WO2018211479A1

WO2018211479A1 - Stabilized compositions of angiotensin ii inhibitors and neutral endopeptidase inhibitors and process for preparation thereof

Info

Publication number: WO2018211479A1
Application number: PCT/IB2018/053539
Authority: WO
Inventors: Makarand Krishna Kumar AVACHAT; Nikhil Prabhakar Malewar; Arvind Mohan UPADHYAY; Brijesh PUROHIT; Sachin Kalyan PATHAK
Original assignee: Lupin Limited
Priority date: 2017-05-19
Filing date: 2018-05-19
Publication date: 2018-11-22

Abstract

The invention relates to pharmaceutical composition(s) comprising a combination of angiotensin II receptor inhibitors and neutral endopeptidase inhibitors and/or complex thereof and pharmaceutically acceptable carrier, and processes for preparation thereof. The invention further relates to method of treatment or prevention of cardiovascular disease.

Description

STABILIZED COMPOSITIONS OF ANGIOTENSIN II INHIBITORS AND

NEUTRAL ENDOPEPTIDASE INHIBITORS AND PROCESS FOR PREPARATION THEREOF

Field of the Invention Present invention relate to pharmaceutical composition(s) comprising therapeutic agents and process for its preparation. More specifically, present invention relates to stable and efficacious pharmaceutical compositions comprising combination of angiotensin II receptor inhibitors and neutral endopeptidase inhibitors for the treatment of cardiovascular diseases. Background of the Invention

Hypertension is the most prevalent risk factor for cardiovascular diseases that can lead to death worldwide. A modern life style characterized by less exercise, smoking, drinking and poor diet has increased the risk of developing hypertension, the so-called silent killer, in civilized communities and thus a better defense is needed against hypertension. Multiple classes of drugs have been developed to treat hypertension till date. These include drugs acting on renin angiotensin system as inhibitors, angiotensin II receptor inhibitors, neutral endopeptidase inhibitors, calcium channel blockers, diuretics, aldosterone antagonists, and beta-adrenergic blockers.

Combination of neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable derivatives thereof such as Sacubitril and angiotensin II receptor inhibitor or a pharmaceutically acceptable derivatives thereof such as Valsartan is the combination of drug resulted in a more effective antihypertensive therapy (whether for malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type of hypertension) through improved efficacy as well as a greater responder rate as disclosed in the patent application WO03059345 Al .

However, efficacy of combination of drugs having more effective therapeutic response can be utilized only if the combination is properly formulated into pharmaceutical composition to be administered to patient. There are various factors which may affect the efficacy, such as pharmacokinetic interactions, tolerability, physicochemical characteristics, and stability of formulation over the period of time.

US 20100267786 Al describes solid oral dosage forms of combination of pharmaceutical compounds, namely angiotensin receptor antagonist and neutral endopeptidase inhibitor in supramolecular complex form. The compositions are said to be formulated in such way that therapeutic benefits of the compounds may be delivered to patient in need thereof. The compositions disclosed in US 20100267786 Al may encounter problems of inadequate stability, increased amorphism and dissociation of the components of combination. The inventors of the US 20100267786 Al describes certain lacunas like susceptibility to moisture, excessive heat and/or high shear forces observed in the compositions. Such flaws make them less appropriate for use in dosage forms to achieve desired bioavailability and therapeutic effects.

This could be either result of drug properties or formulation variables. Hence, the person skilled in the art needs to be very vigilant while choosing the optimal values of formulation parameters and process for preparation in order to achieve the virtuous formulation.

The inventors of present application surprisingly found that, by critically controlling formulation variables and optimizing amount of excipients in the invented novel process of formulation, they can successfully develop the formulation with optimized solubility, bioavailability and stability.

Objectives of the Invention

The principal objective of the invention is to formulate stable pharmaceutical composition(s) comprising combination of angiotensin II receptor inhibitor or its pharmaceutically acceptable derivatives and neutral endopeptidase inhibitor or its pharmaceutically acceptable derivatives.

Another objective of the invention is to formulate stable pharmaceutical composition(s) comprising Sacubitril, Valsartan and/or Sacubitril-Valsartan complex or pharmaceutically acceptable derivatives thereof. Yet another objective of the invention is to develop a process for preparation of stable pharmaceutical compositions comprising combination of angiotensin II receptor inhibitor or its pharmaceutically acceptable derivatives and neutral endopeptidase inhibitor or its pharmaceutically acceptable derivatives. Another objective of the invention is to develop a process for preparation of stable solid oral compositions comprising Sacubitril, Valsartan and/or Sacubitril-Valsartan complex, wherein Sacubitril, Valsartan and/or Sacubitril-Valsartan complex may be present as crystalline, partially crystalline, amorphous, partially amorphous or polymorphous form or mixtures thereof. Yet another objective of the invention is to develop a process for preparation of stable pharmaceutical compositions, wherein process comprises in situ conversion of crystalline form of angiotensin II receptor inhibitor or neutral endopeptidase inhibitor and/or complex thereof to amorphous or partially amorphous or polymorphous form or mixtures thereof or vice-versa. A further objective of the invention is to prepare robust, efficacious and stable pharmaceutical composition(s) comprising Sacubitril, Valsartan and/or Sacubitril- Valsartan complex or its pharmaceutically acceptable derivatives, including but not limited to addition salts, hydrates, solvates, ethers, esters and mixtures thereof.

