Field of the Invention:

The present invention relates to a pharmaceutical composition of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide and its preparation thereof. Further, the said pharmaceutical composition is useful for the treatment of chronic obstructive pulmonary disease (COPD).

Back ground of the Invention:

N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide with an empirical formula C17H14CI2F2N2O3 and the molecular weight is 403.22 . Structure of the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoro methoxy-benzamide is as follows:

N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is a drug which acts as a selective, long-acting inhibitor of the enzyme PDE -4. It has anti-inflammatory effects and orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease (COPD).

Cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4) are currently of special interest as a new generation of active ingredients for treating inflammatory disorders, especially inflammations of the airways such as asthma or airway obstructions (for example COPD: chronic obstructive pulmonary disease).
N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is commercially available as a tablet for oral administration (Daliresp®, marketed by Forest Res. in US and Daxas® is marketed by Nycomed, Europe).

N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

US Patent No. 5712298 describes a fiuoroalkoxy-substituted benzamide, known as N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, which is used as cyclic nucleotide phosphodiesterase inhibitors.
US Patent No. 7951397 discloses the pharmaceutical composition comprising of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide and polyvinyl pyrrolidone as a binder provides a dosage form with improved bioavailability.

The solubility of PDE-4 inhibitor class is very low in water and aqueous systems which may be depending on the chemical structure of the active ingredient. Thus, the solubility in water found for the PDE-4 inhibitor N-(3,5 dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, which is described in US5712298, is only 0.53 mg/1 at 21°C. The bioavailability of a medicinal substance depends essentially on the release of the medicinal substance from the pharmaceutical form. Faster release and dissolution of the medicinal substance from the formulation means faster absorption thereof. Medicinal substances, which are slightly soluble in water, may have lower dissolution. Therefore, the bioavailability is frequently limited by the solubility or rate of dissolution. This makes it very difficult to produce suitable dosage forms.

Henceforth, there is a need in the art to develop a pharmaceutical composition, which enhances the solubility. Without being bound by any particular theory, the inventors of the present invention surprisingly found that, the better dissolution profile is observed using pregelatinized starch.

The present invention provides the pharmaceutical composition for N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide in the form of oral dosage form having the following advantages:

> Enriched release profile is observed with pregelatinized starch (starch 1500) because it acts both as disintegrant as well as binder.
> Usage of pregelatinized starch (starch 1500) as a binder enhanced the stability of the formulation when compared to the other binders such as hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone.
> Superior physical properties were observed with pregelatinized starch (starch 1500) when compared with other binders.
Summary of the Invention:

One embodiment of the present invention is to provide an improved process for the preparation of oral dosage pharmaceutical composition of N-(3,5-dichloro pyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide.

Another embodiment a pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, diluent, disintegrant and a lubricant.

In an another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, pregelatinized starch and optionally a pharmaceutically acceptable excipient.
In other embodiment a stable pharmaceutical composition comprising N-(3,5-
dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, lactose monohydrate, pregelatinized starch and magnesium stearate.

In yet another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is prepared by wet granulation technique.

In a preferred embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is prepared by wet granulation technique; preferably with non-aqueous granulation.
In another embodiment of the present invention relates to an improved process for the solid oral dosage pharmaceutical composition which comprising of the following steps:

a) weighing quantities of N-(3,5-dichloropyridin-4-yl)-3-cyclopropyl methoxy-4-difluoromethoxy-benzamide, lactose monohydrate, pregelatinized starch (starchl500), magnesium stearate and passing through a appropriate mesh,
b) mixing the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoro methoxy-benzamide, lactose monohydrate, and pregelatinized starch (starchl500),
c) granulating the above blend with purified water,
d) drying the granules,
e) sieving the dried granules and mixing with pregelatinized starch,
f) lubricating the above dried granules with magnesium stearate,
g) compressing into tablets,
h) optionally coating the core tablet.

Yet another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide having the % drug release is not less than 75% in 10 min in 1000 ml of 0.1 N HC1+0.1% sodium lauryl sulfate, 50 RPM, Paddle (or) 1000 ml of pH 6.8 Phosphate buffer + 0.1 % sodium lauryl sulfate, 50 RPM, Paddle.
In another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is in the form of tablet, capsule, pellet, mini-tablet, granules & powder.

An another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide for oral administration for the treatment of chronic obstructive pulmonary disease (COPD).

Detailed Description of the Invention:

The present invention relates to a pharmaceutical composition of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, and the process for its preparation thereof. Further, the said pharmaceutical composition is useful for the treatment of chronic obstructive pulmonary disease (COPD).

