PHARMACEUTICAL ORAL SOLID DOSAGE FORMS COMPRISING

VALSARTAN AND NEBIVOLOL

Field of the Invention

The present invention relates to pharmaceutical oral solid dosage forms comprising valsartan and nebivolol as active ingredients in a fixed-dose combination. The invention is further related to methods of preparing such pharmaceutical oral solid dosage forms.

Background of the Invention

Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the ATi receptor subtype. It is chemically described as N-(l-oxopentyl)-N-[[2'- ( lH-tetrazol-5 -yl) [1, 1 '-biphenyl] -4-yl]methyl] -L-valine . Valsartan was first disclosed in U.S. Patent No. 5,399,578.

Nebivolol is an orally active selective beta-blocker acting on the β-l receptor subtype. It is chemically described as (lRS,l 'RS)-l,l '-[(2RS,2'SR)bis(6-fluoro-3,4-dihydro-2H-l- benzopyran-2-yl)]-2,2'-iminodiethanol hydrochloride, and is a racemate composed of d- Nebivolol and /-Nebivolol with the stereochemical designations of [SRRR] -nebivolol and [RSSS] -nebivolol, respectively. Nebivolol was first disclosed in U.S. Patent No. 4,654,362.

U.S. Patent No. 7,838,552 discloses fixed-dose combinations of valsartan and nebivolol for the treatment of hypertension. This patent does not disclose working examples of any formulation comprising valsartan and nebivolol, or any other beta blocker.

There exists a need for pharmaceutical oral solid dosage forms of valsartan and nebivolol having good dissolution, good stability, and robust composition, which can be economically and commercially manufactured.

In the present invention, the inventors have successfully developed such a pharmaceutical oral solid dosage form comprising valsartan and nebivolol.

Summary of the Invention

In one aspect, the present invention provides a pharmaceutical oral solid dosage form which comprises valsartan, nebivolol, and other pharmaceutically acceptable excipients in a fixed-dose combination wherein valsartan and nebivolol are present in separate components. In one embodiment of the above aspect, one component is the core and the other component surrounds the core.

In another embodiment of the above aspect, the components may be formulated as separate layers within a single oral solid dosage form, for example, a bilayered tablet.

In another embodiment of the above aspect, the components may be formulated as a bilayered tablet wherein one layer of the bilayered tablet comprises valsartan and the other layer comprises nebivolol.

In another embodiment of the above aspect, the first layer and the second layer of the bilayered tablet are in a side by side arrangement such that the dissolution of valsartan and nebivolol occur independently of each other.

In another embodiment of the above aspect, the pharmaceutically acceptable excipients include diluents, disintegrants, lubricants, and film-forming agents.

In another aspect, the present invention provides a process for the preparation of a pharmaceutical oral solid dosage form which comprises valsartan and nebivolol as active ingredients, and other pharmaceutically acceptable excipients in a fixed-dose combination wherein the process comprises the steps of:

(a) preparing a component comprising the specified amount of valsartan;

(b) preparing another component comprising the specified amount of nebivolol; and

(c) processing both components into a final single oral solid dosage form.

In one embodiment of the above aspect, the core component comprises valsartan, and nebivolol is coated over the core component.

In another embodiment of the above aspect, the core component comprises nebivolol, and valsartan is coated over the core component.

In yet another embodiment of the above aspect, the solid dosage form is a bilayered tablet wherein one layer comprises valsartan and the other layer comprises nebivolol.

The details of the various embodiments of the invention are set forth in the description below. Other features and advantages of the invention will also be apparent from the description. Brief Description of the Drawings

Figure 1 depicts a side-by-side configuration of a bilayered tablet that may be used for the tablet containing a nebivolol layer and a valsartan layer.

Figure 2 depicts an arrangement in which valsartan is present as a core surrounded by a coating of nebivolol.

Figure 3 depicts an arrangement in which nebivolol is present as a core surrounded by a coating of valsartan.

Figure 4 depicts a single layered tablet in which an admixture of valsartan and nebivolol is present.

Detailed Description of the Invention

The term "oral solid dosage form", as used herein, includes tablets, mini-tablets, capsules, caplets, granules, beads, pellets, multiparticulates, spheroids, or combinations thereof. If the solid dosage form is a tablet, the tablet can be of any suitable shape such as round, spherical, or oval. The tablet may have a monolithic or a multilayered structure.

The term "component", as used herein, means that the portions comprising valsartan or nebivolol are distinct so that valsartan and nebivolol are separate from each other. The component may be a core or a layer over the core. The core component may contain nebivolol, and valsartan may be coated over the nebivolol core component. Alternatively, the core component may contain valsartan, and nebivolol may be coated over the valsartan core component. The components may also be present as layers such as in the case of a layered tablet, e.g., a bilayered tablet.

