DESC:PHARMACEUTICAL COMPOSITIONS FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS

TECHNICAL FIELD OF THE INVENTION
The present specification relates to once daily dual release compositions of nicorandil. The specification also relates to pharmaceutical unit composition comprising metoprolol and nicorandil or pharmaceutically acceptable salt thereof, wherein the composition is administered once daily. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION
Major adverse cardiovascular events (MACE) includes congestive heart failure, arrhythmia, myocardial infraction (STEMI, NSTEMI), atherosclerosis, chronic stable angina (angina pectoris), STEMI unstable angina, NSTEMI angina, coronary revascularization, including percutaneous coronary intervention, stroke or other cardiovascular disorders. These events are relatively common in patients undergoing non-cardiac surgical procedures.
Angina pectoris, the primary symptom of ischemic heart disease, is caused by transient episodes of myocardial ischemia that are due to an imbalance in myocardial oxygen supply and demand relationship. Imbalance may be caused by an increase in myocardial oxygen supply and demand or by a decrease in myocardial oxygen supply or sometimes by both. According to this, angina has classified as, stable angina and unstable angina. Stable angina is the most common type of angina. Unstable angina is less common. The associated symptoms are unpredictable and often occur at rest. The symptoms are worse in unstable angina; the pain is more frequent, more severe, long lasting, occurs at rest. Angina pectoris is the most common form of cardiovascular diseases that require constant monitoring and therapy.
Metoprolol is a beta1-selective (cardioselective) adrenoceptor blocking agent, available as immediate and extended-release tablets as well as for injection. Chemically, metoprolol succinate is (RS)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol Succinate (2:1) (salt). Metoprolol succinate is a white crystalline powder with a molecular weight of 652.82. It has following structural formula.

Metoprolol reduces the force of contraction of heart muscle and thereby lowers blood pressure. By reducing the heart rate and the force of muscle contraction, metoprolol reduces the need for oxygen by heart muscle. Since heart pain (angina pectoris) occurs when oxygen demand of the heart muscle exceeds the supply of oxygen, metoprolol, by reducing the demand for oxygen, is helpful in treating heart pain. It is selective, moderately lipophilic, without intrinsic sympathomimetic activity, has weak membrane stabilizing activity, and has a short half-life, and therefore must be taken at least twice daily or as a slow-release preparation.

An extended release tablet of metoprolol succinate is currently being marketed as TOPROL XL®. According to the prescribing information TOPROL XL® is indicated for the treatment of hypertension, the long term treatment of angina pectoris, and the treatment of stable symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive or cardiomyopathic origin.

Nicorandil is a nicotinamide derivative, efficacious in the treatment of hypertension and angina pectoris. It is a potassium channel opener providing vasodilatation of arterioles and large coronary arteries. It opens the ATP sensitive K+ channels, thereby causing dilatation of peripheral and coronary resistant arterioles. In addition, it contains a NO2-moiety, which dilates systemic veins and epicardial coronary arteries. Chemically it is known as N-[2-hydroxyethyl] nicotinamide nitrate, having molecular formula of C8H9N3O4 and molecular weight of 211.17. It has following structure.

Nicorandil has a short half-life (approximately 1 hour), and the usual oral dosage regimen is 5 to 40 mg taken 2 to 4 times a day. Nicorandil is well absorbed from the gastrointestinal tract and maximum plasma concentration of nicorandil is linearly related to the administered dose. Commercially, it is available as 10 mg & 20 mg immediate release tablet, marketed under brand name IKOREL. The conventional therapy reports some unwanted side effects like headache, vasodilation, flushing, nausea, vomiting and weakness. This is possibly due to in high fluctuation in plasma concentration of the drug resulting vasodilation and general hypotension. Therefore, frequent administration and side effects are major drawback for nicotinamide treatment. Currently there is no approved composition of nicorandil which could be administered once daily. Thus, there remains an unmet need for once daily single unit nicorandil composition which improves patient compliance and convenience and reduces the unwanted side effects.

Nicorandil is generally stable in solid crystalline state and stored in the conditions of extreme dryness, but when exposed to moisture even if only for short periods at low humidity levels and at room temperature nicorandil degrades. Three factors influence the hydrolysis of nicorandil, the increased percentage of moisture to which the product is exposed, the temperature and the storage period. Further, it has been shown that if crystalline nicorandil is compressed into a tablet form not only does it degrade through contact with moisture, although with more reduced intensity, but the degradation reaches substantially increased levels during subsequent storage periods.
Currently there is no approved/marketed composition comprising metoprolol and nicorandil combination in a single unit composition which could be administered once daily for the treatment or management of major adverse cardiovascular events. Knowing the problem of stability challenges of nicorandil and metoprolol, it is difficult to prepare both the drugs in a single composition. Thus, there exists a need to develop improved, stable formulation of nicorandil and metoprolol in a single composition.
Accordingly, the present invention provides once daily pharmaceutical unit compositions comprising metoprolol and nicorandil or pharmaceutically acceptable salt thereof, which are stable and improves patient compliance and reduces the unwanted side effects. The said unit compositions could also improve the efficacy for the treatment and/or management of major adverse cardiovascular events in combination as compared to monotherapy.