The term "pharmaceutical composition" (synonymously, "formulation") is used herein to refer to a pharmaceutical preparation intended for oral administration, includes such dosage forms as tablets, capsules, minitablets, pellets, granules & spheroids. Preferably, solid oral dosage form is in the form of a tablet or a capsule.
In an embodiment of the present invention is to provide an improved process for the preparation of oral dosage pharmaceutical composition of N-(3,5-dichloro pyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide.
In another embodiment a pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, diluent, disintegrant and a lubricant.

In another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, pregelatinized starch and optionally a pharmaceutically acceptable excipient.
In other embodiment a stable pharmaceutical composition comprising N-(3,5-
dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, lactose monohydrate, pregelatinized starch and magnesium stearate.

The excipients are selected to ensure the delivery of consistent amount of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide in a convenient unit dosage form and to optimize the cost and ease and reliability of the manufacturing process. All the excipients must be inert, organoleptically acceptable, and compatible with the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoro methoxy-benzamide. Generally the excipients used in the solid dosage form include diluents or fillers, disintegrants, binders, lubricants, and coating agents.

Binders are used as a wet granulation excipient to agglomerate the powder mixture of active pharmaceutical ingredient and the other excipients. The binder is selected to improve the flow properties of powder and to improve compatibility. The binders are selected from but are not limited to cellulose derivatives such as hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, gelatin, starch paste, pregelatinized starch, sucrose and natural gums except povidone (i.e., polyvinylpyrrolidone). A preferred binder is pregelatinized starch (starch 1500).
Diluents are included to increase the bulk of the tablet. The various types of diluents are lactose or lactose monohydrate, maize starch, pregelatinized starch, mannitol and microcrystalline cellulose. The most preferred diluent is lactose monohydrate and maize starch.

Disintegrants are included in the tablet formulations to promote the breakup of the tablet into smaller fragments thereby increasing the available surface area and promoting a more rapid dissolution of the active ingredient. Further, it will enhance the bioavailability of the active pharmaceutical ingredients. The disintegrants are selected from but are not limited to starch derivatives like pregelatinized starch, cross linked sodium salt of carboxymethyl ether of starch such as sodium starch glycolate, croscramellose sodium, cellulose derivatives such as microcrystalline cellulose. The most preferred disintegrant is pregelatinized starch (starchl500).

Lubricants are used in the tablet formulation to reduce the friction during the compression stages and to prevent the sticking of the tablet to the punch faces. Lubricant is selected from stearic acid(calcium stearate and magnesium stearate), vegetable oils(corn oil), mineral oils, polyethylene glycol, inorganic salts (such as sodium chloride), organic salts (sodium benzoate, sodium acetate), and polyvinyl alcohols. A preferred lubricant is magnesium stearate.

In an embodiment of the present invention relates to an improved process for the solid oral dosage pharmaceutical composition which comprising of the following steps: a) weighing measures quantities of N-(3,5-dichloropyridin-4-yl)-3-cyclopropyl methoxy-4-difluoromethoxy-benzamide, lactose monohydrate, pregelatinized starch (starchl500), magnesium stearate and passing through an appropriate mesh,
b) mixing the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoro methoxy-benzamide, lactose monohydrate, and pregelatinized starch (starchl500),
c) granulating the above blend with purified water,
d) drying the granules,
e) sieving the dried granules and mixing with pregelatinized starch,
f) lubricating the above dried granules with magnesium stearate,
g) compressing into tablets,
h) optionally coating the core tablet.

In yet another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is prepared by wet granulation technique.

In a preferred embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is prepared by wet granulation technique; preferably with non-aqueous granulation.
Another preferred embodiment a process for preparing a stable pharmaceutical composition comprising the following steps:

a) sifting lactose monohydrate & pregelatized starch in a blender for 15 min,
b) dissolving the N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoro methoxy -benzamide in acetone,
c) adding the solution of step (b) to step (a),
d) granulating the obtained blend with purified water,
e) drying the obtained granules,
f) sifting the obtained granules through ASTM#20,
g) lubricating the resultant granules of step (f) with magnesium stearate,
h) compressing the obtained granules of step (g) into tablets,
i) coating the tablets of step (h) with opadry solution.

Coating may be carried out using coating agents such as Opadry Yellow, Opadry Black, Opadry Red, Opadry White. Solvents that may be used for coating include isopropyl alcohol, methylene dichloride and purified water or mixtures thereof.
Yet another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide having the % drug release is not less than about 75% in 10 min in 1000 ml of 0.1 N HC1+0.1% sodium lauryl sulfate, 50 RPM, Paddle (or) 1000 ml of pH 6.8 Phosphate buffer + 0.1 % sodium lauryl sulfate, 50 RPM, Paddle.

In an embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is in the form of tablet, capsule, pellet, mini-tablet, granules & powder.

