Note: Descriptions are shown in the official language in which they were submitted.
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RAPID DISSOLUTION OF COMBINATION PRODUCTS
Cross-Reference to Related Applications
[0001] This application claims the benefit of U.S. Provisional Application
Serial Nos.
60/922,031, filed Apri14, 2007; 60/932,613, filed May 31, 2007; and
61/070,563, filed
March 21, 2008, the contents of which are hereby incorporated by reference.
Field of the Invention
[0002] The invention encompasses a method for the production of rapid
dissolution
tablets comprising at least two active pharmaceutical ingredients.
Background of the Invention
[0003] Migraine is the most common cause of vascular headache, and afflicts
approximately 15% of women and 6% of men. Typically, migraine is treated with
a single
drug or a combination of drugs known to be effective in treating migraine.
Most drugs
effective in the treatment of migraines are members of one of three major
pharmacologic
classes: anti-inflammatory agents, 5-HT, antagonists, and dopamine
antagonists. See
HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 73-76 (15th ed. 2001).
[0004] Sumatriptan succinate has the chemical name 3-[2-(dimethylamino)ethyl]-
N-
methyl-indole-5-methanesulfonamide succinate and the following chemical
structure:
OOH N -
COOH
H
N
OO
N
H
[0005] Naproxen sodium has the chemical name (S)-6-methoxy-a-methyl-2-
naphthaleneacetic acid, sodium salt, and the following chemical structure:
CH3
O'Na+
O
SUBSTITUTE SHEET (RULE 26)
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[0006] Sumatriptan succinate is a selective 5-hydroxytriptamine, receptor
subtype
agonist currently marketed under the trade name IMITREX for the acute
treatment of
migraine attacks with or without aura in adults. Naproxen sodium is a non-
steroidal anti-
inflammatory drug (NSAID) with analgesic and antipyretic properties. The
mechanism of
action of the naproxen anion, like that of other NSAIDs, is not completely
understood but
may be related to prostaglandin synthetase inhibition. Both actives have been
combined in a
single tablet, which is expected to be marketed under the trade name TREXIMA .
Current
treatments for migraines include a range of over-the-counter analgesics and
triptans. Recent
reports have indicated that combination therapies of triptans and NSAIDs
greatly improve the
relief of migraines in patients. See, e.g., U.S. Patent Nos. 5,872,145;
6,060,499; 6,586,458.
[0007] U.S. Publication No. 2004/0180089 ("the '089 publication") refers to a
dosage
form containing a triptan and an NSAID as therapeutic agents, where the
triptan and the
NSAID are segregated into separate layers, in a side-by-side arrangement, such
that the
dissolution of each therapeutic agent occurs independently of the other. The
`089 publication,
p. 1, 6-7. The '089 publication suggests that in the stomach, the NSAID
naproxen may
form a gel-like matrix, which retards the dissolution of the triptan unless
the two therapeutic
agents are maintained in distinct side-by-side layers. Id. The '089
publication addresses this
dissolution problem by separating the triptan and the NSAID into separate
distinct layers,
such that each layer contains at least 90% of either the triptan or the NSAID,
as opposed to a
single layer tablet matrix containing both agents or one layer forming a core
surrounded by
the other layer. The '089 publication, p. 1, 10. The '089 publication
discloses that such an
arrangement provides for the independent dissolution of each therapeutic
agent, such that the
dissolution rates approximate the rates if the drugs were given separately.
Id.
[0008] However, this technique of preparing bilayer tablets requires
specialized
tabletting equipment, such as a rotary bilayer tablet press. Furthermore, the
process itself is
cumbersome and requires several stages. For example, the NSAID layer is loaded
first,
compacted using a minimal compaction force, and the triptan layer is added
next, and the
tablet compacted using a final compaction force such that a tablet with the
desired
mechanical properties is achieved. See, e.g., the '089 publication, p. 3,
33.
[0009] U.S. Publication No. 2007/0184109 ("the '109 publication") also refers
to
pharmaceutical compositions comprising a 5HTi receptor agonist (such as
sumatriptan
succinate) or a pharmaceutically acceptable derivative thereof in combination
with an NSAID
(such as naproxen sodium) or pharmaceutically acceptable derivative thereof.
