Claims:WE CLAIM:
1. A pharmaceutical tablet composition comprising amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients; wherein said composition is prepared by non-aqueous granulation.
2. The tablet according to claim 1, is further coated with non-aqueous film coating composition.
3. The tablet according to claim 1, wherein premix comprises amorphous sacubitril: valsartan complex and colloidal silicon dioxide.
4. A pharmaceutical tablet comprising:
(a) amorphous sacubitril: valsartan premix comprising amorphous sacubitril: valsartan complex and colloidal silicon dioxide,
(b) one or more pharmaceutically acceptable excipients,
wherein said tablet is prepared by non-aqueous granulation;
wherein said tablet is coated with non-aqueous film coating composition.
5. The pharmaceutical composition according to claim 1 and 4, wherein non-aqueous granulating solution comprises povidone and at least one non-aqueous solvent.
6. The pharmaceutical composition according to claim 1 and 4, wherein non-aqueous film coating composition comprises hydroxypropyl methylcellulose
7. The pharmaceutical composition according to claim 1 and 4, comprises sacubitril: valsartan and colloidal silicon dioxide in the ratio of 1:0.5 to 1:1.
8. A process for the preparation of a tablet comprising amorphous sacubitril: valsartan premix at a temperature of 25? and relative humidity of less than 50% and involves:
(a) amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients were sifted and blended,
(b) granulating solution was prepared by dissolving binder in at least one non-aqueous solvent,
(c) blend of step (a) was granulated with binder solution of step (b), followed by drying and milling to get the desired granules,
(d) granules of step (c) were lubricated and compressed into tablets, and finally,
(e) tablets of step (d) were coated with non-aqueous film coating composition.
9. The process according to claim 8, wherein non-aqueous film coating composition comprises hydroxypropyl methylcellulose.
10. The process according to claim 8, wherein non-aqueous solvent is selected from isopropyl alcohol, methanol, ethanol, ethyl acetate, ethyl lactate, acetone, methylenechloride, 1,1,1 trichloroethane, chloroform and combinations thereof.
, Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION
“STABLE TABLET COMPOSITIONS OF SACUBITRIL: VALSARTAN”

APPLICANT
HETERO LABS LIMITED
Plot No: 22-110, Unit-III, IDA, Jeedimetla, Hyderabad-500 055,
Telangana, India.
Nationality: Indian company.

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of sacubitril and valsartan and a process for the preparation thereof.
BACKGROUND OF THE INVENTION
Sacubitril is a prodrug form of active metabolite Sacubitrilat. It belongs to class of drugs called neprilysin inhibitors that work by inhibiting neutral endopeptidase. Chemically Sacubitril is 4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid and has the following structural formula:

Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype. Valsartan is described chemically as N-(1-oxopentyl)-N-[[2’-(1H-tetrazol-5-yl) [1,1’-biphenyl]-4-yl]methyl]-L-valine with an empirical formula of C24H29N5O3 and a molecular weight of 435.5. The structural formula is:

Sacubitril and Valsartan tablets are marketed in US under the brand name of Entresto® by Novartis.

U.S. Patents 5,217,996 and 5,399,578 disclose sacubitril and valsartan respectively.
U.S. Patent 8,877,938 discloses crystalline valsartan; sacubitril trisodium hemipentahydrate.
U.S. Patent Publication 2010/0267786 discloses tablet composition comprising Sacubitril and Valsartan, prepared by roller compaction process.

Inventors of the present invention have developed compositions of sacubitril and valsartan using novel process with improved stability.

SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical composition comprising amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients.

One embodiment of the present invention relates to a pharmaceutical tablet composition comprising amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients, wherein said composition is prepared by non-aqueous granulation.

Another embodiment of the present invention relates to a pharmaceutical tablet comprising: (a) amorphous sacubitril: valsartan premix comprising amorphous sacubitril: valsartan complex and colloidal silicon dioxide, (b) one or more pharmaceutically acceptable excipients, wherein said tablet is prepared by non-aqueous granulation; wherein said tablet is coated with non-aqueous film coating composition.

Another embodiment of the present invention relates to a process for the preparation of a tablet comprising amorphous sacubitril: valsartan premix processed at a temperature of 25? and relative humidity of less than 50% and involves following steps: (a) amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients were sifted and blended, (b) granulating solution was prepared by dissolving binder in at least one non-aqueous solvent, (c) blend of step (a) was granulated with binder solution of step (b), followed by drying and milling to get the desired granules, (d) granules of step (c) were lubricated and compressed into tablets and finally coated with non-aqueous film coating composition.

