STABLE DOSAGE FORMS OF IMATINIB MESYLATE
Field of the Invention
The present invention relates to a stable oral pharmaceutical dosage form
comprising imatinib mesylate and one or more pharmaceutically acceptable excipients,
wherein the amount of imatinib calculated as free base is more than 80% by weight based
on the total weight of the oral pharmaceutical dosage form, and wherein the oral dosage
form does not show polymorphic conversion after storage at 40°C and 75% relative
humidity for three months. It also relates to processes for the preparation thereof
Background of the Invention
Imatinib is indicated for the treatment of non-malignant and malignant
proliferative disorders such as chronic myelogeneous leukemia (CML), gastrointestinal
stromal tumors (GIST), and other conditions. Currently, it is marketed in United States by
Novartis under the trade name Gleevec® as film coated tablets containing imatinib
mesylate equivalent to 100 mg or 400 mg of imatinib free base. Imatinib mesylate is
designated chemically as 4-[(4-methyl-l-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-
pyridinyI)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate. Gleevec®
capsules, 50 mg and 100 mg, were the subject of NDA 21335, held by Novartis
Pharmaceutical Corp., and was initially approved on May 10, 2001.
U.S. Patent No. 5,521,184 discloses imatinib, processes for its preparation, and its
use, especially as an antitumor agent.
WO Publication No. 2003/090720 discloses a tablet comprising a
pharmacologically effective amount of imatinib, or a pharmaceutically acceptable salt
thereof, in an amount from about 30% to 80% by weight of the active moiety based on the
total weight of the tablet.
U.S. Patent No. 6,894,051 describes the alpha and the beta crystalline forms of
imatinib mesylate. U.S. Patent No. 7,544,799 discloses a crystalline form of imatinib
mesylate having non-needle-shaped crystals.
WO Publication No. 2009/042803 describes a pharmaceutical composition
comprising imatinib mesylate in an amount of about 23% to 29% w/w of the total
composition. Further, WO Publication No. 2009/042809 discloses a pharmaceutical
composition comprising an initial polymorphic form of imatinib mesylate, wherein less
than 10% of the polymorphic form of imatinib mesylate is converted to Form a or Form P
after storage at 40°C at 75% relative humidity for one month. WO Publication No.
01/47507 exemplifies a pharmaceutical composition or tablet containing about 22% w/w
of imatinib mesylate. Also, U.S. Publication Nos. 2006/0275372 and 2009/0136579
describe nanoparticulate compositions of imatinib.
WO Publication No. 2011/121593 exemplifies film coated tablets comprising
imatinib mesylate in an amount of 90% to 97% based on total weight of the coated tablet,
where the tablets are coated with a film coating comprising polyvinyl alcohol applied to
the tablet core in an amount of 1% to 2% w/w of the tablet.
U.S. Patent No. 6,958,335 describes the use of imatinib or a pharmaceutically
acceptable salt thereof in the treatment of gastrointestinal stromal tumors (GIST).
WO Publication No. 2005/077933 discloses pharmaceutical compositions
comprising imatinib mesylate ai-Form in the range of 45% to 60% w/w, wherein the
excipients used are selected from microcrystalline cellulose, lactose, crospovidone XL,
colloidal silicon dioxide, magnesium stearate, talc, or mixtures thereof
Imatinib mesylate is typically prescribed in high doses, e.g., 400 mg to 800 mg
daily as a treatment of leukemia in adults. Imatinib is generally known to be a
hygroscopic material. Thus, in view of the high dosage needed for the therapy and the
nature of the active ingredient, there is a further need to optimize the pharmaceutical
dosage forms comprising imatinib mesylate so that it is convenient to manufacture,
administer, and simultaneously provide the requisite daily dosage of imatinib. It is also
required that the said pharmaceutical dosage forms exhibit polymorphic stability upon
storage, as this is essential to ensure an adequate shelf life of the final dosage form. It is
therefore an objective of the present invention to develop an optimized stable
pharmaceutical dosage form that contains a high dosage amount of imatinib mesylate and
also exhibits polymorphic stability throughout the shelf life.
Summary of the Invention
In one general aspect, the present invention relates to a stable oral pharmaceutical
dosage form comprising imatinib mesylate and one or more pharmaceutically acceptable
excipients, wherein the amount of imatinib calculated as free base is more than 80% by
weight based on the total weight of the oral pharmaceutical dosage form, and wherein the
oral pharmaceutical dosage form does not show polymorphic conversion after storage at
40°C and 75% relative humidity for three months.
