DESC:Field of the invention
The present invention relates to pharmaceutical compositions comprising sacubitril-valsartan complex. More particularly, the present invention relates to a stable composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients and process for preparing such compositions.

Background of the invention
Sacubitril is chemically known as 4-{ [(25,4R)-l-(4-biphenylyl)-5-ethoxy-4-methyl-5- oxo-2-pentanyl] amino }-4-oxobutanoic acid, which is a neprilysin inhibitor. Sacubitril (AHU-377) is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases.
Valsartan is chemically known as (5)-3-methyl-2-(N-{ [2'-(2H-l,2,3,4-tetrazol-5-yl)biphenyl-4- yl] methyl }pentanamido)butanoic acid, which is Angiotensin II Receptor Blocker (ARBs).
The supramolecular complex is a neprilysin inhibitor and angiotensin II receptor blocker combination shown to reduce the risk of death and hospitalization in patients with chronic heart failure. It is a first-in-class combination of the angiotensin II receptor blocker, valsartan and the neprilysin (NEP) inhibitor, sacubitril.
The complex of valsartan/sacubitril is marketed in the form of tablets under the brand name ENTRESTO® by Novartis in the US. The combination drug valsartan/sacubitril, known during trials as LCZ696.
The isolated active substance is a co-crystal complex of the sodium salts of two individual active components, sacubitril and valsartan, in hydrated form.
Said supramolecular complex is an aggregate which is comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively. The complex is chemically described as Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4oxobutanoate)hexakis(N-pentanoyl-N-{[2´-(1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)-water (1/15).
Following oral administration, the complex dissociates into sacubitril. It is a prodrug which is further metabolized to LBQ657 (sacubitrilat) and valsartan.
The supramolecular complex of sacubitril and valsartan is first disclosed in US 8877938. The patent discloses the supramolecular complex in the form of trisodium sacubitril- valsartan hemipentahydrate.
US 7468390 discloses a combination composition comprising valsartan and Sacubitril, where in the combination achieves a greater anti-hypertensive effect than individual drugs.
US 8101659 and US 8404744 discloses a composition comprising Valsartan and Sacubitril which are administered in combination in 1:1 ratio.
US 8796331 discloses a method of treating hypertension and heart failure by administering a combination of Valsartan and Sacubitril administered in one unit dose form or in two separate unit dose forms.
US 8877938 disclosed trisodium sacubitril-valsartan hemipentahydrate in crystalline form.
US 9388134 discloses a method for treatment of a cardiovascular condition or disease, wherein the cardiovascular condition or disease is heart failure or hypertension by administering trisodium sacubitril-valsartan hemipentahydrate.
US 2010/0267786 discloses a dosage form comprising trisodium sacubitril-valsartan hemipentahydrate in a concentration from about 4% to about 90% by weight of the composition; and at least one pharmaceutically acceptable excipient.
US 9517226 discloses a method for the treatment of heart failure with preserved ejection fraction (HF-PEF) by administering trisodium salt complex of valsartan and sacubitril hemipentahydrate.
WO 2016/037552 discloses a complex of crystalline trisodium sacubitril-valsartan X. H2O.
WO 2016/049663 A1 discloses a formulation comprising a unit dosage of crystalline Form I, crystalline Form II or crystalline Form III of trisodium salt of sacubitril-valsartan complex hydrate and one or more excipients selected from the group consisting of fillers, disintegrants, glidants, and lubricants.
WO 2016/051393 A1 discloses a formulation comprising a unit dosage of crystalline Form IV of trisodium salt of sacubitril-valsartan complex hydrate and one or more excipients.
WO 2017/009784 A1 discloses composition comprising an amorphous trisodium salt of sacubitril-valsartan complex and composition comprising crystalline Form II or Form IV of trisodium salt of valsartan sacubitril complex.
WO 2017/020841 A1 discloses a composition comprising crystalline powder containing LCZ696 (sacubitril-valsartan complex), a filler, a disintegrant, and a binder, wherein the crystalline powder of LCZ696 used in the pharmaceutical composition is having a particle size of 20 µm = D90 = 100 µm.
WO 2017/037596 A1 discloses an amorphous solid dispersion of LCZ-696 (sacubitril-valsartan complex) with one or more carrier.
WO 2016125123 discloses amorphous trisodium sacubitril-valsartan.
The above prior art references discloses compositions comprising trisodium salt of sacubitril-valsartan complex hemipentahydrate in crystalline form. None of the above references discloses composition comprising trisodium salt of sacubitril-valsartan complex trihydrate. The inventors of the present invention have surprisingly found that a tablet composition comprising more than 60% w/w of trisodium salt of sacubitril-valsartan complex trihydrate showed good stability and does not show any change in polymorphic form after accelerated stability studies.