In yet another embodiment of the present invention relates to use of present composition 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical composition comprising sacubitril and valsartan as active agents.
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.
As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure so forth.
The term “active ingredient” or “active agent” used interchangeably, is defined to mean active drug (e.g. sacubitril and valsartan), that induce a desired pharmacological or physiological effect. The active ingredient of the present invention is in the form of premix comprising amorphous sacubitril: valsartan complex. Particularly, premix comprising amorphous sacubitril: valsartan complex and colloidal silicon dioxide; wherein the ratio of sacubitril: valsartan complex to colloidal silicon dioxide is in the range of 1:0.5 to 1:1. Colloidal silicon dioxide was added to amorphous sacubitril: valsartan complex, in order to increase the stability and to reduce the hygroscopicity of amorphous sacubitril: valsartan complex.
The present invention relates to pharmaceutical composition comprising amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients.

Excipients of the present invention comprise diluents, binders, disintegrants, glidants, lubricants and combinations thereof.

Diluents according to the present invention include but are not limited to microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, calcium silicate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, talc, sugar, starches, sorbitol, inorganic salts, cellulose derivatives, calcium sulfate, xylitol, lactitol, kaolin, sucrose, sorbitol, dextrates, dextrin, maltodextrin, dextrose and the like, and combinations thereof.
Binders according to the present invention include but are not limited to polyvinyl pyrrolidone, hydroxypropyl cellulose, copovidone, hydroxypropyl methylcellulose, pregelatinized starch, powdered acacia, gelatin, guar gum, carbomers and the like, and combinations thereof.
Disintegrants according to the present invention include but are not limited to crospovidone, croscarmellose sodium, polacrilin potassium, sodium starch glycolate, carboxymethyl cellulose calcium, starches such as corn starch, potato starch, pre-gelatinized and modified starches, microcrystalline cellulose and the like, and combinations thereof.
Glidants according to the present invention include but are not limited to colloidal silicon dioxide (SYLOID® 244 FP, AEROSIL®, AEROPERL® or etc.), magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica and the like, and combinations thereof.
Lubricants according to the present invention include but are not limited to magnesium stearate, aluminium stearate, sucrose stearate, stearic acid, talc, fumaric acid, palmitic acid, sodium stearyl fumarate, glyceryl monostearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like and combinations thereof.
One aspect of the present invention relates to a pharmaceutical tablet composition comprising amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients, wherein said composition is prepared by non-aqueous granulation.

Non-aqueous solvents according to the present invention include but are not limited to C1-C3 alcohol, e.g. ethanol or isopropyl alcohol, methanol, ethyl acetate, ethyl lactate, acetone, methylenechloride, 1,1,1-trichloroethane, chloroform and the like and combinations thereof. Non-aqueous solvents can be useful for the preparation granulating solution and as a film coating solution.

Another aspect of the present invention relates to a pharmaceutical tablet comprising: (a) amorphous sacubitril: valsartan premix comprising amorphous sacubitril: valsartan complex and colloidal silicon dioxide, (b) one or more pharmaceutically acceptable excipients, wherein said tablet is prepared by non-aqueous granulation; wherein said tablet is coated with non-aqueous film coating composition comprising hydroxypropyl methylcellulose.

Tablet composition of amorphous sacubitril: valsartan premix according to the present invention is processed at a temperature of 25? and relative humidity of less than 50%.

The film coated tablet of amorphous sacubitril: valsartan premix according to the present invention is preferably, processed at a temperature of 25? and relative humidity of less than 40%.

Another aspect of the present invention relates to a process for the preparation of a tablet comprising amorphous sacubitril: valsartan premix processed at a temperature of 25? and relative humidity of less than 50% and involves following steps: (a) amorphous sacubitril: valsartan premix and one or more pharmaceutically acceptable excipients were sifted and blended, (b) granulating solution was prepared by dissolving binder in at least one non-aqueous solvent, (c) blend of step (a) was granulated with binder solution of step (b), followed by drying and milling to get the desired granules, (d) granules of step (c) were lubricated and compressed into tablets and finally coated with non-aqueous film coating composition.

Sacubitril: Valsartan film coated tablets were packed into blister packs of 10's count were stored for three months at 40°C/ 75% RH, 30°C/ 65% RH and 25°C/ 60% RH using silica gel and molecular sieves to ensure the stability conditions.
In yet another aspect of the present invention relates to use of present composition 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.

EXAMPLES

The following examples further illustrate the invention and do not limit the scope of the invention.

Example 1: Pharmaceutical tablet composition of Sacubitril and Valsartan:
Ingredients mg/ tab
Amorphous sacubitril: valsartan premix 377.00
Microcrystalline cellulose 20.00
Low substituted hydroxypropyl cellulose 20.00
Povidone 15.00
Isopropyl alcohol q.s.
Crospovidone 5.00
Colloidal silicon dioxide 1.00
Magnesium stearate 2.00
Core tablet weight 440.00
Film coating:
Opadry® white 06A580019* 18.00
Isopropyl alcohol q.s.
Dichloro methane q.s.
Film coated tablet weight 458.00
*Opadry® white composition: hypromellose, di-acetylated monoglyceride and titanium dioxide.

