WO2023175573A1

WO2023175573A1 - Pharmaceutical compositions comprising a β-blocker and an sglt2 inhibitor

Info

Publication number: WO2023175573A1
Application number: PCT/IB2023/052613
Authority: WO
Inventors: Kannan Essakimuthu MUTHAIYYAN; Pranav Dhirajbhai Jogani; Ravindra Mittal; Vinay Satishchandra UPADHYAY; Hardik Satish BODIWALA; Rohit Girdharlal VAISHNANI; Nilay Yagnesh SHAH
Original assignee: Zydus Lifesciences Limited
Priority date: 2022-03-17
Filing date: 2023-03-17
Publication date: 2023-09-21

Abstract

The invention relates to once-a-day pharmaceutical compositions comprising a fixed dose combination of a β-blocker or a pharmaceutically acceptable salt or ester thereof and an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof with one or more pharmaceutically acceptable excipients. In addition, the present invention also relates to use of such pharmaceutical compositions in patients for the prevention or treatment of heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, and chronic heart failure.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING A P-BLOCKER AND AN SGLT2 INHIBITOR

FIELD OF THE INVENTION

The present invention relates to once-a-day pharmaceutical compositions comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof and an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof with one or more pharmaceutically acceptable excipients. The invention further relates to use of such pharmaceutical compositions in patients for the prevention or treatment of heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, and chronic heart failure.

BACKGROUND OF THE INVENTION

Heart failure with reduced ejection fraction (HFrEF) is a common and frequently morbid condition with high short-term mortality. Heart failure is a life-threatening medical condition in which the heart cannot pump enough blood sufficiently to sustain the organs of the body. While heart failure refers to the clinical syndrome resulting in dyspnea, exercise intolerance, or fluid retention, a reduced left ventricular ejection fraction is the sine qua non of HFrEF. Heart failure affects approximately 64 million people worldwide (half of whom have a reduced ejection fraction (HFrEF)) and the prevalence and incidence of Heart failure continues to increase globally. (Cannie D.E. et al, European Cardiology Review 14(2):S9-96 (2019)). Heart failure is a chronic and degenerative disease where half of the patients will die within five years of diagnosis (Mamas, M.A. et al., European Journal of Heart Failure 19: 1095- 1104 (2017)). Heart failure is the leading cause of hospitalization for those over the age of 65 and represents a significant clinical and economic burden (Azad, N. et al, Journal of Geriatric Cardiology 77:329- 337 (2014)).

Based on the disease condition and diagnosis, the physicians tend to prescribe a combination of two or more drugs to a patient. Such combinations are expected to provide a better control over cardiovascular mortality. The combinations can be given as two separate drugs administered separately at the same time or at different timings. Several fixed dose combinations of cardiovascular drugs are available in the market. Wherever possible, a fixed dose combination is used by physicians to simplify the dosing regimen. However, these fixed dose combinations do not provide physician an option to modulate the dose of drugs within these fixed dose combinations according to need of a patient.

Further, this multiple medication administration, complex drug regimen, and frequent dose administration complicates the patient's compliance. Since cardiovascular disorders are often chronic disorders, complex drug regimen involving several drugs has a negative impact on patient's life leading to non-compliance. Most of the patients tend to forget dosage regimen quite often. Further, it becomes difficult for the physician to prescribe appropriate doses of different drugs when used in combination. Moreover, because of the complexity of dosage regimen, it becomes difficult for the pharmacist to explain the treatment regimen to the patient being treated. Thus, non-compliance occurs at all three levels, i.e., at physician, pharmacist, and patient's level.

A single drug acts mainly on a single pathophysiological mechanism, whereas it is widely known that heart failure involves 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. The current standard of care treatment paradigm for heart failure includes the simultaneous administration of one or more of the following classes of drugs, e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers (ARBs), betablockers, mineralocorticoid receptor agents like mineralocorticoid-receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), digoxin, diuretics, selective sinus node inhibitors, blood vessel dilators, and calcium channel blockers (unless the patient has systolic heart failure). Even with the best possible treatment, however, the five-year survival rate for heart failure is worse than for most cancers. (Braunwald, E. et. al., Lancet 385:812-824 (2015)). Morbidity and mortality for patients with heart failure remain high, and patient outcomes need improvement. For instance, it has been reported that combinations of diuretics and 0-blockers adversely affect glycolipid metabolism or that combinations of ACE inhibitors and angiotensin II receptor blockers (ARBs) have high likelihood of transition to end-stage renal failure. Additional methods of treating patients with heart failure, and especially HFrEF, are needed to reduce cardiovascular mortality, reduce heart failure events and the worsening of heart failure symptoms, and improve patient outcomes by slowing disease progression. Hence, there is an unmet need to provide a safe fixed dose combination to the patients of HFrEF with or without diabetes, which are devoid of the above-mentioned adverse effects and provide an improvement with regards to the risk of hospitalization, related morbidity, and mortality.