In an embodiment of the above aspect, the pharmaceutically acceptable excipients
are selected from diluents, binders, disintegrants, lubricants, glidants, granulating solvents,
and coloring agents.
In another embodiment, imatinib mesylate is present in alpha crystalline form.
In yet another embodiment, the alpha crystalline form does not convert to the beta
crystalline form when the oral pharmaceutical dosage form is stored at 40°C and 75%
relative humidity for three months.
In another embodiment, the stable oral pharmaceutical dosage form is a tablet.
In another embodiment, the stable oral pharmaceutical dosage form is a capsule.
In a ftirther embodiment, the stable oral pharmaceutical dosage form is dispensed
in a package comprising blister packs or high-density polyethylene (HDPE) bottles.
In a fiuther embodiment, the package may additionally contain a desiccant.
In another general aspect, the present invention relates to a process for preparing a
stable oral pharmaceutical dosage form comprising imatinib mesylate and one or more
pharmaceutically acceptable excipients, wherein the amount of imatinib calculated as free
base is more than 80% by weight based on the total weight of the oral pharmaceutical
dosage form, and wherein the oral dosage form does not show polymorphic conversion
after storage at 40°C and 75% relative humidity for three months, and wherein the process
comprises the conventional processes of dry granulation or wet granulation.
Detailed Description of the Invention
The present invention provides stable oral pharmaceutical dosage forms
comprising imatinib mesylate in a polymorphic form, for example, alpha crystalline form,
and one or more pharmaceutically acceptable excipients such that the amount of imatinib
calculated as free base is more than 80% by weight based on the total tablet weight.
The stable oral pharmaceutical dosage forms can be tablets or capsules.
As used herein, the term "pharmaceutically acceptable excipient" includes
conventional pharmaceutical additives known in the art such as diluents, binders.
disintegrants, lubricants, glidants, granulating solvents, coloring agents, or combinations
thereof.
Preferred diluents include microcrystalline cellulose, silicified microcrystalline
cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate,
calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose,
dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate,
magnesium oxide, and the like.
Preferred binders include polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone,
cellulose gums (e.g., carboxymethyl cellulose, hydroxypropyl methylcellulose, and
hydroxypropyl cellulose), pregelatinized starch, acacia, guar gum, alginic acid, carbomer,
dextrin, maltodextrin, and the like.
Preferred disintegrants include mannitol, alginic acid, carboxymethylcellulose,
hydroxypropylcellulose, microcrystalline cellulose, croscarmellose sodium, povidone,
crospovidone, magnesium aluminum silicate, methylcellulose, sodium alginate, starches or
modified starches such as sodium starch glycolate, com starch, potato starch or
pregelatinized starch, and the like.
Preferred lubricants include magnesium stearate, zinc stearate, calcium stearate,
stearic acid, sodium stearyl fumarate, vegetable oil, mineral oil, and the like.
Preferred glidants include talc, colloidal silicon dioxide, com starch, and the like.
Preferred granulating solvents include water, ethanol, methanol, isopropyl alcohol,
methylene chloride, acetone, and the like.
Suitable coloring agents include those approved for use by the United States Food
and Dmg Administration (FDA), such as iron oxide, and are well known to those skilled in
the art.
The tablets or capsules may be prepared by conventional processes, for example,
by dry granulation or wet granulation.
When the pharmaceutical dosage form is a tablet, it may further be coated using
conventional coating techniques. The tablets may be coated with one of the commercially
available coating systems such as Opadry® or any polymeric film coating routinely used in
the formulation of pharmaceutical compositions such as ethyl cellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl
cellulose, hydroxyl methylcellulose, cellulose acetate, waxes such as polyethylene glycol,
methacrylic acid polymers, and the like.
The term "stable", as recited herein, refers to the polymorphic stability of imatinib
mesylate in the oral pharmaceutical dosage form which implies that imatinib mesylate
remains in its initial polymorphic form, i.e., alpha crystalline form without undergoing
polymorphic conversion to the beta crystalline form, for example, upon storage at 40°C
and 75% relative humidity during the period of three months. Several factors may affect
the stability of the active ingredient, for example, the type of coating material used may
influence the stability of the drug and hence may contribute towards the shelf life of the
final tablet dosage form. Besides this, the type of packaging may also contribute to the
stability of the drug. The packaging material may be comprised of high-density
polyethylene bottle (HDPE) bottles, various types of blister packs, or similar
pharmaceutically acceptable packaging material. The package may additionally contain a
desiccant. A desiccant is any drying agent that removes moisture from the air. Desiccants
include, but are not limited to, silica gel, clay desiccants, calcium sulfate, calcium
chloride, calcium oxide, zeolite, activated alumina, activated charcoal, and the like.
