WO2016120746A1 - A pharmaceutical composition comprising roflumilast - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising Roflumilast. Particularly, the present invention provides a pharmaceutical composition in the form of a tablet or a capsule comprising Roflumilast and pharmaceutically acceptable excipients and a process for preparing the same.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING ROFLUMILAST

Priority Document:

This patent application claims priority to Indian Provisional Patent Application number 299/MUM/2015 (filed on 29th January 2015), the contents of which are incorporated by reference herein.

Technical field of the invention:

The present invention relates to a pharmaceutical composition comprising Roflumilast. Particularly, the present invention provides a pharmaceutical composition in the form of a tablet or a capsule comprising Roflumilast and pharmaceutically acceptable excipients and a process for preparing the same. Background of the invention:

COPD, or chronic obstructive pulmonary disease, is a progressive disease that blocks the airflow and causes difficulty in breathing. If untreated, the disease gets worse over time. Emphysema and chronic bronchitis are the two most common conditions that are related to COPD. Chronic bronchitis is an inflammation of the lining of bronchial tubes. Emphysema occurs when the air sacs (alveoli) at the end of the smallest air passages (bronchioles) in the lungs are gradually destroyed.

Roflumilast is a pharmaceutical agent that is used to treat severe exacerbations caused by COPD. It is a phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor. It blocks the degradative action of PDE4 on cyclic adenosine monophosphate (cAMP). cAMP acts as a messenger which is responsible for many biological processes. Roflumilast exerts its effect on the body by its active metabolite

(Roflumilast N-oxide). The chemical name of Roflumilast is N-(3, 5- dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its empirical formula is C17H CI2F2N2O3 and the molecular weight is 403.22. The chemical structure is:

ROFLUMILAST

The chemical name for Roflumilast N-oxide is 3-(Cyclopropylmethoxy)- N-(3, 5-dichloro-1 -oxido-4-pyridinyl)-4-(difluoromethoxy) benzamide; N-(3,5- Dichloro -1 -oxopyridin-4-yl)-4-difluoromethoxy-3-cyclopropyl- methoxy benzamide and the chemical structure is:

ROFLUMILAST N-OXIDE Roflumilast is available as Daliresp® tablets (by Forest

Pharmaceuticals, Inc) in US market. It is once-a-day tablet containing 500mcg of Roflumilast which is used as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Daliresp® contains the following inactive ingredients: Lactose monohydrate, corn starch, povidone and magnesium stearate.

US5712298 discloses Roflumilast generically. US8431 154 discloses a dosage form of Roflumilast for oral administration in the form of a tablet or pellet form which is prepared using the aqueous solution of polyvinyl pyrrolidone. US20130345265 discloses a dosage form of Roflumilast along with excipients like polyvinyl pyrrolidone, lactose, corn starch and magnesium stearate. WO2013030789 discloses dosage form of Roflumilast with pharmaceutically acceptable excipients wherein the binder is selected from a saccharide, protein or synthetic polymer.

However, there still exists a need of alternative of pharmaceutical composition for poorly water soluble drug like Roflumilast which can be economical. The present inventors have developed a pharmaceutical composition comprising Roflumilast along with pharmaceutically acceptable excipients like maize starch, lactose monohydrate, hydroxypropyl cellulose and magnesium stearate wherein the weight ratio of maize starch to lactose is 1 :1 to 2:1 .

Summary of the invention:

The present invention relates to a pharmaceutical composition comprising Roflumilast.

In an embodiment, the present invention relates to a pharmaceutical composition comprising Roflumilast along with pharmaceutically acceptable excipients like maize starch, lactose monohydrate, hydroxypropylcellulose and magnesium stearate wherein the weight ratio of maize starch to lactose is 1 :1 to 2:1 .

In an aspect of the embodiment, the pharmaceutical composition is in the form of a tablet or a capsule. In another aspect of the embodiment, the pharmaceutical composition comprises lactose monohydrate with typical particle size distribution wherein

(a) 50%-65% particles are smaller than 45μηι;

(b) More than 90% particles are smaller than 100μηι;

(c) 100% particles are smaller than 150μηι ; In yet another aspect of the embodiment, the pharmaceutical composition comprises maize starch wherein particle size of maize starch is between 1 μηι to 500μηι. In another embodiment, the pharmaceutical composition comprises roflumilast in an amount of 0.1 %-1 .4% by weight, lactose in an amount of 15%-60% by weight, hydroxypropylcellulose in an amount of 1 .5%-3.5% by weight, maize starch in an amount of 25%-75% by weight and magnesium stearate in an amount of 0.5%-2% by weight.

A process for preparing a pharmaceutical composition comprising the steps of:

(a) preparing solutions of roflumilast and hydroxypropylcellulose separately in suitable solvents;

(b) mixing lactose and maize starch to prepare a dry mix;

(c) granulating the dry mix of step (b) with the solution prepared in step (a) to form granules;

(d) compressing the granules to form a tablet or filling into capsules. Detailed description of the invention:

The present invention relates to a pharmaceutical composition comprising Roflumilast.

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.

The term 'pharmaceutical composition' denotes a composition which shows immediate release. The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes Roflumilast or its pharmaceutically acceptable salt. The term "pharmaceutically acceptable inert excipients", denotes any of the components of a pharmaceutical composition other than the active and which are approved by regulatory authorities or are generally 'regarded as safe' for human or animal use. In an embodiment a pharmaceutical composition comprises roflumilast and pharmaceutically acceptable excipients like maize starch, lactose monohydrate, hydroxypropylcellulose and magnesium stearate wherein the weight ratio of maize starch to lactose is 1 :1 to 2:1 . Examples of pharmaceutically acceptable inert excipients include, but are not limited to diluents, lubricants, binders, wetting agents, antifoaming agents, solvents and plasticizers. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch (maize starch); microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and other materials known to one ordinarily skilled in the art and mixtures thereof.

