PHARMACEUTICAL COMPOSITION OF ROFLUMILAST
FIELD OF INVENTION
Present invention relates to multiparticulate pharmaceutical composition having first
inert component comprising one or more pharmaceutical excipients and at least one
subsequent component comprising roflumilast, wherein said first inert component is
free of roflumilast. Invention also relates to process of preparation of said
pharmaceutical composition and its use in the treatment of COPD.
BACKGROUND
Roflumilast, N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide,
a phosphodiesterase 4 (PDE-4) inhibitor, is approved in several countries
to reduce the risk of chronic obstructive pulmonary disease (COPD), exacerbations in
patients with severe COPD associated with chronic bronchitis and a history of
exacerbations. It is available commercially in USA as Daliresp® 500mcg oral
immediate release tablet for once a day administration.
Chronic obstructive pulmonary disease (COPD) is characterized by a gradual and
progressive loss of lung function. Two main pathophysiological processes occur in
COPD: inflammation and unopposed oxidation. Through selective inhibition of the
PDE4 enzyme, Roflumilast prevents the breakdown of cyclic AMP, which plays an
important role in regulating inflammatory cell activity.
US 5712298 discloses various PDE 4 inhibitors including Roflumilast and their NOxide
and process of preparation. Roflumilast is poorly water soluble drug and has
been categorized as BCS class II drug (high permeability, low solubility). Therefore,
it is desirable to design a formulation which improves the rate of dissolution and thus
improving the bioavailability of the drug. Further, Roflumilast being a potent drug
having very low dose formulation, there is a need to develop a robust process with
reproducible content uniformity within the batches as well as improve batch to batch
consistency.
Prior art discloses various techniques to improve dissolution of poorly water soluble
drugs, however, selection of suitable technique & excipients largely depends upon the
overall characteristics of the molecule, which eventually plays critical role in
designing formulation strategy to achieve desired in-vivo dissolution and plasma
profile to get the desired therapeutic outcome.
US6074670 discloses composition of fenofibrate, a poorly soluble drug, a hydrophilic
polymer and a surfactant, wherein API was granulated with solution of hydrophilic
polymer such as polyvinylpyrrolidone to have improved dissolution profile.
Similar to fenofibrate formulation of US607467, US8431 154 discloses the
composition of Roflumilast to improve its release and improved pharmacokinetic
profile by using aqueous solution of polyvinylpyrrolidone (PVP) for granulation of
roflumilast by preparing solid solution or solid dispersion.
US7951398 discloses solid dispersion of poorly soluble drug roflumilast, wherein
Roflumilast is dispersed in matrix comprising fatty alcohol, triglyceride and fatty acid
ester at high temperature, and then cooling and granulating it with a hydrophilic
polymer.
Similarly, Indian patent application 685/DEL/2006 discloses preparation of adsorbate
or solid dispersion of Roflumilast and hydrophilic carriers preferably
hydroxypropylmethylcellulose to improve dissolution of Roflumilast, in which
hydrophilic carrier is dispersed in the mixture of Roflumilast-Solvent resulting in
formation of adsorbate or solid dispersion.
WO 2013030789 discloses pharmaceutical oral dosage form of Roflumilast with
polymeric binders selected from saccharides, protein or synthetic polymers,
preferably hydroxylpropylcellulose or hydroxypropylmethylcellulose. The
composition prepared by wet granulation using binder solution to granulate
Roflumilast.
To summarize, all above mentioned prior arts teach to improve the dissolution of
poorly soluble drugs like roflumilast by way of close association of API with using
polymeric binder solution or by preparing dispersion of roflumilast with fatty
lipophilic substances at high temperature and finally converting it in to dosage form.
Thus, there still exists a need for simpler and economically viable process to prepare
stable & bioequivalent pharmaceutical composition, having desired content
uniformity.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide multiparticulate pharmaceutical
composition having first inert component comprising one or more pharmaceutical
excipients and at least one subsequent component comprising roflumilast, wherein
said first inert component is free of roflumilast.
Another aspect of present invention is to provide multiparticulate pharmaceutical
composition prepared by granulation process, having first inert component
comprising one or more pharmaceutical excipients and at least one subsequent
component comprising roflumilast, wherein said first inert component is free of
roflumilast.
Another aspect of present invention is to provide multiparticulate pharmaceutical
composition having first inert component prepared by granulation process comprising
one or more pharmaceutical excipient and at least one subsequent component
comprising roflumilast and optionally one or more pharmaceutical excipient, wherein
said subsequent component is prepared by granulation of roflumilast and optionally
one or more pharmaceutical excipient with said first inert component.