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic drug with salutary effects on glucose control, body weight, and blood pressure. Emerging evidence now indicates that these drugs may have a beneficial effect on outcomes in heart failure with reduced ejection fraction (HFrEF). Post-approval cardiovascular outcomes data for three of these agents (canagliflozin, empagliflozin, and dapagliflozin) showed an unexpected improvement in cardiovascular endpoints, including heart failure hospitalization and mortality, among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or risk factors (Genuardi MV, et. al., The dawn of the four- drug era? SGLT2 inhibition in heart failure with reduced ejection fraction; Ther. Adv. Cardiovasc. Dis.; 2021,15: 1-12).

Dapagliflozin is an inhibitor of sodium dependent glucose transporter, which is chemically represented as (lS)-l,5-anhydro-l-C-{4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl }-D-glucitol having structural formula as represented by formula (I).

Currently, Dapagliflozin is approved under the brand name Farxiga®, 5 mg and 10 mg in the form of tablets, which is marketed by AstraZeneca. U.S. Patent No. 6,515,117 discloses dapagliflozin as a compound. U.S. Patent No. 7,919,598 discloses the (S)-propylene glycol solvate of dapagliflozin and processes for the preparation thereof. The commercially available formulations of dapagliflozin contain the propanediol (propylene glycol) monohydrate solvate of dapagliflozin as the active ingredient. Empagliflozin is a known SGLT2 inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus, for example in WO 05/092877, WO 06/117359, WO 06/120208, WO 2010/092126, WO 2010/092123, WO 2011/039107, WO 2011/039108.

Beta blockers, (0-blockers, beta-adrenergic blocking agents, beta antagonists, beta- adrenergic antagonists, beta-adrenoreceptor antagonists, or beta-adrenergic receptor antagonists) are a class of drugs that are typically used for the management of cardiac arrhythmias, protecting the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention), and, in certain cases, hypertension. Beta blockers are also well known for their reductive effect on heart rate.

Metoprolol, i.e., 1 -(lsopropylamino)-3-[4-(2-methoxyethyl)-phenoxy]- propan-2-ol, is a selective 01 (adrenergic) receptor blocker normally used in the treatment of various disorders of the cardiovascular system, and in particular hypertension.

Carvedilol, i.e., ((±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2- methoxyphenoxy) ethyl] amine) is a mixed, i.e., nonselective alpha and beta blocker. It is traditionally used in the treatment of mild to severe congestive heart failure (CHF) and high blood pressure.

Beta-blockers and SGLT2 inhibitors have different mechanism of action, and these actions complement each other and provide an improvement in the body weight, blood pressure, and arterial stiffness. This may decrease afterload and thus cardiac workload and myocardial oxygen (O2) consumption. Changes in arterial stiffness associated with SGLT2 inhibitors may not be just a decreased blood volume effect; an analysis of patients taking empagliflozin suggested that patients with the most marked change in markers of vascular stiffness also had the greatest reductions in high-sensitivity C-reactive protein, suggesting an anti-inflammatory mechanism. [Journal of Medicinal Chemistry, vol. 42, p. 5311 (1999); British Journal of Pharmacology, vol. 132, p. 578 (2001)]. Further, patients with chronic heart failure have prolonged sympathetic stimulation and subsequent worsening of the failing heart function. Beta-blockers (non-selective, cardio-selective, and non-selective with ancillary properties) counteract the effects of prolonged sympathetic stimulation. Beta-blocker therapy results in the improvement of the left ventricular systolic and diastolic function, reversal remodeling, heart rate control, effective prevention of the malignant arrhythmias, and lowering of both, cardiac afterload, and preload in patients with chronic heart failure. Hence, two classes of medications, which can act on different physiological systems and could be combined into a single dosage unit, would have an additive effect.

U.S. Patent Publication No. 2008/010772 discloses pharmaceutical compositions comprising beta-adrenergic receptor blocking agents for controlled release and diuretics for immediate release.

U.S. Patent Publication No. 2014/0302125 discloses a once-a-day therapeutically synergistic pharmaceutical dosage form for treatment of cardiovascular disorders, wherein the dosage form comprises a fixed dose combination of metoprolol in extended- release form and one or more calcium channel blocker, angiotensin II receptor blocker, or angiotensin converting enzyme inhibitor along with one or more rate controlling excipient.

International (PCT) Publication No. WO2021037400 discloses methods of treating patients with heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes, with an SGLT2 inhibitor, such as dapagliflozin.

U.S. Patent No. 10,980,822 B2 discloses a pharmaceutical composition comprising an effective amount of a sodium glucose cotransporter-2 (SGLT-2) inhibitor and an effective amount of an angiotensin receptor blocker to control blood pressure, wherein the SGLT-2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt or solvate thereof, and wherein the angiotensin receptor blocker is olmesartan, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof.