Brief manufacturing method:
The process for the preparation of a tablet comprising amorphous sacubitril: valsartan premix processed at a temperature of 25? and relative humidity of less than 50% and involves following steps:
(i) Sacubitril: Valsartan premix, microcrystalline cellulose and low substituted hydroxypropyl cellulose were sifted and blended,
(ii) non-aqueous granulating solution was prepared by dissolving povidone in isopropyl alcohol,
(iii) blend of step (i) was granulated using non-aqueous solution of step (ii), followed by, drying and milling to get the desired granules,
(iv) crospovidone and colloidal silicon dioxide were sifted,
(v) granules of step (iii) were blended with sifted materials of step (iv),
(vi) magnesium stearate was sifted,
(vii) blend of step (v) was lubricated with sifted magnesium stearate of step (vi),
(viii) lubricated blend of step (vii) was compressed into tablets, and finally,
(ix) tablets of the step (viii) were film coated using non-aqueous based Opadry® white 06A580019 film coating dispersion.

Dissolution study:

Dissolution medium : pH 6.8 Phosphate Buffer
Volume : 900 ml
Apparatus : USP II
Speed : 50 RPM

Time in minutes Example 1
% of Sacubitril dissolved % of Valsartan dissolved
5 17 17
10 51 52
15 72 75
20 85 88
30 92 95
45 95 98

Stability study:
Sacubitril: Valsartan blister packs of 10's count were stored for three months at 40°C/ 75% RH, 30°C/ 65% RH and 25°C/ 60% RH as follows:
Month 40°c/75% RH 30°c/65% RH, 25°c/60% RH
1 Intact in amorphous form Intact in amorphous form Intact in amorphous form
2 Intact in amorphous form Intact in amorphous form Intact in amorphous form
3 Intact in amorphous form Intact in amorphous form Intact in amorphous form

Above data reveals that amorphous sacubitril: valsartan is intact up to three months.
Example 2: Pharmaceutical tablet composition of Sacubitril and Valsartan:
Ingredients mg/ tab
Amorphous sacubitril: valsartan premix 300.00
Microcrystalline cellulose 20.00
Hydroxypropyl cellulose 20.00
Povidone 15.00
Isopropyl alcohol q.s.
Croscarmellose sodium 5.00
Colloidal silicon dioxide 1.00
Magnesium stearate 2.00
Core tablet weight 363.00
Film coating:
Opadry® white 06A580019 18.00
Isopropyl alcohol q.s.
Dichloro methane q.s.
Film coated tablet weight 381.00

Brief manufacturing method:
The process for the preparation of a tablet comprising amorphous sacubitril: valsartan premix processed at a temperature of 25? and relative humidity of less than 50% and involves following steps:
(i) Sacubitril: Valsartan premix, microcrystalline cellulose and hydroxypropyl cellulose were sifted and blended,
(ii) non-aqueous granulating solution was prepared by dissolving povidone in isopropyl alcohol,
(iii) blend of step (i) was granulated using non-aqueous solution of step (ii), followed by, drying and milling to get the desired granules,
(iv) croscarmellose sodium and colloidal silicon dioxide were sifted,
(v) granules of step (iii) were blended with sifted materials of step (iv),
(vi) magnesium stearate was sifted,
(vii) blend of step (v) was lubricated with sifted magnesium stearate of step (vi),
(viii) lubricated blend of step (vii) was compressed into tablets, and finally,
(ix) tablets of the step (viii) were film coated using non-aqueous based Opadry® white 06A580019 film coating dispersion.

Example 3: Pharmaceutical tablet composition of Sacubitril and Valsartan:
Ingredients mg/ tab
Amorphous sacubitril: valsartan premix 377.00
Lactose monohydrate 20.00
Microcrystalline cellulose 20.00
Hydroxypropyl cellulose 15.00
Isopropyl alcohol q.s.
Croscarmellose sodium 5.00
Colloidal silicon dioxide 1.00
Magnesium stearate 2.00
Core tablet weight 463.00
Film coating:
Opadry® white 06A580019 18.00
Isopropyl alcohol q.s.
Dichloro methane q.s.
Film coated tablet weight 481.00

Brief manufacturing method:
The process for the preparation of a tablet comprising amorphous sacubitril: valsartan premix processed at a temperature of 25? and relative humidity of less than 50% and involves following steps:
(i) Sacubitril: Valsartan premix, lactose monohydrate and microcrystalline cellulose were sifted and blended,
(ii) non-aqueous granulating solution was prepared by dissolving hydroxypropyl cellulose in isopropyl alcohol,
(iii) blend of step (i) was granulated using non-aqueous solution of step (ii), followed by, drying and milling to get the desired granules,
(iv) croscarmellose sodium and colloidal silicon dioxide were sifted,
(v) granules of step (iii) were blended with sifted materials of step (iv),
(vi) magnesium stearate was sifted,
(vii) blend of step (v) was lubricated with sifted magnesium stearate of step (vi),
(viii) lubricated blend of step (vii) was compressed into tablets, and finally,
(ix) tablets of the step (viii) were film coated using non-aqueous based Opadry® white 06A580019 film coating dispersion.