OBJECT OF THE INVENTION
The present specification relates to once daily dual release compositions of nicorandil.
In one aspect, the present specification relates to once daily dual release compositions of nicorandil comprising:
i) immediate release formulations of nicorandil, and
ii) modified release formulations of nicorandil.

In another aspect, the present specification relates to once daily dual release compositions of nicorandil comprising:
i) immediate release multi-particulate formulations of nicorandil, and
ii) extended or delayed release multi-particulate formulations of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil present in the dual release composition is 40 mg.

In one aspect, the present specification relates to pharmaceutical unit composition comprising:
i) metoprolol or pharmaceutically acceptable salts thereof, and
ii) nicorandil or pharmaceutically acceptable salts thereof,
wherein the said composition is administered once daily.

In another aspect, the present specification relates to once daily pharmaceutical unit composition comprising metoprolol and nicorandil or pharmaceutically acceptable salts thereof, wherein metoprolol and nicorandil are present in the pharmaceutical unit composition in the form of:
i) extended release compositions of metoprolol, and
ii) dual release compositions of nicorandil.

In another aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release compositions of metoprolol or pharmaceutically acceptable salts thereof, and
ii) dual release compositions of nicorandil or pharmaceutically acceptable salts thereof, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in an amount of 25-200 mg and 20-80 mg respectively.

In yet another aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) immediate release formulations of nicorandil, and
b) extended or delayed release formulations of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil present in the dual release composition is 40 mg.

In yet another aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release multi-particulate compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) immediate release multi-particulate formulations of nicorandil, and
b) extended or delayed release multi-particulate formulations of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil present in the dual release composition is 40 mg.

In one aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) immediate release formulations of nicorandil, and
b) extended or delayed release formulations of nicorandil and one or more rate controlling polymer, wherein the amount of nicorandil present in immediate release formulations is less than the amount of nicorandil present in extended or delayed release formulations and total amount of nicorandil present in the immediate release formulations and extended or delayed release formulations is 40 mg.

In yet another aspect, the present specification relates to a capsule composition for once daily administration comprising:
i) extended release pellets compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) one or more immediate release mini-tablets of nicorandil, and
b) one or more extended release mini-tablets of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil in the said combined mini-tablets is 40 mg.

The present specification also relates to use of pharmaceutical unit composition comprising metoprolol and nicorandil for the treatment and/or management of major adverse cardiovascular events such as congestive heart failure, arrhythmia, myocardial infraction (STEMI, NSTEMI), atherosclerosis, chronic stable angina (angina pectoris), STEMI unstable angina, NSTEMI angina, coronary revascularization, including percutaneous coronary intervention, stroke or other cardiovascular disorders.
In yet another aspect, the present specification relates to use of pharmaceutical unit composition comprising metoprolol and nicorandil for the treatment and/or management of major adverse cardiovascular events, for reduction in infarct size and major adverse cardiovascular events in patients with STEMI (ST segment elevation myocardial infarction) who had undergone PCI (percutaneous coronary intervention), wherein the said unit composition comprising:
i) extended release compositions of metoprolol or pharmaceutically acceptable salts thereof, and
ii) dual release compositions of nicorandil or pharmaceutically acceptable salts thereof, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in an amount of 25-200 mg and 20-80 mg respectively.

BRIEF DESCRIPTION OF FIGURES

Figure 1: Dissolution profile of nicorandil and metoprolol of the pharmaceutical unit composition at initial stage.

Figure 2: Dissolution profile of nicorandil and metoprolol of the pharmaceutical unit composition after 6 month storage at stability condition (25 °C/60% RH).

DESCRIPTION OF INVENTION
The present specification relates to once daily dual release compositions of nicorandil.
In one aspect, the present specification relates to once daily dual release compositions of nicorandil comprising:
i) immediate release formulations of nicorandil, and
ii) modified release formulations of nicorandil.

In another aspect, the present specification relates to once daily dual release compositions of nicorandil comprising:
i) immediate release multi-particulate formulations of nicorandil, and
ii) extended or delayed release multi-particulate formulations of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil present in the dual release composition is 40 mg.

In one aspect, the present specification relates to pharmaceutical unit composition comprising:
i) metoprolol or pharmaceutically acceptable salts thereof, and
ii) nicorandil or pharmaceutically acceptable salts thereof,
wherein the said composition is administered once daily.

In another aspect, the present specification relates to once daily pharmaceutical unit composition comprising metoprolol and nicorandil or pharmaceutically acceptable salts thereof, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in the form of:
i) extended release compositions of metoprolol, and
ii) dual release compositions of nicorandil.

In another aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release compositions of metoprolol or pharmaceutically acceptable salts thereof, and
ii) dual release compositions of nicorandil or pharmaceutically acceptable salts thereof, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in an amount of 25-200 mg and 20-80 mg respectively.

In yet another aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) immediate release formulations of nicorandil, and
b) extended or delayed release formulations of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil present in the dual release composition is 40 mg.

In yet another aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release multi-particulate compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) immediate release multi-particulate formulations of nicorandil, and
b) extended or delayed release multi-particulate formulations of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil present in the dual release composition is 40 mg.

