DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITION COMPRISING SACUBITRIL AND VALSARTAN AND PROCESS FOR PREPARATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:
FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising dual acting superstructures of Angiotensin receptor antagonist/blocker (ARB) and neutral endopeptidase (NEP) inhibitor, for example LCZ696.

The present invention specifically relates to a pharmaceutical composition comprising sacubitril valsartan trisodium complex and suitable pharmaceutical excipients, process of preparation thereof and administration of such compositions for the treatment of cardiovascular diseases.

BACKGROUND OF THE INVENTION

The magnitude of cardiovascular diseases continue to accelerate globally. Cardiovascular diseases are disorders of the heart and blood vessels and include heart failure, coronary heart disease, rheumatic heart disease and other conditions. Each year 17.9 million people die from cardiovascular diseases, an estimated 31% of all deaths worldwide. Heart failure is a global pandemic affecting at least 26 million people worldwide and is increasing in prevalence. Around half of these patients with heart failure have reduced ejection fraction, which is associated with significant morbidity and mortality.

A dual-acting compound or combination, in particular a supramolecular complex of two active agents with different mechanisms of action, or linked pro-drug or in particular a supramolecular complex of two active agents with different mechanisms of action, namely an angiotensin receptor antagonist and a neutral endopeptidase inhibitor has been disclosed in U.S. Patent Application Nos. 60/735,093 filed Nov. 9, 2005; 60/735,541 filed Nov. 10, 2005; 60/789,332 filed Apr. 4, 2006; and 60/822,086 filed Aug. 11, 2006 and in International publication no. WO2007/056546 which are hereby incorporated by reference in their entirety. Such supramolecular complexes may be used for the treatment of patients with various cardiovascular and/or renal diseases. A particularly useful therapeutic agent is the supramolecular complex, trisodium [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl {2''-(tetrazol-5-ylate) biphenyl-4'-ylmeth-yl} amino) butyrate] hemipentahydrate also referred to as LCZ696.

One of the approved therapies in USA to improve outcome in these patients include a fixed dose combination (LCZ696) of Sacubitril, a neprilysin inhibitor; and Valsartan, an angiotensin receptor blocker. It is a salt complex comprising Sacubitril (AHU377), Valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5. Following oral administration, LCZ696 dissociates into Valsartan and the pro-drug AHU377, which is further metabolized to the NEP inhibitor Sacubitrilat (LBQ657). LCZ696 inhibits neprilysin via LBQ657, the active metabolite of Sacubitril, and blocks the angiotensin II type-1 receptor via Valsartan.

The approved dosage for fixed dose combination of Sacubitril and Valsartan is available in USA under brand name Entresto® marketed by Novartis Pharmaceuticals. Entresto is an oral film coated tablet available in three strengths viz. 50mg (24mg; 26mg), 100mg (49mg; 51mg) and 200mg (97mg; 103mg).

Entresto comprises fixed dose combination of Sacubitril and Valsartan i.e. LCZ696 which has a molecular mass of 957.99 and a molecular formula of C48H55N6O8Na3•2.5 H2O. The chemical structure of LCZ696 is:

US Patent 8,877,938 discloses a supramolecular complex of trisodium Sacubitril-Valsartan hemipentahydrate crystalline form.

US20100267786 of Novartis discloses solid oral dosage forms, especially tablets, comprising a supramolecular complex i.e. trisodium Sacubitril-Valsartan hemipentahydrate, which can be formed from a direct compression process or a compaction process such as roller compaction. Several other references including WO2017009784A1, WO2018078592A1, WO2017042700A1, US20180353430, US20180273493, WO2018069833A1, WO2017037596A1, WO2017085573A1, US20190112278, US20190112278, WO2018178295, WO2018211479, WO2017154017A1 and WO2019180735A1 disclose crystalline and/or amorphous sacubitril valsartan trisodium complex, and pharmaceutical compositions thereof.

There exists couple of problems in formulation development of sacubitril valsartan trisodium complex with the use of conventional pharmaceutical excipients and/or processes. One of the problems with wet granulation process is that the exposure of the therapeutic agent to moisture, excessive heat and/or high shear forces possesses a number of formulation incompatibilities and difficulties during the formulation process, which may lead to degradation or dissociation of the therapeutic agent and/or increased amorphism of the components of the dual acting compound selected for this invention. The other problem is that since, sacubitril-valsartan supramolecular complex is a BCS class IV compound, there is a problem of low bioavailability to deal with. In dry blending processes as known in the art, some critical excipients, for eg. Wetting agents and/or bioenhancers may not be uniformly distributed throughout the composition due to differences in particle size and mass that may lead to dissolution and bioavailability issues. Thus there is a need to choose suitable excipients and also a best process of making the compositions to attain desired invitro release profile and/or target pharmacokinetic parameters. Hence, there is an unmet need and a great challenge to formulate such a supramolecular complex into pharmaceutical compositions, especially solid oral dosage forms, such that the therapeutic benefits of the compounds may be delivered to a patient in need thereof.