The term "pharmaceutically acceptable excipients", as used herein, includes diluents, binders, disintegrants, wetting agents, lubricants, and film-forming agents.

Preferred examples of diluents include, but are not limited to, calcium phosphate- dibasic, calcium carbonate, lactose, glucose, microcrystalline cellulose, cellulose powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch pregelatinized, and polyols such as mannitol, sorbitol, xylitol, maltitol, and sucrose.

Preferred examples of binders include, but not are limited to, starch, pregelatinized starch, carboxymethyl cellulose, sodium cellulose, microcrystalline cellulose, hydroxyproyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crospovidone, and combinations thereof.

Preferred examples of disintegrants include, but are not limited to, crosslinked cellulose, crosslinked-polyvinylpyrrolidone (crosspovidone), sodium starch glycolate, polyvinylpyrrolidone (polyvidone, povidone), sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), hydroxypropyl cellulose, hydroxypropyl methylcellulose, xanthan gum, alginic acid, and soy polysaccharides.

Preferred examples of wetting agents include, but are not limited to, polysorbate, sodium lauryl sulphate, and glyceryl stearate.

Preferred examples of lubricants include, but are not limited to, sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and zinc stearate. Suitable glidants include colloidal silicon dioxide and talc.

These solid dosage forms may be further coated with one or more functional and/or non-functional coating layers comprising film-forming polymers with or without coating additives.

Examples of film-forming agents include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose,

carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate; polyethylene glycol; and methacrylic acid polymers such as Eudragit ^® RL and Eudragit ^® RS. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Kollicoat ^® Protect and Opadry ^® may also be used as film- forming polymers.

Preferred examples of solvents used for the granulation or for preparing a coating solution include, but are not limited to, methylene chloride, isopropyl alcohol, acetone, propylene glycol, methanol, ethanol, chloroform, ether, water, and combinations thereof.

The term "fixed-dose combination", as used herein, includes specific dosage strengths for valsartan and nebivolol in the pharmaceutical oral solid dosage form which include but are not limited to: (1) 5 milligrams of nebivolol and 80 milligrams of valsartan;

(2) 5 milligrams of nebivolol and 160 milligrams of valsartan;

(3) 10 milligrams of nebivolol and 160 milligrams of valsartan;

(4) 10 milligrams of nebivolol and 320 milligrams of valsartan; and

(5) 20 milligrams of nebivolol and 320 milligrams of valsartan;

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1 :

Procedure:

A. Procedure for preparing granules of valsartan

1. Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS #18 sieve.

2. Magnesium stearate was sifted through a BSS # 60 sieve and added to the blend of step 1.

3. The materials of step 1 and step 2 were blended in a blender for 15 minutes.

4. The material of step 3 was compressed into a compact. 5. The compact of step 4 was milled to obtain desired granules.

B. Procedure for preparing granules of nebivolol:

1. Nebivolol hydrochloride, pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, talc, and one part of magnesium stearate were sifted through a BSS # 22 sieve.

2. The material of step 1 was compressed into a compact.

3. The compact of step 2 was milled to obtain desired granules.

4. The other part of magnesium stearate was sifted through a BSS # 60 sieve and added to the granules of step 3.

C. Procedure for preparing bilavered tablets:

1. The granules of part A and the granules of part B were compressed into tablets

comprising a lower layer of valsartan and an upper layer of nebivolol using suitable tooling.

D. Procedure for Opadry ^® coating:

1. A dispersion of Opadry ^® was prepared in water by continuously stirring.

2. The dispersion of step 1 was sprayed over the bilayered tablets of part C.

Example 2:

Procedure:

A. Procedure for preparing granules of valsartan:

1. Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS # 18 sieve.

2. Magnesium stearate was sifted through a BSS # 60 sieve and added to the blend of step 1.

3. The materials of step 1 and step 2 were blended in a blender for 15 minutes.

4. The material of step 3 was compressed into a compact.

5. The compact of step 4 was milled to obtain desired granules.

6. Extra-granular crospovidone and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended in a blender for 15 minutes.

7. Magnesium stearate was sifted through a BSS # 60 sieve and added to the blend of step 6. B. Procedure for preparing granules of nebivolol

1. Nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium were sifted through a BSS # 22 sieve.

2. Polysorbate and hydroxypropyl methyl cellulose were dissolved in water under

continuous stirring to obtain a clear solution.

3. The sifted blend of step 1 was loaded in the product container of a top spray fluidized bed granulator.

4. The solution of step 2 was sprayed on to the fluidized bed of step 3.

5. The granules of step 4 were dried.

6. Extra-granular ferric oxide red, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended for 15 minutes.

7. Magnesium stearate was sifted through a BSS # 60 sieve and added to the blend of step 6.

C. Procedure for preparing bilayered tablets:

1. The granules of part A and the granules of part B were compressed into tablets

comprising a lower layer of valsartan and an upper layer of nebivolol using suitable tooling.