Summary of the Invention The present invention feature a stable pharmaceutical composition(s) comprising angiotensin II receptor inhibitor or its pharmaceutically acceptable derivatives and neutral endopeptidase inhibitor or its pharmaceutically acceptable derivatives.

The invention provide a pharmaceutical composition(s) comprising Sacubitril, Valsartan and/or Sacubitril-Valsartan complex or its pharmaceutically acceptable derivatives, including but not limited to addition salts, hydrates, solvates, ethers, esters and mixtures thereof, and at least one pharmaceutically acceptable excipient.

In another aspect, present invention feature stable pharmaceutical composition(s) comprising Sacubitril, Valsartan and/or Sacubitril-Valsartan complex or its pharmaceutically acceptable derivatives, which may be present as crystalline, partially crystalline, amorphous, partially amorphous or polymorphous form or mixtures thereof in solid oral dosage form.

The stable pharmaceutical composition(s) of the present invention may be prepared by using various known granulation processes such as wet granulation, dry granulation, fluid granulation, fluidized bed granulation as well as by direct compression, fluid drying, compaction, and briquetting.

The inventors of the present application successfully controlled formulation variables and optimized the amount of excipients in the invented novel process to develop the formulation with optimized solubility, bioavailability and stability,

Detailed Description of the Invention

The present invention relates to pharmaceutical composition(s) comprising combination of angiotensin II receptor inhibitor or its pharmaceutically acceptable derivatives and neutral endopeptidase inhibitor or its pharmaceutically acceptable derivatives, specifically useful in the treatment of cardiovascular into the patients in need thereof.

As used herein, the term, "cardiovascular diseases" refers to a disease or condition, such as hypertension, heart failure (acute and chronic), congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction and stroke. As used herein, the term "therapeutic agent" refers to Sacubitril, Valsartan and/or Sacubitril-Valsartan complex or its pharmaceutically acceptable derivative, including but not limited to addition salts, hydrates, solvates, ethers, esters and mixtures thereof.

As used herein, the term, "cardiovascular agent" refers to a therapeutic compound useful for treating or preventing cardiovascular diseases. Examples of suitable cardiovascular agents include but are not limited to angiotensin II converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers (ARB), adrenergic blockers, neutral endopeptidase inhibitors (NEPi), adrenergic agonists, agents for pheochromocytoma, antianginal agents, antiarrhythmic agents, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, anti-inflammatory agents, calcium channel blockers, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodilators, vasopressors, advanced glycosylation end-product crosslink breakers (AGE crosslink breakers), advanced glycosylation end-product formation inhibitors (AGE formation inhibitors) and combinations thereof.

The neutral endopeptidase inhibitor (NEP) in the composition of present invention is selected from the group comprising of Omapatrilat, Sampatrilat, Gemopatrilat, Sacubitril, Ecadotril, Candoxatril, SQ 28,603, N-[N-[1 (S)-carboxyl-3-phenylpropIyl]-(S)- phenylalanyl]- (S)-isoserine, N-[N-[((1 S)-carboxy-2-phenyl)ethyl]-(S)-phenylalanyl]- - alanine, N-[2(S)- mercaptomethyl- 3 -(2-methyIphenyl)-propionyl] methionine, (cis-4-[[[l- [2-carboxy-3-(2- methoxyethoxy)propyl]-cyclopentyl]carbonyl]amino]- cyclohexanecarboxylic acid), thiorphan, retro-thiorphan, phosphoramidon, SQ 29072, N- (3-carboxy- l-oxopropyl)-(4S)-p- phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester, (S)-cis-4-[l-[2-(5- indanyloxycarbonyl)-3-(2-methoxyethoxy)propyl]- l- cyclopentanecarboxamido]-l- cyclohexane carboxylic acid, 3-(l-[6-endo- hydroxymethylbicyclo[2,2, l]heptane-2-exo- carbamoyl]cyclopentyl)-2-(2- methoxyethyl)propanoic acid, N-(l-(3-(N-t-butoxycarbonyl-(S)- prolylamino)-2(S)-t- butoxy-carbonylpropyl)cyclopentanecarbonyl)-0-benzyl-(S)-serine methyl ester, 4-[[2- (Mercaptomethyl)- 1 -oxo-3 -phenylpropyl] amino]benzoic acid, 3 - [ 1 -(Cis-4- carboxycarbonyl-cis-3-butylcyclohexyl-r-l-carboamoyl)cyclopentyl]-2S-(2- methoxyethoxymethyl)propanoic acid, N-((2S)-2-(4-biphenylmethyl)-4-carboxy-5- phenoxyvaleryl) glycine, N-( 1 -(N-hydroxycarbamoylmethyl)- 1 -cyclopentanecarbonyl)-L- phenylalanine, (S)-(2-biphenyl-4-yl)-l-(lH-terrazol-5-yl)ethylamino) methylphosphonic acid, (S)-5-(N-(2-(phosphonomethylamino)-3-(4-biphenyl)propionyl)-2- aminoethyl)tetrazole, β- Alanine, 3-[l , l'-biphenyl]-4-yl-N-