In one aspect, the present specification relates to once daily pharmaceutical unit composition comprising:
i) extended release compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) immediate release formulations of nicorandil, and
b) extended or delayed release formulations of nicorandil and one or more rate controlling polymer, wherein the amount of nicorandil present in immediate release formulations is less than the amount of nicorandil present in extended or delayed release formulations and total amount of nicorandil present in the immediate release formulations and extended or delayed release formulations is 40 mg.

In yet another aspect, the present specification relates to a capsule composition for once daily administration comprising:
i) extended release pellets compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) one or more immediate release mini-tablets of nicorandil, and
b) one or more extended release mini-tablets of nicorandil and one or more rate controlling polymer, wherein total amount of nicorandil in the said combined mini-tablets is 40 mg.

In yet another aspect, the present specification relates to use of pharmaceutical unit composition comprising metoprolol and nicorandil for the treatment and/or management of major adverse cardiovascular events, for reduction in infarct size and major adverse cardiovascular events in patients with STEMI (ST segment elevation myocardial infarction) who had undergone PCI (percutaneous coronary intervention), wherein the said unit composition comprising:
iii) extended release compositions of metoprolol or pharmaceutically acceptable salts thereof, and
iv) dual release compositions of nicorandil or pharmaceutically acceptable salts thereof, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in an amount of 25-200 mg and 20-80 mg respectively.

The term “once daily” as used herein refers to once in a day administration of the compositions to the subject in the need thereof. The once daily administration could be any time of the day, before or after meal.
The term “pharmaceutical unit composition” as used herein refers to oral dosage forms preferably in the form of tablets, capsules, sachets and the like. These solid dosage forms are generally prepared by using suitable pharmaceutically acceptable excipients. The term composition or formulation are used herein interchangeably.
The term “immediate release” as used herein refers to immediate release of drug from the compositions or formulations after administration. The term “modified release” relates to release of drug from the compositions wherein said release only occurs some times after the administration or for a prolonged period of time or to a specific target in the body. Modified release systems can be further classified as: delayed release, where drug is released only at some point after the initial administration; extended release or sustained release: prolongs the release at a controlled rate to reduce dosing frequency. These terms are also used by the pharmacopoeias and the FDA. Whilst immediate-release dosage forms are designed to give a fast onset of drug action, modifications in drug release are often desirable to increase the stability, safety and efficacy of the drug, to improve the therapeutic outcome of the drug treatment and/or to increase patient compliance and convenience of administration.
The term “dual release” as used herein refers to composition or formulation which is having both immediate release and modified release profile, e.g. immediate release and extended or delayed release profile. Preferably the dual release composition is having some immediate release formulations/portions which will release the drug from the formulations immediately after administration and extended or delayed release formulation/portion which will release the drug from formulations for a prolong time after administration. The dual release profile of a composition aims to achieve an initial plasma peak of a drug which is essential for quick onset of action and followed by extended release of drug to maintain the required therapeutically effective plasma concentration throughout the day.
The term “metoprolol” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Preferably metoprolol is present in the salt form, e.g. metoprolol tartrate, metoprolol succinate. The therapeutic effective dose of metoprolol or pharmaceutically acceptable salts thereof is 25-400 mg. A standard dose of 100 mg metoprolol tartrate per day has been recommended for the treatment of angina pectoris or heart failure. The amount of metoprolol or pharmaceutically acceptable salts thereof are employed in the present composition is in the range of 25-400 mg, preferably in the range of 25-200 mg, e.g. 50 mg, 100 mg.
The term “nicorandil” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. The amount of nicorandil or pharmaceutically acceptable salts thereof are employed in the present composition is in the range of 20-80 mg, e.g. 20 mg, 40 mg.
The term “multi-particulate” or “multi-particulate compositions” as used herein, can be, but not limited to mini-tablets, spheroids, pellets, granules, powders, microcapsules, multiple unit particles, and the like. Multi-particulate formulations/compositions can be filled in but not limited to sachet, capsules and the like or can be further processed in the form of solid dosage forms. Solid dosage forms can be but not limited to tablets, bilayer tablets, inlay tablets, capsules and the like. The preferred “multi-particulate” compositions is mini-tablets or pellets. The term “mini-tablets” as used herein refers to small round or cylindrical tablets, typically 2 to 7 mm in diameter and are produced by tableting technology, typically rotary presses with minor modifications. The mini-tablets offer finished dosage form flexibility in that they can be delivered as capsules, sachets or compressed into larger tablets. The size/dimension of the mini-tablets are selected in such a way, that it can be accommodated in a capsule of a suitable size.
The term “rate controlling polymers” as used in the context of the present specification relates to one or more pharmaceutically acceptable polymers which controls the drug release from the formulation. The rate controlling polymers helps to achieve extended release or delayed or sustained release profile.
Suitable "rate controlling polymers" may include but not limited to one or more hydrophilic polymers, hydrophobic polymers, natural polymers, bioadhesive polymer, pH-dependent or pH-independent, enteric, degradable, non-degradable, enteric polymers, melt extrusion polymers and the like.
Suitable hydrophilic polymers may include one or more of cellulosic polymers/copolymers or its derivatives including, but not limited to methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or acrylamide derivatives, and the like.
Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates and the like.
Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate and the like.
Suitable bioadhesive polymers selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly( valeric acid), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof and the like.
Other rate controlling polymers suitable for use in the invention include, but are not limited to, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobiityl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrol idone, polyvinylphenol, Polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)), polyorthoesters, blends and copolymers thereof and the like. Methacrylates can be but not limited to Eudragit® L; Eudragit® S; Eudragit® FS 30 D; Eudragit® L30D-55; and Eudragit® L100-55, Eudragit RL PO, Eudragit RL 100, Eudragit RL 30 D, Eudragit?® E, Eudragit?® NE and the like.
Suitable rate controlling polymer may include one or more enteric coatings are usually formulated with synthetic polymers that contain ionisable functional groups that render the polymer water soluble at a pH value.
All enteric polymers that remain intact at pH value lower than about 4.0 and dissolve at pH values higher than 4.0, preferably higher than 5.0, most preferably about 6.0, are considered useful as rate controlling agents for this composition.
Suitable enteric polymers may include but not limited to one or more of methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, hydroxyethyl ethyl cellulose phthalate, cellulose acetate tetrahydrophtalate, acrylic resin and the like.
Suitable melt extrusion polymers can be, but not limited to derivatised cellulose, poly(methacrylate) derivative, poly(ethylene-co-vinyl acetate), poly(ethylene), poly(vinyl acetate-co-methacrylic acid), epoxy resins and caprolactones, poly(ethylene oxide), poly(ethylene glycol) and others including various waxes, fats, lipid-based excipients, including the Gelucire®, Witepsol®, Labrafil® and the like.