SUMMARY OF INVENTION

The present invention features a pharmaceutical composition comprising a therapeutic agent, a supramolecular complex.

An aspect of the present invention relates to featured supramolecular complex is a dual acting compound. A dual-acting compound or combination features a supramolecular complex of two active agents with different mechanisms of action, or linked pro-drug or in particular a supramolecular complex of two active agents with different mechanisms of action, namely an angiotensin receptor antagonist and a neutral endopeptidase inhibitor.

An aspect of the present invention relates to a pharmaceutical composition comprising trisodium [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl {2''-(tetrazol-5-ylate) biphenyl-4'-ylmeth-yl} amino) butyrate].

An aspect of the present invention relates to a pharmaceutical composition comprising sacubitril valsartan trisodium complex and atleast one pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, glidants, lubricants, wetting agents and others. The sacubitril valsartan trisodium complex in the pharmaceutical composition of the present invention can be either a crystalline or an amorphous form.

An aspect of the present invention relates to a pharmaceutical composition comprising an amorphous and anhydrous solid dispersion of sacubitril valsartan trisodium complex and Copovidone.

An aspect of the present invention relates to a pharmaceutical composition comprising amorphous sacubitril valsartan trisodium complex, Copovidone, Microcrystalline cellulose, Poloxamer, Low substituted Hydroxypropyl cellulose (L-HPC), Crospovidone, Talc, Colloidal silicon dioxide and Magnesium stearate.

An aspect of the present invention relates to a process for preparing the pharmaceutical composition comprising sacubitril valsartan trisodium complex and atleast one pharmaceutically acceptable excipients.

In another aspect of the present invention, relates to a pharmaceutical composition comprising sacubitril valsartan trisodium complex and atleast one pharmaceutically acceptable excipients and use of such compositions for the treatment of cardiovascular diseases.

DETAILED DESCRIPTION OF THE INVENTION

However, before further describing this invention, the following terms are defined.

As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

The term “comprising” is not intended to limit inventions to only claiming the present invention with such comprising language. Any invention using the term comprising could be separated into one or more claims using “consisting” or “consisting of” claim language and is so intended.

The terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and/or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising”. As used herein, the terms “include”, “includes”, and “including” are meant to be non-limiting.

The term “treatment” includes prophylactic and/or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the subject of one or more of the pharmaceutical compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

The term “cardiovascular disease(s)” refers to a disorder of the heart and blood vessels, and includes disorders of the arteries, veins, arterioles, venules, and capillaries. Non-limiting examples of cardiovascular diseases include cardiac hypertrophy, myocardial infarction, stroke, arteriosclerosis, and heart failure. Additional examples of cardiovascular diseases are known in the art. One of the uses of the present invention compositions is to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

The term “administration” or “administering” refers to a method of giving a dosage of a pharmaceutical composition to a subject. The preferred method of administration may depend on a variety of factors, e.g., the components of the pharmaceutical composition or condition, and severity of the disease, disorder, or condition.

The term “patient”, “subject” or “individual”is used interchangeably and refers to a vertebrate, preferably a mammal. Non-limiting examples include mice, dogs, rabbits, farm animals, sport animals, pets, and humans.

The term “bioavailability” can denote the degree to which a drug or other substance becomes available to the target tissue after administration.
The term “pharmaceutically acceptable excipient(s)” or “excipient(s)” refers to those substances that are well accepted by the industry and regulatory agencies such as those listed in monographs published in compendia such as USP-NF, Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide and in 21 CFR parts 182 and 184 that lists substances that are generally regarded as safe (GRAS) food ingredients.

The term “pharmaceutical composition” refers to a pharmaceutical preparation that contains a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and is suitable for administration to a patient for therapeutic purposes.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

The term “% by weight” is based on the weight of the total composition.

In an embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutic agent, a supramolecular complex.

In an embodiment, the present invention relates to featured supramolecular complex is a dual acting compound. A dual-acting compound or combination features a supramolecular complex of two active agents with different mechanisms of action, or linked pro-drug or in particular a supramolecular complex of two active agents with different mechanisms of action, namely an angiotensin receptor antagonist and a neutral endopeptidase inhibitor.