An another embodiment a stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide for oral administration for the treatment of chronic obstructive pulmonary disease (COPD).

The embodiments of the present invention will be more fully understood from the below mentioned examples. The following examples are intended to illustrate the benefits of the present invention, but do not exemplify the full scope of the invention.

Procedure:

N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy benzamide, lactose monohydrate, pregelatinized starch (starch 1500) were mixed together and passed through an appropriate mesh. To the above mixture purified water was added to form granules. The granules were then dried and sieved. The sieved granules were lubricated with magnesium stearate. Finally compressed in to the tablets. The obtained tablets were coated in a coating pan with Opadry yellow.

Procedure:

N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, lactose monohydrate, pregelatinized starch (starch 1500) were mixed together and passed through an appropriate mesh. To the above mixture purified water was added to form granules. The granules were then dried and sieved. The sieved granules were mixed with pregelatinized starch (starch 1500) and lubricated with magnesium stearate. Finally compressed into the tablets. The obtained tablets were coated in a coating pan with Opadry yellow.

Procedure:

N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, lactose monohydrate, maize starch, pregelatinized starch (starch 1500) were mixed together and passed through a appropriate mesh. To the above blend purified water was added to form granules. The granules were then dried and sieved. The sieved granules were lubricated with magnesium stearate. Finally compressed in to tablets. The obtained tablets were coated in a coating pan with Opadry yellow.

Process:
a) Lactose monohydrate & pregelatinized starch in a blender for 15min,
b) N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy- benzamide was dissolved in acetone,
c) the above drug solution was added to step (a),
d) purified water was added to the obtained blend to prepare granules,
e) the obtained granules were dried and sifted through ASTM #20,
f) the resultant granules of step (e) were lubricated with magnesium stearate,
g) the obtained granules of step (f) were compressed into tablets, h) the tablets of step (g) were coated with opadry solution.

Dissolution Method:

Test-1:

In vitro dissolution studies on N-(3,5-dichloropyridin-4-yl)-3-cyclopropyl methoxy-4-difluoromethoxy-benzamide tablets according to example-4 were carried out using USP apparatus 2 (Paddle) at 50 rpm in 1000 ml of 0.0IN HC1 + 0.5% Sodium lauryl sulfate as a dissolution medium maintained at a temperature of 37±0.5°C.

Test-2:

In vitro dissolution studies on N-(3,5-dichloropyridin-4-yl)-3-cyclopropyl methoxy-4-difluoromethoxy-benzamide tablets were carried out using USP apparatus 2

(Paddle) at 50 rpm in 1000ml of pH 6.8 Phosphate buffer + 0.1 % Sodium lauryl sulfate as a dissolution medium maintained at a temperature of 37±0.5°C.
According to the in vitro dissolution studies performed in discriminating media, the % drug release of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is not less than about 75% in 10 min in 1000 ml of 0.1 N HC1+0.1% sodium lauryl sulfate, 50 RPM, paddle (or) 1000 ml of pH 6.8 Phosphate buffer + 0.1 % sodium lauryl sulfate, 50 RPM, paddle.

Claims:

1. A pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclo propylmethoxy-4-difluoromethoxy-benzamide, diluent, disintegrant and a lubricant.

2. A stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, pregelatinized starch and optionally a pharmaceutically acceptable excipient.

3. A stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide, lactose monohydrate, pregelatinized starch and magnesium stearate.

4. A stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide having the % drug release is not less than 75% in 10 min in 1000 ml of 0.1 N HC1+0.1% sodium lauryl sulfate, 50 RPM, Paddle, 1000 ml (or) 1000 ml of pH 6.8 Phosphate buffer + 0.1 % sodium lauryl sulfate, 50 RPM, Paddle.

5. A stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is prepared by wet granulation technique.

6. A stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is prepared by wet granulation technique; preferably with non-aqueous granulation.

7. A stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is in the form of tablet, capsule, pellet, mini-tablet, granules & powder.

8. A process for preparing a stable pharmaceutical composition comprising the following steps:

a) sifting lactose & pregelatized starch in a blender for 15 min,
b) dissolve N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide in acetone,
c) adding the solution of step (b) to step (a),
d) granulating the obtained blend with purified water,
e) drying the obtained granules,
f) sifting the obtained granules through ASTM#20,
g) lubricating the resultant granules of step (f) with magnesium stearate,
h) compressing the obtained granules of step (g) into tablets,
i) coating the tablets of step (h) with opadry solution.

9. A stable pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide for oral administration for the treatment of chronic obstructive pulmonary disease (COPD).

10. The pharmaceutical composition and process for the preparation of pharmaceutical composition substantially as herein described and illustrated by the examples.