Pharmaceutically acceptable excipients
The compositions of the present inventions further comprises one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipients” include, but not limited to, diluents, disintegrants, binders, lubricants, glidants, acidifying agent, alkalizing agent, stabilizers, surfactants, sweetener, film coating materials, plasticizers, pigments, opacifiers, coloring agents and the like.
Suitable diluents, may be selected from, but not limited to the group consisting of different grades of starches, such as maize starch, potato starch, corn starch, wheat starch, pregelatinised starch, fully Pregelatinised starch; cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such as mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose; oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium hydrogenphosphate; particularly preferably the fillers are selected from the group consisting of, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, spray dried lactose, and anhydrous lactose and the like.
Suitable disintegrants may be selected from, but not limited to the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, crosslinked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose, and disintegrating aids such as magnesium alumino-metasilicate and ion exchange resins like polacrilin potassium; particularly preferably the disintegrants are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone and the like.
Suitable binders may be selected from, but not limited to the group consisting of polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch and the like.
Suitable lubricants may be selected from, but not limited to the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium stearate; particularly preferably the lubricant is magnesium stearate and sodium stearyl fumarate and the like.
Suitable glidants, may be selected from, but not limited to the group consisting of colloidal silica, hydrophobic colloidal silica and magnesium trisilicate, such as talc and the like.
Composition may contain acidifying and alkalinizing agent. Acidifying agents can be selected from, but not limited to citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and mixtures thereof and the like. Alkalizing agent can be selected from, but not limited to magnesium oxide, aluminium oxide, ammonium hydroxide, magaldrate, an alkali metal salt or alkaline earth metal salt, such as sodium bicarbonate, calcium carbonate or sodium citrate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide or calcium carbonate and meglumine and the like.
Composition may contain surfactants. Suitable surfactants as component can be selected from, but not limited to the group consisting of anionic surfactants, preferably sodium lauryl sulphate; polyethylene glycols (PEGs), preferably those PEGs having molecular weight in the range of about 2000 to 10000, more preferably PEG 3350, PEG 4000, PEG 6000, PEG 8000; Polysorbates, preferably Tween 20, Tween 80 or Span 80; fatty acid esters, preferably propylene glycol caprylates such as Capmul PG-8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleates and caprylates (Capmul MCM); esters of polyethylene glycol and fatty acids, such as Labrasol and Solutol; castor oil ethoxylate (glycerol polyethylene glycol ricinoleate) such as Cremophor EL and Cremophor RH 40. More preferably the surfactant is selected from the group consisting of sodium lauryl sulphate; PEG 3350, PEG 4000, PEG 600 or, PEG 8000 and preferably PEG 6000; Tween 20 or Tween 80; and esters of polyethylene glycol and fatty acids, most preferably sodium lauryl sulphate and PEG 6000 and in particular sodium lauryl sulphate and the like.
Suitable sweeteners may be selected from, but not limited to the group consisting of aspartame, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.
Suitable film-forming agents and coating materials, if used, may include, but are not limited to hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, polyvinylalcohol, , methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, shellac, liquid glucose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester and the like.
Suitable plasticizers, if used, may include, but are not limited to polyethylene glycol, diethyl phthalate and glycerol, acetyl tributyl citrate. Preference is given to polyethylene glycol and the like.
Metoprolol compositions
The metoprolol or pharmaceutically acceptable salt thereof compositions of the present specification are preferably in solid oral dosage forms, and having extended release profile. Examples of said solid oral dosage form includes, are but not limited to tablets, mini-tablets, pellets or other multi-particulates compositions. The multi-particulates compositions are being preferred. The extended release metoprolol formulation further comprise one or more rate controlling polymers and one or more pharmaceutically acceptable excipients. The use of rate controlling polymer aids to achieve extended release profile. The extended metoprolol compositions can be prepared by one or more of various methods, but not limited direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like. Such processes are well known in the art.
Nicorandil compositions
The nicorandil or pharmaceutically acceptable salt thereof compositions of the present specification are preferably in solid oral dosage forms, and having dual release profile. Examples of such dosage form includes, are but not limited to tablets, mini-tablets, pellets or other multi-particulates compositions. The multi-particulates compositions are being preferred.
The dual release nicorandil compositions comprises two different portions, namely immediate release formulations/portions and extended or delayed release formulations/portions. Typically the amount of nicorandil present in the immediate release formulations is less than the amount of nicorandil present in the extended release formulations. It is specifically designed in such a way that upon administration the required amount of nicorandil to be released from immediate release formulation for quick onset of action (potassium channel opening) and followed by maintenance amount of nicorandil to be released from extended release formulation. The extended release nicorandil formulation typically maintains 6-12 hr. release profile.
The immediate release nicorandil formulations/portions are prepared by using one or more pharmaceutically acceptable excipients. The extended release nicorandil formulations/portion comprise one or more rate controlling polymers and one or more pharmaceutically acceptable excipients. The use of rate controlling polymer aids to achieve extended release profile. The hydrophobic rate controlling polymers are being preferred. The rate controlling polymer is present in the extended release nicorandil formulations in an amount of about 10% (w/w) to about 40 % (w/w). The extended release nicorandil formulation contains drug loading more than 20% (w/w), preferably more than 30% (w/w). The drug loading refers to amount of nicorandil present in the formulation based on the total weight of the formulation. The immediate and extended nicorandil formulations/portions can be prepared by one or more of various methods, but not limited direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like. Such processes are well known in the art.
The dual release nicorandil formulation of the present specifications when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 50 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of nicorandil or pharmaceutically acceptable salts thereof in the manner of:
i) releases no more than 55% in 0.5 hour,
ii) releases at least about 35% and no more than 85% in 2 hours, and
iii) releases at least about 75% in 6-12 hours.