In an embodiment, the present invention relates to a pharmaceutical composition comprising trisodium [3-((1S, 3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate-(S)-3'-methyl-2'- (pentanoyl {2''-(tetrazol-5-ylate) biphenyl-4'-ylmeth- yl} amino) butyrate]. The sacubitril valsartan trisodium complex in the pharmaceutical composition of the present invention can be either a crystalline or an amorphous form. The active ingredients Sacubitril and Valsartan may be present in the form of free base(s), its salt(s), polymorph(s), hydrate(s), solvate(s), conjugate(s), complex(s), prodrug(s), and derivative as alone or in combination thereof which may be present in the form of a complex, a premix, an amorphous powder, a solid dispersion, an anhydrous solid dispersion a solid solution, a physical mixture and the like. In certain embodiments, the present invention provides a pharmaceutical composition comprising amorphous sacubitril valsartan trisodium complex in about 45 % by weight to about 70 % by weight of the total composition.

In an embodiment, the present invention relates to a pharmaceutical composition comprising sacubitril valsartan trisodium complex and atleast one pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, glidants, lubricants, wetting agents and others. The sacubitril valsartan trisodium complex in the pharmaceutical composition of the present invention can be either a crystalline or an amorphous form.

In an embodiment, the present invention relates to a pharmaceutical composition comprising an amorphous/anhydrous solid dispersion of sacubitril valsartan trisodium complex and atleast one pharmaceutically acceptable excipient(s). The excipient used in the present invention is selected from the group of polymeric compounds like methacrylic acid copolymers, polyvinylpyrrolidone, 4-vinylpyrrolidone-vinyl acetate copolymer (copovidone), hydroxy propyl cellulose, hydroxypropylmethyl cellulose, hypromellose phthalate and the like. In certain embodiments, the present invention provides copovidone, wherein the solid dispersion is prepared by dissolving sacubitril or its salt and valsartan or its salt in a suitable solvent (for eg. Ethanol), adding a base (for eg. NaoH), concentrating the solution to residue, mixing the residue with copovidone in a suitable solvent (for eg. Water) and removing the solvent. The final product is obtained by filtration followed by lyophilization. In particular embodiments, the present invention provides a solid dispersion of sacubitril-valsartan complex with copovidone in a predefined weight ratio of about 1:1:0.25 to about 1:1:2, with optional water molecule.

In an embodiment, the present invention relates to a pharmaceutical composition comprising an amorphous sacubitril-valsartan trisodium with copovidone premix, which is prepared by removing the solvent from the solution containing sacubitril, valsartan, a base and copovidone in a suitable solvent.

Examples of the diluent(s) or filler(s) include but not limited to cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, and compressible sugars. In the present invention diluents are added in an amount from about 10% to about 90% by weight of the total composition. In certain embodiments, the present invention provides a pharmaceutical composition comprising sacubitril valsartan trisodium complex and microcrystalline cellulose as a diluent.

Examples of binder(s) for use in accordance with the present invention include but not limited to cellulose and its derivatives including hydroxypropylmethyl cellulose (hypromellose), hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), cellulose acetate, ethylcellulose, methylcellouse, and hydroxyethyl cellulose; starch and its derivatives; pregelatinized starch, hydrocolloids; sugar; polyvinyl pyrrolidone, copovidone, methacryclic acid copolymers and combinations thereof, and the like. In the present invention binders in an amount from about 1% to about 10% by weight of the total composition.

Examples of disintegrant(s) suitable for use herein include but not limited to croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, low substituted hydroxypropyl cellulose (L-HPC) and other known disintegrant(s). In the present invention disintegrants in an amount from about 1% to about 15% by weight of the total composition. In certain embodiments, the present invention provides a pharmaceutical composition comprising sacubitril valsartan trisodium complex and disintegrants selected from crospovidone, low substituted hydroxypropyl cellulose or mixtures thereof.

Examples of wetting agent(s) suitable for use herein include but not limited to poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and docusate sodium. In the present invention wetting agents in an amount from about 1% to about 10% by weight of the total composition. In certain embodiments, the present invention provides a pharmaceutical composition comprising sacubitril valsartan trisodium complex and poloxamer as a wetting agent.

Examples of lubricant(s) suitable for use herein include but not limited to sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristic acid and hydrogenated vegetable oils and fats. In the present invention lubricants in an amount from about 1% to about 5% by weight of the total composition. In certain embodiments, the present invention provides a pharmaceutical composition comprising sacubitril valsartan trisodium complex and magnesium stearate as lubricant.