The '109
publication compares the dissolution of sumatriptan succinate in two
compositions of
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sumatriptan succinate and naproxen sodium, the first having the sumatriptan
succinate and
the naproxen sodium in the same zone and the second having the sumatriptan
succinate and
the naproxen sodium in separate layers of a bilayer tablet. '109 publication,
pp. 9-10, tables 3
and 4. The '109 publication states that the dissolution of the first
composition was "slower
than expected," and that the slow dissolution "led to the conclusion that the
naproxen sodium
was disabling the dissolution of the sumatriptan granules when blended
together." See id. at
p. 9, 97. As to the second composition, the '109 publication states that
"[c]ombining the
two formulations as separate layers in a bilayer tablet allowed for the rapid
release of
sumatriptan succinate from the tablet, without as much interference from
naproxen sodium."
See id. at p. 10, 100.
[0010] Therefore, there is a need for an efficient simple process which does
not
require specialized equipment, while maintaining the dissolution properties of
each of the
therapeutic agents.
Summary of the Invention
[0011] In one embodiment, the invention encompasses an oral dosage form
comprising a therapeutically effective amount of a triptan and a
therapeutically effective
amount of an NSAID, wherein the dosage form includes at least one zone in
which particles
of the triptan and the NSAID are admixed, and not less than about 60% of the
triptan
dissolves in 30 minutes in 200 ml of 0.O1N HCl solution in a USP Type II
Dissolution
Apparatus at a rotation speed of 40 rpm and a temperature of 37 C. Preferably,
not less than
about 70% of the triptan dissolves in 30 minutes, and more preferably not less
than about
80% of the triptan dissolves in 30 minutes.
[0012] In one preferred embodiment, the oral dosage form further comprises at
least
one additive selected from the group consisting of (i) a carbonate, (ii) a
bicarbonate, and (iii)
a superdisintegrant, with the proviso that the superdisintegrant is not
croscarmellose sodium.
[0013] In another preferred embodiment, the oral dosage form is in the form of
a
porous tablet. Preferably, the porosity of the tablet is at least about 10%.
[0014] In yet another embodiment, the invention encompasses an oral dosage
form
comprising: (a) a therapeutically effective amount of a triptan, (b) a
therapeutically effective
amount of an NSAID, and (c) at least one additive selected from the group
consisting of (i) a
carbonate, (ii) a bicarbonate, and (iii) a superdisintegrant, wherein the
dosage form includes
at least one zone in which particles of the triptan and the NSAID are admixed,
the additive is
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present in an amount of more than 10% by weight of the oral dosage form, and
the
superdisintegrant is not croscarmellose sodium.
[0015] In another embodiment, the invention encompasses an oral dosage form
comprising: (a) a therapeutically effective amount of a triptan, (b) a
therapeutically effective
amount of an NSAID, and (c) at least one additive selected from the group
consisting of (i) a
carbonate, (ii) a bicarbonate, and (iii) a superdisintegrant, wherein the
dosage form includes
at least one zone in which particles of the triptan and the NSAID are admixed,
the ratio of the
amount of NSAID to the total amount of additives is less than about 5, and the
superdisintegrant is not croscarmellose sodium.
[0016] In another embodiment, the invention encompasses a method for preparing
the
above-described oral dosage forms comprising separately granulating each of
the triptan and
the NSAID, combining the separate granulates with at least one extragranular
pharmaceutically acceptable excipient to form a mixture, and compacting the
mixture into the
oral dosage form.
[0017] In another embodiment, the invention encompasses a method for preparing
the
above-described oral dosage forms comprising granulating one of the triptan or
the NSAID
with at least one pharmaceutically acceptable excipient to form a granulate,
adding to the
granulate a dry blend comprising at least the other of the triptan or the
NSAID and at least
one pharmaceutically acceptable excipient to form a mixture, and compacting
the mixture
into the oral dosage form.
[0018] In another embodiment, the invention encompasses a method for preparing
the
above-described oral dosage forms comprising coating an inert core with a
layer comprising a
triptan and an NSAID.
[0019] In another embodiment, the invention encompasses a method of treating
acute
migraines comprising administering a therapeutically effective amount of at
least one of the
above-described dosage forms to a patient in need thereof. Preferably, the
triptan is
sumatnptan and the NSAID is naproxen.
Brief Description of the Drawings
[0020] Figure 1 illustrates exemplary tablet forms of triptan and NSAID. In
Figure 1,
"A" comprises the triptan and, optionally, at least one pharmaceutically
acceptable excipient;
"B" comprises the NSAID and, optionally, at least one phannaceutically
acceptable
excipient; and "C" comprises an additional active material and/or at least one
pharmaceutically acceptable excipient.
