PROCESS OF PREPRATION OF PHARMACEUTICAL COMPOSITIONS
COMPRISING AMORPHOUS MIRABEGRON WITHOUT PRIOR ISOLATION
OFAMORPHOUSMIRABEGRON
FIELD OF THE INVENTION
The present invention relates a process of preparation of stable pharmaceutical
compositions comprising amorphous Mirabegron.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an
appropriate technical context and to help understand the invention better. Reference to
any prior art in this specification should not be construed as an admission that such art is
widely known or forms part of common general knowledge in the field.
Mirabegron is a beta-3 adrenergic agonist that relaxes a muscle involved with the storage
of urine in the bladder and used for the treatment of overactive bladder in adults with
symptoms of urge urinary incontinence, urgency and urinary frequency. Mirabegron
activates the ~3 adrenergic receptor in the detrusor muscle in the bladder, which leads to
muscle relaxation and an increase in bladder capacity. Mirabegron relaxes the detrusor
smooth muscle during the storage phase of the urinary bladder fill-void cycle by
activation ofbeta-3 adrenergic receptors which increases bladder capacity.
Mirabegron, is chemically 2-(2-aminothiazol-4-yl)-N-[ 4-(2-{ [(2R)-2-hydroxy2-
phenylethyl]amino }ethyl)phenyl]acetamide or 2-amino-N-[ 4-[2-[( (2R)-2-hydroxy-2-
phenylethyl]amino ]ethyl]phenyl]-4-thiazoleacetamide, having a Formula 1. Mirabegron,
has valuable pharmacological properties. In fact, it is a beta-3 adrenergic agonist
indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary
incontinence, urgency, and urinary frequency.
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{2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy2-
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011
Mirabegron is a novel, once-daily, orally active, first-in-class, potent ~3-adrenoceptor
agonist recently approved by the United States Food and Drug Administration for
overactive bladder therapy. Phase II studies and four large-scale phase III multinational
randomized, controlled trials have supported the efficacy and tolerability of mirabegron
in the clinical trial setting of patients with overactive bladder for up to 12 weeks of
therapy and in the long term (12 months). The reported incidence and severity of
treatment-emergent and serious adverse effects were similar to antimuscarinics, but with
a more than threefold lower incidence of dry mouth compared with tolterodine.
Mirabegron is an orally active beta-3 adrenoceptor agonist and is approved in USA and
Europe for the potential treatment of urinary frequency, urinary incontinence, or urgency
associated with overactive bladder by Astellas Pharma. Mirabegron is also approved in
Japan. U.S. Pat. No. 6,346,532 B 1 discloses mirabegron or a salt thereof and process for
its preparation. U.S. Pat. No. 7,342,117 B2 discloses a.-form crystal and ~-form crystal of
Mirabegron.
Amorphous forms can be thought of as liquids that have been solidified by the removal of
thermal energy or a solvent, in a manner that circumvents crystallization. The amorphous
form can have different solubility, stability, and mechanical behavior that can be
exploited by pharmaceutical scientists. The solubility of a given solid is a sum of crystal
packing energy, cavitation, and solvation energy. Different crystalline forms of a given
drug will have different crystal packing energies. The amorphous forms of the same drug
require minimal packing energy disruption when dissolving due to absence of an ordered
3
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crystal lattice. Thus, the amorphous forms provide the maximal solubility advantage as
. compared to the crystalline forms of a drug. The 'apparent solubility' and dissolution
advantage offered by these systems is a vital approach to enhance bioavailability of
poorly water soluble drugs.
However, the amorphous forms of Mirabegron are found to be unstable at room
temperature. Therefore, amorphous Mirabegron is difficult to formulate m a
pharmaceutical compositions after prior isolation. There is therefore a need to develop a
process which helps eliminate the step of prior isolation of amorphous Mirabegron while
formulating compositions comprising amorphous Mirabegron.
Typically, crystalline forms of drug candidates are used in the process of preparation of·
pharmaceutical compositions. This tends to ensure a high level of purity and stability,
particularly if the crystal is in its most thermodynamically stable form. By introducing
thermal and mechanical energy, processing can lead to full or partial loss of crystallinity
and the formation of amorphous or disordered crystalline material. Whereas crystals
exhibit long-range molecular order, molecules in the amorphous state have no long-range
order but retain the short-range order typical of liquids.
