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 fluid bed granulation technique.

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 hemi pentahydrate, and one or more pharmaceutically acceptable excipients and processes for the preparation of formulation comprising Sacubitril; Valsartan by wet granulation or dry granulation.

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

In one of the embodiments of the present invention is to provide a stable immediate release tablet oral dosage form of crystalline Sacubitril; Valsartan tri sodium hemi pentahydrate and one or more pharmaceutically acceptable excipients thereof and processes for the preparation by pre-warming Sacubitril-Valsartan tri sodium hemi pentahydrate 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 hemi pentahydrate and one or more pharmaceutically acceptable excipients like diluent, binder, glidant, lubricant, solubilizer, antacid, 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 hemi pentahydrate 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 hemi pentahydrate 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 hemihydrate 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.

In one of the embodiments of the present invention is to provide a process of preparation
oral dosage form of Sacubitril; Valsartan or its pharmaceutically acceptable salts where the process involves co-sifting of Sacubitril; Valsartan complex with microcrystalline cellulose L-HPC, Colloidal silicon dioxide and the sift Magnesium stearate, blend the above sifted ingredients and compacted in to slugs using roller compacter. The slugs obtained are milled and sieved to obtained desired size of granules. To the above obtained granules are mixed with other extra granular ingredients, the resultant mixture is lubricated and punched into tablets and coated with suitable film coating or the lubricated granules filled into suitable size capsules.

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.

Composition of Sacubitril and Valsartan immediate release tablets.
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 hemi pentahydrate Active Ingredient 56.55 113.10 226.20 62.83
2 Microcrystalline cellulose PH 112 Diluent 14.95 29.90 59.80 16.61
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 PH 112 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

Manufacturing Process:
1. Sifting: Co sift Sacubitril and Valsartan API Complex, 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 Sacubitril; Valsartan or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where in the Sacubitril; Valsartan present in the composition more than 60% w/w of the total weight of the composition.

2) The pharmaceutical composition as claimed in claim 1, wherein the Sacubitril; Valsartan is in the form of Sacubitril; Valsartan tri sodium hemi pentahydrate.

3) The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients used in the composition are diluent, binder, glidant, lubricant, solubilizer, antacid, 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 pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical process for the preparation comprising Sacubitril; Valsartan by fluid bed granulation technique.

7) The process of preparation of a pharmaceutical composition as claimed in claim 1, comprising pre-warming Sacubitril-Valsartan tri sodium hemi pentahydrate 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.

8) The process of preparation of a pharmaceutical composition as claimed in claim 1, process involves co-sifting of Sacubitril; Valsartan complex with microcrystalline cellulose L-HPC, colloidal silicon dioxide and sift Magnesium stearate, blend the above sifted ingredients and compacted in to slugs using roller compacter. The slugs obtained are milled and sieved to obtained desired size of granules. To the above obtained granules are mixed with other extra granular ingredients, the resultant mixture is lubricated and punched into tablets and coated with suitable film coating or the lubricated granules filled into suitable size capsules.

9) 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.