Therefore, there is an unmet medical need for methods, medicaments, and pharmaceutical compositions with a good efficacy with regard to heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes. Further, in the dosage form with multiple APIs, the physico-chemical properties of API's are very critical in formation of stable unit dosage form and also the choice of excipients play an important role in assessing the overall stability and therapeutic effect of said unit dosage form. Also, size of the tablet plays important role in patient compliance. Therefore, there is an unmet need for a stable once daily pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof and an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof with one or more pharmaceutically acceptable excipients in a single unit dosage form in small size tablets.

SUMMARY OF THE INVENTION

In one general aspect, the present invention provides a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients.

In one general aspect, the present invention provides a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form, wherein the composition releases at least 80% of the P- blocker or a pharmaceutically acceptable salt or ester thereof in 24 hours, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutically acceptable excipient may include a binder, a diluent, a disintegrating agent, a surfactant, a lubricant, a glidant and/or an anti -adherent, a solvent, a plasticizer, a sweetener/taste-masking agent, a colorant, a flavor, and the like.

In another general aspect, a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended- release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form consists of extended-release pellets or granules comprising a P-blocker or a pharmaceutically acceptable salt or ester thereof that is coated with an optional seal coating layer and then with an extended-release coating. The extended-release pellets or granules are mixed with immediate release granules comprising an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof and one or more pharmaceutically acceptable excipients and are either compressed into tablets or filled into a capsule.

In another aspect, the present invention provides a once-a-day pharmaceutical composition comprising a fixed dose combination of about 25 mg to 200 mg of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form and about 2.5 mg to about 25 mg of an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form.

In yet another aspect, the present invention provides a process for preparing a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients, the process comprising mixing extended- release pellets comprising a P-blocker or a pharmaceutically acceptable salt or ester thereof and immediate release granules comprising an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof and one or more pharmaceutically acceptable excipients; and forming the mixture thus obtained into pharmaceutical composition in the form of a tablet, a capsule, granules, powder, pellets, minitablets, microtablets, or a sachet.

In yet another general aspect of the invention, there is provided use of a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof and an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients in patients for the prevention or treatment of heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, and chronic heart failure.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention discovered that the patients with heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes have increased risk of hospitalization for heart failure and cardiovascular death in patients following an acute myocardial infarction. Therefore, there is a need of dosage form which provides extended therapeutic effect with added advantage of two different active ingredients, wherein one active ingredient immediately provides the therapeutic effect whereas other will be in modified release form to provide extended therapeutic effect for 24 hours. Hence, provide better patient compliance with a prescribed therapeutic regimen due to fewer dose administrations, and maintenance of a more constant, safe, and therapeutically effective blood serum concentration, thereby providing a more consistent therapeutic effect over an extended duration of time. It is also recognized that extended-release dosage forms may employ less total drug to achieve a desired therapeutic effect, thereby minimizing undesirable side effects and providing improved economics.

Further, formulation design and process development for fixed dose combination (FDC) products are typically more challenging than corresponding single entity products. Many factors can contribute to the complexity in a formulation design and process development. The most critical is the tablet size of the FDC product in achieving patient acceptance due to higher combined drug strengths. The inventors of the present invention surprisingly found that a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients provides therapeutic effects for 24 hours.

For the purpose of the present invention, “once-a-day” means that the composition of the present invention is administered only once over a 24 hour period thereby providing therapeutically beneficial blood levels of the active agents.

In one embodiment, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, remogliflozin, sotagliflozin, or their pharmaceutically acceptable salts or esters.

In yet another embodiment, the beta-blocker is selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol, or their pharmaceutically acceptable salts or esters.

In preferred embodiment, a fixed dose combination of the present invention includes about 2.5 mg to about 25 mg of an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof and about 25 mg to about 200 mg of a P-blocker or a pharmaceutically acceptable salt or ester thereof.

In yet another embodiment, a once-a-day pharmaceutical composition comprising a fixed dose combination of the present invention includes about 2.5 mg to about 10 mg of dapagliflozin or a pharmaceutically acceptable salt or ester thereof and about 25 mg to about 200 mg of metoprolol or a pharmaceutically acceptable salt or ester thereof.

In yet another embodiment, a once-a-day pharmaceutical composition comprising a fixed dose combination of the present invention includes about 5 mg to about 25 mg of empagliflozin or a pharmaceutically acceptable salt or ester thereof and about 25 mg to about 200 mg of metoprolol or a pharmaceutically acceptable salt or ester thereof.

More particularly, the once-a-day pharmaceutical compositions comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended- release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients, wherein the extended-release form comprises one or more of release-modifying excipients.

By "release-modifying excipient" is meant an agent that, in a pharmaceutical composition, affects the release rate of an active ingredient incorporated in the dosage form, such dosage form then releasing the active ingredient at a rate that is slower than would be achieved compared to an immediate release form.

In preferred embodiment, a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended- release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients, wherein the extended-release form is present as extended-release pellets or extended-release granules.

