DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF INVENTION
The present invention relates to a pharmaceutical composition of a complex of valsartan and sacubitril, known as sacubitril/ valsartan complex (SVC), alkalizing agent and/or surfactant and process of preparation of such pharmaceutical compositions.
BACKGROUND OF INVENTION
Valsartan and sacubitril combination also known as LCZ-696 is a dual-acting compound or combination, in particular a supramolecular complex of two active agents with different mechanisms of action namely an angiotensin receptor antagonist (Valsartan) and a neutral endopeptidase inhibitor (Sacubitril) in 1:1 molar ratio. LCZ-696 is marketed under the trade name ENTRESTO by Novartis for treatment of heart failure. The approved product exists as a co-crystallized complex of anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively.
Valsartan is specific angiotensin II antagonist acting on the AT1 receptor subtype and is indicated for hypertension and heart failure. Valsartan is a BCS class II molecule having low solubility and high permeability and exhibit pH dependent solubility. Being a weakly acidic drug (pKa?=?4.37), valsartan is generally in the ionized form at higher pH, and thus has greater solubility. Sacubitril is an inhibitor of neprilysin (neutral endopeptidase; NEP) and thus enhances the level of natriuretic peptides (NPs), which are reported to have beneficial cardiovascular and renal effects. Sacubitril is reported to be a BCS class IV molecule having low solubility and low permeability.
Pharmaceutical compositions comprising valsartan or pharmaceutically acceptable salts and a neutral endopeptidase (NEP) inhibitor or pharmaceutically acceptable salts for treatment of heart failure are described in the patent application WO2003/059345.
Valsartan and sacubitril supramolecular complex exists as a cocrystal. Pharmaceutical combinations containing such cocrystal, methods of its preparation and its compositions are disclosed in WO2007/056546.
WO2009/061713 discloses compositions comprising solid oral dosage forms of supramolecular complex trisodium [3-((1 S,3R)-1 -biphenyM-ylmethyl-S-ethoxycarbonyl-i -butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate)biphenyl-4' ylmethyl}amino)butyrate]hemipentahydrate (LCZ-696) and process of making such compositions.
WO2016/125123 discloses amorphous form of trisodium sacubitril valsartan and processes for the preparation thereof.
WO2017/012600 discloses pharmaceutical compositions containing valsartan or its pharmaceutically acceptable salts and sacubitril or its pharmaceutically acceptable salts, methods for preparation and stabilization of such compositions by storing it in an inert atmosphere maintained by nitrogen.
The solubility and dissolution of sacubitril/ valsartan complex (SVC) is low and appears to be a challenge for development of a stable composition.
Hence, a well-designed composition that improves the solubility and drug release of valsartan and sacubitril is desirable for promoting favorable pharmacokinetics of sacubitril/ valsartan complex (SVC).
SUMMARY OF INVENTION
The present specification relates to a composition of sacubitril/ valsartan complex (SVC) with pharmaceutically acceptable excipients having favorable solubility and dissolution.
In one aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex; and
(ii) alkalizing agents.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex; and
(ii) surfactants.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) alkalizing agents; and
(iii) surfactants.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) carbonates; and
(iii) non-ionic surfactant.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) calcium carbonate; and
(iii) polyoxyethylene glycol sorbitan alkyl esters.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) alkalizing agents and/ or surfactants; and
(iii) disintegrants.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) alkalizing agents and/ or surfactants,
(iii) one disintegrant
(iv) pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients are selected from diluents, lubricants, carriers, glidants, film forming polymers and solvents.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) silicon dioxide,
(iii) calcium carbonate,
(iv) polyoxyethylene sorbitan monooleate,
(v) crospovidone,
(vi) optionally microcrystalline cellulose; and
(vii) optionally magnesium stearate.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) silicon dioxide,
(iii) calcium carbonate,
(iv) crospovidone,
(v) optionally microcrystalline cellulose; and
(vi) optionally magnesium stearate.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) silicon dioxide,
(iii) polyoxyethylene sorbitan monooleate,
(iv) crospovidone,
(v) optionally microcrystalline cellulose; and
(vi) optionally magnesium stearate.