[diphenoxyphosphinyl)methyl] -L-alanyl, N-(2-carboxy-4- thienyl)-3 -mercapto-2- benzylpropanamide, 2-(2-mercaptomethyl-3 - phenylpropionamido)thiazol-4-ylcarboxylic acid, (L)-(l -((2,2-dimethyl-l ,3-dioxolan-4-yl)- methoxy)carbonyl)-2-phenylethyl)-L- phenylalanyl)- -alanine, N-[N-[(L)-[ 1 -[(2,2-dimethyl- 1 ,3-dioxolan-4-yl)- methoxy] carbonyl] -2-phenyl ethyl] -L- phenylalanyl] -(R)-alanine, N- [N- [(L)- 1 -carboxy-2- phenyl ethyl] -L-phenylalanyl] -(R)- alanine, N- [2-acetylthiomethyl-3 -(2-methyl- phenyl)propionyl] -methionine ethyl ester, N-[2- mercaptomethyl-3-(2- methylphenyl)propioyl]-methionine, N-[2(S)-mercaptomethyI-3-(2- methylphenyl)propanoyl]-(S)-isoserine, N-(S)-[3-mercapto-2-(2- methylphenyl)propionyl]-(S)- 2-methoxy-(R)-alanine, N-[l -[[l (S)-benzyloxycarbonyl-3- phenylpropyl]amino]cyclopentyIcarbonyl]-(S)-isoserine, N-[l -[[1 (S)-carbonyl-3- phenylpropy] amino] -cyclopentylcarbonyl]-(S)-isoserine, l, l'-[dithiobis-[2(S)-(2- methylbenzyl)- 1 -oxo-3, 1 -propanediyl]]-bis-(S)-isoserine, 1 , 1 '-[dithiobis-[2(S)-(2- methylbenzyl)- 1 -oxo-3, 1 - propanediyl]]-bis-(S)-methionine, N-(3-phenyl-2- (mercaptomethyl)-propionyl)-(S)-4- (methylmercapto)methionine, N-[2- acetylthiomethyl-3 -phenyl -propionyl] -3 -aminobenzoic acid, N-[2-mercaptomethyl-3- phenyl-propionyl]-3-aminobenzoic acid, N-[l-(2-carboxy-4- phenylbutyl)- cyclopentanecarbonyl] -(S)-isoserine, N- [ 1 -(acetylthiomethyl)cyclopentane- carbonyl] - (S)-methionine ethyl ester, 3(S)-[2-(acetylthiomethyl)-3-phenyI-propionyl]amimo-e- caprolactam and N-(2-acetylthiomethyI-3-(2-methylphenyl)propionyl)-methionine ethyl ester, or in each case, a pharmaceutically acceptable derivative thereof and combinations thereof.

The angiotensin receptor antagonist (ARB) in the composition of present invention is selected from group comprising of Valsartan, Losartan, Irbesartan, Telmisartan, Eprosartan, Candesartan, Olmesartan, Saprisartan, Tasosartan, Elisartan, Fimasartan, Azilsartan, or in each case, a pharmaceutically acceptable derivative thereof and/or combinations thereof. As used herein the term, "complex" refers to an interaction between two or more pharmaceutically active agents with or without complexing agent by means of non- covalent or covalent intermolecular bonding between them. The complex as used herein, includes but is not limited to cyclodextrin complex, co-crystal complex, supramolecular complex and the like.

As used herein the term, "complexing agent" refers to one or more complexing agent(s) and mixtures thereof. The complexing agents includes but are not limited to naturally occurring cyclodextrin or a chemically modified cyclodextrin such as a- cyclodextrin, β- cyclodextrin, 2-hydroxypropyl-cyclodextrin, randomly methylated β-cyclodextrin, sulfobutylether- cylodextrin, γ-cyclodextrin and 2-hydroxypropyl- γ-cyclodextrin, ethylenediaminetetraacetic acid, diethyl enetriaminepentaacetic acid, trans- 1,2- cyclohexanediaminotetraacetic acid, 1,4,7, 10-tetraazacyclododecanetetraacetic acid, 1,4,7-triazacyclononanetriacetic acid, 1,4,8, 1 1-tetraazatetradecanetetraacetic acid or 1 ,5,9-triazacyclododecanetriacetic acid. As used herein the term, "supramolecular complex" refers to large molecules formed by grouping or bonding smaller molecules together, specifically by an interaction between two or more pharmaceutically active agents, cations and solvent, by means of noncovalent, intermolecular bonding between them. This interaction leads to an association of the species present in the supramolecular complex distinguishing this complex over a physical mixture of species.

As used herein the term, "In situ" refers to chemical, physical, biological, thermal or electrical conversion processes that modify, remove, generate, degrade, stabilize and/or encapsulate the components in physical and/or chemical terms (for e.g. sol-gel conversions, sol-gel-sol conversions, polymorph/form conversions) within the system (for e.g. during manufacturing process).

As used herein the term "pharmaceutical composition(s)" refers to solid dosage forms, but are not limited to tablets (single layer, bilayer, multilayer, tablet in tablet and the like) which may be uncoated, film coated, sugar coated, powder coated, enteric coated, seal coated, capsules (filled with powders, powders for reconstitution, pellets, beads, mini- tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres, nanoparticles, and the like or combinations thereof), soft gelatin capsules, sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres, nanoparticles, and the like or combinations thereof) and sprinkles. The other dosage forms such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, micro emulsions, sprays, spot-on and the like), solid dispersion, injection preparations, gels, aerosols, ointments, creams, controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like may also be envisaged under the ambit of the invention

Preferably, pharmaceutical composition(s) according to the present invention are in the form of a solid oral dosage form. More preferably, pharmaceutical composition(s) according to the present invention are in the form of a tablet(s).