Examples of glidant(s) suitable for use herein include talc, colloidal silicon dioxide, silicic acid, cornstarch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, starch, castor wax. In the present invention lubricants in an amount from about 1% to about 5% by weight of the total composition. In certain embodiments, the present invention provides a pharmaceutical composition comprising sacubitril valsartan trisodium complex and colloidal silicon dioxide as glidant.

In an embodiment, the present invention relates to a pharmaceutical composition comprising a solid dispersion of sacubitril valsartan trisodium complex and copovidone alongwith a wetting agent, for eg. Poloxamer.

In certain embodiments, pharmaceutical composition(s) of the present invention may be provided in any pharmaceutically acceptable oral solid dosage form(s). Preferably, the oral solid dosage form is selected from the group consisting of tablets, mini-tablets, multilayer tablets, inlaid tablets, tablet in tablet, granules, multi-unit particulate systems (MUPS), pellets, beads, pellets presented in a sachet, capsules such as soft and hard gelatin capsules or lozenges and the like. In certain embodiments, of the present invention provides a tablet comprising amorphous sacubitril valsartan trisodium complex, Copovidone, Microcrystalline cellulose, Low substituted Hydroxypropyl cellulose, Crospovidone, Talc, Colloidal silicon dioxide and Magnesium stearate.

The process of preparation of dosage forms in accordance with the embodiments are designed by considering the couple of problems of sacubitril valsartan trisodium complex, especially it is strictly ensured that there is no exposure of the therapeutic agent to moisture, no exposure of excessive heat and/or high shear forces as these possess a number of formulation incompatibilities and difficulties during the formulation process, which may lead to degradation or dissociation of the therapeutic agent and/or increased amorphism of the components of the dual acting compound selected for this invention. According to the literature sacubitril-valsartan supramolecular complex is a BCS class IV compound which resembles a low solubility and low permeability. Also formulation scientists have encountered a problem of non-uniform distribution of wetting agent, for eg. Poloxamer during granulation and/or blending the formulation development of sacubitril-valsartan supramolecular complex.

Surprisingly, the inventors of the present invention have overcome the aforementioned problems and developed a novel process for preparing a pharmaceutical composition comprising amorphous sacubitril valsartan trisodium complex with copovidone comprising of: i) sifting a diluent; ii) preparing granulating fluid comprising of poloxamer and water; iii) granulating the diluent of step (i) with granulating fluid of step (ii) followed by drying; iv) blending the dried granules of step (iii) with extragranular components comprising amorphous sacubitril valsartan trisodium complex with copovidone and at least one pharmaceutically acceptable excipient; v) compressing or filling the blend of step (iv) into an oral solid dosage form; vi) optionally coating the oral solid dosage form of step v.

In certain embodiments, the present invention relates to a process for preparing a pharmaceutical composition comprising amorphous sacubitril valsartan trisodium complex with copovidone comprising of: i) sifting microcrystalline cellulose; ii) preparing granulating fluid comprising poloxamer and water; iii) granulating the microcrystalline cellulose with granulating fluid of step (ii) followed by drying; iv) blending the dried granules of step (iii) with extragranular components comprising of amorphous sacubitril valsartan trisodium complex with copovidone, L-HPC, crospovidone, talc, colloidal silicon dioxide and magnesium stearate; v) compressing or filling the blend of step (iv) into an oral solid dosage form; vi) optionally coating the oral solid dosage form of step v.

Surprisingly, the inventors of the present invention have overcome the aforementioned problems and developed a novel process for preparing a pharmaceutical composition comprising Sacubitril-Valsartan complex, wherein the
process comprises: i) sifting intragranular excipient(s) selected from the group consisting of diluent(s), binder(s), disintegrant(s) and lubricant(s); ii) preparing granulating fluid comprising wetting agent and water; iii) granulating the intragranular excipient(s) with granulating fluid of step (ii) in rapid mixer granulator (RMG) and drying and milling; iii) blending the milled material with extragranular components comprising Sacubitril-Valsartan complex and excipient(s) selected from the group consisting of disintegrant(s), glidant(s), and lubricant(s); iv) compacting the lubricated blend by roller compaction and milling;
v) sifting milled material with extragranular excipient(s) selected from the group consisting of disintegrant(s), glidant(s) and lubricant(s); vi) compressing or filling the blend of step (v) into the desired oral solid dosage form; and vii) optionally coating the oral solid dosage form.