In one embodiment of the present invention, an extended-release granule may comprise a P- blocker or a pharmaceutically acceptable salt or ester thereof, and one or more release-modifying excipients.

In one embodiment of the present invention, an extended-release pellet may comprise a P- blocker or a pharmaceutically acceptable salt or ester thereof, and one or more release-modifying excipients.

In another embodiment, an extended-release pellet may comprise a core and a coating, wherein one or more release-modifying excipients are incorporated in the coating. In yet another embodiment, an extended-release pellet may comprise a core, wherein the active ingredient is incorporated in the core.

In some embodiments, an extended-release pellet may comprise a matrix and the active ingredient may be embedded within the matrix formed by one or more release-modifying excipients, which may be selected from the group of lipids, waxes, water soluble polymers, and water-insoluble polymers.

In some embodiments, an extended-release pellet is formed by extrusion of active ingredient together with excipients in a wet extrusion or melt extrusion process.

In the frame of the present invention the term “extended” release should be understood in contrast to an immediate release, the active ingredient is gradually, continuously liberated over time, sometimes slower or faster, dependent, or independent from the pH value. In particular, the term indicates that the formulation does not release the full dose of the active ingredient immediately after oral dosing and that the formulation allows a reduction in dosage frequency, following the definition for extended release.

In a further embodiment, the present invention provides a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients, wherein the composition exhibits a dissolution profile such that less than 10% of a P-blocker is released within 1 hour; about 25% to 50% of a P- blocker is released within 8 hours and at least 80% of a P-blocker is released after 24 hours, wherein the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C±0.5°C as a dissolution medium.

In yet another embodiment, a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended- release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form consists of extended-release pellets comprising a P-blocker or a pharmaceutically acceptable salt or ester thereof that is coated with an optional seal coating layer and then with an extended-release coating. The extended-release pellets are mixed with immediate release granules comprising an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof and one or more pharmaceutically acceptable excipients and are either compressed into tablets or filled into a capsule.

In another embodiment, the seal coating layer formulation will include up to 95% of polymer based on the weight of the seal coating layer and may be prepared as described hereinbefore. The formulation will contain at least one coating layer polymer and a coating solvent as described above, which preferably is water, which is used for processing and removed by drying. The coating layer polymer may be hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers or hydroxypropyl cellulose, preferably PVA. The coating layer may also optionally include a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; and an anti-adherent or glidant such as talc, fumed silica, or magnesium stearate, opacifying agent such as titanium dioxide.

In some embodiments, extended release pellets capable of releasing at least 80% of a P-blocker or a pharmaceutically acceptable salt or ester thereof in 24 hours, wherein extended release pellets of the pharmaceutical composition comprises a P-blocker or a pharmaceutically acceptable salt or ester thereof, optionally a binder, a release-modifying excipient and conventional pharmaceutically acceptable excipients, the blend is compressed or extruded and the formed granules or pellets are further optionally coated with a functional coating. The functional coating optionally comprises of a channeling agent which can be a hydrophilic polymer or a water-soluble substance. The composition may be further coated with a polymer based nonfunctional coating. The extended-release pellets are mixed with immediate release granules comprising an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof and one or more pharmaceutically acceptable excipients and are either compressed into tablets or filled into a capsule. In another embodiment, the functional coating may comprise a polymer selected from, but not limited to, one or more of cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof vinyl derivatives, polymers, copolymers or mixtures thereof: maleic acid copolymers; polyalkylene oxides or copolymers thereof, acrylic acid polymers and acrylic acid derivatives; or any combinations thereof.

Examples of release-modifying excipient are but not limited to alkylcelluloses, such as, ethyl cellulose, methyl cellulose; hydroxyalkylcelluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; hydroxyalkyl alkylcelluloses, such as, hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; carboxyalkylcelluloses, such as, carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses, such as, sodium carboxymethylcellulose; carboxyalkylalkylcelluloses, such as, carboxymethyl ethyl cellulose; carboxyalkylcellulose esters; other natural, semisynthetic, or synthetic polysaccharides, such as, alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabicum, guar gum, xanthan gum, starches, pectins, such as sodium carboxymethylamylopectin, chitin derivates such as chitosan, polyfructans, inulin; polyacrylic acids and the salts thereof; polymethacrylic acids and the salts thereof, methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, and mixtures thereof.

Examples of channeling agent are but not limited to copolyvidone, polyvinyl pyrrolidone, polyethylene glycols, hydroxyethyl cellulose, hydroxypropyl methylcellulose and mixtures thereof.

The pharmaceutically acceptable excipients for use in the once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients may include one or more of a binder, a diluent, a disintegrating agent, a surfactant, a lubricant, a glidant and/or an anti-adherent, a solvent, a plasticizer, a sweetener/taste-masking agent, a colorant, a flavor, and the like.