The pharmaceutical composition(s) according to the present invention may comprise carriers/excipients suitable for formulating the same.

Accordingly, pharmaceutical composition(s) according to the present invention may comprise one or more excipients such as, diluent, filler, glidant, anti-adherent, binder, disintegrant, lubricant, surfactant, solubilizer, anticaking agent, buffer, polymer, sweetener, solvents, co-solvents, vehicle, viscosity enhancing agent, carrier, adsorbent, channeling agent and opacifier.

Suitable polymers or polymers blends, according to the present invention, may include but are not limited to one or more water soluble, water insoluble or water swellable polymers, homopolymers or co-polymers of N-vinyl lactams, N-vinyl pyrrolidone e.g. polyvinylpyrrolidone (PVP), co-polymers of PVP and vinyl acetate, co-polymers of N- vinyl pyrrolidone and vinyl acetate (Copovidone) or vinyl propionate, dextrins such as grades of maltodextrin, cellulose esters and cellulose ethers, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide, propylene oxide, acrylic copolymers e.g. Eudragit El 00 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl- Eze, polyvinyl acetate, for example, Kollicoat SR 30D, cellulose derivatives such as ethyl cellulose, cellulose acetate e.g. Surelease, Aquacoat ECD and Aquacoat CPD, polyethylene oxide; poly (hydroxy alkyl methacrylate); poly (vinyl) alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; Carbopol^®, carbomer which is an acidic carboxy polymer; Cyanamer^® polyacrylamides; cross-linked water swellable indene- maleic anhydride polymers; Goodrich^® polyacrylic acid; starch graft copolymers; AquaKeeps^® acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan, and the like; Amberlite^® ion exchange resins; Explotab^® sodium starch glycolate; Ac-Di-Sol^® croscarmellose sodium and the like or combinations thereof.

The amount of polymer that may be present in the pharmaceutical composition can range from about 0.5% to about 60%.

Suitable solvents/co-solvents/vehicle that may be used in the pharmaceutical composition of present invention, include but are not limited to polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 65, polysorbate 85, Polyoxyl 35 castor oil, Phosal^® 50 PG (Phosphatidylcholine concentrate with propylene glycol), hydro genated castor oil, medium and/or long chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soyabean oil, peanut oil, corn oil, corn oil mono glycerides, corn oil di glycerides, corn oil triglycerides, polyethylene glycol, sorbitol, caprylocaproyl macroglycerides, caproyl 90, propylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, hydrogenated castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, water, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methylisobutyl ketone, methylethyl ketone, glycerol, sorbitol, glycerol monolinoleate, water and the like and combinations thereof.

The amount of solvents/co-solvents/vehicle that may be present in the pharmaceutical composition of present invention can range from about 1% to about 30%. According to the present invention, pharmaceutically acceptable diluents or fillers for use in pharmaceutical composition(s) of the present invention may include but are not limited to lactose anhydrous, lactose monohydrate, spray-dried lactose, lactose available under the trade mark Tablettose^®, various grades of lactose available under the trade mark Pharmatose^® or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, silicified microcrystalline cellulose, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), (HPMC, methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) and the like and mixtures thereof. The amount of diluents or fillers that may be present in pharmaceutical composition(s) of the present invention can range from about 5% to about 90%.

According to the present invention, glidants, anti-adherents and lubricants may also be incorporated in pharmaceutical composition(s) of present invention, which may include, but are not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium stearate, magnesium aluminosilicate and/or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil), or mixtures thereof.

The amount of glidants, anti-adherents and lubricants that may be present in the pharmaceutical composition can range from about 0.1% to about 7%.

According to the present invention, suitable binders may also be present in pharmaceutical composition(s) of the present invention, which may include but are not limited to polyvinyl pyrrolidone (also known as povidone), copovidone, polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose (for example HPC SSL, SL, L, M, H, Nisso®, HXF Pharm, MXF Pharm, GXF Pharm, JXF Pharm, LXF Pharm, E CS, EXF Pharm and ELF Pharm, Klucel™), L-HPC (low-substituted HPC), hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, maltodextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone -vinyl acetate copolymers (for example Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolysed starch, alginates or xanthan or mixtures thereof or any other suitable binder.

The amount of binder that may be present in pharmaceutical composition(s) can range from about 0.1% to about 25%.

According to the present invention, suitable disintegrants may also be present in pharmaceutical composition(s), which may include but are not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, crospovidone, croscarmellose sodium, starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, sodium glycolate of potato starch, sodium starch glycolate, crystalline cellulose, alginic acid or a salt thereof, such as sodium alginate or their equivalents and mixtures thereof.

The amount of disintegrant that may be present in pharmaceutical composition(s) of the present invention can range from about 5% to about 50%.

The solid dosage form, according to the present invention may be coated or uncoated. The coating may include but are not limited to seal coating, film coating, enteric coating or a combination thereof. Additional excipients such as film forming polymers, solvents, plasticizers, anti-adherents, opacifiers, colorants, pigments, anti-foaming agents, and polishing agents can be used in coatings.