The stable oral pharmaceutical dosage forms comprising imatinib mesylate as
described herein may take the form of several different embodiments.
In one embodiment, the stable oral pharmaceutical dosage forms is a tablet which
comprises the alpha crystalline form of imatinib mesylate and one or more
pharmaceutically acceptable excipients, such that the amount of imatinib calculated as free
base is about 82% by weight based on the total tablet weight. The tablet may then be
coated with a commercially available Opadry® dispersion.
In another embodiment, the stable oral pharmaceutical dosage form is a tablet
which comprises the alpha crystalline form of imatinib mesylate and one or more
pharmaceutically acceptable excipients, such that the amount of imatinib calculated as free
base is about 83% by weight based on the total tablet weight.
In both of the above embodiments, the tablets may be dispensed in packaging
made with usual packaging materials such as HDPE bottles or blister packs.
In one embodiment, the tablet may be prepared by:
a. granulating imatinib mesylate alone or mixed with one or more
pharmaceutically acceptable excipients with a granulating solvent;
b. drying and sizing the granules of step (a);
c. optionally, mixing with one or more pharmaceutically acceptable excipients;
d. compressing the resultant blend into tablets using appropriate tooling; and
e. optionally, coating the tablets with a coating.
In another embodiment, the tablet may be prepared by:
a. compacting imatinib mesylate alone or mixed with one or more
pharmaceutically acceptable excipients by slugging;
b. milling and sizing the slugs into granules;
c. optionally, mixing the granules with one or more pharmaceutically
acceptable excipients;
d. compressing the resultant blend into tablets using appropriate tooling; and
e. optionally, coating the tablets with a coating.
In another embodiment, the stable oral pharmaceutical dosage form is a capsule
which comprises alpha crystalline form of imatinib mesylate and one or more
pharmaceutically acceptable excipients, such that the amount of imatinib calculated as free
base is about 83% by weight based on the total capsule fill weight.
In the above embodiment, the said capsule may be dispensed in packs made with
usual packaging materials such as HDPE bottles or blister packs.
In one embodiment, the capsules may be prepared by:
a. granulating imatinib mesylate alone or mixed with one or more
pharmaceutically acceptable excipients with a granulating solvent;
b. drying and sizing the granules of step (a);
c. optionally, mixing with one or more pharmaceutically acceptable excipients;
and
d. filling the resultant blend into suitable sized capsules.
In another embodiment, the capsules may be prepared by:
a. granulating imatinib mesylate with a mixture of isopropyl alcohol and water;
b. drying and sizing the granules of step (a);
c. mixing the granules of step (b) with magnesium stearate; and
d. filling the resultant blend into suitable sized capsules.
From the above, it is apparent that various modifications and combinations of the
formulations detailed in the text may be made without departing from the spirit and scope
of the invention. The invention as described herein may be illustrated by the following
examples but is not to be construed to be limited by them.
EXAMPLES
Example 1:
S/N Ingredients
Intragranular
1. Imatinib mesylate (alpha form)
Quantity in mg/tablet
Example 1
478.0
Comparative Example 1
478.0
Granulating solvent
2. Ispropyl alcohol rpurified water q.s. q.s.
Extragranular
3. Magnesium stearate
Tablet Weight
2.0
480.0
2.0
480.0
Coating
4.
5.
6.
Opadry® brown
Opadry® clear
Purified water
Coated Tablet Weight
9.0
-
q.s.
489.0
-
4.0
q.s.
484.0
Procedure:
Imatinib mesylate was granulated with a mixture of isopropyl alcohol and purified
water. The granules obtained were dried and sized. The resultant granules were blended
with magnesium stearate and compressed into tablets. The obtained tablets were coated
with Opadry® brown aqueous dispersion in purified water in Example 1 and Opadry® clear
aqueous dispersion in purified water in Comparative Example 1.
The above-prepared tablets were dispensed in suitable packs. To further assess the
polymorphic stability, these were subjected to accelerated stability testing at 40°C/75%
relative humidity for three months. The percentage of beta crystalline form of imatinib
mesylate was determined during and after three months interval. It was found that the
tablets coated with Opadry® brown were stable while the tablets coated with Opadry®
clear were unstable and showed polymorphic conversion. The results of the stability
studies are summarized in Table 1 below.
