DESC:Present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients and processes for the preparation of formulation comprising Sacubitril; Valsartan by wet granulation or dry granulation or direct compression method.

Present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein the Sacubitril; Valsartan having above 60% w/w of the composition.

The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.

The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "immediate release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that Sacubitril; Valsartan.

The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.

The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, fillers, diluents, carriers and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.

By the term “composition” as used herein refers to a solid dosage form suitable for oral administration, such as a tablet, capsule, spheroids, mini-tablets, pellets, granules, pills and the like; preferably, oral tablets.

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, or combinations thereof.

Binders according to the present invention include but not limited to hydroxypropyl methylcellulose, Low substituted Hydroxy Propyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, Polysorbate 80, sodium alginate, microcrystalline cellulose and the like or combinations thereof.

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.

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.

Lubricants and/or glidants according to the present invention include but not limited to colloidal silicon dioxide, stearic acid, magnesium stearate, syloid XDP, calcium stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, and mixtures thereof.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients thereof and processes for the preparation of formulation comprising Sacubitril; Valsartan.

In one of the embodiments of the present invention is to provide a stable immediate release oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients thereof and manufacturing processes for the preparation comprising Sacubitril; Valsartan.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients and processes for the preparation of formulation comprising Sacubitril; Valsartan.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan tri-sodium hydrate, and one or more pharmaceutically acceptable excipients and processes for the preparation of formulation comprising Sacubitril; Valsartan by wet granulation or dry granulation or direct compression method.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form contain crystalline Form-P of Sacubitril; Valsartan tri sodium hydrate and one or more pharmaceutically acceptable excipients thereof and processes for the preparation of formulation comprising Sacubitril; Valsartan by granulation technique.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form contain crystalline Form-P of Sacubitril; Valsartan tri sodium hydrate and one or more pharmaceutically acceptable excipients thereof and processes for the preparation by pre-warming Sacubitril-Valsartan tri sodium hydrate with pharmaceutically acceptable excipients where in the process of preparation of Sacubitril-Valsartan involves spraying of drug solution along with surfactant optionally with binder on to the excipients for granulation of pharmaceutical composition of Sacubitril-Valsartan.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein the Sacubitril; Valsartan having above 60% w/w of the composition.

In one of the embodiments of the present invention relates to a process for the preparation of Sacubitril; Valsartan 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.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan tri sodium hydrate and one or more pharmaceutically acceptable excipients like diluent, binder, glidant, lubricant, solubilizer, stabilizer, disintegrant and colorant.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan tri sodium hydrate and one or more pharmaceutically acceptable excipients like microcrystalline cellulose, low substituted hydroxy propyl cellulose, colloidal silicon dioxide, talc, magnesium stearate.

In one of the embodiments of the present invention is to provide a stable immediate release oral dosage form of Sacubitril; Valsartan tri sodium hydrate and more pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients like microcrystalline cellulose, Low substituted hydroxy propyl cellulose, colloidal silicon dioxide, Talc, magnesium stearate.

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients thereof wherein the Sacubitril; Valsartan tri-sodium hydrate having above 60% w/w of the composition.

In one of the embodiments of the present invention is to provide a method for treatment of a cardiovascular diseases by administering an immediate release pharmaceutical formulation comprising Sacubitril; Valsartan and its pharmaceutically acceptable salts.

One embodiment of the present invention is to provide new crystalline Form P of trisodium Sacubitril valsartan hydrate, which is characterized by its Powder X-Ray Diffraction (PXRD) pattern having characteristic peaks at about 4.17, 4.91, 12.52, 16.91, 20.10 ± 0.2 degrees of two-theta.

According to the embodiment of the present invention is to provide new crystalline Form P of trisodium Sacubitril valsartan hydrate, which is characterised by its X-Ray powder diffraction pattern having additional peaks at about 4.17, 4.91, 5.99, 8.34, 9.08, 10.24, 12.52, 13.33, 13.97, 15.33, 16.01, 16.91, 17.64, 19.34, 20.10, 20.84, 22.57, 24.24, 26.34, 27.10, 29.18. 30.59 ± 0.2 degrees of two-theta.