Objective of the invention
The main objective of the present invention relates to a stable composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.
The present invention also relates to a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.
The present invention also relates to a process for the preparation of a stable composition trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients having comparable dissolution properties, content uniformity, stability and equivalent bioavailability w.r.t commercialized valsartan sacubitril complex dosage form.

Summary of the invention
Accordingly, the present invention provides a stable pharmaceutical composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.
The present invention also relates to a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.

Detailed description of the invention
The present invention relates to a stable pharmaceutical composition comprising trisodium salt of sacubitril-valsartan complex and one or more pharmaceutically acceptable excipients.
The present invention relates to a stable pharmaceutical composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.
The present invention relates to a stable pharmaceutical composition comprising trisodium salt of sacubitril-valsartan complex trihydrate in crystalline form and one or more pharmaceutically acceptable excipients.
The present invention also relates a process for the preparation of a stable pharmaceutical composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.
The present invention relates to a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex and one or more pharmaceutically acceptable excipients.
The present invention relates to a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.
The present invention relates to a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate in crystalline form and one or more pharmaceutically acceptable excipients.
The present invention relates to a stable tablet composition comprising more than 60% w/w of trisodium salt of sacubitril-valsartan complex trihydrate in crystalline form and one or more pharmaceutically acceptable excipients.
The present invention also relates a process for the preparation of a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.
In an embodiment, “valsartan” according to the present invention includes but not limited to valsartan and its pharmaceutically acceptable salts, ethers, esters, prodrugs and derivatives thereof.
In an embodiment, “sacubitril” according to the present invention includes but not limited to sacubitril and its pharmaceutically acceptable salts, ethers, esters, prodrugs and derivatives thereof.
As used herein, the term “% w/w” refers to the weight of the component based on the total weight of a composition comprising the component.
“Pharmaceutically acceptable excipient/s” are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc.
In another embodiment, the composition according to the present invention further comprises one or more pharmaceutically acceptable excipients which include but not limited to diluents, disintegrants, binders, surfactants, glidants and lubricants. These excipients may be present intragranularly or extragranularly.

Diluents according to the present invention include but not limited to lactose monohydrate, lactose anhydrous, fructose, dextrose, dextrates, dextrins, mannitol, lactitol, sorbitol, starch, sucrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, kaolin and the like or combinations thereof. The diluent can be used in the range of about 5-90% w/w of the composition.

Binders according to the present invention include but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, sodium alginate, microcrystalline cellulose and the like or combinations thereof. The binder can be used in the range of about 0-15% w/w of the composition.

Disintegrants according to the present invention include but not limited to starches or modified starches such as pregelatinized starch, croscarmellose sodium, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose and the like or combinations thereof. The disintegrant can be used in the range of about 1-20% w/w of the composition.

