside observed at 1 month (40°C/75 RH accelerated conditions) in monolayer formulation.

3.3 Rivaroxaban/Amlodipine bilaver tablets 20mq/10mq

A bilayer tablet (067D) was prepared according to the following process. The rivaroxaban part was prepared by wet granulation 80% drug in dry mix and 20% drug dispersion spraying in fluidised bed processor (FBP) and the amlodipine part by direct compression.

Part I - Granulation in FBP - rivaroxaban part

Load the blend of material 1 , 2 & 3 in the FBP Prepare the dispersion of material 6, 7 & 8 in water Spray the dispersion on blend in FBP Dry the material in FBP Mill the dried granules

Lubrication, mix the above step granules with magnesium stearate

Part II Direct compression process blending amlodipine part

Co-sift material 1 to 5 and mix in blender

Add pre sifted magnesium stearate and mix in blender

Combining step Compression of bilayer tablet of rivaroxaban/amlodipine

Compress the blend of part I and part II as bilayer tablets

The composition of the tablet is shown in Table 3.3.1 , and the associated dissolution data is shown in Table 3.3.2.

Table 3.3.1

Table 3.3.2

Conclusion: Dissolution of rivaroxaban is satisfactory. Dissolution of amlodipine is slower than brand. These data are also illustrated in Figures 3 and 4. 3.4 Rivaroxaban/Amlodipine bilaver tablets 20mq/10mq

Three bilayer tablets (066D, 073D and 099D) were prepared according to the following process. The rivaroxaban part was prepared by wet granulation 100% drug in dispersion spraying in FBP and the amlodipine part by direct compression.

Part I - Granulation in FBP - rivaroxaban part

Load the blend of material 2 & 3, and 4 & 5 in the FBP Prepare the dispersion of material 1 , 6 & 7 in water Spray the dispersion on blend in FBP Dry the material in FBP Mill the dried granules

Lubrication, mix the above step granules with magnesium stearate

Part II Direct compression process blending amlodipine part

Co-sift material 1 to 7 and mix in blender

Add pre sifted magnesium stearate and mix in blender

Combining step Compression of bilayer tablet of rivaroxaban/amlodipine

Compress the blend of part I and part II as bilayer tablets

The compositions of the tablets are shown in Table 3.4.1 , and the associated dissolution data is shown in Table 3.4.2.

Table 3.4.1

Table 3.4.2

Conclusion: Dissolution of rivaroxaban is satisfactory. Dissolution of amlodipine is slower than brand. These data are also illustrated in Figures 5 and 6. 3.5 Rivaroxaban/Amlodipine bilaver tablets 20mq/10mq

A bilayer tablet (071 D) was prepared according to the following process. The rivaroxaban part and the amlodipine part were prepared by direct compression.

Part I - Direct compression process blending - rivaroxaban part

Co-sift material 1 & 5 and mix in blender

Co-sift material 2, 3 to 4 with above step material and mix in blender Co-sift material 2, 3 to 4 with above step material and mix in blender

Part II Direct compression process blending amlodipine part

Co-sift material 1 to 7 and mix in blender - Add pre sifted magnesium stearate and mix in blender

Combining step Compression of bilayer tablet of rivaroxaban/amlodipine

Compress the blend of part I and part II as bilayer tablets

The composition of the tablet is shown in Table 3.5.1 , and the associated dissolution data is shown in Table 3.5.2.

Table 3.5.1

Table 3.5.2

Conclusion: Dissolution of rivaroxaban is satisfactory. Dissolution of amlodipine is slower than brand. These data are also illustrated in Figures 7 and 8.

3.6 Rivaroxaban/Amlodipine bilaver tablets 20mq/10mq

Six bilayer tablets (080D, 085D, 089D, 091 D, 095D and 096D) were prepared according to the following process. The rivaroxaban part was prepared by wet granulation 80% drug in dry mix and 20% drug dispersion in HSMG and the amlodipine part by direct compression.