Suitable film-forming agents include, but are not limited to, cellulose derivatives, such as, soluble alkyl- or hydroalkyl-cellulose derivatives such as methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum arabic, xanthan, alginates, polyacrylic acids, polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof, chitosan and derivatives thereof, shellac and derivatives thereof, waxes, fat substances and any mixtures or combinations thereof.

Suitable enteric coating materials include but are not limited to, cellulosic polymers like cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, methacrylic acid polymers and copolymers and any mixtures or combinations thereof.

Suitable excipients are used as adjuvant to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives, polishing agents, and the like. Suitable plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, and mixtures thereof.

Suitable opacifiers includes but are not limited to titanium dioxide, FD&C or D&C lakes, and iron oxide pigments. Suitable anti-adhesives include but are not limited to talc, silicon dioxide, magnesium stearate, kaolin, zinc stearate, stearic acid, hydrogenated vegetable oils.

Suitable solvents used in the processes of preparing pharmaceutical composition(s) of the present invention, include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, Ν,Ν-dimethylformamide, tetrahydrofuran, and mixtures thereof. Further, pharmaceutical composition(s) according to the present invention may further comprise at least one additional active ingredient such as but are not limited to aromatase inhibitor, antiestrogen, anti-androgen, gonadorelin agonist, topoisomerase I inhibitor, topoisomerase II inhibitor, microtubule active agent, alkylating agent, anti-neoplastic, anti-metabolite, platin compound, anti-angiogenic compound, cyclooxygenase inhibitor, bisphosphonate, heparanase inhibitor, telomerase inhibitor, protease inhibitor, matrix metalloproteinase inhibitor, proteasome inhibitor, somatostatin receptor antagonist, antileukemic compound, ribonucleotide reductase inhibitor, S-adenosylmethionine decarboxylase inhibitor; ACE inhibitor, antibiotics such as gentamicin, amikacin, tobramycin, ciprofloxacin, levofloxacin, ceftazidime, cefepime, cefpirome, piperacillin, ticarcillin, meropenem, imipenem, polymyxin B, colistin and aztreonam; cyclosporin A, cyclosporin G, rapamycin, and combinations thereof.

The pharmaceutical composition(s) of the present invention may be manufactured by using various known granulation processes such as wet granulation, dry granulation, fluid granulation, fluidized bed granulation as well as by direct compression, fluid drying, compaction, and briquetting or combinations thereof.

Therapeutic agents of the present invention may be present as crystalline, partially crystalline, amorphous, partially amorphous or polymorphous form, as a starting material.

In finalized composition of the present invention, the therapeutic agent may be present as crystalline, partially crystalline, amorphous, partially amorphous or polymorphous form.

The processes for preparation of stable pharmaceutical composition(s) as described above comprise in situ conversion of crystalline form of angiotensin II receptor inhibitor or neutral endopeptidase inhibitor and/or complex thereof to amorphous or partially amorphous or polymorphous form or mixtures thereof or vice-versa. In case of Angiotensin receptor blockers, preferred dosage forms are tablets or capsules comprising dosage of from about 20 mg to about 320 mg. The application of the active ingredient may occur up to three times a day, starting e. g. with a daily dose of 20 mg or 40 mg of Valsartan, increasing via 80 mg daily and further to 160 mg daily up to 320 mg daily. In case of preferred NEP inhibitors, preferred dosage forms are tablets or capsules comprising dosage of from about 5 mg to about 500 mg, preferably from about 15 mg to about 300 mg, even more preferably from about 20 mg to about 200 mg, administered once a day.

When the objective of present invention is to convert the form of active ingredient(s) in pharmaceutical composition (which could be crystalline, partially crystalline, amorphous, partially amorphous or polymorphous form or mixtures thereof), the same may be confirmed by analytical techniques such as XRD or DSC or FTIR or TGA or Raman spectroscopy studies and combinations thereof.

The following examples are for the purpose of illustration of present invention only and are not intended in any way to limit the scope of the present invention.

Example 1

Tablet preparation using granules with direct compression

Sacubitril and Valsartan with other intragranular materials were sifted and further blended in blender. Then, the talc and remaining quantity of crospovidone was added and further blended. Obtained granules were lubricated with magnesium stearate. Lubricated blend was then compressed using suitable tooling into a tablet. Tablets were coated using opadry.

Example 2

Tablet preparation using granules with direct compression

Supramolecular complex of Sacubitril-Valsartan

Sacubitril-Valsartan Trisodium complex and intragranular materials were sifted through sieve. Resultant sieved mixture was then blended with talc and crospovidone. Further, obtained granules were lubricated with magnesium stearate and compressed using suitable tooling into tablet. Resultant tablets were coated using opadry.

Example 3

Tablet preparation using granules with roller compaction process

Ingredients Percentage

(wt/wt)

Sacubitril 24.25%

Valsartan 25.75%

Microcrystalline Cellulose 22.50%

Low Substituted Hydroxy Propyl Cellulose 10.00% Crospovidone 1 1.25%

Colloidal Silicon Dioxide 1.00%

Talc 1.25%

Magnesium Stearate 4.00%

Total weight 100%

Sacubitril and Valsartan with intragranular materials were sifted and mixed. The material then compacted. Compacted flakes further sifted and milled through comminuting mill to separate out oversized material. Resultant Granules were lubricated with sifted extra granular material and compressed using suitable tooling. Further, tablets were coated using opadry.