In yet another aspect, the pharmaceutical composition is prepared by a conventional process selected from physical mixing direct compression, dry granulation, and wet granulation.
In one aspect, the process for preparing the pharmaceutical composition of the present invention comprises the steps of:
(i) preparing the drug solution with or without surfactant,
(ii) spraying the drug solution on silicon dioxide; and
(iii) granulating the contents of step (ii).
(iv) processing the granules to pharmaceutical composition.

DESCRIPTION OF INVENTION
Generally, poorly water-soluble compounds are weakly acidic or basic and, hence, show pH-dependent solubility. For this reason, modulation of pH in dosage forms, known as ‘microenvironmental pH’ (pHM), is a promising way to modify the release rate of several pH-dependent and ionizable compounds. The solubility and dissolution of a compound can be modified by altering the micro environmental pH of solid dosage forms. Microenvironmental pH affects the dissolution behavior and hence the bioavailability of many compounds. A pH modifier can be added to a composition which can modulate the microenvironmental pH and subsequently the performance of a composition.
Similarly, surface active agents (usually referred as surfactants) can be used to increase the solubility of poorly soluble compounds because they reduce the interfacial tension between the medium and the compound and lead to increase in solubility and thus increase in bioavailability.
In one aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex; and
(ii) alkalizing agents.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex; and
(ii) surfactants.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) alkalizing agents; and
(iii) surfactants

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) carbonates; and
(iii) non-ionic surfactant.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) calcium carbonate; and
(iii) polyoxyethylene glycol sorbitan alkyl esters.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) alkalizing agents and/ or surfactants; and
(iii) disintegrants.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) alkalizing agents and/ or surfactants,
(iii) one disintegrant
(iv) pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients are selected from diluents, lubricants, carriers, glidants, film forming polymers and solvents.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) silicon dioxide,
(iii) calcium carbonate,
(iv) polyoxyethylene sorbitan monooleate,
(v) crospovidone,
(vi) optionally microcrystalline cellulose; and
(vii) optionally magnesium stearate.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) silicon dioxide,
(iii) calcium carbonate,
(iv) crospovidone,
(v) optionally microcrystalline cellulose; and
(vi) optionally magnesium stearate.

In another aspect, the present invention relates to a pharmaceutical composition comprising:
(i) sacubitril/ valsartan complex,
(ii) silicon dioxide,
(iii) polyoxyethylene sorbitan monooleate,
(iv) crospovidone,
(v) optionally microcrystalline cellulose; and
(vi) optionally magnesium stearate.

In yet another aspect, the pharmaceutical composition is prepared by a conventional process selected from physical mixing, direct compression, dry granulation, and wet granulation.
In one aspect, the process for preparing the pharmaceutical composition of the present invention comprises the steps of:
(i) preparing the drug solution with or without surfactant,
(ii) spraying the drug solution on silicon dioxide,
(iii) granulating the contents of step (ii) ; and
(iv) processing the granules to pharmaceutical composition.