Part I - Granulation in HSMG - rivaroxaban part

Load the blend of material 1 , 2 & 3, and 4 & 5 in the HSMG Prepare the dispersion of material 9, 10 & 11 in water Granulate the blend using API + binder dispersion in HSMG Dry the material in fluid bed dryer Mill the dried granules Lubrication, mix the above step granules with magnesium stearate

Part II Direct compression process blending amlodipine part

Co-sift material 1 to 7 and mix in blender

Add pre sifted magnesium stearate and mix in blender

Combining step Compression of bilayer tablet of rivaroxaban/amlodipine

Compress the blend of part I and part II as bilayer tablets

The composition of the tablet is shown in Table 3.6.1 , and the associated dissolution data is shown in Table 3.6.2 (rivaroxaban) and Table 3.6.3 (amlodipine).

Table 3.6.1

Table 3.6.2

Conclusion: Dissolution of rivaroxaban from 080D, 089D, 095D and 096D are satisfactory, at initial time point release rate is higher than brand. Whereas 085D is slower than brand in which croscarmellose sodium was replaced by sodium starch glycolate.

Table 3.6.3

Conclusion: Dissolution of 080D and 089D is slower than brand. Dissolution of 091 D, 095D and 096D are satisfactory and matching with brand. These data are also illustrated in Figures 9 and 10.

Therefore, 095D and 096D display dissolution profiles for both rivaroxaban and amlodipine which are equivalent to the dissolution profiles of each of the mono-products Xarelto and Istin.

Claims

1. A fixed-dose pharmaceutical composition comprising:

• from 1 to 25 mg rivaroxaban or apixaban;

• amlodipine, torasemide, bisoprolol or metoprolol; and

• a pharmaceutically acceptable excipient.

2. A fixed-dose pharmaceutical composition according to claim 1 , comprising:

• rivaroxaban and amlodipine;

• rivaroxaban and torasemide;

• rivaroxaban and bisoprolol;

• apixaban and torasemide; or

• apixaban and metoprolol; and a pharmaceutically acceptable excipient.

3. A fixed-dose pharmaceutical composition according to claim 2, comprising from 10 mg to 20 mg rivaroxaban and from 5 mg to 10 mg amlodipine.

4. A fixed-dose pharmaceutical composition according to claim 2, comprising from 10 mg to 20 mg rivaroxaban and from 5 mg to 20 mg torasemide.

5. A fixed-dose pharmaceutical composition according to claim 2, comprising from 10 mg to 20 mg rivaroxaban and from 2.5 mg to 10 mg bisoprolol.

6. A fixed-dose pharmaceutical composition according to claim 2, comprising from 5 mg to 10 mg apixaban and from 5 mg to 10 mg torasemide.

7. A fixed-dose pharmaceutical composition according to claim 2, comprising from 2.5 mg to 5 mg apixaban and from 50 mg to 100 mg metoprolol.

8. A fixed-dose pharmaceutical composition according to any preceding claim, wherein the composition is an oral dosage form.

9. A fixed-dose pharmaceutical composition according to claim 8, wherein the oral dosage form is a tablet, for example a monolayer or bilayer tablet, or a capsule.

10. A fixed dose pharmaceutical composition according to claim 1 , comprising from 10 mg to 20 mg rivaroxaban and from 5 mg to 10 mg amlodipine and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form selected from a monolayer or bilayer tablet, or a capsule.

11. A fixed dose pharmaceutical composition according to claim 1 , comprising from 10 mg to 20 mg rivaroxaban and from 5 mg to 20 mg torasemide and a pharmaceutically acceptable excipient, wherein the composition is an oral dosage form selected from a monolayer or bilayer tablet, or a capsule.

12. A fixed-dose pharmaceutical composition according to any preceding claim for use in the treatment or prevention of stroke and systemic embolism.