Example 4

Tablet preparation using granules with roller compaction process

Sacubitril-Valsartan complex and intragranular materials were sifted and mixed with magnesium stearate. Resultant material was then compacted. Compacted flakes then sifted and milled for separation of oversized material. Compression was done with lubricated granules and resultant tablets were optionally coated. Example 5

Capsule preparation using granules with roller compaction process

Sacubitril, Valsartan, Sacubitril-Valsartan Trisodium complex and intragranular materials were sifted and mixed with sifted intragranular magnesium stearate. Resultant mixture was then compressed on roller compactor and further milled. Obtained granules were then lubricated and filled in suitable size capsules.

Example 6

Tablet preparation using granules with rapid mixing granulation process

Ingredients Percentage

(wt/wt)

Sacubitril 23.09%

Valsartan 24.52%

Microcrystalline Cellulose 38.09% Hydroxy Propyl Cellulose 5.95%

Crospovidone 3.57%

Water Q.S.

Extragranular

Crospovidone 2.85%

Colloidal Silicon Dioxide 0.47%

Talc 0.47%

Magnesium Stearate 0.94%

Total weight 100%

Sacubitril, Valsartan, crospovidone, microcrystalline cellulose were loaded in rapid mixer granulator and granulated with granulating liquid containing hydroxy propyl cellulose. Obtained granules were dried and lubricated with magnesium stearate. Tablets were compressed using lubricated blend and optionally coated.

Example 7

Tablet preparation using granules with rapid mixing granulation process

Ingredients Percentage

(wt/wt)

Sacubitril 15.87%

Valsartan 15.87%

Sacubitril-Valsartan complex 15.87%

Microcrystalline Cellulose 35.71%

Hydroxy Propyl Cellulose 8.33%

Crospovidone 3.57%

Water Q.S.

Extragranular

Crospovidone 2.85%

Colloidal Silicon Dioxide 0.47%

Talc 0.47% Magnesium Stearate 0.94%

Total weight 100%

Crospovidone, hydroxy propyl cellulose, Sacubitril, Valsartan and Sacubitril-Valsartan complex was sifted with microcrystalline cellulose and wet granulation was carried out. Obtained granules were dried, sifted and lubricated. Tablets were compressed using lubricated blend and optionally coated.

Example 8

Tablet preparation using granules with rapid mixing granulation process

Crospovidone and microcrystalline cellulose was granulated with hydroxy propyl cellulose (HPC) and Sacubitril-Valsartan Trisodium complex containing granulating medium. Obtained granules were dried and lubricated. Resultant granules compressed into tablets. Example 9

Tablet preparation using granules with fluidized bed granulation process

Crospovidone, microcrystalline cellulose was sifted and further granulated with granulating liquid containing povidone, methanol and Sacubitril-Valsartan Trisodium complex. Obtained granules were lubricated and compressed into tablets and optionally coated.

Example 10

Tablet preparation using granules with fluidized bed granulation process

Ingredients Percentage

(wt/wt)

Sacubitril 21.46%

Valsartan 22.78%

Microcrystalline Cellulose 35.39%

Hydroxy Propyl Cellulose 1 1.06%

Crospovidone 3.53% Methanol Q.S.

Extragranular

Crospovidone 3.53%

Colloidal Silicon Dioxide 0.44%

Talc 0.44%

Magnesium Stearate 1.32%

Total weight 100%

Crospovidone, microcrystalline, Sacubitril and Valsartan were granulated with hydroxy propyl cellulose- methanol solution. Obtained granules lubricated and compressed into tablets. Compressed tablets were coated.

Example 11

Tablet preparation using granules with fluidized bed granulation process

Percentage

Name of the ingredient (wt/wt)

Intragranular

Sacubitril and Valsartan complex 42.01%

Microcrystalline Cellulose 34.90%

Crospovidone 7.83%

Colloidal Silicon Dioxide 0.88%

Copovidone 5.83%

Methanol Q.S.

Compaction

Talc 0.39%

Magnesium Stearate 0.49%

Extragranular

Colloidal Silicon Dioxide 0.39%

Talc 0.39%

Crospovidone XL (Polyplasdone XL) 6.21%

Magnesium Stearate 0.68%

Total weight 100% Granulating liquid was prepared by mixing Sacubitril- Valsartan complex with copovidone, methanol and colloidal silicon dioxide and was used in granulation of crospovidone and microcrystalline cellulose blend. Resultant granules were compacted and compressed into tablets and further coated.

Example 12

Tablet preparation using granules with roller compaction process

Sacubitril- Valsartan Trisodium complex was sifted with intragranular materials and granulated using compaction-decompaction process. Further compression was carried out with lubricated compacted granules and resultant tablets were coated.

Example 13

Tablet preparation using granules with fluidized bed granulation process

Percentage

Name of the ingredient (wt/wt)

Intragranular

Sacubitril- Valsartan Trisodium complex 42.01% Lactose 27.34%

Crospovidone 7.99%

Colloidal Silicon Dioxide 1.55%

Copovidone 6.83%

Methanol Q.S.