Pharmaceutical unit composition
The pharmaceutical unit composition comprising combination of metoprolol and nicorandil can be prepared by making the individual compositions or components of nicorandil or metoprolol, which can then be formulated in to a suitable dosage forms like tablets, capsules, sachets and the like. For example, the individual components can be filled in a capsule or a sachet. The size/dimensions of the individual compositions can be modified in such a way that it can be filled in the capsule of a suitable size. Alternatively, the individual components can be further processed to form a bilayer tablet or inlay tablet. The individual components can be prepared by the one or more of various methods, but not limited direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like.
The pharmaceutical unit composition of the present specification comprising nicorandil and metoprolol may have different release profile. For example, immediate release, sustained release or delayed release or extended release, dual release. Typically, nicorandil formulations are prepared in dual release profile and metoprolol formulations are prepared in extended release profile. The release profile are selected based on the need, and therapeutic effective dose of the nicorandil and metoprolol, so that the unit composition can be administered once daily. In order to achieve such release profile, the said compositions can be further coated with suitable film-forming agents and/or coating materials to form a subcoating or enteric coating. Such coating methods are well known in the art.
The pharmaceutical unit compositions of the present specification may be suitably packed in to any conventional pack like stick pack, blister pack, HDPE bottle or any other packaging well known in the art.
The pharmaceutical unit composition comprising nicorandil and metoprolol of the present specification can be used for the treatment and/or management of major adverse cardiovascular events such as congestive heart failure, arrhythmia, myocardial infraction (STEMI, NSTEMI), atherosclerosis, chronic stable angina (angina pectoris), STEMI unstable angina, NSTEMI angina, coronary revascularization, including percutaneous coronary intervention, stroke or other cardiovascular disorders.
The pharmaceutical unit composition comprising nicorandil and metoprolol of the present specification can be used for the reduction in infarct size, and major adverse cardiovascular events in patients with STEMI (ST segment elevation myocardial infarction) who had undergone PCI (percutaneous coronary intervention).
The pharmaceutical unit compositions of the present specification is expected to be stable throughout the shelf life which can be established by subjecting the compositions to accelerated and long term stability studies.
The following examples will further describe certain specific aspects and embodiments of the invention in greater details and are not intended to limit the scope of invention.

EXAMPLES
Example 1: Multi-particulate immediate release (IR) formulations of nicorandil.
Nicorandil IR formulations
Ingredients Example 1a
(% w/w) Example 1b
(% w/w) Example 1c
(% w/w) Example 1d
(% w/w)
Nicorandil 15 11 9 15
Corn Starch 1 1 1 1
Mannitol 51 75 77 -
Lactose 20 - - 75
Croscarmallose Sodium 5 5 - -
Crospovidone - - 5 3
Stearic acid 8 8 8 6

Process:
1. Nicorandil along with other excipients- corn starch, mannitol, lactose, croscarmallose sodium, crospovidone were sifted through mesh and collected.
2. Sifted materials obtained in step 1were then blended in to a blender.
3. The blended materials obtained in step 2 were lubricated with stearic acid and compressed in to mini-tablets of suitable size.
4. The mini tablets were filled in capsule as per required therapeutic dose.