D. Procedure for Opadry ^® coating:

1. A dispersion of Opadry ^® was prepared in water by continuously stirring.

2. The dispersion of step 1 was sprayed over the bilayered tablets of step C.

Example 3:

Procedure:

A. Procedure for preparing granules of valsartan:

1. Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS # 18 sieve.

2. Magnesium stearate was sifted through a BSS # 60 sieve and added to the blend of step 1.

3. The materials of step 1 and step 2 were blended in a blender for 15 minutes.

4. The material of step 3 was compressed into a compact.

5. The compact of step 4 was milled to obtain desired granules.

6. Extra-granular crospovidone and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended in a blender for 15 minutes. 7. Magnesium stearate was sifted through a BSS # 60 sieve and added to the blend of step 6.

B. Procedure for preparing granules of nebivolol:

1. Nebivolol Hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium were sifted through a BSS # 22 sieve.

2. Polysorbate and hydroxypropyl methyl cellulose were dissolved in water under

continuous stirring to obtain a clear solution and nebivolol hydrochloride was added to this solution under continuous stirring to obtain a uniform dispersion.

3. The sifted blend of step 1 was loaded in the product container of a top spray fluidized bed granulator.

4. The dispersion of step 2 was sprayed on to the fluidized bed of step 3.

5. The granules of step 4 were dried.

6. Extra-granular ferric oxide red, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended in a blender for 15 minutes.

7. Stear-O-Wet™ was sifted through a BSS # 60 sieve and added to the blend of step 6.

C. Procedure for preparing bilayered tablets:

1. The granules of part A and the granules of part B were compressed into tablets

comprising a lower layer of valsartan and an upper layer of nebivolol using suitable tooling.

D. Procedure for Opadry ^® coating:

1. A dispersion of Opadry ^® was prepared in water by continuously stirring.

2. The dispersion of step 1 was sprayed over the bilayered tablets of part C.

Comparative Example

Procedure:

A. Procedure for preparing granules of valsartan:

1. Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS # 18 sieve.

2. Magnesium stearate was sifted through a suitable sieve and added to the blend of step 1.

3. The materials of step 1 and step 2 were blended in a blender for 15 minutes.

4. The material of step 3 was compressed to prepare a compact.

5. The compact of step 4 was milled to obtain desired granules.

6. Extra-granular crospovidone and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended in a blender for 15 minutes. 7. Magnesium stearate was sifted through a BSS # 60 sieve and added to the blend of step 6. B. Procedure for preparing granules of nebivolol:

1. Nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium were sifted through a BSS # 22 sieve.

2. Polysorbate and hydroxypropyl methyl cellulose were dissolved in water under

continuous stirring to obtain a clear solution.

3. The sifted blend of step 1 was loaded in the product container of a top spray fluidized bed granulator.

4. The solution of step 2 was sprayed on to the fluidized bed of step 3.

5. The granules of step 4 were dried.

6. Extra granular ferric oxide red, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended in a blender for 15 minutes.

7. Stear-O-Wet™ was sifted through a BSS # 60 sieve and added to the blend of step 6. C. Procedure for preparing single layered tablets:

1. The final materials of part A (step7) and part B (step 7) were blended in a blender for 15 minutes.

2. Tablets were compressed using the final blend of part C (step 1) using suitable tooling. D. Procedure for Opadry ^® coating:

1. A dispersion of Opadry ^® was prepared in water by continuously stirring.

2. The dispersion of step 1 was sprayed over the tablets of part C.

The in-vitro dissolution profiles were used to assess the release of valsartan and nebivolol from the tablets of Example 3 and the Comparative Example. The dissolution was carried out in USP Apparatus Type II, at 50 RPM, in 1000 mL of 0.0 IN HC1. The results of the studies are presented in Table 1 and Table 2 below. Table 1: In-vitro release of nebivolol hydrochloride from the single layered tablets and bilayered tablets in the specified dissolution conditions.

Table 2: In-vitro release of nebivolol hydrochloride from the single layered tablets and bilayered tablets at specified dissolution conditions

In the dissolution studies it was observed that the bilayered tablets of valsartan and nebivolol in the separate layers provided a better release profile of nebivolol hydrochloride than the single layered tablets containing a physical admixture of valsartan and nebivolol hydrochloride. It was observed that the single layered tablets of the Comparative Example showed an incomplete release of nebivolol hydrochloride. While not wishing to be bound by any theory, it believed that the incomplete release of nebivolol is because of the entrapment of nebivolol hydrochloride in the gel matrix of valsartan.