In a certain embodiment, the present invention relates to a pharmaceutical composition comprising Sacubitril-Valsartan complex, wherein the process comprises: i) Sifting microcrystalline cellulose; ii) preparing granulating fluid comprising poloxamer and water; iii) granulating the microcrystalline cellulose with granulating fluid of step (ii) in rapid mixer granulator and drying; iv) blending the dried granules of step (iii) for 10 minutes with extragranular components comprising Solid dispersion of Sacubitril and Valsartan with Copovidone, low-substituted hydroxypropyl cellulose, crospovidone, talc, colloidal silicon dioxide and magnesium stearate; iv) slugging the blend of step (iii) in roller compactor followed by milling; v) blending the milled material with crospovidone for 10 minutes and lubricating with magnesium stearate for 3 minutes; vi) The final blend was compressed into a tablet with a suitable tablet tooling and film-coated in a pan coater.

In a certain embodiment, the present invention relates to a pharmaceutical composition comprising a solid dispersion of sacubitril valsartan trisodium complex with copovidone and a wetting agent, wherein the composition exhibits % drug release of atleast 15% to 20% of sacubitril and atleast 15% to 20% of valsartan in 0.1N HCl at 60 minutes.

In certain embodiments, the tablets of the invention has an optional protective outer layer i.e. tablet coating. The protective outer layer of the tablet is based on the weight of the pharmaceutical formulation. The formulation can contain at least one coating layer polymer and a non-aqueous coating solvent(s), for example, isopropyl alcohol which is used for processing and removed by drying. Suitable examples of polymer(s) for the coating layer include but not limited to hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, and starch.

In one of the particular embodiments of the present invention the film coat composition comprises plasticizer(s). Suitable plasticizer(s) include but not limited to glycerol monocaprylocaprate, triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG)/macrogol, glycerin, and triethyl citrate. The film coating composition may optionally comprises ant adherent(s) or opacifying agent(s) or dye(s) or combinations thereof including but not limited to talc, aluminum lakes, iron oxides, titanium dioxide and natural colors.

In one of the particular embodiments, the film coating composition comprises hypromellose, titanium dioxide, polyethylene glycol (PEG)/macrogol, talc, iron oxide black, iron oxide red and iron oxide yellow.

The term "dissolution" as used herein refers to a process by which a solid substance, here the active ingredients, is dispersed in molecular form in a medium. The dissolution rate of the active ingredients of the pharmaceutical oral fixed dose combination of the invention is defined by the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. The dissolution rate is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP <711> and EP 2.9.3 and JP. For the purposes of this invention, the test is for measuring the dissolution of the individual active ingredients is performed at pH 1.2 using a paddle stirring element at 50 rpm (rotations per minute) or alternatively at 75 rpm using a paddle stirring element as specified. The dissolution medium is preferably a buffer, typically a phosphate buffer or 0.1N HCl, especially one as described in the example "Dissolution Test". In the present invention 0.1N HCl is considered because, it is a differentiating medium for several compositions and thereby it would be easy to predict desired in vitro release profile and/or target pharmacokinetic parameters of active ingredients.

Accordingly, the present invention provides preferably solid oral dosage forms delivering a therapeutically effective amount of valsartan free acid or a pharmaceutically acceptable salt thereof and Sacubitril free acid, or a pharmaceutically acceptable salt thereof. For the purposes of this invention, the present invention provides preferably solid oral dosage forms exhibit an in vitro dissolution profile, when measured by the USP paddle method at about 50 rpm or at about 75 rpm in 900 mL of 0.1N HCl at pH 1.2 and at 37±0.50 C., such that after 60 min, from a mean of about 10% to a mean of about 20% (by weight) of valsartan free acid, or a pharmaceutically acceptable salt thereof and Sacubitril free acid, or a pharmaceutically acceptable salt thereof, is released. Surprisingly, it was found that the dissolution profile in 0.1N HCl (considering it as differentiating drug release media) & PK/PD profile as obtained with the solid oral dosage form comprising an amorphous/anhydrous solid dispersion of sacubitril valsartan trisodium complex of the present invention are comparable to the commercially available ENTRESTO Tablets.

The following examples are intended to serve as illustrations of the present invention only and do not restrict the scope of the invention in any manner whatsoever.