Example 2: Multi-particulate extended release (ER) formulations of nicorandil.
Nicorandil ER formulations
Ingredients Example 2a
(% w/w) Example 2b
(% w/w) Example 2c
(% w/w) Example 2d
(% w/w)
Nicorandil 26.6 30.9 26.6 33.0
Glyceryl behenate 31.9 31.9 - 21.9
Glyceryl mono stearate - - - 10
Ethyl cellulose - - 35.8 -
Mannitol 34.0 29.8 - 27.7
Lactose - - 30.0 -
Stearic acid 5.3 5.3 4.5 5.3
Colloidal silica 2.2 2.1 3.1 2.1

Process:
1. Nicorandil along with other excipients- glyceryl behenate, glyceryl mono stearate, ethyl cellulose, mannitol, lactose, colloidal silica were sifted through mesh and collected.
2. Sifted materials obtained in step 1, were then blended in to a blender.
3. The blended materials obtained in step 2 were lubricated with stearic acid and compressed in to mini-tablets of suitable size.
4. The mini tablets were filled in capsule as per required therapeutic dose.

Example 3: Nicorandil Pellets
Seal coating mg/unit
1 Microcrystalline Cellulose (Celphere CP-305) 25.5
2 Ethyl cellulose 2.318
3 Tiethyl citrate 0.232
4 Isopropyl alcohol QS
5 Water QS
Subtotal 28.05
Drug loading-1
6 Nicorandil 25
7 Hydroxypropyl cellulose 1.25
8 Methanol QS
Subtotal 54.3
ER coat-1
9 Ethyl cellulose 7.60
10 Hydroxy Propyl cellulose, 3.26
11 Isopropyl alcohol QS
12 Methanol QS
Subtotal 65.16
Drug loading-2
13 Nicorandil 15
14 Hydroxypropyl cellulose 0.90
15 Methanol QS
Subtotal 81.06
Over coating
16 Hydroxypropyl cellulose 10.447
17 Talc 5.223
18 Isopropyl alcohol (IPA) QS
19 water QS

Process:
1. Dispensing: All the materials were dispensed as per batch formula.
2. Seal coating: Seal coating was performed by the ethyl cellulose and tiethyl citrate in solution mixture of IPA and water.
3. Drug loading on seal coated pellets: Seal coated pellets of step 2 were coated with drug polymer solution to achieve the desired drug loading.
4. Extended release coating drug loaded pellets: Drug coated pellets of step 3 were coated with extended release polymer solution to achieve the desired polymer coating.
5. Drug loading on ER coated pellets: ER coated pellets were coated with drug polymer solution to achieve the desired drug loading.
6. Over coating: Drug loaded pellets of step5 were coated with over coated polymer solution to achieve the desired polymer coating.

Example 4: Multi-particulate extended release (ER) compositions of metoprolol
Metoprolol ER pellets compositions
S. No. Ingredients Example (mg/unit)
1 Metoprolol Succinate* 95
2 Microcrystalline cellulose Spheres 25.5
3 Ethyl Cellulose 10 cps 37.32
4 Hydroxypropyl methyl cellulose 5.52
5 Hydroxypropyl cellulose 42.97
6 Acetyl Tributyl citrate 0.765
7 PEG 6000 10.93
* EQ 100MG TARTRATE
Process:
1. Dispensing: All the materials were dispensed as per batch formula.
2. Seal coating: Seal coating of the MCC spheres was performed by the ethyl cellulose and acetyl tributyl citrate in solution mixture of methylene chloride and isopropyl alcohol.
3. Drug loading on seal coated pellets: Seal coated pellets of step 2 were loaded into the FBP bowl and coated with drug polymer solution (Metoprolol succinate and Hydroxypropyl methyl cellulose in water) to achieve the desired drug loading.
4. ER coating drug loaded pellets: Drug coated pellets of step 3 were coated with extended release polymer solution (hydroxypropyl cellulose and ethyl cellulose in isopropyl alcohol and methylene chloride solution) to achieve the desired polymer coating.
5. Drug loading on ER coated pellets: ER coated pellets of step 4 were further coated with drug polymer solution to achieve the desired drug loading.
6. Over coating: Finally, drug loaded pellets were loaded coated with polymer solution (hydroxypropyl cellulose and PEG6000 in isopropyl alcohol, methylene chloride and water solution) to achieve the desired polymer coating, and thereafter pellets were dried. The dried over coated pellets were sifted through mesh to collect required fraction.