The term “pharmaceutical composition,” as used herein may include solid dosage forms suitable for oral administration such as tablets, capsules, pills, granules, caplets and the like. In particular the pharmaceutical composition is a tablet.
Tablet may be an immediate release tablet, a delayed release tablet, a modified release tablet, a chewable tablet, a confectionary tablet, an oral disintegrating tablet. The tablet may be coated with film coating or sugar coating with the aim to prevent abrasion, masking bitterness, improving stability, and the like.
The term “sacubitril/ valsartan complex” (SVC) as used herein refers to complex of valsartan and sacubitril as free base or pharmaceutically acceptable salt, stereoisomer, prodrug, solvate, clathrate, thereof.
Valsartan and sacubitril are present in a molar ratio of 1:1, 1:0.25, 1:0.5, 1:1.5, 1:2, 1:2.5, 0.25:1, 0.5:1, 1.5:1, 2:1, 2.5:1 in the sacubitril/ valsartan complex.
Sacubitril/ valsartan complex may be either in amorphous form or in crystalline form.
Sacubitril/ valsartan complex can be used directly in composition or can be processed to form a premix with carrier. Suitable carriers are selected from magnesium alumino-metasilicate, silicified microcrystalline cellulose, mannitol, dicalcium phosphate, colloidal silicon dioxide, silicon dioxide. The ratio of sacubitril/ valsartan complex and carrier may be in the range from 1:0.1 to 1:0.8. In particular the carriers are mannitol, dicalcium phosphate, colloidal silicon dioxide, silicon dioxide, silica and combinations thereof. In particular the ratio of sacubitril/ valsartan complex and carrier is from 1:0.25 to 1:0.5.
The term "alkalizing agent" as used herein refers to an agent that increases the dissolution and solubility of compounds by adjusting the pH of microenvironment of the composition. The present invention may contain one or more alkalizing agents but are not limited to meglumine, triethanolamine, diethanolamine, monoethanolamine, alkaline hydroxides (e.g. sodium hydroxide, magnesium hydroxide), alkaline carbonates (e.g. calcium carbonate, sodium carbonate), alkaline bicarbonates (e.g. sodium bicarbonate), alkaline phosphates (e.g. sodium phosphate, potassium phosphate), alkaline sulfates, alkaline borates, alkaline citrates (e.g. potassium citrate, sodium citrate), ammonia, tris(hydroxymethyl)aminomethane,, arginine or combinations thereof. In particular the alkalizing agents are calcium carbonate, meglumine, sodium carbonate and combinations thereof.
The present invention may contain one or more surfactants or emulsifiers or wetting agents selected from nonionic surfactants, cationic surfactants and anionic surfactants but are not limited to polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, polyoxyethylene glycol sorbitan alkyl esters (polysorbate), sorbitan alkyl esters (span), block copolymers of polyethylene glycol and polypropylene glycol (poloxamer), cetyl trimethylammonium bromide, benzalkonium chloride cetyl trimethylammonium chloride, benzethonium chloride, dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide, octenidine dihydrochloride, ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate (sodium lauryl ether sulfate or SLES), and sodium myreth sulfate, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, perfluorononanoate, perfluorooctanoate, perfluorooctanesulfonate, perfluorobutanesulfonate, phospholipids and combinations thereof. In particular the surfactants are sodium lauryl sulfate, block copolymers of polyethylene glycol and polypropylene glycol, polyoxyethylene glycol sorbitan alkyl esters and combinations thereof.
The present invention may contain one or more diluents selected from, but are not limited to microcrystalline cellulose, e.g., microcrystalline cellulose PH 112, microcrystalline cellulose PH 101, and microcrystalline cellulose PH 102; lactose e.g., lactose monohydrate, directly compressible lactose, lactose anhydrous, and spray dried lactose; Sugars e.g., dextrose, sucrose, dextrates hydrated, maltodextrin, maltose, and isomaltose; invert sugar e.g., levulose (fructose); Sugar alcohols e.g., xylitol, sorbitol, erythritol, mannitol, maltitol, and Isomalt starch, e.g., pregelatinized starch; polyethylene glycol; dicalcium phosphate; calcium sulfate; calcium carbonate and combinations thereof. In particular the diluents are microcrystalline cellulose, lactose, mannitol and combinations thereof.
The present invention may contain one or more disintegrants selected from, but are not limited to croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, l- hydroxypropyl cellulose, crospovidone, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, gums, alginic acid or alginates, pregelatinized starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, clays (e.g. veegum HV), resins (e.g. polacrilin), fine powders (e.g. magnesium aluminium silicate) and combinations thereof. In particular the disintegrants are crospovidone, l-hydroxypropyl cellulose, croscarmellose sodium and combinations thereof.
The present invention may contain one or more glidant selected from, but are not limited to talc, magnesium stearate, stearic acid, calcium stearate, colloidal silicon dioxide, starch, talc and combinations thereof.
The present invention may contain one or more lubricants selected from, but are not limited to magnesium stearate, stearic acid, silica and combinations thereof.
The tablet may be coated with film coating using suitable film forming polymers.
Suitable film forming polymers are selected from the group comprising cellulose ethers e.g., methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose; acrylic polymers and copolymers; polyethylene glycols; polyvinylpyrrolidone; polyvinyl alcohol and combinations thereof.
Plural terms used in the present specification are intended to encompass singular version of term as well.
For example “alkalizing agents” used in specification shall encompass one or more alkalizing agent.
“Surfactants” used in specification shall encompass one or more surfactant.
“Excipients” used in specification shall encompass one or more excipient.
The specification will now be described in more detail by reference to the following non-limiting examples.
EXAMPLES
Example 1.
Ingredients Quantity/unit in mg
SVC 227.0
Methanol QS
Silicon dioxide 90.8
Microcrystalline Cellulose (Avicel PH 101/Avicel PH 102/Avicel PH 302/Avicel PH 112/Avicel PH113) 103.2
Low substituted Hydroxypropyl cellulose (LH 11/LH 22) 48.0
Talc 4.0
Magnesium stearate NF 2.0
Tablet Weight 475.0
Opadry Yellow 23.75
IPA:DCM Qs
Coated Tablet Weight 498.75