Another aspect of present invention is to provide multiparticulate pharmaceutical
composition having first inert component and at least one subsequent component
prepared by a process comprising the steps:
a) Preparing first inert component comprising one or more pharmaceutical
excipients, by granulation.
b) Adding at least one subsequent component comprising roflumilast with the
component prepared according to step a.
c) Optionally adding one or more subsequent components in the mixture/blend
of step b.
d) Preparing a pharmaceutical composition from the mixture or blend of step b
or c.
Another aspect of present invention is to provide process of preparing
multiparticulate pharmaceutical composition having first inert component and at least
one subsequent component comprising the steps:
a) Preparing first inert component comprising one or more pharmaceutical
excipients, by granulation.
b) Adding at least one subsequent component comprising roflumilast with the
first inert component.
c) Optionally adding one or more subsequent components in the mixture/blend
of step b.
d) Preparing a pharmaceutical composition from the mixture or blend of step b
or c.
DETAILED DESCRIPTION OF THE INVENTION
A phosphodiesterase-4 (PDE-4) inhibitor, Roflumilast is known to be effective for
reduction in risk of chronic obstructive pulmonary disease (COPD), exacerbations in
patients with severe COPD associated with chronic bronchitis and a history of
exacerbations.
Present invention relates to a novel approach of providing the stable pharmaceutical
composition of roflumilast having required content uniformity wherein said
composition provides desired dissolution profile and thus a bioequivalent product.
The use of the terms "a" and "an" and "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to be
construed to cover both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the
words "comprise", "have" and "include" and variations such as "comprises",
"comprising", "having" "includes", "including" are to be interpreted inclusively,
unless the context requires otherwise. That is, the use of these words may imply the
inclusion of an element or elements not specifically recited.
The term "Roflumilast" as used herein includes Roflumilast free base, its
pharmacologically active metabolites including roflumilast-N-oxide, its
pharmaceutically acceptable salt or its polymorphs. Preferably, Roflumilast is
Roflumilast free base. Roflumilast present in the composition according to present
invention can be in crystalline form or amorphous form. Particle size distribution
(PSD- D90) of roflumilast used according to present invention may vary from 1-25
microns, preferably D90 is less than 10 microns, most preferably D90 is less than 5
microns.
The term "multiparticulate" as used herein means state of matter which is
characterized by the presence of particles, pellets, beads or granules irrespective of
their size, shape or morphology. Such said multiparticulate may be formulated in the
form of compressed tablets, can be filled in a capsule or can be used as such as a
pharmaceutical composition.
The term "inert component" which is free of roflumilast as used herein means a
component wherein roflumilast or any other active pharmaceutical ingredient is not
added during processing. The term excludes the active pharmaceutical ingredient
which is adsorbed or absorbed inside the said first inert component after its
preparation.
The term "first inert component" as used herein means any component which is free
of roflumilast and is mixed or added with at least one subsequent component.
Meaning of the term should not be construed on the basis of order of preparing or
mixing/adding of the components. Thus, any component prepared according to
present invention, wherein roflumilast is not added, can be a first inert component
irrespective of order of preparation or mixing/adding with subsequent component/s.
The term "subsequent component" as used herein means one or more component
other than said first inert component present in the composition. At least one of the
said subsequent component comprises roflumilast. Meaning of the term should not be
construed on the basis of order of preparing or mixing/adding of the components.
The term "D90" as used herein means at least 90% of the particles have volume
diameter in the specified range when measured by a suitable method for example
laser diffraction using a Malvern Mastersizer® laser diffraction instrument.
The term "Granulation" as used herein means a method used to prepare
multiparticulate composition. Said methods include any suitable granulation methods
including wet granulation, dry granulation, roller compaction and melt granulation.
Preferably wet granulation is used for the preparation of multiparticulate composition.
The first embodiment of the present invention provides multiparticulate
pharmaceutical composition having first inert component comprising one or more
pharmaceutical excipients and at least one subsequent component comprising
roflumilast, wherein said first inert component is free of roflumilast.
First inert component according to present invention comprises one or more
pharmaceutical excipient such as one or more diluent, binder, disintegrant, surfactant
or lubricant. Preferably, pharmaceutical excipient is one or more diluent and/or
binder.
First inert component according to present invention can be prepared by any known
process in the art. Preferably, first inert component is in the form of granules prepared
by wet granulation, which is free of roflumilast. More preferably, first inert
component is prepared by aqueous granulation.