Surfactants according to the present invention may be selected from anionic, cationic or non- ionic surface-active agents or surfactants. Suitable anionic surfactants include but not limited to carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include but not limited to those containing long chain cations, such as benzalkonium chloride, bis-2- hydroxyethyl oleyl amine or the like. Suitable non-ionic surfactants include but not limited to polyoxyethylene sorbitan fatty acid esters (polysorbates), fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols; polyglycolized glycerides such as gelucire; polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol. The surfactant can be used in the range of about 0-20% w/w of the composition.

Lubricants and/or glidants according to the present invention include but not limited to colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, and mixtures thereof. The Lubricants and/or glidants can be used in the range of 0.01-10% w/w of the composition.

In one embodiment of the present invention, the stable composition comprises trisodium salt of sacubitril-valsartan complex trihydrate in an amount of more than 60% w/w of the composition.
In another preferred embodiment of the present invention, the trisodium salt of sacubitril-valsartan complex trihydrate is in the form selected from crystalline and amorphous.
In another preferred embodiment, the present invention provides a stable composition comprising trisodium salt of sacubitril-valsartan complex trihydrate in crystalline form and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more pharmaceutically acceptable excipients,
(ii) formulating the blend of step (i) into suitable dosage form.

In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more pharmaceutically acceptable excipients,
(ii) optionally, lubricating the blended material of step (i) with a lubricant, and
(iii) preparing the lubricated material of step (ii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more pharmaceutically acceptable excipients,
(ii) compressing the blend of step (i) into tablet dosage form.

In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more
pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i),
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable
excipients, and
(iv) compressing the lubricated blend of step (iii) into tablet dosage form.

In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more pharmaceutically acceptable excipients, and
(iii) filling the blend of step (i) into capsules.

In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more pharmaceutically acceptable excipients,,
(ii) lubricating the blended material of step (iii) with a lubricant, and
(iii) filling the lubricated material of step (ii) into capsules.
In another embodiment, the pharmaceutical composition according to the present invention is in the form of tablets, capsules, granules, powder, pellets and sachets.
In another embodiment, the blend is formulated into a suitable dosage form like tablets or capsules using different techniques which are well known in the prior art.
In another embodiment, the compositions of the present invention may be prepared using any method known in the art, but are not limited to encapsulation, wet granulation, dry granulation, roller compaction and direct compression.
In another embodiment, the solvents used for granulation process may be selected from water, isopropyl alcohol, methanol, ethanol, methylene chloride or combination thereof.
The pharmaceutical composition may be further film coated with functional or non functional layer. The coating may be selected from amongst one or more of those suitable coating materials known in the art. For example, the coating material can be Opadry or Opadry AMB. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
Coloring agent may be selected from FDA approved colorants such as Iron Oxide, Lake of Tartrazine, Allura Red, Lake of Quinoline Yellow, Lake of Erythrosine, Titanium Dioxide and the like.
In one preferred embodiment, the pharmaceutical composition according to the present invention is in the form of tablets.
In another preferred embodiment, the present invention provides a stable composition comprising trisodium salt of sacubitril-valsartan complex trihydrate in crystalline form.

In another preferred embodiment, the present invention provides a process for the preparation of stable pharmaceutical composition comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more
pharmaceutically acceptable excipients selected from diluent, binder, disintegrant
and glidant;
(ii) optionally, lubricating the blended material of step (i) with a lubricant; and
(iii) preparing the lubricated material of step (ii) into a suitable composition.

In another preferred embodiment, the present invention provides a stable pharmaceutical composition comprising:
(i) more than 60% w/w of trisodium salt of sacubitril-valsartan complex trihydrate;
(ii) about 5-50 % by weight of a diluent;
(iii) about 1-20% by weight of a disintegrant;
(iv) about 0-15% by weight of a binder;
(v) about 0.1-10% by weight of a glidant and/or lubricant.