Examples of binders suitable for use herein include, but are not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP) (typical molecular weight ranging from about 5,000 to about 1,000,000, preferably about 40,000 to 50,000), hydroxypropyl methylcellulose (HPMC), lactose, gum acacia, ethyl cellulose, cellulose acetate, as well as a wax binder such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax, as well as other conventional binding agents and/or mixtures of two or more thereof.

Examples of diluents suitable for use herein include, but are not limited to, mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and combinations thereof.

Examples of disintegrating agents suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrating agents. Several specific types of disintegrant are suitable for use in the formulations described herein. For example, any grade of crospovidone can be used, including for example crospovidone XL- 10, Kollidon CL®, Polyplasdone XL®, Kollidon CL- M®, Polyplasdone XL- 10®, and Polyplasdone INF- 10®.

Examples of lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitostearate, glyceryl behenate, myristic acid and hydrogenated vegetable oils and fats, as well as other known lubricants, and/or mixtures of two or more thereof.

Examples of glidants and/or anti-adherents suitable for use herein include, but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica. Examples of surfactants suitable for use herein include, but are not limited to, mono fatty acid esters of polyoxyethylene sorbitan such as those sold under the brand name Tween® ; sodium lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the brand name Cremophor®, polyethoxylated fatty acids and their derivatives, propylene glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, sugar esters, polyoxyethylene-polyoxypropylene block copolymers such as those sold under the brand name Poloxamer, soy lecithin, sodium stearyl fumarate, and the like.

Examples of solublizers suitable for use herein include, but are not limited to, water, methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and 1,1,1 -trichloroethane.

Examples of plasticizers suitable for use herein include, but are not limited to, triethyl citrate, diethyl phthalate, polyethylene glycol, propylene glycol, glycerin, butyl phthlate, castor oil and the like.

Suitable taste masking agents may include one or more of polymers. Examples of polymers include one or more of cellulose acetate, polymethacrylates, cellulose derivatives Such as hydroxylethyl cellulose, and the like. Examples of sweeteners include but not limiting to one or more of aspartame, glycyrrhizin, and the like.

Suitable sweeteners that may be used, comprise saccharides such as aspartame, sugar derivatives. Other examples of sweeteners comprise sodium saccharin; aspartame (sugarless sweeteners), hydrogenated starch hydrolysates, alone or in combination.

Suitable flavoring agents that may be used, comprise citric acid, cinnamon, Wintergreen, eucalyptus, spearmint, peppermint, menthol, anise as well as fruit flavors such as apple, pear, peach, vanilla, strawberry, cherry, apricot, orange, watermelon, banana, and the like; bean- derived flavors such as coffee, cocoa, and the like, or mixtures thereof. In some embodiments, the dosage form of the present invention may be in form of tablet, a capsule, granules, powder, pellets, minitablets, microtablets, or a sachet.

In another embodiment, the present invention provides combination therapies that comprise the stable oral pharmaceutical composition of the present invention in combination with one or more of anti-diabetics; anti-hyperglycemic agents; hypolipidemic/lipid lowering agents; anti-obesity agents; anti-hypertensive agents appetite suppressants; insulin secretagogues, insulin sensitizers, glucokinase activators, glucocorticoid antagonist, fructose 1,6-bis phosphatase inhibitors, AMP kinase activators, modulators of the incretin pathway such as incretin secretagogues such as GPR119 or GPR40 agonists, incretin mimics, and incretin potentiators, bile acid sequestrants or bile acid receptor agonists such as TGR5 agonists, dopamine receptor agonists such as Cycloset, aldose reductase inhibitors PPARy agonists, PPARa agonists, PPAR5 antagonists or agonists, PPARa/y dual agonists, 11-P-HSD-l inhibitors, dipeptidyl peptidase IV (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1), GLP-1 agonists, and PTP-1B inhibitors. Also, weight loss agents acting to decreasing food intake such as sibutrimine, CB1 antagonists, 5HT2C agonists, MCHR1 antagonists, and agents which decrease nutrient absorption (such as lipase inhibitors (Orlistat)), and agents which increase energy expenditure such as thyromimetics, or slow GI motility such as amylin mimetics or ghrelin antagonists.

Therefore, according to one embodiment the pharmaceutical composition according to the invention is characterized in that a P-blocker or a pharmaceutically acceptable salt or ester thereof and an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof are present in a single dosage form and the third active agent may be present in a separate dosage form or may be a part of same single dosage form. A pharmaceutical composition which is present as a separate or multiple dosage form, preferably as a kit of parts, is useful in combination therapy to flexibly suit the individual therapeutic needs of the patient.

In yet another embodiment, a solid bulk of granulate mass, which is necessary for manufacturing tablets, can be manufactured using two main processes, wet granulation or dry granulation. Tablets may also be manufactured using direct compression. Direct compression relates to the tableting process itself rather than preparation of the starting material. In wet granulation, components are typically mixed and granulated using a wet binder. The wet granulates are then sieved, dried_t and optionally ground prior to compressing into tablets. It is also well known in the art that in order to get uniform tablets the bulk to be tableted should be homogeneous and should have good flow characteristics.