Table 1; Percentage of beta crystalline form of imatinib mesylate in tablets prepared
as per the above Example 1 and Comparative Example 1 when stored at 40°C/75%
relative humidity in respective packs
Time
Pack
Exanplel
Comparative
Exampiel
Initial
ND
ND
Percentage of beta crystalline form of imatinib mesylate
1 month
CFB
ND
D
DCFB
-
-
HDPE
Bottle
without
deaccant
0.97
-
HDPE
Bottle
with
desiccant
-
-
3 months
CFB
ND
106.6
DCFB
ND
-
HDPE
Bottle
without
deaccant
58.03
106.57
HDPE
Bottfe
with
desiccant
ND
-
Meanings of abbreviations: D - Detectable, ND - Not detectable, HDPE - High-density
polyethylene, CFB - Cold form blister, DCFB - Desiccant embedded cold form blister. (-)
symbolizes that data was not available/generated at the time.
Examples 2-6
S/N Ingredients
Intragranular
1.
2.
3.
Imatinib mesylate (alpha form)
Iron oxide yellow
Iron oxide red
Granulating solvent
4.
5.
6.
Isopropyl alcohol rpurified water
Isopropyl alcohol
Purified water
Extragranular
7.
8.
Polyplasdone XL
Magnesium stearate
Tablet Weight
Coating
9.
10.
11.
Opadry® brown
Purified water
Isopropyl alcohol :methylene
chloride
Coated Tablet Weight
2
478.0
-
-
q.s.
-
-
-
2.0
480.0
9.0
-
q.s.
489.0
Quantity in mg/tablet
Examples
3
478.0
-
-
-
q.s.
-
-
2.0
480.0
9.0
-
q.s.
489.0
4
478.0
-
-
-
-
q.s.
-
2.0
480.0
9.0
q.s.
-
489.0
5
478.0
-
-
-
-
-
-
2.0
480.0
9.0
-
q.s.
489.0
6
478.0
0.488
0.488
q.s.
-
-
3.264
1.76
484.0
-
-
-
Procedure:
Example 2:
Imatinib mesylate was granulated with a mixture of isopropyl alcohol and purified
water. The granules obtained were dried and sized. The resultant granules were blended
with magnesium stearate and compressed into tablets. The obtained tablets were coated
with Opadry® brown non-aqueous dispersion in a mixture of isopropyl alcohol and
methylene chloride.
Example 3:
Imatinib mesylate was granulated with isopropyl alcohol. The granules obtained
were dried and sized. The resultant granules were blended with magnesium stearate and
compressed into tablets. The obtained tablets were coated with Opadry® brown nonaqueous
dispersion in a mixture of isopropyl alcohol and methylene chloride.
Example 4:
Imatinib mesylate was granulated with purified water. The granules obtained were
dried and sized. The resultant granules were blended with magnesium stearate and
compressed into tablets. The obtained tablets were coated with Opadry® brown aqueous
dispersion in purified water.
Example 5:
Imatinib mesylate was compacted by slugging. The slugs obtained were milled
and sized into granules. The resultant granules were blended with magnesium stearate and
compressed into tablets. The obtained tablets were coated with Opadry® brown nonaqueous
dispersion in a mixture of isopropyl alcohol and methylene chloride.
Example 6:
Imatinib mesylate, iron oxide yellow, and iron oxide red were granulated with a
mixture of isopropyl alcohol and purified water. The granules obtained were dried and
sized. The resultant granules were blended with polyplasdone XL and magnesium stearate
and compressed into tablets.
The above tablets of Examples 1-6 were dispensed in several kinds of packs. To
further assess the polymorphic stability, these were subjected to accelerated stability
testing at 40°C/75% relative humidity for three months. The percentage of beta crystalline
10
form of imatinib mesylate was determined during and after three months interval. The
results of the stability studies are summarized in Table 2 below.
Table 2: Percentage of beta crystalline form of imatinib in tablets prepared as per
above Examples 2-6 when stored at 40''C/75% relative humidity in respective packs
Time
Pack
Example 2
Example 3
Example 4
Example 5
Example 6
Initial
ND
ND
ND
ND
ND
Percentage of beta crystalline form of imatinib mesylate
1 month
CFB
ND
-
D
-
-
DCFB
ND
ND
ND
ND
-
HDPE
Bolfle
without
desiccant
4221
-
D
-
-
HDPE
Botde
wilh
de^ocant
ND
ND
ND
ND
-
3 months
CFB
ND
-
-
-
ND
DCFB
ND
ND
-
ND
-
F©PE
Botde
without
desiccant
D
-
-
-
735
HDPE
Botde
with
desiccant
ND
ND
-
ND
-
Meanings of abbreviations: D - Detectable, ND - Not detectable, HDPE - High-density
polyethylene, CFB - Cold form blister, DCFB - Desiccant embedded cold form blister. (-)
symbolizes that data was not available/generated at the time.