In another preferred embodiment, the present invention provides a stable tablet composition comprising:
(i) more than 60% w/w of trisodium salt of sacubitril-valsartan complex trihydrate in
crystalline form;
(ii) about 5-50 % by weight of a diluent selected from microcrystalline cellulose,
lactose and combination thereof,
(iii) about 1-20% by weight of a disintegrant selected from crospovidone, low
substituted hydroxypropyl cellulose and combination thereof,
(iv) about 0.1-10% by weight of a glidant and/or lubricant selected from colloidal
silicon dioxide, talc, magnesium stearate and combination thereof.

In another preferred embodiment, the present invention provides a process for the preparation of stable tablet composition of trisodium salt of sacubitril-valsartan complex comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with diluent selected from microcrystalline cellulose, lactose and combination thereof, disintegrant selected from crospovidone, low substituted hydroxypropyl cellulose and combination thereof, glidant/lubricant selected from colloidal silicon dioxide, talc and combination thereof,
(ii) lubricating the blend of step (i) with a lubricant,
(iii) granulating the lubricated blend of step (ii) by roller compaction,
(iv) blending the granules of step (iii) with a disintegrant selected from crospovidone,
low substituted hydroxypropyl cellulose and combination thereof and a
glidant/lubricant selected from colloidal silicon dioxide, talc and combination
thereof,
(v) lubricating the blend of step (iv) with a lubricant,
(vi) compressing the lubricated blend of step (v) into tablets, and
(vii) optionally coating the tablets prepared in step (vi) with a film coating
composition.

As used herein, the term “stable” means less than 1% of known and/or unknown impurities and less than 5% of total impurities.

In another embodiment, the present invention provides a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate, and the tablet composition is chemically stable when stored at 40°C / 75% RH for 6 months.
In another embodiment, the present invention provides a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate, having a moisture content in the range of 0-10% w/w, preferably in the range of 0-5% w/w and more preferably in the range of 0-3% w/w.

In another embodiment, the present invention provides a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate, having assay in the range of 95.0% to 105.0%.

In another embodiment, the present invention provides a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate, having a dissolution not less than 80% of the labeled amount of valsartan and sacubitril in 30 minutes.

In yet another embodiment, the present invention provides a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate in the range of about 1mg to about 1000 mg.

In another embodiment, the present invention provides a stable tablet composition comprising trisodium salt of sacubitril-valsartan complex trihydrate 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 invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Tablet compositions comprising trisodium salt of sacubitril-valsartan complex trihydrate
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Sacubitril-Valsartan (as a sodium salt complex trihydrate) 228.340
2 Microcrystalline cellulose 20.410
3 Crospovidone 12.000
4 Low substituted Hydroxypropyl cellulose 18.000
5 Colloidal silicon dioxide 1.250
6 Talc 2.000
7 Magnesium stearate 4.000
Extra-granular
8 Low substituted Hydroxypropyl cellulose 40.000
9 Talc 1.000
10 Magnesium stearate 3.000
Total Core tablet 330.000
Film Coating
11 Opadry® (00F540021) Pink 10.000

The processing steps involved in manufacturing the tablets were given below:
(i) Sacubitril-Valsartan complex was blended with microcrystalline cellulose, crospovidone, low substituted Hydroxypropyl cellulose, colloidal silicon dioxide and talc,
(ii) the blend of step (i) was lubricated with magnesium stearate,
(iii) the lubricated blend of step (ii) was compacted using roller compacter and the obtained flakes were milled and sifted,
(iv) the granules of step (iii) were blended with extra-granular low substituted hydroxypropyl cellulose and talc,
(v) the blend obtained in step (iv) was lubricated with magnesium stearate,
(vi) the lubricated blend of step (v) was compressed into tablets,
(vii) the tablets obtained in step (vi) was coated with Opadry® coating solution.