In another embodiment, the process for preparing a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients, the process comprising mixing extended-release pellets comprising a P-blocker or a pharmaceutically acceptable salt or ester thereof and immediate release granules comprising an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof and one or more pharmaceutically acceptable excipients; and forming the mixture thus obtained into pharmaceutical dosage form.

In yet another embodiment, the process for preparing the extended-release form comprising a P- blocker or a pharmaceutically acceptable salt or ester thereof, wherein the process comprising:

1) physical blending of the P-blocker or the pharmaceutically acceptable salt or ester thereof and one or more of pharmaceutically acceptable excipients to prepare core pellets or granules;

2) optionally coating the pellets or granules of step 1) with functional coating; and

3) sizing and blending of pellets or granules of step 2) to form final pellets or granules.

In yet another embodiment, the process for preparing the immediate release form comprising a SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof, wherein the process comprising:

1) co-sifting the one or more pharmaceutically acceptable excipients with an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof;

2) preparing binder solution by dissolving the binder into a solvent;

3) granulating the blend of step 1) with the solution of step 2); and

4) lubricating the granules of step 3). In another embodiment, the process of preparing once-a-day pharmaceutical composition further comprising mixing extended-release form; immediate release form; one or more pharmaceutically acceptable excipients; and forming the mixture thus obtained into a tablet, a capsule, granules, powder, pellets, minitablets, microtablets, or a sachet.

In yet another embodiment, the once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof in an extended- release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients retains at least 80% by weight of the total content of a P-blocker or a pharmaceutically acceptable salt or ester thereof and an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

The invention further provides the use of a the once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof and an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients pharmaceutical composition of a present invention in patients for the prevention or treatment of heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, and chronic heart failure.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

Example-1: Dapagliflozin and Metoprolol ER Tablets A) Dapagliflozin granules:

B) Metoprolol ER Pellets:

Manufacturing process:

Dapagliflozin granules

1. Dapagliflozin propanediol monohydrate, calcium hydrogen phosphate anhydrous, lactose monohydrate, and low-substituted hydroxypropyl cellulose were sifted through 30# sieve,

2. sifted ingredients of step 1) were mixed in RMG,

3. hydroxypropyl cellulose was dispersed in a mixture of isopropyl alcohol and methylene chloride to prepare a binder solution,

4. dry mix mass of step 2) was granulated using the binder solution of step 3) in RMG, 5. wet mass of step 4) was dried in a fluid bed dryer to obtain desired LOD,

6. dried granules of step 5) were sifted and milled to get granules of desired size,

7. sized granules were mixed with sifted low-substituted hydroxypropyl cellulose and iron oxide red in a blender,

8. blend of step 7) was lubricated with sifted with sodium stearyl fumarate in a blender. Metoprolol ER pellets:

9. Metoprolol succinate, microcrystalline cellulose and methyl cellulose were co-sifted,

10. blend of step 9) was loaded in RMG for granulation,

11. polyvinylpyrrolidone and glycerin were dispersed in purified water,

12. blend of step 10) was granulated by solution of step 11),

13. the mass of step 12) was passed through a screw extruder,

14. the extrudes of step 13) were spheronised in a spherodizer,

15. the pellets of step 14) were dried in FBD,

16. the pellets of step 15) were sized using a fraction sifter,

17. hydroxypropylmethyl cellulose, polyethylene glycol, and ethyl cellulose were dispersed in isopropyl alcohol and methylene chloride to form functional coating solution,

18. pellets of step 16) were coated using dispersion of step 17),

19. coated pellets of step 18) were sized and blended.

Manufacturing process for base granules and lubrication with metoprolol ER pellets:

20. microcrystalline cellulose and croscarmellose sodium were co-sifted,

21. polyvinylpyrrolidone was dispersed in purified water under stirring,

22. blend of step 20) was granulated with the dispersion of step 21),

23. granules of step 22) were dried in FBD until desired LOD was achieved,

24. dried granules of step 23) were milled using co-mill fitted with a suitable sieve,

25. the functional coated pellets of step 19) and base granules of step 24) were mixed with sifted microcrystalline cellulose, purified talc, and colloidal silicon dioxide in a blender,

26. mixture of step 25) was lubricated with sifted magnesium stearate.