EXAMPLES:
Comparative Example: Sacubitril-Valsartan Tablet without a wetting agent.
Ingredients % w/w
Intra granular
Solid dispersion of Sacubitril and Valsartan with Copovidone (1:1:0.75) 62.513
Microcrystalline Cellulose 19.780
Low Substituted Hydroxypropyl Cellulose 3.467
Crospovidone 4.623
Talc 0.462
Colloidal silicon dioxide 0.462
Magnesium stearate 0.462
Extra granular
Crospovidone 4.623
Talc 0.231
Magnesium stearate 0.462
Core tablet weight 97.085
Film coating
Opadry Pink 03F540294 2.915
IPA: water (70:30) ,(for 8% solid content) --
Total weight (Coated tablets) 100.00

Manufacturing Procedure:
Amorphous Solid dispersion of Sacubitril and Valsartan with Copovidone was sifted with Microcrystalline Cellulose, Low Substituted Hydroxypropyl Cellulose, Crospovidone, Talc, Colloidal silicon dioxide and Magnesium stearate. The sifted materials were blended in octagonal blender for 10 minutes. The blended material was then compacted in roller compactor and milled. The milled material was sifted and blended with Crospovidone and Talc for 10 minutes and lubricated with the previously sifted Magnesium stearate for 5 minutes. The lubricated blend was compressed into a tablet with a suitable tablet tooling and film-coated in a pan coater.

Example 1: Sacubitril-Valsartan Tablet with Polysorbate-80.
Ingredients % w/w
Intra granular
Solid dispersion of Sacubitril and Valsartan with Copovidone (1:1:0.75) 62.513
Microcrystalline Cellulose 15.897
Low Substituted Hydroxypropyl Cellulose 3.467
Crospovidone 4.623
Talc 0.462
Colloidal silicon dioxide USNF 0.462
Magnesium stearate USNF 0.462
Polysorbate-80 3.883
Extra granular
Crospovidone 4.623
Talc 0.231
Magnesium stearate 0.462
Core tablet weight 97.085
Film coating
Opadry Pink 03F540294 2.915
IPA: water (70:30),(for 8% solid content)
Total weight (Coated tablets) 100.00

Manufacturing Procedure:
Amorphous Solid dispersion of Sacubitril and Valsartan with Copovidone was co-milled. The Milled complex was sifted with Polysorbate-80 and again co-sifted with Microcrystaline cellulose, Low substitued hydroxy propyl cellulose, Crospovidone, Talc and Colloidal Silicon dioxide. The sifted materials were blended in octagonal blender for 20 minutes and then lubricated with the previously sifted magnesium stearate for 3 minutes. The lubricated blend was compacted by roller compaction and milled. The milled material was blended with Crospovidone and Talc. Magnesium stearate was added to the obtained blend and compressed into a tablet with a suitable tablet tooling and film-coated in a pan coater.

Example 2: Sacubitril-Valsartan Tablet with Sodium Lauryl Sulphate
Ingredients % w/w
Intra granular
Solid dispersion of Sacubitril and Valsartan with Copovidone (1:1:0.75) 62.496
Microcrystalline Cellulose 17.855
Sodium Lauryl Sulfate (SLS) 1.942
Low Substituted Hydroxypropyl Cellulose 3.467
Crospovidone 4.623
Talc 0.462
Colloidal silicon dioxide 0.462
Magnesium stearate 0.462
Extra granular
Crospovidone 4.623
Talc 0.231
Magnesium stearate 0.462
Core tablet weight 97.085
Film coating
Opadry Pink 03F540294 2.915
IPA: water (70:30) ,(for 8% solid content)
Total weight (Coated tablets) 100.00

Manufacturing Procedure:
Amorphous Solid dispersion of Sacubitril and Valsartan with Copovidone was co-sifted with SLS, Microcrystalline Cellulose, Low Substituted Hydroxypropyl Cellulose, Crospovidone, Talc, Colloidal silicon dioxide and Magnesium stearate and blended in an octagonal blender for 10 minutes. The blend was compacted by roller compactor and milled. The milled material was loaded in a blender with Crospovidone and Talc and blended for 10 minutes. To this blend the sifted Magnesium stearate was added for lubrication and blended for 3 minutes. The lubricated blend was compressed into a tablet with a suitable tablet tooling and film-coated in a pan coater.