Subsequent component of said multiparticulate composition prepared according to
present invention comprises roflumilast optionally with one or more pharmaceutical
excipient, but free of hydrophilic polymeric binder. Said subsequent component is
added or mixed with said first inert component. The term "adding" "added" "mixing"
or "mixed" as used herein are to be interpreted inclusively, unless the context requires
otherwise. That is, the use of these words may imply mixing, adding, granulating of
one of the said components with other component to form mixture or blend.
Said subsequent component is either present as a separate component in any physical
form such as powder, granules, beads and the like or can be granulated with said first
inert component. Alternatively, subsequent component can be coated over said first
component. Preferably, subsequent component is granulated with first inert
component using wet granulation, more preferably using non-aqueous granulation.
For increasing processability ease, a part of first inert component is granulated with
said subsequent component. Preferably, about 90-96% of total first inert component
is granulated with said subsequent component. Granulation can be performed using
any of the known method such as rapid mixer granulation or fluid bed granulation. It
is preferable that all the said components are dried before addition of other
component.
The term "non-aqueous granulation" as used herein means granulation to prepare any
of the components of multiparticulate composition according to present invention
wherein organic or inorganic solvent is used for granulation, preferably organic
solvent is used for granulation, which is substantially free of water.
The term "substantially free" as used herein means less than 10% of water is present
in the organic solvent. Preferably, less than 5%, most preferably less than 1% of
water is preset in the solvent.
A further embodiment of present invention provides a multiparticulate
pharmaceutical composition having first inert component comprising one or more
pharmaceutical excipients and at least one subsequent component comprising
roflumilast, wherein said first inert component is free of roflumilast and said
subsequent component is free of hydrophilic polymeric binder.
The term "free of hydrophilic polymeric binder" means any subsequent component
which comprises roflumilast, wherein roflumilast is not mixed with any hydrophilic
polymeric binder, preferably aqueous solution of hydrophilic polymeric binder,
during the preparation of said subsequent component.
In addition to first inert component and one subsequent component comprising
roflumilast, compositions may further comprise one or more subsequent components.
Such said subsequent component/s may or may not comprise roflumilast.
The composition prepared according to present invention not only provides consistent
content uniformity but also provides a stable product with desired characteristics such
as hardness and/or dissolution profile. It is noteworthy that composition according to
present invention does not require any complex process or use of polymeric binder
solution to modify API characteristics, but still provides desired dissolution profile,
which provides bioequivalent product. Additionally, multiparticulate composition
prepared by the process according to present invention has acceptable flow
properties.
Another embodiment of present invention provides multiparticulate pharmaceutical
composition having first inert component and at least one subsequent component
prepared by a process comprising the steps of:
a) Preparing first inert component comprising one or more pharmaceutical
excipients, by granulation.
b) Adding at least one subsequent component comprising roflumilast with the
component prepared according to step a.
c) Optionally adding one or more subsequent components in the mixture/blend
of step b.
d) Preparing a pharmaceutical composition from the mixture or blend of step b
or c.
The order of steps in the process of preparation of pharmaceutical compositions
according to present invention is for the purpose of representation only and should
not limit the scope of the embodiments with respect to performance of steps in the
mentioned sequence.
Another embodiment of present invention provides process of preparing
multiparticulate pharmaceutical composition having first inert component and at least
one subsequent component comprising the steps of:
a) Preparing first inert component comprising one or more pharmaceutical
excipients, by granulation.
b) Adding at least one subsequent component comprising roflumilast with the
component prepared according to step a.
c) Optionally adding one or more subsequent components in the mixture/blend
of step b.
d) Preparing a pharmaceutical composition from the mixture or blend of step b
or c.
Preferably, pharmaceutical composition according to present invention is prepared by
a process comprising:
a) Preparing first inert component comprising one or more diluent, binder,
disintegrant, surfactant or lubricant, by granulation.
b) Adding at least one subsequent component comprising roflumilast and
optionally one or more pharmaceutical excipient, with said first inert
component.
c) Optionally adding one or more diluent, disintegrant, surfactant or lubricant in
the mixture/blend of step b.
d) Granulating the mixture of blend of step b or c.
e) Optionally adding one or more diluent, disintegrant, surfactant or lubricant in
the granules of step d.
f) Preparing a pharmaceutical composition from the mixture or blend of step e.
Diluent, disintegrant, surfactant or lubricant used in each of the preceding steps can
be same or different.
