Priority Document:
This patent application claims priority to Indian Provisional Patent
5 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
10 compns1ng 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.
15 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
20 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
25 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.
30 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 C17H14CbF2N203 and the molecular weight is 403.22. The
chemical structure is:
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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-
5 Dichiara -1-oxopyridin-4-yl)-4-difluoromethoxy-3-cyclopropyl- methoxy
benzamide and the chemical structure is:
10
ROFLUMILAST N-OXIDE
15 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
20 inactive ingredients: Lactose monohydrate, corn starch, povidone and
magnesium stearate.
US5712298 discloses Roflumilast generically.
25 US8431154 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.
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US20130345265 discloses a dosage form of Roflumilast along with
excipients like polyvinyl pyrrolidone, lactose, corn starch and magnesium
stearate.
5 W02013030789 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
10 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
15 1 : 1 to 2 : 1 .
20
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
25 1 : 1 to 2 : 1 .
In an aspect of the embodiment, the pharmaceutical composition is in
the form of a tablet or a capsule.
30 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 4511m;
(b) More than 90% particles are smaller than 10011m;
(c) 100% particles are smaller than 15011m;
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In yet another aspect of the embodiment, the pharmaceutical
composition comprises maize starch wherein particle size of maize starch is
between 111m to 5001Jm.
5 In another embodiment, the pharmaceutical composition comprises
10
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;
15 (b) mixing lactose and maize starch to prepare a dry mix;
20
(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
25 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.
30 The term 'pharmaceutical composition' denotes a composition which
shows immediate release.
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The term "active ingredient" (used interchangeably with "active" or
"active substance" or "drug") as used herein includes Roflumilast or its
pharmaceutically acceptable salt.
5 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.
10 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.
15 Examples of pharmaceutically acceptable inert excipients include, but
20
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
25 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
30 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
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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.
5 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
10 thereof.
Lubricants may be selected from, but are not limited to, those
conventionally known in the art such as Mg, AI or Ca or Zn stearate,
polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate,
15 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,
20 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
25 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
30 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
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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
5 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-
10 tablets or a combination thereof.
15
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 4511m;
(b) More than 90% particles are smaller than 10011m;
(c) 100% particles are smaller than 15011m;
Lactose monohydrate is a white, almost white crystalline powder freely
but soluble in water, practically insoluble in ethanol. Particle size distribution
20 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
25 between 111m to 50011m.
30
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
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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
5 steps of:
10
(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
15 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
SN Ingredients Quantity (m~
1. Lactose Monohydrate 1-50
2. Roflumilast 0.5
3. Hydroxypropyl cellulose 1-2
4. Maize Starch 1-60
5. Isopropyl alcohol q. s. L;)
6. Dichloromethane q. s.
7. Magnesium Stearate 0.5-2.5
30 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.
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5
(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.
10 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.
15 4) Lubrication & Compression:
20
Granules obtained in step 3 were lubricated with magnesium stearate & the
mixture was compressed.
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We Claim:
1. A pharmaceutical composition comprising roflumilast and
pharmaceutically acceptable excipients like maize starch, lactose
monohydrate, hydroxypropylcellulose and magnesium stearate wherein
5 maize starch and lactose monohydrate are present in a ratio of 1 :1 to
2:1.
10
2. The pharmaceutical composition according to claim 1, wherein the
composition is in form of a tablet or a capsule.
3. The pharmaceutical composition according to claim 1, wherein the
composition further comprises pharmaceutically acceptable excipients.
4. The pharmaceutical composition according to claim 3, wherein the
15 pharmaceutically acceptable excipients are diluents, lubricants,
binders, wetting agents, antifoaming agents, solvents and plasticizers.
5. The pharmaceutical composition according to claim 1, wherein the
particle size distribution of lactose monohydrate is as follows:
20 (a) 50%-65% particles are smaller than 4511m;
(b) More than 90% particles are smaller than 1 0011m;
(c) 100% particles are smaller than 15011m.
6. The pharmaceutical composition according to claim 1, wherein particle
25 size of maize starch is between 111m to 50011m.
7. A pharmaceutical composition comprising:
8. 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.