Manufacturing Process
(i) SVC was dissolved in methanol (~20-25% solids) and stirred to get a clear drug solution.
(ii) Drug solution was sprayed onto the silicon dioxide and granulated.
(iii) The granulated blend obtained in step (ii) was dried and milled.
(iv) The milled blend was mixed with microcrystalline cellulose, low substituted hydroxypropyl cellulose and talc.
(v) The blend of step (iv) was lubricated with magnesium stearate and finally compressed into tablet.
(vi) The tablets were film coated and packed.

Example 2.
Ingredients Quantity/unit in mg
SVC-Silicon dioxide Premix 317.8
Microcrystalline Cellulose (Avicel PH 101/Avicel PH 102/Avicel PH302, Avicel PH112/Avicel PH113) 103.2
Crospovidone
(Kollidone CL/CLM/CL-SF) 48.0
Talc 4.0
Magnesium stearate NF 2.0
Tablet Weight 475.0
Opadry Yellow 23.75
IPA:DCM Qs
Coated Tablet Weight 498.75

Manufacturing Process
(i) Sacubitril/Valsartan-Silicon dioxide premix was prepared by dissolving Sacubitril/Valsartan complex in methanol and subjected the solution to a rotary cone vacuum drying process, whereupon requisite quantity of silicon dioxide was added and blended together generate the Sacubitril/Valsartan-Silicon dioxide premix (SVC-Silicon dioxide premix).
(ii) SVC- silicon dioxide premix, part of microcrystalline cellulose, and part of crospovidone were blended.
(iii) The blend obtained in step (ii) was roller compacted and milled.
(iv) The roller compacted blend was mixed with remaining half of microcrystalline cellulose, crospovidone and talc.
(v) The blend of step (iv) was lubricated with magnesium stearate and compressed into tablet.
(vi) The tablets were film coated and packed.

Example 3
Ingredients Quantity/unit in mg
SVC- Silicon dioxide Premix 317.800
Microcrystalline Cellulose 97.830
Crospovidone 28.500
Silicon dioxide 3.560
Calcium Carbonate 23.75
Magnesium stearate 3.560
Tablet Weight 475.0
Opadry Clear 14.25
IPA:DCM QS
Coated Tablet Weight 489.25

Manufacturing Process
(i) Sacubitril/Valsartan-Silicon dioxide premix was prepared by dissolving Sacubitril/Valsartan complex in Methanol and subjected the solution to a rotary cone vacuum drying process, whereupon requisite quantity of silicon dioxide was added and blended together generate the Sacubitril/Valsartan-Silicon dioxide premix (SVC-Silicon dioxide premix).
(ii) SVC- Silicon dioxide premix, part of microcrystalline cellulose, and part of crospovidone were blended.
(iii) The blend obtained in step (ii) was roller compacted and milled.
(iv) The roller compacted blend was mixed with remaining half of microcrystalline cellulose, crospovidone, calcium carbonate and silicon dioxide.
(v) The blend of step (iv) was lubricated with magnesium stearate and compressed into tablet.
(vi) The tablets were film coated and packed.