Mixing of Dapagliflozin granules and Metoprolol ER pellets:

27. Dapagliflozin granules of step 8) and Metoprolol ER pellets of step 26) were blended for 10 minutes.

Tablet compression:

28. Tablets were compressed using the blend of step 27) on a rotary compression machine with suitable punches to achieve desired physical parameters. Dissolution Data of Dapagliflozin and Metoprolol ER Tablets:

Example-2: Dapagliflozin and Metoprolol ER Capsule

Manufacturing process:

Dapagliflozin granules

1. Dapagliflozin propanediol monohydrate, calcium hydrogen phosphate anhydrous, lactose monohydrate, low-substituted hydroxypropyl cellulose were sifted,

2. sifted ingredients of step 1) were mixed in RMG,

3. hydroxypropyl cellulose was dispersed in mixture of isopropyl alcohol and methylene chloride to prepare a binder solution,

4. dry mix mass of step 2) was granulated using binder solution of step 3) in RMG, 5. wet mass of step 4) was dried in fluid bed dryer to obtain desired LOD,

6. dried granules of step 5) were sifted and milled to get granules of desired size, 7. sized granules were mixed with sifted low-substituted hydroxypropyl cellulose and iron oxide red in blender,

8. blend of step 7) was lubricated with sifted with sodium stearyl fumarate in blender.

Metoprolol ER pellets:

10. blend of step 9) was loaded in RMG for granulation,

11. polyvinylpyrrolidone and glycerin were dispersed in purified water,

12. blend of step 10) was granulated by solution of step 11),

13. the mass of step 12) was passed through the screw extruder,

14. the extrudes of step 13) were spheronised in a spherodizer,

15. the pellets of step 14) were dried in FBD,

16. the pellets of step 15) were sized using fraction sifter,

18. pellets of step 16) were coated using dispersion of step 17),

19. coated pellets of step 18) were sized and blended.

Capsule filling

20. Dapagliflozin granules and Metoprolol ER Pellets were filled in hard gelatin capsules.

Dissolution Data of Dapagliflozin and Metoprolol ER Capsules:

Example-3: Empagliflozin and Metoprolol ER tablet A) Empagliflozin granules:

B) Metoprolol ER part:

Manufacturing process:

Empagliflozin granules: 1. Empagliflozin, mannitol, pregelatinized starch, colloidal silicon dioxide, crospovidone and polyvinylpyrrolidone were sifted,

2. the sifted materials of step 1 ) were mixed in RMG,

3. dry mix mass of step 2) was granulated using purified water in RMG,

4. wet mass of step 3) was dried in fluid bed dryer to obtain desired LOD,

5. dried granules of step 4) were sifted and milled to get granules of desired size,

6. sized granules of step 5) were lubricated with sifted magnesium stearate in a blender.

Metoprolol ER pellets:

7. Metoprolol succinate, microcrystalline cellulose and methyl cellulose were co-sifted,

8. blend of step 7) was loaded in RMG for granulation,

9. polyvinylpyrrolidone and glycerin were dispersed in purified water,

10. blend of step 8) was granulated by solution of step 9),

11. the mass of step 10) was passed through the screw extruder,

12. the extrudes of step 11) were spheronised in a spherodizer,

13. the pellets of step 12) were dried in FBD,

14. the pellets of step 13) were sized using fraction sifter and lubricated with magnesium stearate,

15. hydroxypropylmethyl cellulose, polyethylene glycol, and ethyl cellulose were dispersed in isopropyl alcohol and methylene chloride to form functional coating solution,

16. pellets of step 14) were coated using dispersion of step 15),

17. coated pellets of step 16) were sized and blended.

18. microcrystalline cellulose and croscarmellose sodium were co-sifted through #40,

19. Polyvinylpyrrolidone was dispersed in purified water under stirring,

20. blend of step 18) was granulated with the dispersion of step 19),

21. granules of step 20) were dried in FBD until desired LOD was achieved,

22. dried granules of step 21) were milled using co-mill fitted with suitable sieve,

23. the functional coated pellets of step 17) and base granules of step 22) were mixed with sifted microcrystalline cellulose, purified talc, and colloidal silicon dioxide in blender, 24. mixture of step 23) was lubricate with sifted magnesium stearate.

Mixing of Empagliflozin granules and Metoprolol ER pellets:

25. Empagliflozin granules of step 6) and Metoprolol ER pellets of step 24) were blended for 10 minutes.

Tablet compression:

26. Tablets were compressed using blend of step 25) on rotary compression machine with suitable punches to achieve desired physical parameters.

Analytical Results:

Example-4: Empagliflozin and Metoprolol ER capsules

A) Empagliflozin granules:

B) Metoprolol ER part:

Manufacturing process:

Empagliflozin granules:

1. Empagliflozin, mannitol, pregelatinized starch, colloidal silicon dioxide, crospovidone, and polyvinylpyrrolidone were sifted,

2. the sifted materials of step 1) were mixed in RMG,

3. dry mix mass of step 2) was granulated using purified water in RMG,

4. wet mass of step 3) was dried in fluid bed dryer to obtain desired LOD,

6. sized granules of step 5) were lubricated with sifted magnesium stearate in blender.