In ·pharmaceutical composition, several amorphous and disordered crystalline materials
are encountered. It is worthwhile to mention that several polymers and other excipierits
intrinsically exist in these forms, e.g., PVP, microcrystalline cellulose, and magnesium
stearate. Similarly, lyophilized or spray-dried mixtures of proteins with various
cryoprotectants and lyoprotectants are purposefully prepared in amorphous forms to
physically stabilize biopharmaceut.ical products, while many hydrophobic drugs are made
amorphous by co-precipitation or co-melting from mixtures with polymeric excipients to
enhance their aqueous dissolution rates and, hence, oral bioavailability. In the same line,
very often, it is observed that upon crystallization a material is not completely crystalline.
Moreover, crystalline drugs may be inadvertently rendered disordered or partially
amorphous through processing such as milling, compaction, drying, granulation, and
polymer film coating.
4
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Therefore, from the formulation perspective, whenever amorphous materials are present,
there must be significant concern since, relative to the crystalline state, the amorphous
state is less thermodynamically stable. Consequently, molecules in the amorphous state
generally exhibit greater chemical instability, enhanced dissolution rates, altered
mechanical properties, and greater hygroscopicity. When these properties are not
anticipated, prevented, or controlled, they can lead to great difficulty on processing,
storage, and use of pharmaceutical products. Also, since the amorphous state is
metastable relative to the crystalline state, there is always the potential for unexpected
crystallization during storage, leading to macroscopic changes in specific surface area,
flow, and concretion. Such observations led to the hypothesis that most solid-state
instabilities of pharmaceutical interest preferentially occur in the disordered
noncrystalline regions of the solid. (C. Ahlneck and G. Zografi "The Molecular Basis for
Moisture Effects on the Physical and Chemical Stability of Drugs in the Solid-State," Int.
J. Pharm. 1990, 62, 87-95.)
In view of the above, there is a need to provide for a process for manufacture of stable
pharmaceutical compositions comprising amorphous Mirabegron wherein the process
does not involve prior isolation of amorphous Mirabegron. The present invention serves
to provide a solution to the above referred problem in the prior art.
The present invention provides for a process of preparation of a pharmaceutical
composition comprising amorphous Mirabegron wherein the process does not involve
prior isolation of amorphous Mirabegron. . The present invention further provides for a
novel, simple, efficient, cost effective, reproducible, industrially applicable process of
manufacture of stable pharmaceutical compositions comprising amorphous Mirabegron.
U.S. Pat. No. 7 ,342,117 B2 discloses the preparation of a-form crystal and ~-form crystal
of mirabegron.
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The methods for the preparation of a-form crystal and ~-form crystal of Mirabegron as
per the document involves the use of rapid cooling, use of seed material and use of
solvents water and ethanol only. The methods for the preparation of a-form crystal and ~form
crystal of Mirabegron described in the literature suffer from one or .more drawbacks
such as reproducibility, use of seed material, less yield, limited solvents, which does not
result an industrially feasible process.
The prior art does not describe a process of preparation of stable pharmaceutical
compositions comprising amorphous Mirabegron wherein the process does not involve
prior isolation of amorphous Mirabegron. Therefore, there is a need to provide a simple,
reproducible, environment friendly, cost effective, industrially feasible processes for the
preparation of stable pharmaceutical compositions comprising amorphous Mirabegron.
U.S. Pat. No. 2,014,020,672,9 AI discloses amorphous Mirabegron and processes for
crystal forms of Mirabegron. However, the said specification does not disclose or relate
to a process of preparation of a pharmaceutical composition comprising amorphous
Mirabegron wherein the process does not involve a step of prior isolation of amorphous
Mirabegron.
Indian Patent application number 2221/CHE/2012 for example in Example 20 teaches
how to prepare pure amorphous Mirabegron using spray drying process in a spray dryer
followed by making a composition with excipients. The said specification does not
disclose or relate to a process of the claimed invention wherein there is no separate
process to prepare amorphous Mirabegron prior to making of the pharmaceutical
composition.
Indian Patent application number 2588/MUM/2012 for example in Example 1 teaches ·
preparation of pure amorphous Mirabegron using spray drying process in a spray dryer
followed by making a composition with excipients. The said specification does not
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disclose or relate to the process of the claimed invention wherein, there is no separate
process to prepare amorphous Mirabegron prior making any formulation.
The present invention therefore provides a process of manufacture of stahle
pharmaceutical compositions comprising amorphous Mirabegron wherein amorphous
Mirabegron is not isolated separately before employing in the process of manufacture.