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[0021] Figure 2 illustrates comparative dissolution of 2 separate tablets of
sumatriptan
and naproxen (Compositions 10 and 11), homogeneous compositions of sumatriptan
and
naproxen with sodium bicarbonate and the superdisintegrant crospovidone
(Compositions 6
and 8), and a bi-layer tablet of sumatriptan and naproxen (Composition 13).
Detailed Description of the Invention
[0022] The invention addresses the above-described shortcomings of the prior
art by
providing rapidly dissolving tablets comprising a triptan and an NSAID,
wherein the triptan
and the NSAID are present in a single zone and each of the triptan and the
NSAID maintains
its individual dissolution characteristics irrespective of the presence of the
other.
[0023] When naproxen or a similar NSAID and a triptan are in a non-segregated
tablet, it has been reported that the NSAID, which is usually present in a
high dose compared
with the triptan, tends to form a gel-like matrix in the presence of an
aqueous medium. The
gel-like matrix erodes slowly and is likely to entrap the triptan, thereby
delaying its release.
It has now been surprisingly found, however, that when rapidly dissolving
tablets are used,
the formation of the gel is prevented, allowing for the rapid dissolution of
the triptan.
[0024] As used herein, unless otherwise defined, the term "triptan" means a
triptan or
a pharmaceutically acceptable salt or solvate thereof.
[0025] As used herein, unless otherwise defined, the term "NSAID" means an
NSAID or a pharmaceutically acceptable salt or solvate thereof.
[0026] As used herein, unless otherwise defined, the term "sumatriptan" means
sumatriptan free base or a pharmaceutically acceptable salt or solvate
thereof. A preferred
form of sumatriptan is sumatnptan succinate.
[0027] As used herein, unless otherwise defined, the term "naproxen" means
naproxen free acid or a pharmaceutically acceptable salt or solvate thereof. A
preferred form
of naproxen is naproxen sodium.
[0028] As used herein, unless otherwise defined, the term "therapeutically
effective
dosage" means a dosage sufficient to treat migraines. The person of ordinary
skill in the art
would be able to determine a therapeutically effective dosage based upon the
description
herein coupled with the general knowledge in the art. For a particular
patient, a
therapeutically effective dosage may depend on variables such as age, gender,
weight, and
extent of condition.
[0029] As used herein, unless otherwise defined, the term "zone" means a
region in a
dosage form that has a distinct composition. Preferably, the region has a
substantially
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homogeneous composition, i.e., the region contains a substantially homogeneous
mixture of
particles of triptan and particles of NSAID. In one preferred embodiment, the
region
contains a substantially homogeneous mixture of granulates of triptan,
granulates of NSAID,
and extragranular excipients. For example, a zone may be a core, a coating
layer, or other
type of layer in the oral dosage form, examples of which are depicted in
Figure 1.
[0030] The invention encompasses oral dosage fornms and compositions
comprising a
triptan and an NSAID. Suitable triptans include, but are not limited to,
sumatriptan,
eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan, and
naratriptan. Preferably, the
triptan is sumatriptan. Suitable NSAIDs include, but are not limited to,
flurbiprofen,
ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac,
nabumetone, mefanamic
acid, piroxicam, lornoxicam, meloxicam, rofecoxib, celecoxib, etoricoxib, and
valdecoxib.
Preferably, the NSAID is naproxen or rofecoxib. More preferably, the NSAID is
naproxen.
[0031] Typically, the oral dosage forms of the invention are in the form of
rapidly
dissolving tablets in which the triptan and the NSAID are combined in a single
zone, while
each of the triptan and the NSAID maintains its individual dissolution
characteristics
irrespective of the presence of the other.
[0032] Typically, a rapid dissolution will be understood to mean that not less
than
about 60% of the triptan in the oral dosage form dissolves in acidic media in
30 minutes.
Preferably not less than about 70% of the triptan dissolves in acidic media in
30 minutes, and
more preferably not less than about 80% of the triptan dissolves in acidic
media in 30
minutes. As used herein, unless otherwise defined, the term "acidic media"
means 200 ml of
0.01N HCl solution in a USP Type II Dissolution Apparatus at a rotation speed
of 40 rpm.
[0033] In one embodiment of the invention, the rapid dissolution of the oral
dosage
form is achieved through the use of an effervescent couple. The effervescent
couple
comprises a basic ingredient and an acidic ingredient, the basic ingredient
liberating carbon
dioxide when it and the acidic ingredient are contacted with water. The
effervescent couple
can be formed, for example, by including both the base component and the acid
component
as extra-granular excipients in the oral dosage form. In another example, the
effervescent
couple can be formed by including only the base component as an extra-granular
excipient in
the oral dosage form, and using stomach acid as the acid component, i.e., the
base component
reacts with stomach acid to form the effervescent couple once the oral dosage
form is
administered to a patient.