The crystalline Form P is further characterized by an infrared absorption spectrum comprising peaks at about 3401.33, 3114.09, 3009.06, 2958.95, 2355.74, 1712.75, 1690.25, 1638.75, 1599.57, 1497.81, 1487.93, 1480.81, 1435.51, 1403.05, 1315.03 1296.23, 1266.89, 1213.19, 1176.33, 1150.02, 1085.64, 1045.47, 1010.08, 923.9, 763.88, 742.29, 698.79, 560.13 cm-1.

According to present invention, Form P can be further characterized by water content within the range of 5 to 8 %, preferably 5-7 %. Thermogravimetric analysis (TGA) was performed using a TGA55 Thermogravimety Samples of 7 to 10 milligrams and operating at heating rate of 20°C/min.

Examples
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example: 1
Manufacturing Formula:
S. No. Ingredients Category Qty/ Tablet (mg) % w/w
24/26 mg 49+51 mg 97+103 mg
Intra granular Part
1 Sacubitril and Valsartan tri sodium hydrate (Form P) Active Ingredient 57.082 114.165 228.33 63.42
2 Microcrystalline cellulose (Hicel XLM 90) Diluent 14.418 28.835 57.67 16.02
3 Low substituted Hydroxy Propyl cellulose (L-HPC 11) Dry Binder 7.50 15.00 30.00 8.33
4 Colloidal silicon dioxide (Aerosil 200 Pharma) Glidant 1.00 2.00 4.00 1.11
5 Magnesium Stearate (Ligamed MF 2V) Lubricant 0.50 1.00 2.00 0.56
Extragranular Part
6 Microcrystalline cellulose (Hicel XLM 90) Diluent 5.00 10.00 20.00 5.56
7 Talc (Luzenac Pharma) Glidant 1.00 2.00 4.00 1.11
8 Crospovidone Xl 10 Disintegrant 2.25 4.50 9.00 2.50
9 Colloidal silicon dioxide (Aerosil 200 Pharma) Glidant 0.75 1.50 3.00 0.83
10 Magnesium stearate ( Ligamed MF 2V) Lubricant 0.50 1.00 2.00 0.56
Total weight of uncoated tablet 90.00 180.00 360.00 100.00
Coating Materials
11 Colorozy pink 17F540247$ Film coating agents 2.70 -- -- 3.00
12 Colorozy Yellow 17F520349€ -- 5.40 -- 3.00
13 Colorozy pink 17F540248p -- -- 10.80 3.00
14 Iso Propyl Alcohol Solvent q.s. q.s. q.s. q.s.
15 Di Chloro Methane Solvent q.s. q.s. q.s. q.s.
Total weight of coated Tablet 92.70 185.40 370.80

Manufacturing Process:
1. Sifting: Co sift Sacubitril and Valsartan API Complex, Microcrystalline cellulose (Hicel XLM 90), Low substituted Hydroxy propyl cellulose, Colloidal silicon Di oxide through #40 mesh.
2.Sifting: Sift Magnesium stearate through #60 mesh
3.Blending: Add sstep 2 blend to step 1 and blend in a suitable blender upto 15 minutes.
4.Roll compaction: Compact the step 3 with roll compactor and milled with 1.00 mm screen in multi mill to attain desired granules and continued compaction and milling process until all the granules passes through 30# mesh.
5.Prelubrication: Sift Microcrystalline cellulose (Hicel XLM 90), Talc, Crosspovidone XL 10, Colloidal silicon Di oxide through 30 # mesh.Add this to step 4 Blend and blend in a suitable blender upto 15 minutes.
6.Sift Magnesium stearate through 60# mesh.
7.Lubrication: Add ste6 blend to step 5 Blend and Blend for 5 mins.
8.Compression: Compress the above blend by using suitable punches.
9.Film Coating: Prepare the coating dispersion by dispersing Colorozy Pink, Yellow and Pink in purified water under stirring and coat the compressed tablets of step 8 with the coating dispersion.