Another embodiment of present invention provides multiparticulate pharmaceutical
composition having first inert component comprising one or more pharmaceutical
excipient and at least one subsequent component comprising roflumilast, wherein at
least one of the said components is prepared by wet granulation and said first inert
component is free of roflumilast.
Another embodiment of present invention provides multiparticulate pharmaceutical
composition having first inert component comprising one or more pharmaceutical
excipient and at least one subsequent component comprising roflumilast, wherein
said first inert component and at least one subsequent component are prepared by wet
granulation and said first inert component is free of roflumilast. Preferably, said first
inert component is prepared by the wet granulation using aqueous granulation and at
least one subsequent component is prepared by wet granulation using non-aqueous
granulation.
Solvent used for non-aqueous granulation of roflumilast to prepare pharmaceutical
composition according to present invention include acetone, methylene chloride,
isopropyl alcohol, ethanol, chloroform, dichloromethane, ether methanol and the like
or combination thereof.
Pharmaceutical excipient according to present invention comprises diluent, binder,
disintegrant, surfactant, lubricant and the like.
Compositions according to present invention may optionally further comprises one or
more glidant, coloring agent, flavoring agent, preservatives, antioxidants and the like.
Example and suitable amount of said excipient is known to a skilled person or as
given in Handbook of pharmaceutical excipients (sixth edition, 2009).
A diluent according to present invention include powdered cellulose, microcrystallme
cellulose, silicified microcrystallme cellulose, starch, dibasic calcium phosphate,
dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose, lactose
or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures
thereof. Preferably, diluent is lactose, starch or mixture thereof. Pharmaceutical
composition comprises diluent in the amount of 50-98% w/w of the total
composition.
A binder according to present invention include polyvinyl alcohol, starch,
pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystallme
cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose,
hydroxypropyl cellulose, hydroxyethyl cellulose; gelatin, zein, polymethacrylates,
sodium alginate, gums, synthetic resins or mixtures thereof. Preferably, binder is
polyvinyl alcohol. Pharmaceutical composition comprises binder in the amount of 2-
30% w/w of the total composition.
A disintegrant according to present invention include carboxymethyl cellulose and its
salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium,
cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone,
sodium starch glycolate, pregelatinized starch, low substituted hydroxypropyl
cellulose, and mixtures thereof. Preferably, disintegrant is carboxymethylcellulose
calcium. Pharmaceutical composition comprises disintegrant in the amount of 0.6 -
8.0 w/w of the total composition.
A surfactant according to present invention is selected from one or more non-ionic or
ionic (i. e., cationic, anionic and Zwitterionic) surfactants suitable for use in
pharmaceutical compositions. Suitable surfactants include mono fatty acid esters of
polyoxyethylene sorbitan such as those sold under the brand name Tween®; sodium
lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the
brand name Cremophor®, polyethoxylated fatty acids and their derivatives, propylene
glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and
their derivatives, sugar esters, polyoxyethylene-polyoxypropylene block copolymers
such as those sold under the brand name Poloxamer®, soy lecithin, or mixtures
thereof. Pharmaceutical composition comprises surfactant in the amount of 0.01-7 %
w/w of the total composition.
A lubricant according to present invention include talc, metallic stearate such as
magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely
divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl
palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate,
magnesium trisilicate or mixtures thereof. Preferably, lubricant is magnesium
stearate. Pharmaceutical composition comprises lubricant in the amount of 0.2-2%
w/w of the total composition.
Pharmaceutical compositions prepared according to present invention, comprises
roflumilast in the amount of 0.01-2%, preferably 0.1-1%, most preferably 0.6 0.9%
w/w of the total composition.
First inert component according to present invention can be present in the amount of
70 to 99% w/w of the total composition. Preferably, first inert component is present
in the amount of 90-99% w/w of the total composition, most preferably, it is 95-99%
w/w of the total composition. Particle size (D90) of first inert component can be less
than 400 microns. Preferably particle size (D90) of first inert component is less than
300 microns, more preferably particle size(D90) is less than 200 microns.
One or more subsequent components according to present invention can be present in
the amount of 1 to 30% w/w of the total composition. Preferably, one or more
subsequent components are present in the amount of 1-10% w/w of the total
composition; most preferably, it is 1-5% w/w of the total composition.
A pharmaceutical composition according to present invention is a solid composition
for immediate release for oral or nasal administration and it can be in the form of
tablet, powder or capsule. Preferably, said composition is in the form of tablet or
capsule for oral administration.