Mirabegron is moreover an active ingredient which has the disadvantage of having a very
low bioavailability and, as a consequence, a large inter-individual variability. The
characteristic feature of the molecule therefore generally entails higher dose of the active
ingredient in the pharmaceutical compositions. There is therefore a need to prepare
pharmaceutical compositions comprising amorphous Mirabegron wherein the
pharmaceutical compositions are stable.
The present invention therefore relates to stabilization of amorphous form in
pharmaceutical compositions comprising amorphous Mirabegron.
Accordingly, the technical problem posed is to provide for stable pharmaceutical
compositions comprising amorphous Mirabegron wherein the compositions are
compatible for use in the pharmaceutical industry, especially in terms of stability and
storage under customary conditions.
A solution known to the person skilled in the art consists of forming a dispersion of the
active ingredient in a solid matrix which surrounds the molecules and prevents them from
forming a crystal lattice. The more dilute the active ingredient within the matrix, the
greater the amorphous formation. However, the shortcoming of using the above referred
process is that the size of tablets containing the amorphous active ingredient increases
substantially with the matrix. Since the patients have to eventually swallow the tablets,
the size of the tablets constitutes a major drawback for the patients. Accordingly, another
challenge lies in minimizing the amount of matrix used, to the benefit of the active
ingredient, whilst still preventing the crystal lattice form forming.
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The Applicant has now discovered that it is possible to obtain a stable formulation of
mirabegron in amorphous form in reproducible and industrially feasible manner. This
new stabilized form allows envisaging its use in the pharmaceutical industry.
OBJECTIVES OF THE PROPOSED INVENTION
The objective of the present invention is process of manufacturing of stable
pharmaceutical compositions comprising amorphous Mirabegron wherein amorphous
Mirabegron is not isolated separately before employing in the process of manufacture. A
further objective of the invention is to maintain the stability and arnorphousity of
Mirabegron on storage of the pharmaceutical compositions.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process of preparation of a stable pharmaceutical
compositions comprising amorphous Mirabegron wherein amorphous Mirabegron is not
isolated separately before employing in the process of manufacture.
In another embodiment, the present invention relates to the stable pharmaceutical
composition prepared by using the above referred process. By "stabilized" it is
understood that the amorphous form of mirabegron is preserved when it is stored in
product shelf life for longer duration.
More specifically, the present invention relates to a process of preparation wherein there
is preparation of amorphous mirabegron within an organic polymer directly without the
need of isolating the amorphous form from mixture thereof.
In a preferred embodiment, the invention relates to a formulation wherein the percentage
by weight of mirabegron is from 1.6 to 50%, and mor.e preferably from 10 to 40 %. Even
8
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at those percentages of active ingredient contents, the amorphous form of mirabegron is
preserved in a manner that is stable over time. It is possible, depending on the organic
polymer chosen, to increase this percentage by weight ofMirabegron in dosage form.
PROCESS OF PREPERATION OF A PHARMCEUTICAL COMPOSITIONS
COMPRISING AMORPHOUS MIRABEGRON:
The process of preparation of pharmaceutical composition comprising amorphous
Mirabegron involves dissolving Mirabegron in a solvent(s). The mixture is then stirred
until the Mirabegron get completely dissolved or dispersed or homogeneous solution is
obtained. The solution(s) is/are then evaporated off by spraying on the drymix bed
consisting of polymer and diluent at a temperature of 1 ooc to 80°C in a fluid bed
processor. The mixture obtained is finally to yield the blend which is used further in the
preparation of the pharmaceutical composition.
The process of preparation of pharmaceutical composition broadly comprises the
following process steps:
1. Sifting: The Polymers/Excipients like HPC, PEG & PEO are first co-sifted
through suitable sieve;
2. Preparation of Drug Solution: Mirabegron & antioxidant like BHT are dissolved
in solvent like Methanol under continuous stirring to get a clear solution;
3. Granulation: Spraying the drug solution over the fluidized bed of polymer &
other excipients at suitable temp. e.g. between 10 and 80°C;
4. Sifting & Blending: Dried granules sifted through suitable sieve and lubricated
with suitable lubricants;
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5. Compression and subsequent Film Coating/Capsule Filling/ Dry Powder: The
granules are then formulated as suitable formulations using formulation
techniques.