Hydroxypropyl cellulose is nonionic water-soluble cellulose ether. It combines organic solvent solubility, thermoplasticity and surface activity with the aqueous thickening and stabilizing properties. Hydroxypropyl cellulose is available in various grades with corresponding varying viscosities and molecular weights. Depending on the necessity of the composition, suitable grade of hydroxypropyl cellulose can be incorporated. Diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate and other materials known to one ordinarily skilled in the art and mixtures thereof.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc and other materials known to one ordinarily skilled in the art and mixtures thereof.

Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one ordinarily skilled in the art and mixtures thereof.

Solvents include, but are not limited to purified water, acetone, ethyl alcohol, isopropyl alcohol dichloromethane and other materials known to one ordinarily skilled in the art and mixtures thereof.

It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden.

The amount of each type of additive employed may vary within ranges conventional in the art.

In an aspect of the embodiment, the extended release pharmaceutical composition is in form of a tablet or a capsule. The terms tablet or a capsule include tablet, capsules, pills, granules, tablets in capsules, caplets, mini- tablets or a combination thereof.

In another aspect of the embodiment, the pharmaceutical composition comprises lactose monohydrate with typical particle size distribution wherein (a) 50%-65% particles are smaller than 45μηι;

(b) More than 90% particles are smaller than 100μηι;

(c) 100% particles are smaller than 150μηι ;

Lactose monohydrate is a white, almost white crystalline powder freely but soluble in water, practically insoluble in ethanol. Particle size distribution can be determined by various methods like Sieve analysis, Microscopy, Laser diffraction method, sedimentation techniques and many more.

In yet another aspect of the embodiment, the pharmaceutical composition comprises maize starch wherein particle size of maize starch is between 1 μηι to 500μηι.

Starch occurs as an odorless and tasteless, fine, white to off-white powder. It consists of very small spherical or ovoid granules or grains whose size and shape are characteristic for each botanical variety.

In another embodiment, the pharmaceutical composition comprises roflumilast in an amount of 0.1 %-1 .4% by weight, lactose in an amount of 15%-60% by weight, hydroxypropylcellulose in an amount of 1 .5%-3.5% by weight, maize starch in an amount of 25%-75% by weight and magnesium stearate in an amount of 0.5%-2% by weight.

A process for preparing a pharmaceutical composition comprising the steps of:

(a) preparing solutions of roflumilast and hydroxypropylcellulose separately in suitable solvents;

(b) mixing lactose and maize starch to prepare a dry mix;

(c) granulating the dry mix of step (b) with the solution prepared in step (a) to form granules;

(d) compressing the granules to form a tablet or filling into capsules.

The foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.

Example 1 : Pharmaceutical composition comprising Roflumilast

Manufacturing Process:

1 ) Drug solution and binder preparation :

(a) Roflumilast was dispersed in mixture of Isopropyl alcohol Dichloromethane under continuous stirring to form a clear solution. (b) Hydroxypropyl cellulose was dispersed in mixture of Isopropyl alcohol & Dichloromethane under continuous stirring to form a clear solution.

(c) Solution of step (b) was added into solution of step (a) under continuous stirring.

2) Dry Mixing:

Lactose Monohydrate and Maize starch was loaded in Fluid Bed Equipment & was fluidized. 3) Top spray granulation & drying:

Solution prepared in step 1 (c) was sprayed on the materials loaded in Fluid Bed Equipment in step 2. The granules thus obtained were dried and sifted as required. 4) Lubrication & Compression:

Granules obtained in step 3 were lubricated with magnesium stearate & the mixture was compressed.

Claims

We Claim:

1 . A pharmaceutical composition comprising roflumilast and pharmaceutically acceptable excipients like maize starch, lactose monohydrate, hydroxypropylcellulose and magnesium stearate wherein maize starch and lactose monohydrate are present in a ratio of 1 :1 to 2:1 .

The pharmaceutical composition according to claim 1 , wherein the composition is in form of a tablet or a capsule.

The pharmaceutical composition according to claim 1 , wherein the composition further comprises pharmaceutically acceptable excipients.

The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable excipients are diluents, lubricants, binders, wetting agents, antifoaming agents, solvents and plasticizers.

The pharmaceutical composition according to claim 1 , wherein the particle size distribution of lactose monohydrate is as follows:

(a) 50%-65% particles are smaller than 45μηι;

(b) More than 90% particles are smaller than 100μηι;

(c) 100% particles are smaller than 150μηι.

The pharmaceutical composition according to claim 1 , wherein particle size of maize starch is between 1 μηι to 500μηι.

7. A pharmaceutical composition comprising:

Ingredients %w/w

Lactose monohydrate 15-60

Roflumilast 0.1 -1 .4

Hydroxypropylcellulose 1 .5-3.5

Maize starch 25-75 5

Isopropyl alcohol q.s

Dichloromethane q.s

Magnesium stearate 0.5-2 A process for preparing a pharmaceutical composition comprising the steps of:

(a) preparing solutions of roflumilast and hydroxypropylcellulose separately in suitable solvents;

(b) mixing lactose and maize starch to prepare a dry mix;

(c) granulating the dry mix of step (b) with the solution prepared in step

(a) to form granules;

(d) compressing the granules to form a tablet or filling into capsules.