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 30-55% 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, 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.

Antacid according to the present invention include but not limited to Precipitated Calcium Carbonate.

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 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 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 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 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.

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 having 30-55% 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, syloid XDP, polysorbate 80, Methanol, Precipitated Calcium Carbonate, Crospovidone, Colloidal silicon dioxide and Magnesium stearate.

In one of the embodiments of the present invention is to provide a stable immediate release oral dosage form of Sacubitril; Valsartan and more pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients like microcrystalline cellulose, syloid XDP, polysorbate 80, methanol, precipitated calcium carbonate, crospovidone, colloidal silicon dioxide and 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 having 30-55% w/w of the composition.

In one of the embodiments of the present invention manufacturing process is pre-warming: Load Syloid XDP 3150 in Fluid Bed Processor (Top Spray Bowl) and pre warm the material for 10 minutes prepare binder Solution, take required amount of Methanol and add Sacubitril/Valsartan API complex under stirring and continue stirring until to get the clear solution, add Polysorbate 80 to above solution and mix for 10 minutes, spray the step No. 2 solution onto the step no.1 with Top spray approach with suitable in Process Parameters, after completion of the coating Dry the materials until to get the LOD between 2 – 4% w/w (Target 3% w/w), sift the dried granules through #30 mesh and collect the #30 mesh retained granules and mill the retained granules through Quadro co mill with 24 R Screen with slow speed, sift Microcrystalline cellulose PH 102, precipitated calcium carbonate, crospovidone XL 10, colloidal silicon Di oxide through 30 # mesh. Add this to step 6 Blend to step 5 and blend in a suitable blender up to 15 minutes, add ste6 blend to step 5 Blend and Blend for 5 mins, compress the above blend by using suitable punches, 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.

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: Composition of Sacubitril and Valsartan immediate release tablets.

S. No Ingredients Qty/ Tablet (mg)
24/26 mg 49+51 mg 97+103 mg
Intra granular Part
1. Microcrystalline cellulose PH 101 2.50 5.00 10.00
2. Syloid XDP 3150 20.00 40.00 80.00
Binder Solution
3. Sacubitril and Valsartan tri sodium hemi pentahydrate 56.55
113.10 226.20
4. Polysorbate 80 5.00 10.00 20.00
5. Methanol q.s. q.s. q.s.
Extragranular
6. Microcrystalline cellulose PH 102 14.17 28.34 56.68
7. Precipitated Calcium Carbonate 5.00 10.00 20.00
8. Crospovidone Xl 10 5.00 10.00 20.00
9. Colloidal silicon dioxide (Aerosil 200 Pharma) 0.90 1.79 3.58
10. Magnesium stearate ( Ligamed MF 2V) 0.90 1.79 3.58
Total weight of uncoated tablet 110.00 220.00 440.00
Coating Materials

Manufacturing process:
1.0 Pre Warming: Load Syloid XDP 3150 in Fluid Bed Processor (Top Spray Bowl) and pre warm the material for 10 minutes.
2. Binder Solution preparation: Take required amount of Methanol and add Sacubitril/Valsartan API complex under stirring and continue stirring until to get the clear solution. Add Polysorbate 80 to above solution and mix for 10 minutes.
3. Granulation: Spray the step No. 2 solution onto the step no.1 with Top spray approach with suitable in Process Parameters.
4. Drying: After completion of the coating Dry the materials until to get the LOD between 2 – 4% w/w (Target 3% w/w)
5. Sifting and Milling: Sift the Dried Granules through #30 mesh and collect the #30 mesh retained granules and mill the retained granules through Quadro co mill with 24 R Screen with slow speed.
6. Pre-lubrication: Sift Microcrystalline cellulose PH 102, Precipitated Calcium Carbonate, Crospovidone XL 10, Colloidal silicon Di oxide through 30 # mesh. Add this to step 6 Blend to step 5 and blend in a suitable blender up to 15 minutes.
7. Lubrication: Add step 6 blend to step 5 Blend and Blend for 5 mins.
8. Compression: Compress the above blend by using suitable punches.
9. Film Coating: 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, wherein the composition is prepared using the wet granulation method and fluid bed granulation technique.

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

3) The pharmaceutical composition as claimed in claim 1, wherein the Sacubitril; Valsartan is dissolved or dispersed in the binding solution.

4) The pharmaceutical composition as claimed in claim 1, wherein the composition is tablet oral composition contain Sacubitril; Valsartan salt and one or more pharmaceutically acceptable excipients.

5) The pharmaceutical composition as claimed in claim 1, where in one or more pharmaceutically acceptable excipients such as diluent, binder, glidant, lubricant, solubilizer, stabilizer, disintegrant and colorant.

6) The process of preparation of a pharmaceutical composition as claimed in claim 1 involves:
a. Preparation of a binding solution by mixing Sacubitril; Valsartan with methanol and Polysorbate 80,
b. Spraying the above solution onto microcrystalline cellulose and syloid.
c. Drying the mixture from step 2 and adding extra-granular materials, then mixing.
d. Blending the pre-lubricated mixture with a glidant and lubricant, and
e. Punching the lubricated blend into tablets and coating them with a suitable film coating.

7) The pharmaceutical composition as claimed in claim 1 is intended for the treatment of a cardiovascular disease.