Talc 0.38%

Magnesium Stearate 0.48%

Extragranular

Poloxamer 5.83%

Colloidal Silicon Dioxide 0.38%

Talc 0.39%

Crospovidone 6.21%

Magnesium Stearate 0.68%

Total Weight 100%

Granulating liquid was obtained by mixing Sacubitril- Valsartan Trisodium complex and colloidal silicon dioxide with copovidone and Methanol. Granulation of crospovidone and Lactose blend was carried out using granulating liquid. Further compaction was carried out with excipients followed by compression.

Example 14

Tablet preparation using granules with fluidized bed granulation process

Percentage

Name of the ingredient (wt/wt)

Sacubitril- Valsartan Trisodium complex 44.22%

Microcrystalline Cellulose 30.73%

Crospovidone 6.13%

Colloidal Silicon Dioxide 0.82%

Copovidone 6.13%

Methanol Q.S.

Compaction

Sodium Bicarbonate 3.07%

Talc 0.41%

Magnesium Stearate 0.51%

Extragranular Colloidal Silicon Dioxide 0.41%

Talc 0.48%

Crospovidone 6.54%

Magnesium Stearate 0.71%

Total Weight 100%

Granulating liquid was prepared by mixing Sacubitril- Valsartan Trisodium complex, copovidone, methanol, and colloidal silicon dioxide. The resultant liquid was used for granulation of crospovidone and microcrystalline cellulose blend. Obtained granules were compacted, lubricated, compressed and optionally coated.

Example 15

Tablet preparation using granules with roller compaction process

Sacubitril-Valsartan complex and intragranular materials were sifted and mixed with magnesium stearate. Resultant material was then compacted and further subjected to compression after lubrication. Resultant tablets were optionally coated. Example 16

Tablet preparation using granules with fluidized bed granulation process

Sacubitril-Valsartan Trisodium complex was mixed with copovidone, methanol, and colloidal silicon dioxide to form the granulating liquid. The resultant liquid was used for granulation of crospovidone and microcrystalline cellulose blend. Granules were compacted and further lubricated followed by compression. Resultant tablets were optionally coated.

Claims

1. A pharmaceutical composition comprising angiotensin II receptor inhibitor and neutral endopeptidase inhibitor and/or complex thereof and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein angiotensin II receptor inhibitor is selected from Valsartan, losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, saprisartan, tasosartan, elisartan, fimasartan, azilsartan, or pharmaceutically acceptable derivative thereof and/or combinations thereof.

3. The pharmaceutical composition of claim 1, wherein neutral endopeptidase inhibitor is selected from omapatrilat, sampatrilat, gemopatrilat, Sacubitril, ecadotril, candoxatril, SQ 28,603, N-[N-[1 (S)-carboxyl-3-phenylpropIyl]-(S)-phenylalanyl]- (S)-isoserine, N-[N- [((1 S)-carboxy-2-phenyl)ethyl]-(S)-phenylalanyl]- -alanine, N-[2(S)- mercaptomethyl-3- (2-methyIphenyl)-propionyl]methionine, (cis-4-[[[ 1 -[2-carboxy-3-(2- methoxyethoxy)propyl]-cyclopentyl]carbonyl]amino]-cyclohexanecarboxylic acid), thiorphan, retro-thiorphan, phosphoramidon, SQ 29072, N-(3-carboxy-l-oxopropyl)-(4S)- p- phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester, (S)-cis-4-[l-[2-(5- indanyloxycarbonyl)-3 -(2-methoxyethoxy)propyl] - 1 -cyclopentanecarboxamido] - 1 - cyclohexane carboxylic acid, 3-(l-[6-endo-hydroxymethylbicyclo[2,2, l]heptane-2-exo- carbamoyl]cyclopentyl)-2-(2-methoxyethyl)propanoic acid, N-(l -(3-(N-t-butoxycarbonyl- (S)- prolylamino)-2(S)-t-butoxy-carbonylpropyl)cyclopentanecarbonyl)-0-benzyl-(S)- serine methyl ester, 4-[[2-(Mercaptomethyl)-l-oxo-3-phenylpropyl]amino]benzoic acid, 3-[ 1 -(Cis-4- carboxycarbonyl-cis-3-butylcyclohexyl-r- 1 -carboamoyl)cyclopentyl]-2S-(2- methoxyethoxymethyl)propanoic acid, N-((2S)-2-(4-biphenylmethyl)-4-carboxy-5- phenoxyvaleryl) glycine, N-( 1 -(N-hydroxycarbamoylmethyl)- 1 -cyclopentanecarbonyl)-L- phenylalanine, (S)-(2-biphenyl-4-yl)-l-(lH-tetrazol-5-yl)ethylamino) methylphosphonic acid, (S)-5-(N-(2-(phosphonomethylamino)-3-(4-biphenyl)propionyl)-2- aminoethyl)tetrazole, β- Alanine, 3-[l , l'-biphenyl]-4-yl-N- [diphenoxyphosphinyl)methyl] -L-alanyl, N-(2-carboxy-4- thienyl)-3 -mercapto-2- benzylpropanamide, 2-(2-mercaptomethyl-3 - phenylpropionamido)thiazol-4-ylcarboxylic acid, (L)-(l -((2,2-dimethyl-l ,3-dioxolan-4-yl)- methoxy)carbonyl)-2-phenylethyl)-L- phenylalanyl)- -alanine, N-[N-[(L)-[ 1 -[(2,2-dimethyl- 1 ,3-dioxolan-4-yl)- methoxy] carbonyl] -2-phenyl ethyl] -L- phenylalanyl] -(R)-alanine, N- [N- [(L)- 1 -carboxy-2- phenyl ethyl] -L-phenylalanyl] -(R)- alanine, N- [2-acetylthiomethyl-3 -(2-methyl- phenyl)propionyl] -methionine ethyl ester, N-[2- mercaptomethyl-3-(2- methylphenyl)propioyl]-methionine, N-[2(S)-mercaptomethyI-3-(2- methylphenyl)propanoyl]-(S)-isoserine, N-(S)-[3-mercapto-2-(2- methylphenyl)propionyl]-(S)- 2-methoxy-(R)-alanine, N-[l -[[l (S)-benzyloxycarbonyl-3- phenylpropyl]amino]cyclopentyIcarbonyl]-(S)-isoserine, N-[l -[[1 (S)-carbonyl-3- phenylpropy] amino] -cyclopentylcarbonyl]-(S)-isoserine, l, l'-[dithiobis-[2(S)-(2- methylbenzyl)- 1 -oxo-3, 1 -propanediyl]]-bis-(S)-isoserine, 1 , 1 '-[dithiobis-[2(S)-(2- methylbenzyl)- 1 -oxo-3, 1 - propanediyl]]-bis-(S)-methionine, N-(3-phenyl-2- (mercaptomethyl)-propionyl)-(S)-4- (methylmercapto)methionine, N-[2- acetylthiomethyl-3 -phenyl -propionyl] -3 -aminobenzoic acid, N-[2-mercaptomethyl-3- phenyl-propionyl]-3-aminobenzoic acid, N-[l-(2-carboxy-4- phenylbutyl)- cyclopentanecarbonyl] -(S)-isoserine, N- [ 1 -(acetylthiomethyl)cyclopentane- carbonyl] - (S)-methionine ethyl ester, 3(S)-[2-(acetylthiomethyl)-3-phenyI-propionyl]amimo-e- caprolactam and N-(2-acetylthiomethyI-3-(2-methylphenyl)propionyl)-methionine ethyl ester, or pharmaceutically acceptable derivative thereof and/or combinations thereof.