Example 3: Sacubitril-Valsartan Tablet with Sodium Lauryl Sulphate
Ingredients % w/w
Inert Granules manufacturing in RMG (Part -1)
Microcrystalline Cellulose 22.197
Granulating Fluid
Sodium Lauryl sulfate 2.91
Purified Water q.s.
Intragranular Ingredients (Part-2)
Dried granules (Part-1) --
Solid dispersion of Sacubitril and Valsartan with Copovidone (1:1:0.75) 62.51
Low Substituted Hydroxypropyl Cellulose 3.47
Crospovidone 4.62
Talc 0.46
Colloidal silicon dioxide 0.46
Magnesium stearate 0.46
Core tablet weight 97.087
Film Coating
Opadry pink 03F540294 2.913
Purified Water USP/Ph.Eur --
Isopropyl Alcohol USP --
Coated tablet weight 100.00

Manufacturing Procedure:
A granulating fluid comprising 25% w/w Sodium Lauryl Sulfate and water was prepared and granulated with Microcrystalline Cellulose which was drymixed already in Rapid Mixer Granulator. The wet mass was kneaded and discharged from Rapid Mixer Granulator in to Fluid Bed Equipment bowl and dried. The dried granules was sifted and co-sifted with Sacubitril-Valsartan complex, Low Substituted Hydroxypropyl Cellulose, Crospovidone, Talc and Colloidal silicon dioxide. The sifted material was blended for 10 minutes and then lubricated with Magnesium stearate and for 3 minutes. The final blend was compressed into a tablet with a suitable tablet tooling and film-coated in a pan coater.

Example 4: Sacubitril-Valsartan Tablet with Poloxamer
Ingredients % w/w
Inert Granules manufacturing in RMG (Part -1)
Microcrystalline Cellulose 16.87
Granulating Fluid
Poloxamer 2.91
Purified Water q.s.
Intragranular Ingredients for Roller compaction Process (Part-2)
Dried granules (Part-1) --
Solid dispersion of Sacubitril and Valsartan with Copovidone (1:1:0.75) 62.51
Low Substituted Hydroxypropyl Cellulose 3.47
Crospovidone 4.62
Talc 0.46
Colloidal silicon dioxide 0.46
Magnesium stearate 0.46
Extra granular (Lubrication)
Crospovidone 4.62
Talc 0.23
Magnesium stearate 0.46
Core tablet weight 97.07
Film Coating
Opadry pink 03F540294 2.93
Purified Water --
Isopropyl Alcohol --
Coated tablet weight 100.00

Manufacturing Procedure:
i) Sifting microcrystalline cellulose; ii) preparing granulating fluid comprising poloxamer and water; iii) granulating the microcrystalline cellulose with granulating fluid of step (ii) in rapid mixer granulator and drying; iv) blending the dried granules of step (iii) for 10 minutes with extragranular components comprising Solid dispersion of Sacubitril and Valsartan with Copovidone, low-substituted hydroxypropyl cellulose, crospovidone, talc, colloidal silicon dioxide and magnesium stearate; iv) slugging the blend of step (iii) in roller compactor followed by milling; v) blending the milled material with crospovidone for 10 minutes and lubricating with magnesium stearate for 3 minutes; vi) The final blend was compressed into a tablet with a suitable tablet tooling and film-coated in a pan coater.

Example 5: Sacubitril-Valsartan Tablet with Poloxamer
Ingredients % w/w
Intragranular Ingredients for RMG (Part -1)
Microcrystalline Cellulose 13.870
Granulating Fluid
Poloxamer 2.913
Purified Water --
Ingredients for Direct Compression (Part-2)
Dried granules (Part-1) --
Solid dispersion of Sacubitril and Valsartan with Copovidone (1:1:0.75) 62.513
Microcrystalline Cellulose 2.998
Low Substituted Hydroxypropyl Cellulose 3.467
Crospovidone 9.246
Talc 0.693
Colloidal silicon dioxide 0.462
Magnesium stearate 0.925
Core tablet weight 97.087
Film Coating
Opadry pink 03F540294 2.913
Purified Water --
Isopropyl Alcohol --
Coated tablet weight 100.00

Manufacturing Procedure:
A granulating fluid comprising 25% w/w Poloxamer and water was prepared and granulated with Microcrystalline Cellulose which was drymixed already in Rapid Mixer Granulator. The wet mass was kneaded and discharged from Rapid Mixer Granulator in to Fluid Bed Equipment bowl and dried. The dried granules was sifted and co-sifted with Sacubitril-Valsartan complex, Low Substituted Hydroxypropyl Cellulose, Crospovidone, Talc and Colloidal silicon dioxide. The sifted material was blended for 10 minutes and then lubricated with Magnesium stearate and for 3 minutes. The final blend was compressed into a tablet with a suitable tablet tooling and film-coated in a pan coater.

Example 6: Dissolution Test
The aforementioned Sacubitril-Valsartan Tablets of Comparative example, Examples 1-5 & ENTRESTO Tablets (Reference) were subjected to dissolution test to measure the dissolution of the individual active ingredients in 0.1N HCl at pH 1.2 using a paddle stirring element at 50 rpm (rotations per minute), in which compositions of example 4 and 5 were observed promising. Surprisingly, it was found that the extent of drug release especially at 45minutes & 60minutes of example 4 and 5 were comparable to the extent of drug release of ENTRESTO Tablets and hence, it could be predictable that PK/PD profile of example 4 and 5 tablets would be comparable to the PK/PD profile of ENTRESTO Tablets.