Example 2:
Manufacturing Formula:
S. No. Ingredients Category Qty/ Tablet (mg) % w/w
24/26 mg 49+51 mg 97+103 mg
Intra granular Part
1 Sacubitril and Valsartan tri sodium hydrate (Form P) Active Ingredient 57.082 114.165 228.33 57.08
2 Microcrystalline cellulose (Hicel XLM 90) Diluent 24.418 48.835 97.67 24.41
3 Low substituted Hydroxy Propyl cellulose (L-HPC 11) Dry Binder 7.50 15.00 30.00 7.50
4 Colloidal silicon dioxide (Aerosil 200 Pharma) Glidant 1.00 2.00 4.00 1.00
5 Magnesium Stearate (Ligamed MF 2V) Lubricant 0.50 1.00 2.00 0.50
Extragranular Part
6 Microcrystalline cellulose (Hicel XLM 90) Diluent 5.00 10.00 20.00 5.00
7 Talc (Luzenac Pharma) Glidant 1.00 2.00 4.00 1.00
8 Crospovidone Xl 10 Disintegrant 2.25 4.50 9.00 2.25
9 Colloidal silicon dioxide (Aerosil 200 Pharma) Glidant 0.75 1.50 3.00 0.75
10 Magnesium stearate ( Ligamed MF 2V) Lubricant 0.50 1.00 2.00 0.50
Total weight of uncoated tablet 100.00 200.00 400.00 100.00
Coating Materials
11 Colorozy pink 17F540247$ Film coating agents 3.00 -- -- 3.00
12 Colorozy Yellow 17F520349€ -- 6.00 -- 3.00
13 Colorozy pink 17F540248p -- -- 12.00 3.00
14 Iso Propyl Alcohol Solvent q.s. q.s. q.s. q.s.
15 Di Chloro Methane Solvent q.s. q.s. q.s. q.s.
Total weight of coated Tablet 103.00 206.00 412.00
Manufacturing Process:
1. Sifting: Co sift Sacubitril and Valsartan API Complex, Microcrystalline cellulose (Hicel XLM 90), Low substituted Hydroxy propyl cellulose, Colloidal silicon Di oxide through #40 mesh.
2. Sifting: Sift Magnesium stearate through #60 mesh
3. Blending: Add sstep 2 blend to step 1 and blend in a suitable blender upto 15 minutes.
4. Roll compaction: Compact the step 3 with roll compactor and milled with 1.00 mm screen in multi mill to attain desired granules and continued compaction and milling process until all the granules passes through 30# mesh.
5. Prepublication: Sift Microcrystalline cellulose (Hicel XLM 90), Talc, Crosspovidone XL 10, Colloidal silicon Di oxide through 30 # mesh.Add this to step 4 Blend and blend in a suitable blender upto 15 minutes.
6. Sift Magnesium stearate through 60# mesh.
7. Lubrication: Add ste6 blend to step 5 Blend and Blend for 5 mins.
8. Compression: Compress the above blend by using suitable punches.
9. Film Coating:
Prepare the coating dispersion by dispersing Colorozy Pink, Yellow and Pink in purified water under stirring and coat the compressed tablets of step 8 with the coating dispersion.