13. A fixed-dose pharmaceutical composition according to any preceding claim for use in the treatment or prevention of stroke and systemic embolism in patients with essential hypertension.

14. A fixed-dose pharmaceutical composition for use according to claim 12 or 13, wherein the composition is administered once-daily.

15. A fixed-dose pharmaceutical composition for use according to claim 12 or 13, wherein the composition is administered twice-daily.

16. A fixed-dose composition according to claim 9, wherein the oral dosage form is a bilayer tablet comprising a rivaroxaban part and an amlodipine part, wherein the rivaroxaban part is obtained by o dissolving at least a binding agent and a wetting agent in water to provide a dispersion solution; o suspending rivaroxaban in the dispersion solution to provide a dispersion suspension; o mixing at least a diluent, a disintegrant and optionally rivaroxaban together to form a pre-mixture; and o spraying the dispersion suspension onto the pre-mixture to form rivaroxaban granules in a wet granulation step wherein the amlodipine part is obtained by o mixing amlodipine, and at least a diluent, disintegrant and glidant; and wherein the bilayer tablet is obtained by bringing together the rivaroxaban part and the amlodipine part.

17. A fixed-dose composition according to claim 16, wherein 100% of the rivaroxaban that is required to be contained in the final dosage form is suspended in dispersion solution, or wherein 10 to 30% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 70-90% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture; or wherein 15 to 25% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 75-85% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture; or wherein 20% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 80% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture.

18. A fixed-dose composition according to claim 16 or 17, wherein the pre-mixture does not include sodium starch glycolate as a diluent.

19. A fixed-dose composition according to any one of claims 16-18, wherein the amlodipine part does not include lactose as a diluent.

20. A fixed dose composition according to claim 9, wherein the oral dosage form is a bilayer tablet comprising:

• a first layer comprising o rivaroxaban; o a filler, such as lactose, microcrystalline cellulose, calcium phosphate or starch; and o a disintegrant, such as croscarmellose sodium; and o one or more additional pharmaceutically acceptable excipients as defined herein; and

• a second layer comprising o amlodipine (e.g. amlodipine besilate); o a filler, such as microcrystalline cellulose, calcium phosphate or starch; and o one or more additional pharmaceutically acceptable excipients as defined herein.

21 . A fixed dose composition according to claim 9, wherein the oral dosage form is a monolayer tablet comprising:

• rivaroxaban;

• amlodipine (e.g. amlodipine besilate);

22. A fixed-dose composition according to any one of claims 16 to 21 , wherein the composition includes 20 mg rivaroxaban and 10 mg amlodipine, or 20 mg rivaroxaban and 5 mg amlodipine.

23. A process for preparing a fixed-dose composition according to any one of claims 1 to 11 , wherein the composition is an oral dosage form bilayer tablet, comprising a rivaroxaban part and an amlodipine part, comprising the steps of: o dissolving at least a binding agent and a wetting agent in water to provide a dispersion solution; o suspending rivaroxaban in the dispersion solution to provide a dispersion suspension; o mixing at least a diluent, a disintegrant and optionally rivaroxaban together to form a pre- mixture; o spraying the dispersion suspension onto the pre-mixture to form rivaroxaban granules in a wet granulation step, to provide the rivaroxaban part, and o mixing amlodipine, and at least a diluent, disintegrant and glidant, to provide the amlodipine part; and o bringing together the rivaroxaban part and the amlodipine part to form a bilayer tablet.

24. A process for preparing a fixed-dose composition according to claim 23, wherein 100% of the rivaroxaban that is required to be contained in the final dosage form is suspended in dispersion solution, or wherein 10 to 30% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 70-90% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture; or wherein 15 to 25% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 75-85% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture; or wherein 20% of the rivaroxaban that is required to be contained in the final dosage form is suspended in the dispersion solution, and 80% of the rivaroxaban that is required to be contained in the final dosage form is included in the pre-mixture.