A pharmaceutical composition according to present invention may be a nasal
composition for immediate release, suitable for inhalation. Said composition is in the
form of powder.
A multiparticulate pharmaceutical composition of the present invention, when
formulated for nasal administration, the particle size of each component is critical.
Desired particle size of the components can be obtained by suitable technique i.e
milling, homogenization or any other technique known in the art.
Another preferred embodiment of present invention provides a multiparticulate
pharmaceutical composition suitable for nasal administration, having first inert
component comprising one or more pharmaceutical excipients and at least one
subsequent component comprising roflumilast, wherein said first inert component is
free of roflumilast and particle size (D90) of said components is less than 10 microns.
Preferably, particle size (D90) of said components is less than 5 microns, more
preferably particle size (D90) is less than 2 microns.
Another embodiment of present invention provides a multiparticulate pharmaceutical
composition suitable for nasal administration, having first inert component
comprising one or more pharmaceutical excipients and at least one subsequent
component comprising roflumilast comprising the steps of:
a) Preparing first inert component comprising one or more pharmaceutical
excipients, by granulation.
b) Milling or homogenizing the granules obtained in step (a) to obtain the first
inert component having particle size (D90) of less than 10 microns.
c) Adding at least one subsequent component comprising roflumilast with the
component prepared according to step b.
d) Optionally adding one or more subsequent components in the mixture/blend
of step c.
e) Optionally milling or homogenizing one or subsequent components to obtain
particle size (D90) of mixture/blend of less than 10 microns.
f) Preparing a pharmaceutical composition suitable for nasal administration from
the mixture or blend of step d or e.
A multiparticulate pharmaceutical composition suitable for nasal administration
prepared according to present invention can be filled in a capsule or in any suitable
nasal or inhalation device for administration of it through nasal route. Such said nasal
device and its use is generally known in the art.
A pharmaceutical composition according to present invention may optionally
comprise a coating.
Coating according to present invention may be functional or non-functional coating,
preferably coating is non-functional coating.
Non-functional coating comprises a film forming polymer and one or more excipients
suitable for said coating.
Another embodiment of present invention provides a composition comprising
roflumilast prepared according to present invention, wherein at least one subsequent
component may comprise one or more active ingredient other than roflumilast. Said
other active ingredient is preferably selected from bronchodilators such as salmeterol,
formoterol, indacaterol, bambuterol, tiotropium, ipratropium, theophylline,
levosalbutamol, pirbuterol, epinephrine, ephedrine, terbutaline, or leukotriene
antagonist selected from montelukast, zafirlukast, pranlukast and zileuton and
pharmaceutically acceptable salts thereof.

We Claim:
1. A multiparticulate pharmaceutical composition comprising first inert component
comprising one or more pharmaceutical excipients and at least one subsequent
component comprising roflumilast, wherein said first inert component is free of
roflumilast.
2 . The composition as claimed in claim 1, further comprises subsequent components.
3 . The composition as claimed in claim 1, wherein subsequent component comprising
roflumilast, is free of hydrophilic polymeric binder.
4 . The composition as claimed in claim 1, wherein first inert component is prepared
by granulation process.
5. A multiparticulate pharmaceutical composition having first inert component and at
least one subsequent component prepared by a process comprising the steps of:
a) Preparing first inert component comprising one or more pharmaceutical excipients,
by granulation.
b) Adding at least one subsequent component comprising roflumilast with the
component prepared according to step a).
c) Optionally adding one or more subsequent components in the mixture/blend of step
b).
d) Preparing a pharmaceutical composition from the mixture or blend of step b) or c).
6 . The composition according to any proceeding claims, which is suitable for oral and
nasal administration.
7 . The composition according to claim 6, is suitable for oral administration.
8. The composition according to any preceding claims, wherein pharmaceutical
excipients are selected from diluent, binder, disintegrant, surfactant and lubricant or
mixture thereof.
9 . A process of preparing multiparticulate pharmaceutical composition having first
inert component and at least one subsequent component comprising the steps:
a) Preparing first inert component comprising one or more pharmaceutical excipients,
by granulation.
b) Adding at least one subsequent component comprising roflumilast with the
component prepared according to step a .
c) Optionally adding one or more subsequent components in the mixture/blend of step
b.
d) Preparing a pharmaceutical composition from the mixture or blend of step b or c .
10. A multiparticulate pharmaceutical composition as herein described with reference
to the examples accompanying the specification.