Example 5: Some pharmaceutical unit composition comprising multi-particulate nicorandil and metoprolol formulations as per the present specification are described below:
Examples API* Dosage form Dose/Amount
Example 4a Nicorandil Immediate Release multi-particulate 9 mg
Extended release multi-particulate 31 mg
Metoprolol# Extended release multi-particulate 100 mg

Example 4b Nicorandil Immediate Release mini-tablet 11 mg
Extended release mini-tablet 29 mg
Metoprolol Extended release pellets 100 mg

Example 4c Nicorandil Immediate Release pellets 15 mg
Extended release pellets 25 mg
Metoprolol Extended release pellets 100 mg

Example 4d Nicorandil Immediate Release mini-tablet 17 mg
Delayed release mini-tablet 23 mg
Metoprolol Extended release pellets 200 mg
*API or pharmaceutically acceptable salt thereof
# Metoprolol referred herein as metoprolol tartrate

Process:
1. Multi-particulate immediate release nicorandil formulations were prepared according to example 1.
2. Delayed/extended release nicorandil formulations were prepared according to example 2.
3. Alternatively, immediate and extended release pellets formulations of nicorandil were prepared according to example 3.
4. Multi-particulate extended release pharmaceutical compositions of metoprolol were prepared according to example 4.
5. The compositions prepared in step (1 & 2)/step 3 & step 4 were filled in a capsule of suitable size.

Stability Study:
The stability of the pharmaceutical unit composition comprising nicorandil and metoprolol formulations as per the present specification were evaluated through stability studies. The composition was prepared according to the formula and process of example 4b, and the composition was subjected to stability study at 25 °C/60% RH for six months. The compositions were found to be stable at storage conditions. Table 1 represents the study result data.
Table 1: Stability study of unit composition comprising nicorandil and metoprolol.
Example- 4b
Characteristic Limit Initial 1 Month 3 Months 6 Months
Assay (%)
Nicorandil 90 - 110 101.7 100.9 98.9 97.8
Metoprolol 90 - 110 101.3 101.7 100.2 102.1
Water by KF NMT 8.0% 0.67 0.70 0.96 1.34
Related Substances
a) Nicorandil
Unknown impurities NMT 0.5% 0.05 0.23 0.23 0.27
Total impurities NMT 6.0% 0.14 0.60 1.19 1.16
b) Metoprolol
Unknown impurities NMT 0.5% ND ND ND ND
Total impurities NMT 2.0% ND ND ND ND
ND: Not detected, NMT: Not more than, NLT: Not less than,
Metoprolol referred herein as metoprolol succinate (or EQ. tartrate)

In-vitro dissolution study:

The release profile of the pharmaceutical unit composition comprising nicorandil and metoprolol formulations as per the present specification was evaluated through in-vitro dissolution studies. The unit composition was prepared according to the formula and process of example 4b, and was subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 50 rpm and 37°C using USP type II apparatus (paddle). Table 2 represents the dissolution results data of nicorandil and metoprolol or pharmaceutically acceptable salts. The dissolution profile of the composition was also assessed after storage in stability condition (25 °C/60% RH) for 6 months. Figure 1 & 2 represent the dissolution profile of nicorandil and metoprolol at initial stage and after 6 month storage in stability condition (25 °C/60% RH) respectively.

Table 2: Dissolution study of unit composition comprising nicorandil and metoprolol.

Nicorandil release profile Metoprolol release profile
Time point Time (hour) Initial
Sample
(% of release) 6M
Stability Sample
(% of release) Time (hour) Initial
Sample
(% of release) 6M
Stability Sample
(% of release)
Dissolution study 0.5 hr. 38 36 0.5 hr. 14 14
1 hr. 45 43 1 hr. 15 16
2 hr. 55 54 2 hr. 17 17
4 hr. 71 79 4 hr. 24 24
6 hr. 81 90 6 hr. 34 34
8 hr. 87 92 8 hr. 46 45
10 hr. 58 56
12 hr. 69 66
16 hr. 83 82
20 hr. 90 89
24 hr. 93 92
Metoprolol referred herein as metoprolol succinate (or EQ. tartrate)

Pharmacokinetic study:

The pharmacokinetic parameters of the pharmaceutical unit composition comprising nicorandil and metoprolol formulation as per the present specification was evaluated in-vivo through comparative bioavailability studies. The safety and tolerability of the formulations were also assessed.

The pharmaceutical unit composition comprising 40 mg nicorandil and 100 mg metoprolol was prepared according to the formula and process of example 4b and referred herein as test product (T1). The reference product (R1) for nicorandil used herein was IKOREL® 20 mg Tablets and the reference product (R2) for metoprolol used herein was TOPROL-XL® 100 mg tablets (metoprolol succinate, EQ 100 mg tartrate). The pharmacokinetic parameters of the test and the reference product were assessed in an open label, randomized, three-way, crossover comparative bioavailability study in healthy, adult, and male subjects under fasting conditions. The test product (T1) was administered as single oral dose and the corresponding reference products were administered as two oral doses of 20 mg nicorandil (R1) and single oral dose 100 mg of metoprolol (R2). The measured pharmacokinetic parameters of nicorandil and metoprolol are summarized in table 3. The statistical bioequivalence comparison of the log-transformed Test Reference product are shown in table 4. The %T/R ratios of nicorandil and metoprolol for Cmax, AUC0-t and AUC0-8 was comparable to the corresponding reference products. The test and reference products were well tolerated by the subjects. No adverse event were reported after administration of test products.