Metoprolol ER pellets:

8. blend of step 7) was loaded in RMG for granulation,

9. polyvinylpyrrolidone and glycerin were dispersed in purified water,

10. blend of step 8) was granulated by solution of step 9),

11. the mass of step 10) was passed through the screw extruder,

12. the extrudes of step 11) were spheronised in a spherodizer,

13. the pellets of step 12) were dried in FBD,

14. the pellets of step 13) were sized using fraction sifter,

16. pellets of step 14) were coated using dispersion of step 15),

17. coated pellets of step 16) were sized and blended.

Capsule filling

18. Empagliflozin granules and Metoprolol ER pellets were filled in hard gelatin capsules. Analytical Results

While

invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

Claims:

1. A once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.

2. The once-a-day pharmaceutical composition of claim 1, wherein the P-blocker or a pharmaceutically acceptable salt or ester thereof is in an extended-release form.

3. The once-a-day pharmaceutical composition of claim 1, wherein the SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof is in an immediate release form.

4. The once-a-day pharmaceutical composition of claim 2, wherein the P-blocker or a pharmaceutically acceptable salt or ester thereof is in an extended-release form, wherein the composition releases at least 80% of the P-blocker or a pharmaceutically acceptable salt or ester thereof in 24 hours.

5. The once-a-day pharmaceutical composition of claim 1, wherein the P-blocker comprises one or more of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, sotalol, and timolol, or their pharmaceutically acceptable salts or esters thereof.

6. The once-a-day pharmaceutical composition of claim 1, wherein the SGLT2 inhibitor comprises one or more of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, remogliflozin, and sotagliflozin, or their pharmaceutically acceptable salts or esters thereof.

7. The once-a-day pharmaceutical composition of claim 1, wherein the composition comprises about 2.5 mg to about 25 mg of an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof and about 25 mg to about 200 mg of a P-blocker or a pharmaceutically acceptable salt or ester thereof.

8. The once-a-day pharmaceutical composition of claim 2, wherein the extended-release form comprises one or more of release-modifying excipients.

9. The once-a-day pharmaceutical composition of claim 8, wherein the one or more of releasemodifying excipients are in a matrix with a P-blocker or a pharmaceutically acceptable salt or ester thereof or coated on a core comprising a P-blocker or a pharmaceutically acceptable salt or ester thereof.

10. The once-a-day pharmaceutical composition of claim 8, wherein the release-modifying excipient comprises one or more of alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters; other natural, semisynthetic, or synthetic polysaccharides, carrageenans, galactomannans, tragacanth, agar- agar, gum arabicum, guar gum, xanthan gum, starches, pectins, chitin derivates polymethacrylic acids and the salts thereof, methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; polyalkylene oxides and copolymers of ethylene oxide and propylene oxide, or mixtures thereof.

11. The once-a-day pharmaceutical composition of claim 1, wherein the composition is in the form of a tablet, a capsule, granules, powder, pellets, minitablets, microtablets, or a sachet.

12. The once-a-day pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients comprise one or more of binders, diluents, disintegrating agents, surfactants, lubricants, glidants and/or anti-adherents, solvents, plasticizers, sweeteners/taste- masking agents, colorants, and flavors.

13. The once-a-day pharmaceutical composition of claim 1, wherein less than 10% of a P-blocker is released within 1 hour; about 25% to 50% of a P-blocker is released within 8 hours and at least 80% of a P-blocker is released after 24 hours, wherein the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C±0.5°C as a dissolution medium.

14. A once-a-day pharmaceutical composition comprising a fixed dose combination of a 0- blocker or a pharmaceutically acceptable salt or ester thereof in an extended-release form, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof in an immediate release form, and one or more pharmaceutically acceptable excipients.

15. The once-a-day pharmaceutical composition of claim 14, made by a process comprising mixing extended-release pellets or granules; immediate release granules; one or more pharmaceutically acceptable excipients; and forming the mixture into a tablet, a capsule, granules, powder, pellets, minitablets, microtablets, or a sachet.

16. The once-a-day pharmaceutical composition of claim 15, wherein the extended-release form comprising a 0-blocker or a pharmaceutically acceptable salt or ester thereof is made by a process comprising:

1) physical blending of the 0-blocker or the pharmaceutically acceptable salt or ester thereof and one or more of pharmaceutically acceptable excipients to prepare core pellets or granules;

17. The once-a-day pharmaceutical composition of claim 15, wherein the immediate release form comprising a SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof is made by a process comprising:

2) preparing binder solution by dissolving the binder into a solvent;

3) granulating the blend of step 1) with the solution of step 2); and

4) lubricating the granules of step 3).

18. A method of treating patients with heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, and chronic heart failure, the method comprising administering to a human being in need thereof a once-a-day pharmaceutical composition comprising a fixed dose combination of a P-blocker or a pharmaceutically acceptable salt or ester thereof, an SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.

19. The method of claim 18, wherein the pharmaceutical composition provides an extended- release of the P-blocker or a pharmaceutically acceptable salt or ester thereof, and an immediate release of the SGLT2 inhibitor or a pharmaceutically acceptable salt or ester thereof.