Sacubitril Part

0.1N HCL, 900ml, 50 RPM, USP Apparatus II (Paddle)
Time (min) Mean % Drug release of 6 Tablets

ENTRESTO™
(200 mg tablet)
Comparative Example

Example 1

Example 2

Example 3

Example 4

Example 5

10 3 0 - -- -- - -
15 5 0 0 1 2 1 1
20 7 0 0 2 3 1 1
30 11 1 0 4 5 3 3
45 15 3 2 6 6 14 12
60 18 6 3 8 9 18 16
Infinity 35 10 11 32 37 37 45

Valsartan Part

Dissolution Media: 0.1N HCL, 900ml, 50 RPM, USP Apparatus II (Paddle)
Time (min) Mean % Drug release of 6 Tablets

ENTRESTO™ (200 mg tablet)
Comparative Example

Example 1

Example 2

Example 3

Example 4

Example 5

10 3 0 - -- -- - -
15 6 0 0 1 2 1 0
20 8 1 0 3 3 1 1
30 12 1 1 4 4 3 3
45 16 3 3 5 6 15 11
60 18 8 4 7 8 20 15
Infinity 36 13 14 28 31 43 36

,CLAIMS:I/We claim:

1. A pharmaceutical composition comprising a solid dispersion of sacubitril valsartan trisodium complex with copovidone, and a wetting agent, wherein the composition exhibits % drug release of atleast 15% to 20% of sacubitril and atleast 15% to 20% of valsartan in 0.1N HCl at 60 minutes.

2. A pharmaceutical composition according to claim 1, wherein the composition comprising a solid dispersion of amorphous sacubitril valsartan trisodium complex with copovidone.

3. A pharmaceutical composition according to claims 1, wherein the ratio of sacubitril-valsartan trisodium complex to copovidone is about 1:1:0.25 to about 1:1:2.

4. A pharmaceutical composition according to claim 1, wherein the wetting agent is poloxamer in a concentration of 1% to 10% by weight of the total weight of composition.

5. A pharmaceutical composition according to claim 1, wherein the composition is selected from the group consisting of tablets, mini-tablets, multilayer tablets, inlaid tablets, tablet in tablet, lozenges, granules, multi-unit particulate systems (MUPS), pellets, beads, pellets in a sachet, soft and hard gelatin capsules.

6. A pharmaceutical composition according to claim 1, wherein the composition comprises an amorphous sacubitril-valsartan trisodium with copovidone premix, which is prepared by removing the solvent from the solution containing sacubitril, valsartan, a base and copovidone in a suitable solvent.

7. A pharmaceutical composition according to claim 1, wherein amorphous sacubitril valsartan trisodium complex with copovidone is from 45% to 70% by weight of the total weight of composition.

8. A process for preparing pharmaceutical composition of amorphous sacubitril valsartan trisodium complex with copovidone comprising of:
i) sifting a diluent;
ii) preparing granulating fluid comprising of poloxamer and water;
iii) granulating the diluent of step (i) with granulating fluid of step (ii) followed by drying;
iv) blending the dried granules of step (iii) with extragranular components comprising amorphous sacubitril valsartan trisodium complex with copovidone and at least one pharmaceutically acceptable excipient;
v) compressing or filling the blend of step (iv) into an oral solid dosage form;
vi) optionally coating the oral solid dosage form of step v.

9. A process for preparing pharmaceutical composition of amorphous sacubitril valsartan trisodium complex with copovidone comprising of:
i) sifting microcrystalline cellulose;
ii) preparing granulating fluid comprising poloxamer and water;
iii) granulating the microcrystalline cellulose with granulating fluid of step (ii) followed by drying;
iv) blending the dried granules of step (iii) with extragranular components comprising of amorphous sacubitril valsartan trisodium complex with copovidone, L-HPC, crospovidone, talc, colloidal silicon dioxide and magnesium stearate;
v) compressing or filling the blend of step (iv) into an oral solid dosage form;
vi) optionally coating the oral solid dosage form of step v.

10. A pharmaceutical composition according to claim 1, comprising of amorphous sacubitril valsartan trisodium complex with copovidone, poloxamer, microcrystalline cellulose, L-HPC, crospovidone, talc, colloidal silicon dioxide and magnesium stearate.