Example 3: Dry Granulation Technique (Roller Compaction)
Manufacturing Formula:
S. No. Ingredients Category Qty/ Tablet (mg)
24/26 mg 49+51 mg 97+103 mg
Intra granular Part
1 Sacubitril and Valsartan tri sodium hydrate (equivalent to base) Active Ingredient 50
(eq to base) 100
(eq to base) 200
(eq to base)
2 Microcrystalline cellulose PH 112 Diluent 14.95 29.90 59.80
3 Low substituted Hydroxy Propyl cellulose (L-HPC 11) Dry Binder 7.50 15.00 30.00
4 Colloidal silicon dioxide (Aerosil 200 Pharma) Glidant 1.00 2.00 4.00
5 Magnesium Stearate (Ligamed MF 2V) Lubricant 0.50 1.00 2.00
Extragranular Part
6 Microcrystalline cellulose PH 112 Diluent 5.00 10.00 20.00
7 Talc (Luzenac Pharma) Glidant 1.00 2.00 4.00
8 Crospovidone Xl 10 Disintegrant 2.25 4.50 9.00
9 Colloidal silicon dioxide (Aerosil 200 Pharma) Glidant 0.75 1.50 3.00
10 Magnesium stearate ( Ligamed MF 2V) Lubricant 0.50 1.00 2.00
Total weight of uncoated tablet 90.00 180.00 360.00
Coating Materials
11 Colorozy pink 17F540247$ Film coating agents 2.70 -- --
12 Colorozy Yellow 17F520349€ -- 5.40 --
13 Colorozy pink 17F540248p -- -- 10.80
14 Iso Propyl Alcohol Solvent q.s. q.s. q.s.
15 Di Chloro Methane Solvent q.s. q.s. q.s.
Total weight of coated Tablet

Manufacturing Process:
1. Sifting: Co sift Sacubitril and Valsartan Sacubitril and Valsartan tri sodium complex hydrate, Microcrystalline cellulose PH 112, Low substituted Hydroxy propyl cellulose, Colloidal silicon Di oxide through #40 mesh.
2. Sifting: Sift Magnesium stearate through #60 mesh
3. Blending: Add sstep 2 blend to step 1 and blend in a suitable blender upto 15 minutes.
4. Roll compaction: Compact the step 3 with roll compactor and milled with 1.00 mm screen in multi mill to attain desired granules and continued compaction and milling process until all the granules passes through 30# mesh.
5. Prelubrication: Sift Microcrystalline cellulose PH 112, Talc, Crosspovidone XL 10, Colloidal silicon Di oxide through 30 # mesh.Add this to step 4 Blend and blend in a suitable blender upto 15 minutes.
6. Sift Magnesium stearate through 60# mesh.
7. Lubrication: Add ste6 blend to step 5 Blend and Blend for 5 mins.
8. Compression: Compress the above blend by using suitable punches.
9. Film Coating: Prepare the coating dispersion by dispersing Colorozy Pink, Yellow and Pink in purified water under stirring and coat the compressed tablets of step 8 with the coating dispersion.
,CLAIMS:1) A pharmaceutical composition comprising crystalline Form-P of Sacubitril; Valsartan complex or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

2) The pharmaceutical composition as claimed in claim 1, wherein the Sacubitril; Valsartan is in the form of Sacubitril; Valsartan tri sodium hydrate crystalline form-P.

3) The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients used in the composition are diluent, binder, glidant, lubricant, solubilizer, stabilizer, disintegrant and colorant.

4) The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients used in the composition are microcrystalline cellulose, low substituted hydroxy propyl cellulose, colloidal silicon dioxide, crospovidone, talc, magnesium stearate.

5) The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical process for the preparation comprising Sacubitril; Valsartan by wet granulation or dry granulation method.

6) The process of preparation of a pharmaceutical composition as claimed in claim 1, comprising pre-warming Sacubitril-Valsartan tri sodium hydrate with pharmaceutically acceptable excipients where in the process of preparation of Sacubitril-Valsartan involves spraying of drug solution along with surfactant optionally with binder on to the excipients for granulation of pharmaceutical composition of Sacubitril-Valsartan complex.

7) The pharmaceutical composition as claimed in claim 1, where in the composition is used for the treatment of a cardiovascular diseases by administering an immediate release pharmaceutical formulation comprising Sacubitril; Valsartan and its pharmaceutically acceptable salts.