Example 4
Ingredients Quantity/unit in mg
SVC- Silicon dioxide Premix 317.800
Polysorbate 80 23.750
Microcrystalline Cellulose 97.830
Crospovidone 28.500
Silicon dioxide 3.560
Magnesium stearate 3.560
Tablet Weight 475.000
Opadry Clear 14.250
IPA:DCM QS
Coated Tablet Weight 489.250

Manufacturing Process
(i) Sacubitril/Valsartan-Silicon dioxide premix was prepared by dissolving Sacubitril/Valsartan complex in methanol and subjected the solution to a rotary cone vacuum drying process, whereupon requisite quantity of silicon dioxide was added and blended together generate the Sacubitril/Valsartan-Silicon dioxide premix (SVC-Silicon dioxide premix).
(ii) SVC- Silicon dioxide premix and polysorbate 80 were blended together to obtain free flowing powder.
(iii) The blend obtained in step (ii), part of microcrystalline cellulose, and part of crospovidone were blended.
(iv) The blend obtained in step (iii) was roller compacted and milled.
(v) The roller compacted blend was mixed with remaining half of microcrystalline cellulose, crospovidone and silicon dioxide.
(vi) The blend of step (iv) was lubricated with magnesium stearate and compressed into tablet.
(vii) The tablets were film coated and packed.

Example 5
Ingredients Quantity/unit in mg
SVC- Silicon dioxide Premix 317.800
Polysorbate 80 23.750
Microcrystalline Cellulose 74.080
Crospovidone 28.500
Calcium Carbonate 23.750
Silicon dioxide 3.560
Magnesium stearate 3.560
Tablet Weight 475.000
Opadry Clear 14.250
IPA:DCM QS
Coated Tablet Weight 489.250

Manufacturing Process
(i) Sacubitril/Valsartan-Silicon dioxide premix was prepared by dissolving Sacubitril/Valsartan complex in Methanol and subjecting the solution to a rotary cone vacuum drying process, whereupon requisite quantity of silicon dioxide was added and blended together generate the Sacubitril/Valsartan-Silicon dioxide premix (SVC-Silicon dioxide premix).
(ii) SVC- Silicon dioxide premix and polysorbate 80 were blended together to obtain free flowing powder.
(iii) The blend obtained in step (ii), part of microcrystalline cellulose, and part of crospovidone were blended.
(iv) The blend obtained in step (iii) was roller compacted and milled.
(v) The roller compacted blend was mixed with remaining half of microcrystalline cellulose, crospovidone, calcium carbonate and silicon dioxide.
(vi) The blend of step (iv) was lubricated with magnesium stearate and compressed into tablet.
(vii) The tablets were film coated and packed.
Example 6
Ingredients Quantity/unit in mg
SVC 227.0
Methanol QS
Silicon dioxide 90.8
Microcrystalline Cellulose (Avicel PH 101/Avicel PH 102/Avicel PH 302/Avicel PH 112/Avicel PH113) 65.54
Mannitol (Pearlitol SD 200/SD 100/25C) 65.54
Crospovidone
(Kollidone CL/CLM/CL-SF) 19.0
Silicon dioxide 3.56
Magnesium stearate NF 3.56
Tablet Weight 475.0
Opadry 06A29148 Clear 14.25
IPA:DCM Qs
Coated Tablet Weight 489.25

Manufacturing Process
(i) SVC was dissolved in methanol (~20-25% solids) and stirred to get a clear drug solution.
(ii) Drug solution was sprayed onto silicon dioxide and granulated.
(iii) The granulated blend obtained in step (ii) was dried and milled.
(iv) The milled blend was mixed with microcrystalline cellulose, mannitol, crospovidone and silicon dioxide (Syloid 244FP).
(v) The blend of step (iv) was lubricated with magnesium stearate and finally compressed into tablet.
(vi) The tablets were film coated and packed.

Example 7
Ingredients Quantity/unit in mg
SVC 227.000
Methanol QS
Silicon dioxide 90.800
Microcrystalline Cellulose
(Avicel PH 102) 97.830
Calcium Carbonate (precipitated) 23.750
Crospovidone
(Kollidone CL) 28.500
Silicon dioxide 3.56
Magnesium stearate NF 3.56
Tablet Weight 475.0
Opadry 06A29148 Clear 14.25
IPA:DCM QS
Coated Tablet Weight 489.25

Manufacturing Process
(i) SVC was dissolved in methanol (~20-25% solids) and stirred to get a clear drug solution.
(ii) Drug solution was sprayed onto silicon dioxide and granulated.
(iii) The granulated blend obtained in step (ii) was dried and milled.
(iv) The milled blend was mixed with microcrystalline cellulose, calcium carbonate, crospovidone and silicon dioxide.
(v) The blend of step (iv) was lubricated with magnesium stearate and finally compressed into tablet.
(vi) The tablets were film coated and packed.