Example 2:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Sacubitril-Valsartan (as a sodium salt complex trihydrate) 228.340
2 Microcrystalline cellulose 37.160
3 Crospovidone 30.000
4 Low substituted Hydroxypropyl cellulose 12.000
5 Colloidal silicon dioxide 1.250
6 Talc 2.000
7 Magnesium stearate 4.000
Extra-granular
8 Crospovidone 10.000
9 Colloidal silicon dioxide 1.250
10 Talc 1.000
11 Magnesium stearate 3.000
Total Core tablet 330.000
Film Coating
12 Opadry® (00F540021) Pink 10.000
Example 3:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Sacubitril-Valsartan (as a sodium salt complex trihydrate) 228.340
2 Microcrystalline cellulose 22.160
3 Crospovidone 45.000
4 Low substituted Hydroxypropyl cellulose 12.000
5 Colloidal silicon dioxide 1.500
6 Talc 2.000
7 Magnesium stearate 4.000
Extra-granular
8 Crospovidone 10.000
9 Colloidal silicon dioxide 1.000
10 Talc 1.000
11 Magnesium stearate 3.000
Total Core tablet 330.000
Film Coating
12 Opadry® (00F540021) Pink 10.000

Example 4:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Sacubitril-Valsartan (as a sodium salt complex trihydrate) 57.085
2 Microcrystalline cellulose 5.540
3 Crospovidone 11.250
4 Low substituted Hydroxypropyl cellulose 3.000
5 Colloidal silicon dioxide 0.375
6 Talc 0.500
7 Magnesium stearate 1.000
Extra-granular
8 Crospovidone 2.500
9 Colloidal silicon dioxide 0.250
10 Talc 0.250
11 Magnesium stearate 0.750
Total Core tablet 82.500
Film Coating
12 Opadry® (00F540026) Pink 2.500

Example 5:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Sacubitril-Valsartan (as a sodium salt complex trihydrate) 114.170
2 Microcrystalline cellulose 11.080
3 Crospovidone 22.500
4 Low substituted Hydroxypropyl cellulose 6.000
5 Colloidal silicon dioxide 0.750
6 Talc 1.000
7 Magnesium stearate 2.000
Extra-granular
8 Crospovidone 5.000
9 Colloidal silicon dioxide 0.500
10 Talc 0.500
11 Magnesium stearate 1.500
Total Core tablet 165.000
Film Coating
12 Opadry® (00F520032) Yellow 5.000

The compositions given in Examples 2-5 were prepared using similar procedure described in Example-1.
Dissolution Data: Table-1 given below provides the comparative dissolution profile of sacubitril-valsartan trisodium trihydrate complex tablets prepared according to Example 1 and ENTRESTO® (Sacubitril/Valsartan ) Tablets, 97 mg/103 mg tablets carried out in 900 ml of pH 6.8 phosphate buffer as dissolution medium in USP II apparatus (paddle) at 50 rpm.

Table 1: Comparative dissolution profile of sacubitril-valsartan trisodium trihydrate complex tablets prepared according to Example 1 and ENTRESTO® 97 mg/103 mg mg tablets
Time
(Minutes) ENTRESTO® (Sacubitril/Valsartan ) Tablets, 97 mg / 103 mg Tablets prepared according to Example-1
Cumulative % Sacubitril released
0 0.00 0.00
10 47.1 51.9
15 66.8 73.6
20 82.1 90.0
30 94.9 100.8
45 97.1 102.4
Time
(Minutes) Cumulative % Valsartan released
0 0.00 0.00
10 49.8 54.7
15 70.5 77.6
20 86.6 94.8
30 100.0 105.9
45 102.3 107.8

Stability Data: Table 2 given below shows the impurity profile of sacubitril-valsartan trisodium trihydrate complex tablets prepared according to Example-1 of the present invention after storing at 40°C/75% RH for 6 months.
Table 2: Stability data of sacubitril-valsartan trisodium trihydrate complex tablets prepared according to Example-1 after storing in blister pack at 40°C/75% RH for 6 months