Examples 7-8
S/N Ingredients
Intragranular
1. Imatinib mesylate (alpha form)
Granulating Solvent
2. Isopropyl alcohol rpurified water
Extragranular
3. Magnesium stearate
Capsules Fill Weight
Quantity
Example 7
478.0
q.s.
2.0
480.0
in mg/capsule
Example 8
119.5
q.s.
0.5
120.0
Procedure:
Imatinib mesylate was granulated with a mixture of isopropyl alcohol and purified
water. The granules obtained were dried and sized. The resultant granules were blended
with magnesium stearate and filled into suitable sized capsules.
The above prepared capsules were dispensed in suitable packs. To assess the
polymorphic stability, these capsules were subjected to accelerated stability testing at
40°C/75% relative humidity for three months. The percentage of beta crystalline form of
imatinib mesylate was determined during and after three months interval. The results
11
clearly indicated that the capsules were stable even on storage for a period of three
months. The results of the stability studies are summarized in Table 3 below.
Table 3: Percentage of beta crystalline form of imatinib mesylate in capsules
prepared as per the above Examples 7-8 when stored at 40*075% relative humidity
in respective packs
Time
Pack
Example 7
Example 8
Initial
ND
ND
Percentage of beta crystalline form of imatinib mesylate
1 month
CFB
ND
ND
HDPE
Bottle
without
desiccant
-
-
2 months
CFB
ND
ND
HDPE
Bottle
without
desiccant
-
-
3 months
CFB
ND
ND
HDPE
Bottle
without
desiccant
ND
ND
Meanings of abbreviations: ND - Not detectable, HDPE - High-density polyethylene, CFB
- Cold form blister, (-) symbolizes that data was not available/generated at the time.
12

WE CLAIM:
1. A stable oral pharmaceutical dosage form comprising imatinib mesylate in alpha
crystalline form and one or more pharmaceutically acceptable excipients, wherein the
amount of imatinib calculated as free base is more than 80% by weight based on the total
weight of the oral pharmaceutical dosage form, and wherein the alpha crystalline form
does not convert to beta crystalline form when the said oral pharmaceutical dosage form is
stored at 40°C and 75% relative humidity for three months.
2. The stable oral pharmaceutical dosage form according to claim 1, wherein the
pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants,
lubricants, glidants, granulating solvents, and coloring agents.
3. The stable oral pharmaceutical dosage form according to claim 1, wherein the
stable oral pharmaceutical dosage form is a tablet.
4. The stable oral pharmaceutical dosage form according to claim 1, wherein the
stable oral pharmaceutical dosage form is a capsule.
5. The stable oral pharmaceutical dosage form according to claim 1, wherein the said
stable oral pharmaceutical dosage form is dispensed in a package comprising blister packs
or in high-density polyethylene (HDPE) bottles.
6. The stable oral pharmaceutical dosage form according to claim 5, wherein the
package may additionally contain a desiccant.
7. A process for preparing the stable oral pharmaceutical dosage form of claim 3
comprising:
a. granulating imatinib mesylate alone or mixed with one or more
pharmaceutically acceptable excipients with a granulating solvent;
b. drying and sizing the granules of step (a);
c. optionally, mixing with one or more pharmaceutically acceptable excipients;
d. compressing the resultant blend into tablets using appropriate tooling; and
e. optionally, coating the tablets with a coating.
8. A process for preparing the stable oral pharmaceutical dosage form of claim 3
comprising:
a. compacting imatinib mesylate alone or mixed with one or more
pharmaceutically acceptable excipients by slugging;
b. milling and sizing the slugs into granules;
c. optionally, mixing the granules with one or more pharmaceutically acceptable
excipients;
d. compressing the resultant blend into tablets using appropriate tooling; and
e. optionally, coating the tablets with a coating.
9. A process for preparing the stable oral pharmaceutical dosage form of claim 4
comprising:
a. granulating imatinib mesylate alone or mixed with one or more
pharmaceutically acceptable excipients with a granulating solvent;
b. drying and sizing the granules of step (a);
c. optionally, mixing with one or more pharmaceutically acceptable excipients;
and
d. filling the resultant blend into suitable sized capsules