Table 3: The mean pharmacokinetic parameters of pharmaceutical unit composition comprising 40 mg nicorandil and 100 mg metoprolol.
Parameters
(Units) Arithmetic Mean ± SD
Nicorandil Metoprolol

Reference Product (R1)
(N = 17) Test Product (T1)
(N = 18)
Reference Product (R1)
(N = 17) Test Product (T1)
(N = 18)
Cmax (ng/mL) 256.163±94.98 229.198±85.69 22.252± 16.36 23.564±16.79
Tmax (hr) 0.25 1.00 10.00 12.63
AUC0-t (hr*ng/mL) 587.45±316.17 500.99± 170.10 372.65±297.29 367.95±265.44
AUC0-inf (hr*ng/mL) 666.49±208.46 518.90±185.77 525. 16±499.96 514.04±432.17
t½ el (hr) 4.65±4.86 1.44±0.57 8.68±3.60 8.42±4.78

Table 4: The Statistical Bioequivalence comparison of the log-transformed Test Reference product.
Parameters
(Units) Arithmetic Mean ± SD
Nicorandil Metoprolol

R1 Geo LSM Test Geo LSM %T/R1 R2 Geo LSM Test Geo LSM
%T/R2
Cmax (ng/mL) 234.020
218.568 93.40 19.130 21.061 110.09
AUC0-t (hr*ng/mL) 529.19 489.06 92.42 311.88 323.55 103.74
AUC0-inf (hr*ng/mL) 566.12 511.35 90.33 414.60 417.18 100.62

This study demonstrates that the pharmaceutical unit composition comprising nicorandil and metoprolol formulation according to the present specification could be administered once daily and is expected to reduce the side effects associated with nicorandil immediate release product which was due to in high fluctuation in plasma concentration.
,CLAIMS:We Claim:
1. A pharmaceutical unit composition comprising:
i) metoprolol or pharmaceutically acceptable salts thereof, and
ii) nicorandil or pharmaceutically acceptable salts thereof,
wherein the said composition is administered once daily.
2. The composition of claim 1, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in an amount of 25-200 mg and 20-80 mg respectively.
3. The composition of claim 1, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in an amount of 100 mg and 40 mg respectively.
4. The composition of claim 1, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in the form of:
i) extended release compositions of metoprolol, and
ii) dual release compositions of nicorandil.

5. The composition of claim 4, wherein the dual release compositions comprising:
a) immediate release formulations of nicorandil, and
b) extended or delayed release formulations of nicorandil and one or more rate controlling polymer.

6. The composition of claim 5, wherein the amount of nicorandil present in the immediate release formulations is less than the amount of nicorandil present in the extended or delayed release formulations.
7. The composition of claim 6, wherein total amount of nicorandil present in the immediate release formulations and extended or delayed release formulations is 40 mg.
8. The composition of claim 5, wherein the rate controlling polymer is present in the extended release nicorandil formulations in an amount of about 10% (w/w) to about 40 % (w/w).
9. The composition of claim 5, wherein the rate controlling polymer is selected from one or more of hydrophilic polymers, hydrophobic polymers, natural polymers, bioadhesive polymer pH-dependent or pH-independent, enteric, degradable, non-degradable, enteric polymers and melt extrusion polymers.
10. The composition of claim 5, wherein the nicorandil present in the extended release formulation in an amount more than 20% (w/w) based on the total weight of said nicorandil formulation.
11. The composition of claim 1, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 50 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of nicorandil or pharmaceutically acceptable salts thereof in the manner of:
i) releases no more than 55% in 0.5 hour,
ii) releases at least about 35% and no more than 85% in 2 hours, and
iii) releases at least about 75% in 6-12 hours.

12. The composition of claim 1, wherein the metoprolol and/or nicorandil compositions are present in multi-particulate form.
13. The Composition of claim 1, wherein the unit composition is selected from tablets, capsules and sachet.
14. A capsule composition for once daily administration comprising:
i) extended release pellets compositions of metoprolol, and
ii) dual release compositions of nicorandil, wherein said dual release compositions comprising:
a) one or more immediate release mini-tablets of nicorandil, and
b) one or more extended release mini-tablets of nicorandil and one or more rate controlling polymer, wherein the total amount of nicorandil present in the said combined mini-tablets is 40 mg.

15. The use of pharmaceutical unit composition comprising metoprolol and nicorandil for the treatment and/or management of major adverse cardiovascular events, for the reduction in infarct size, and major adverse cardiovascular events in patients with STEMI who had undergone percutaneous coronary intervention, wherein the said unit composition comprising:
i) extended release compositions of metoprolol or pharmaceutically acceptable salts thereof, and
ii) dual release compositions of nicorandil or pharmaceutically acceptable salts thereof, wherein metoprolol and nicorandil or pharmaceutically acceptable salts thereof are present in the pharmaceutical unit composition in an amount of 25-200 mg and 20-80 mg respectively.

16. The use of claim 15, wherein the said unit composition is administered once daily.
17. The use of claim 15, wherein the major adverse cardiovascular events are selected from one or more of congestive heart failure, arrhythmia, myocardial infraction (STEMI, NSTEMI), atherosclerosis, chronic stable angina (angina pectoris), STEMI unstable angina, NSTEMI angina, coronary revascularization, including percutaneous coronary intervention, stroke or other cardiovascular disorders.

18. The unit composition of claim 1 or capsule composition of claim 14, wherein said composition is used for the reduction in infarct size, and major adverse cardiovascular events in patients with STEMI who had undergone percutaneous coronary intervention.