Impurities Initial 1 month 6 months
Related Substances - Sacubitril
Impurity A Not Detected Not Detected 0.007
Impurity B Not Detected Not Detected 0.040
Impurity C Not Detected Not Detected 0.015
Unknown impurity 0.011 0.010 0.010
Total Impurities 0.011 0.010 0.072
Related Substances - Valsartan
Unknown impurity 0.016 0.023 0.021
Total Impurities 0.030 0.040 0.070

The stability study results of the Tablets of Example 1 indicates that, the tablets remains stable for a period of at least 6 months at 40°C and 75% relative humidity. Further, total related substances were within the specified limits.
,CLAIMS:We claim:
1. A stable pharmaceutical composition comprising more than 60% w/w of trisodium salt of sacubitril-valsartan complex trihydrate and one or more pharmaceutically acceptable excipients.

2. The stable pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutical excipients are selected from diluents, disintegrants, binders, surfactants, glidants and lubricants.

3. The stable pharmaceutical composition as claimed in claim 2, wherein the diluent is selected from lactose monohydrate, lactose anhydrous, microcrystalline cellulose, silicified microcrystalline cellulose, fructose, dextrose, dextrates, dextrins, mannitol, lactitol, sorbitol, starch, sucrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, cellulose powdered, kaolin and combination thereof.

4. The stable pharmaceutical composition as claimed in claim 2, wherein the disintegrant is selected from starch, modified starches, pregelatinized starch, croscarmellose sodium, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose and the like or combinations thereof.

5. The stable pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of tablets, capsules, granules, powder, pellets and sachets.

6. A process for the preparation of stable pharmaceutical composition as claimed in claim 1, comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with one or more
pharmaceutically acceptable excipients selected from diluent, binder, disintegrant
and glidant;
(ii) optionally, lubricating the blended material of step (i) with a lubricant; and
(iii) preparing the lubricated material of step (ii) into a suitable composition.

7. The stable pharmaceutical composition as claimed in claim 5, wherein the process for preparation of the composition is selected from wet granulation, dry granulation, roller compaction, direct compression and encapsulation.

8. A stable pharmaceutical composition comprising:
(i) more than 60% w/w of trisodium salt of sacubitril-valsartan complex trihydrate;
(ii) about 5-50 % by weight of a diluent;
(iii) about 1-20% by weight of a disintegrant;
(iv) about 0-15% by weight of a binder;
(v) about 0.1-10% by weight of a glidant and/or lubricant.

9. A stable tablet composition comprising
(i) more than 60% w/w of trisodium salt of sacubitril-valsartan complex trihydrate in
crystalline form;
(ii) about 5-50 % by weight of a diluent selected from microcrystalline cellulose,
lactose and combination thereof,
(iii) about 1-20% by weight of a disintegrant selected from crospovidone, low
substituted hydroxypropyl cellulose and combination thereof,
(iv) about 0.1-10% by weight of a glidant and/or lubricant selected from colloidal
silicon dioxide, talc, magnesium stearate and combination thereof.

10. A process for the preparation of stable tablet composition of trisodium salt of sacubitril-valsartan complex trihydrate comprising the steps of:
(i) blending trisodium salt of sacubitril-valsartan complex trihydrate with a diluent
selected from microcrystalline cellulose, lactose and combination thereof, a
disintegrant selected from crospovidone, low substituted hydroxypropyl cellulose
and combination thereof, a glidant/lubricant selected from colloidal silicon
dioxide, talc and combination thereof,
(ii) lubricating the blend of step (i) with a lubricant,
(iii) granulating the lubricated blend of step (ii) by roller compaction,
(iv) blending the granules of step (iii) with a disintegrant selected from crospovidone,
low substituted hydroxypropyl cellulose and combination thereof and a
glidant/lubricant selected from colloidal silicon dioxide, talc and combination
thereof,
(v) lubricating the blend of step (iv) with a lubricant,
(vi) compressing the lubricated blend of step (v) into tablets, and
(vii) optionally coating the tablets prepared in step (vi) with a film coating
composition.