Obtaining the stabilized amorphous form of mirabegron has the advantage of making
possible the preparation of pharmaceutical formulations of consistent and reproducible
composition.
According to the invention it is therefore possible to obtain solid pharmaceutical
compositions having amorphous form of mirabegron, which are administrable especially
by the oral, buccal or sublingual route. These pharmaceutical compositions can be
formulated using this fluid bed process mirabegron without any other processing
operation besides packaging. If desired, said pharmaceutical compositions may,
however, undergo processing by grinding or by granulation for filling into capsules or for
compression or may undergo coating.
The pharmaceutical compositions of the invention may also optionally comprise of
pharmacologically acceptable excipients which are selected from the group of binders,
disintegrants, lubricants, diluents, antioxidants, aromatic agents, colorants, preservatives,
sweeteners imd anti- adherents.
Among the pharmaceutical compositions according to the invention, there may be more
especially mentioned tablets or dragees, granules, sublingual tablets, capsules or lozenges
or drinkable suspensions or chewing gums.
The useful dosage can be varied according to the nature and severity of the disorder, the
administration route and the age and weight of the patient. The dosage varies from 10 mg
to 1 00 mg per day of mirabegron in one or more administrations.
The solvents used according to the invention are those capable of dissolving mirabegron
and the selected polymer; preference will be given to polar protic or aprotic solvents such
10
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as acetone, alcohols and more especially methanol and ethanol, water, dichloromethane,
dimethyl sulfoxide, ethyl acetate or mixtures of those solvents.
The polymer used in the present invention relates more especially to poly ethylene oxide
compounds or poly ethylene glycol or cellulosic polymers or Polyacrylic acid polymers
or meth acrylic acid· co-polymers. More especially, the polymers used according to the
invention relate to polyethylene oxide or poly ethylene glycol or cellulosic polymers or
Polyacrylic acid polymers or meth acrylic acid co-polymers. Among the different PEO
products marketed, those preferably used in the context of the invention are PEO WSR
303 and N60K products, more especially PEO WSR N-10 or WSR N-80 or WSR N-750
or WSR-205 or WSR-1105 or WSR N-12K or WSR N-60K or WSR-301 or WSR
Coagulant or WSR-303. These polymers are particularly adapted to all ranges of
mirabegron loading (% by weight of mirabegron). The ethylene glycol polymers
according to the invention relates more especially to polyethylene glycol such as, for
example, PEG 200 or PEG 400 or PEG 600 or PEG 2000 or PEG 4000 or PEG 6000 or
PEG 8000. Among the cellulosic polymers according to the invention relates more
especially to hydroxyl propyl methyl cellulose or hydroxyl propyl cellulose such as, for
example, hypromellose E6 or hypromellose K4M or hypromellose KlOOM or L-HPC
Lll or Klucel LF or Klucel EXF. Polyacrylic acid polymers such as, for example
Carbopol 934 or Carbopol 1342 or Carbopol ETD 2020 and ineth acrylic acid copolymers
for example Eudragit EPO or Eudragit L30D or Eudragit RL or Eudragit RS.
Dissolution is to be carried out in different media for assessing its release kinetics.
Spraying the Mirabegron solution or mirabegron & polymer &. butyl hydroxyl toluene
solution over the bed of drymix consisting of polyethylene oxide or poly ethylene glycol
or cellulosic polymers or butylated hydroxyl toluene is to be carried out in fluidized bed
processor or in rapid mixer gra_nulator or planetary mixer for evaporation of solvents.
An advantageous embodiment of the process for preparation of a stable formulation
having amorphous form of mirabegron within a polymer consists of preparation of
mirabegron with the selected polymer where there is no need of isolating this form from
11
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other crystalline form prior to manufacturing for ease of operation and then this mixture
is introduced into a mill, to obtain granules into the desired size.
In the processes for obtaining the stabilized amorphous form of mirabegron according to
the invention, mirabegron obtained by fluid bed process will be most preferred ..
In the processes according to the invention, the mirabegron loading is greater than or
equal to I.6 % by weight and more especially varies from 5 to 50 % by weight,
preferably from I 0 % to 40 %.
The stabilized amorphous form thereby obtained has value in the treatment of beta-3
adrenergic agonist indicated for the treatment of overactive bladder (OAB) with
symptoms of urge urinary incontinence, urgency, and urinary frequency.