[0034] Typically, the base component is a carbonate or a bicarbonate. Suitable
bicarbonates include, but are not limited to, ammonium bicarbonate, and alkali
metal
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bicarbonates such as potassium bicarbonate and sodium bicarbonate. Preferably,
the
bicarbonate is sodium bicarbonate. Typically, the bicarbonate is present in an
amount of more
than 10% to about 20% by weight of the zone in which both particles of triptan
and particles
of NSAID are present. Preferably, the bicarbonate is present in an amount of
about 11% to
about 17% by weight of the zone in which both particles of triptan and
particles of NSAID
are present.
[0035] The acid component, when included in the oral dosage form, may be any
pharmaceutically acceptable acid. Suitable acids include, but are not limited
to, ascorbic
acid, citric acid, tartaric acid, succinic acid, fumaric acid, malic acid,
lactic acid, propionic
acid, sorbic acid, and benzoic acid. Preferably, the acid is ascorbic acid,
citric acid or tartaric
acid. Typically, the acid component is present in an amount so as to produce
an
approximately a 1:1 molar ratio between the basic groups on the base component
and the
acidic groups on the acid component.
[0036] In another embodiment of the invention, the rapid dissolution of the
oral
dosage form may be achieved by using a large amount of superdisintegrant as an
extragranular excipient, with the proviso that the superdisintegrant is not
croscarmellose
sodium. Suitable superdisintegrants include, but are not limited to,
crospovidone and sodium
starch glycolate. Preferably, the superdisintegrant is crospovidone.
Typically, the
crospovidone is present in an amount of about 7% to about 20% by weight of the
zone in
which both particles of triptan and particles of NSAID are present, and
preferably more than
10% to about 17% by weight of the zone in which both particles of triptan and
particles of
NSAID are present. The skilled artisan would appreciate that the appropriate
amount of
superdisintegrant varies with the type of superdisintegrant used, as well as
the properties of
the active materials and other excipients used, and can determine the
appropriate amount of
superdisintegrant based upon these factors.
[0037] Optionally, the rapid dissolution of the oral dosage form may be
achieved by
using a mixture of additives as extra-granular excipients, i.e., a mixture of
carbonate,
bicarbonate, and/or superdisintegrant. Typically, the additives are present in
a total amount
of more than 10% by weight of the zone in which both particles of triptan and
particles of
NSAID are present. Preferably, the additives are present in a total amount of
more than 10%
to about 60% by weight, more preferably more than 10% to about 50% by weight,
and most
preferably more than 10% to about 40% by weight of the zone in which both
particles of
triptan and particles of NSAID are present.
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[0038] Typically, the ratio of the amount of NSAID to the total amount of
additives is
less than about 5. Preferably, the ratio of the amount of NSAID to the total
amount of
additives is about 1 to about 4.5, more preferably about 2 to about 4.5, and
most preferably
about 2.5 to about 4.5.
[0039] In another embodiment of the invention, the rapid dissolution of the
oral
dosage form may be achieved by producing a highly porous tablet. An increased
dissolution
rate can be obtained by increasing the porosity (void spaces) of the tablet.
Void spaces in the
tablet matrix facilitate the permeation of water to rapidly erode the entire
tablet. This may be
achieved by adding a volatilizable adjuvant to the composition, which is
subsequently
removed by sublimation or thermal decomposition. See, e.g., U.S. Patent Nos.
3,885,026,
5,529,789, 5,853,758; Aly, A.M., Semreen M., and Qato, M.K.,
"Superdisintegrants for solid
dispersion to produce rapidly disintegrating tenoxicam tablets via camphor
sublimation,"
Pharmaceutical Technology, January 2005, pp. 68-78; Koizumi K. et al., "New
method of
preparing high-porosity rapidly saliva soluble compressed tablets using
mannitol with
camphor, a subliming material," Int. J. Pharm. 152 (1997) pp. 127-13 1; Gohel,
M. et al.,
"Formulation design and optimization of mouth dissolve tablets of nimesulfide
using vacuum
drying technique," AAAPS PharmSciTech 2004, 5(3) Article 36, all of which are
hereby
incorporated by reference. The degree of porosity may be expressed as the
percent of weight
lost from the dosage form following removal of the volatilizable adjuvant.