4. The pharmaceutical composition of claim 1, wherein composition comprises Sacubitril, Valsartan and/or Sacubitril- Valsartan complex.

5. The pharmaceutical composition of claim 1, wherein composition comprises Sacubitril and Valsartan and/or Sacubitril-Valsartan complex, which may be present as crystalline, partially crystalline, amorphous, partially amorphous or polymorphous form or mixtures thereof.

6. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition is solid oral dosage form.

7. The pharmaceutical composition of claim 6, wherein said solid oral dosage form is an immediate-release formulation or a modified release formulation.

8. A process for preparation of pharmaceutical composition comprising steps of mixing angiotensin II receptor inhibitor and neutral endopeptidase inhibitor and /or complex thereof with at least one pharmaceutically acceptable carrier to form a blend; directly compressing said blend into a solid oral dosage form.

9. A process for preparation of pharmaceutical composition comprising steps of mixing angiotensin II receptor inhibitor and neutral endopeptidase inhibitor and /or complex thereof with at least one pharmaceutically acceptable carrier to form a blend; compacting the said blend; milling the obtained compact into granules, optionally mixing with pharmaceutically acceptable carriers, and compressing the final blend into a solid oral dosage form.

10. A process for preparation of pharmaceutical composition comprising steps of mixing angiotensin II receptor inhibitor and neutral endopeptidase inhibitor and /or complex thereof with at least one pharmaceutically acceptable carrier to form granules, further adding pharmaceutically acceptable carrier, and optionally compressing the final blend into a solid oral dosage form.

11. The process for preparation of pharmaceutical composition comprising angiotensin II receptor inhibitor and neutral endopeptidase inhibitor and /or complex thereof according to claim 10, wherein granules are formed by dry granulation process.

12. The process for preparation of pharmaceutical composition comprising angiotensin II receptor inhibitor and neutral endopeptidase inhibitor and /or complex thereof according to claim 10, wherein granules are formed by wet granulation process.

13. The process for preparation of pharmaceutical composition of claim 1, wherein process comprises in situ conversion of crystalline form of angiotensin II receptor inhibitor or neutral endopeptidase inhibitor and/or complex thereof to amorphous or partially amorphous or polymorphous form or mixtures thereof or vice-versa.

14. The process for preparation of pharmaceutical composition of claim 13, wherein process comprises in situ conversion of crystalline form of supramolecular complex containing angiotensin II receptor inhibitor or neutral endopeptidase inhibitor to amorphous or partially amorphous or polymorphous form or mixtures thereof or vice- versa.

15. The process for preparation of pharmaceutical composition of claim 14, wherein process comprises in situ conversion of crystalline form of Sacubitril-Valsartan supramolecular complex to amorphous or partially amorphous or polymorphous form or mixtures thereof or vice-versa.

16. A pharmaceutical composition as defined in any preceding claims, for use in treatment or prevention cardiovascular diseases.