EXAMPLES:
1. 100 gm mirabegron is to be placed in a I 000 ml s.s. container with 300 ml of
solvent(s). XRD pattern of mirabegron used is shown in Figure 1. The mixture to be
stirred until get completely dissolved or dispersed or homogeneous solution· is obtained.
The solution(s) is/are evaporated off by spraying on the drymix bed consisting of
polymer and diluent at a temperature of l0°C to 80°C in a fluid bed processor. The dried
granules are sifted through suitable sieve and lubricated with suitable lubricants and
finally used to make suitable formulation of tablets by compression, or capsules by direct
filling into empty capsule shells, or filling in sachets for ready to use blend for
suspension. XRD pattern of finished product is shown in Figure 2. For the sake of
comparison, the XRD pattern of placebo is shown in Figure 3.
Various examples of solvents and polymers are as follows:
Example Solvents
I2
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lMeOH
2EtOH
3 MeOH/EtOH
4 Di Methyl Sulfoxide
5 lso Propyl Alcohol
6 Ethyl Acetate
7 Methylene Chloride
8 Acetone
Example Polymers
I Polyox WSR
2 Polyox N-60K
3 Polyox WSR N-750
4 PEG 6000
5 Klucel LF
6 Methocel E5
2. General process for obtaining the stabilized amorphous form of mirabegron
Mirabegron is dissolved in solvent and then sprayed in a fluid bed processor on the bed of
the polymers I diluents at temperature of not more than 20°C. The granules obtained are
mixed with lubricant to compress and coat.
13
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The stability of the amorphous form obtained to be assessed under various temperature
and relative humidity conditions: 2 - 8°C or 25°C I 60 % RH in an open or closed
container, 30°C I 65 % RH in an open or closed container or 40°C I 15 % RH in an open
or closed container.
Example 1
Excipients of prototype composition are mentioned below
Formulation Composition Function
Mirabegron Active
Polyox WSR Polymer
Polyox N-60K Polymer
PEG 6000 Polymer
Klucel LF Binder
Butyl Hydroxy Toluene Anti Oxidant
Magnesium Stearate Lubricant
Film Coating
Hypromellose Film Coating Polymer
PEG 6000 Plasticizer
Yell ow ferric oxide Colorant
Red ferric oxide Colorant
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%by weight
20
25
15
20
15
1
4
1.5
1
0.2
0.2
CLAIMS:
WE CLAIM
1. A process of preparing a stable pharmaceutical composition comprising amorphous of
Mirabegron comprising the steps of: Dissolving Mirabegron in a solvent(s); Stirring the
mixture until the Mirabegron get completely dissolved or dispersed; Evaporating the
solution by spraying on the drymix bed consisting of polymer and diluent at a
temperature of 1 0°C to 80°C in a fluid bed processor; and using the blend in formulating
the desired formulation oftablets, capsules and dry mix using formulation techniques.
2. The process as claimed in claim 1 wherein the solvents is a polar protic or aprotic
solvents;
3. The process as claimed in claim 1 wherein the solvent is selected from the group
consisting of acetone, alcohols and more especially methanol and ethanol, water,
dichloromethane, di methyl sulfoxide, ethyl acetate or mixtures thereof.
4. The process as claimed in claim 1 wherein the polymers is selected from the group
consisting of polyethylene oxide or poly ethylene glycol or cellulosic polymers or
Polyacrylic acid polymers or meth acrylic acid co-polymers;
5. The process as claimed in claim 1 wherein it involves spraying the mirabegron
solution or mirabegron & polymer & butyl hydroxyl toluene solution over the bed of
drymix consisting of polyethylene oxide or poly ethylene glycol or cellulosic polymers or
Polyacrylic acid polymers or meth acrylic acid co-polymers or butylated hydroxyl
toluene is carried out in fluidized bed processor or in rapid mixer granulator or planetary
mixer followed by heating at 10°C to 80°C until evaporation of the solvents is complete
and this mixture is optionally introduced into a mill to obtain granules of desired size and
finally used to make suitable formulation of tablets by compression, or capsules by direct
filling into empty capsule shells, or filling in sachets for ready to use blend for
suspension.
15
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6. Process for obtaining the stabilized amorphous form of mirabegron, as claimed in
claim 1, characterized in that the percentage of mirabegron by weight is greater than or
equal to 1.6 %.
7. A pharmaceutical composition for the treatment of a beta-3 adrenergic agonist
indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary
incontinence, urgency, and urinary frequency as and when prepared using the steps as
claimed in claims 1 to 6.