[0040] Preferably, the porosity of the tablet is at least about 10%, i.e.,
upon removal
of the volatilizable adjuvant, 10% of the tablet weight is lost. The weight
loss (and thus the
porosity of the tablet) can be measured, for example, by techniques disclosed
in the articles
mentioned in the immediately preceding paragraph. The desired weight loss may
be achieved
by incorporating into the extra granular excipients a solid adjuvant which is
volatilizable at
either elevated temperatures, or reduced pressures, or a combination of both.
Suitable
volatilizable adjuvants include materials that undergo sublimation and
materials that
thermally decompose to gases. Materials that undergo sublimation include, but
are not limited
to, camphor, menthol, benzoic acid, urethane, urea, vanillin, tetramethylene
tetramine, and
naphthalene. Preferably, the material that undergoes sublimation is camphor or
menthol.
Materials that thermally decompose to gases include, for example, ammonium
bicarbonate.
[0041] In another embodiment of the invention, the rate of rapid dissolution
may be
adjusted by controlling the hardness of the tablet. Preferably, the hardness
of the tablet is
about 10 to about 30 SCU, and more preferably about 12 to about 25 SCU.
Hardeness is
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typically measured by the method disclosed in REMINGTON - THE SCIENCE AND
PRACTICE OF
PHARMACY, 882-883 (20th ed. 2000), hereby incorporated by reference.
[0042] The compositions described herein may be prepared in accordance with
methods that are standard in the art. Preferably, the triptan and NSAID are
granulated
separately using any acceptable granulation method, using, for example, a high-
shear
granulator. Any acceptable granulation solvent may be employed, such as, but
not limited to,
water, ethanol, isopropanol, or any combination thereof. More preferably, the
granulation
solvent is water.
[0043] Optionally, the NSAID granulate may be mixed with colloidal silicon
dioxide
before adding the triptan granulate and the remaining inactive ingredients.
[0044] Apart from the active ingredients, any acceptable pharmaceutical
excipient
may be used. For example, the composition may comprise binders (such as
polyvinylpyrrolidone), disintegrants (such as crospovidone, microcrystalline
cellulose, and
sodium starch glycolate), lubricants (such as magnesium stearate and
hydrogenated vegetable
oil), and fillers (such as lactose and mannitol). The tablets may optionally
be coated.
[0045] The invention further encompasses a method of treatment comprising
administering the pharmaceutical fonmulation to a mammal. Preferably, the
mammal is a
human. Preferably, the pharmaceutical formulation comprises sumatriptan
succinate and
naproxen sodium in the form of a rapidly dissolving tablet in which the
sumatriptan succinate
and the naproxen sodium are combined in a single zone and is administered to
treat acute
migraines, which is expected to be the approved use for TREXIMA .
[0046] The amount of active compounds administered and the dosing regimen used
will depend on the particular drug selected, the age and general condition of
the subject being
treated, the severity of the subject's condition, and the judgment of the
prescribing physician.
[0047] Having described the invention with reference to certain preferred
embodiments, other embodiments will become apparent to one skilled in the art
from
consideration of the specification. The invention is further defined by
reference to the
following examples. It will be apparent to those skilled in the art that many
modifications,
both to materials and methods, may be practiced without departing from the
scope of the
invention.
Examples
[0048] In the following examples several fixed-dose combinations of
sumatriptan
succinate and naproxen sodium have been prepared.
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Example 1: Granulation of Sumatriptan succinate
[0049] The composition for sumatriptan succinate granulation is provided in
Table 1.
Table 1. Composition of sumatriptan succinate granulation.
Ingredient Wei ng t% Amount Total
(w/w) m tablet weight
Sumatriptan succinate 56.1 119.00 29.75
Lactose monohydrate 24.1 51.00 12.75
Microcrystalline cellulose 19.8 42.00 10.5
Water -- QS
Total 100.0 212.00 53.0
[0050] Sumatriptan succinate, lactose monohydrate and microcrystalline
cellulose
were mixed for 2 minutes in a high shear granulator at a mixer speed of 460
rpm. Water was
added until a suitable granulation was achieved at a mixer speed of 920 rpm
and a chopper
speed of 2220 rpm. The resulting wet granulate was transferred to a fluid bed
drier (Glatt-2),
with an inlet temperature of 60 C and an outlet temperature of 35 C, and
dried. Loss on
drying (LOD) was determined using a Mettler-Toledo HR73 Halogen Moisture
Analyzer, and
was found to be 0.69%. The dried granulate was then milled using an 18 mesh
screen.