Example 8
Ingredients Quantity/unit in mg
SVC 227.000
Methanol QS
Silicon dioxide 90.800
Microcrystalline Cellulose
(Avicel PH 102) 74.080
Calcium Carbonate (precipitated) 23.750
Polysorbate 80 23.750
Crospovidone
(Kollidone CL) 28.500
Silicon dioxide 3.56
Magnesium stearate NF 3.56
Tablet Weight 475.0
Opadry 06A29148 Clear 14.25
IPA:DCM Qs
Coated Tablet Weight 489.25

Manufacturing Process
(i) SVC was dissolved in methanol (~20-25% solids) and stirred with Polysorbate 80 to get a clear drug solution.
(ii) Drug solution was sprayed onto the silicon dioxide and granulated.
(iii) The granulated blend obtained in step (ii) was dried and milled.
(iv) The milled blend was mixed with microcrystalline cellulose, calcium carbonate, crospovidone and silicon dioxide (Syloid 244FP).
(v) The blend of step (iv) was lubricated with magnesium stearate and finally compressed into tablet.
(vi) The tablets were film coated and packed.
,CLAIMS:WE CLAIM:

1. A pharmaceutical composition of sacubitril/ valsartan complex comprising:
(i) alkalizing agent and/or
(ii) surfactant and /or
(iii) pharmaceutically acceptable excipients.
2. A pharmaceutical composition of claim 1 wherein alkalizing agent is selected from the group consisting of meglumine; triethanolamine; diethanolamine; monoethanolamine; alkaline hydroxides selected from group consisting of sodium hydroxide, magnesium hydroxide; alkaline carbonates selected from group consisting of calcium carbonate, sodium carbonate; alkaline bicarbonates like sodium bicarbonate; alkaline phosphates selected from group consisting of sodium phosphate, potassium phosphate; alkaline sulfates; alkaline borates; alkaline citrates selected from the group consisting of potassium citrate, sodium citrate; ammonia, tris (hydroxymethyl) aminomethane, arginine and combinations thereof.
3. A pharmaceutical composition of claim 1 wherein alkalizing agent is calcium carbonate.
4. A pharmaceutical composition of claim 1 wherein surfactant is selected from group consisting of non-ionic surfactant, cationic surfactant and anionic surfactant.
5. A pharmaceutical composition of claim 1 wherein surfactant is selected from group consisting of polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, polyoxyethylene glycol sorbitan alkyl esters, sorbitan alkyl esters, block copolymers of polyethylene glycol and polypropylene glycol, cetyl trimethylammonium bromide, benzalkonium chloride cetyl trimethylammonium chloride, benzethonium chloride, dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide, octenidine dihydrochloride, ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate, sodium myreth sulfate, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, perfluorononanoate, perfluorooctanoate, perfluorooctanesulfonate, perfluorobutanesulfonate, phospholipids and combinations thereof.
6. A pharmaceutical composition of claim 1 wherein surfactant is polyoxyethylene glycol sorbitan alkyl ester.
7. A pharmaceutical composition of claim 1 wherein composition contains pharmaceutically acceptable excipients selected from group consisting of diluent, binder, disintegrant, glidant, lubricants and coating agents.
8. A pharmaceutical composition of claim 7 wherein composition contains microcrystalline cellulose, silicon dioxide, crospovidone, calcium carbonate, polyoxyethylene sorbitan monooleate and magnesium stearate.
9. The process for preparing pharmaceutical composition of any of the preceding claims comprising the steps of:
(i) preparing the drug solution with or without surfactant,
(ii) spraying the drug solution on silicon dioxide; and
(iii) granulating the contents of step (ii),
(iv) processing the granules to pharmaceutical composition.
10. A pharmaceutical composition as substantially described herein by way of description and examples.