Example 2: Granulation of Naproxen sodium 500 m~
[0051] The composition for naproxen sodium granulation is provided in Table 2.
Table 2. Composition of naproxen sodium granulation.
Ingredient Wei ng t% Amount Total
(w/w) m tablet weight
Naproxen sodium 87.0 500.00 125.0
Microcrystalline cellulose 8.7 50.00 12.5
Povidone 4.3 25 6.25
Water -- QS
Total 100.0 575.00
[0052] Naproxen sodium, microcrystalline cellulose and povidone were mixed for
2
minutes in a high shear granulator at a mixer speed of 460 rpm. Water was
added until a
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seiitable granulation was achieved at a mixer speed of 920 rpm and a chopper
speed of 2220
rpm. The resulting wet granulate was transferred to a fluid bed drier (Glatt-
2), with an inlet
temperature of 60 C and an outlet temperature of 35 C, and dried. Loss on
drying (LOD) was
determined using a Mettler-Toledo HR73 Halogen Moisture Analyzer, and was
found to be
2.84%. The dried granulate was then milled using an 18 mesh screen.
Example 3: Preparation of compositions containing granulates of naproxen and
sumatriptan
[0053] The granulates from Examples 1-2 were combined in pharmaceutical
compositions according to Tables 3a, 3b, 3c, and 3d. About 15-20 tablets were
prepared
from each batch.
Table 3a. Comparative formulations of naproxen and sumatriptan without sodium
bicarbonate or the superdisintegrant crospovidone.
Ingredient Composition 1 Composition 2 Composition 12
Part I Naproxen granulate 68.05% 64.25% 57.10%
Part II Sumatriptan 25.08% 23.695 21.05%
granulate
Part III Microcrystalline 2.37% 2.23% 1.99%
cellulose
Lactose anhydrous 2.37% 2.23% 1.99%
Croscarmellose 1.18% 5.59% 13.90%
sodium
Tartaric acid - -
Sodium bicarbonate - - -
Crospovidone - - -
Colloidal silicon - - 1.98%
dioxide
[AEROSIL 200]
Menthol - -
Part IV Magnesium stearate 0.95% 2.01% 1.99%
Total 100.00% 100.00% 100.00%
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T,able 3b. Formulations of naproxen and sumatriptan with sodium bicarbonate or
the
effervescent couple sodium bicarbonate and tartaric acid.
Ingredient Composition 3 Composition 4
Part I Naproxen granulate 52.80% 57.21%
Part II Sumatriptan granulate 19.47% 21.09%
Part III Microcrystalline cellulose 3.67% 3.98%
Lactose anhydrous 3.67% 3.98%
Croscarmellose sodium - -
Tartaric acid 8.82% -
Sodium bicarbonate 9.92% 11.94%
Crospovidone - -
Colloidal silicon dioxide - -
[AEROSIL 200]
Menthol - -
Part IV Magnesium stearate 1.65% 1.79%
Total 100.00% 100.00%
Table 3c. Formulations of naproxen and sumatriptan with the superdisintegrant
crospovidone.
Ingredient Composition 5 Composition 7
Part I Naproxen granulate 63.54% 57.10%
Part II Sumatriptan granulate 23.43% 21.05%
Part III Microcrystalline cellulose 2.21 % 1.99%
Lactose anhydrous 2.21 % 1.99%
Croscarmellose sodium - -
Tartaric acid - -
Sodium bicarbonate - -
Crospovidone 2.21% 13.90%
Colloidal silicon dioxide - 1.99%
[AEROSIL 200]
Menthol 4.42% -
12
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Part IV Magnesium stearate 2.03% 1.99%
Total 100.00% 100.00%
[0054] The porosity of composition 5 was measured to be about 4.4%.
Table 3d. Formulations of naproxen and sumatriptan with both sodium
bicarbonate and the
superdisintegrant crospovidone.
Ingredient Composition 6 Composition 8 Composition 9*
Part I Naproxen granulate 58.26% 57.10% 57.10%
Part II Sumatriptan 21.48% 21.05% 21.05%
granulate
Part III Microcrystalline 2.03% 1.99% 1.99%
cellulose
Lactose anhydrous 2.03% 1.99% 1.99%
Croscarmellose - - -
sodium
Tartaric acid - - -
Sodium bicarbonate 12.16% 11.92% 11.92%
Crospovidone 2.03% 1.98% 1.98%
Colloidal silicon - 1.98% 1.98%
dioxide
[AEROSIL 200]
Menthol - - -
Part IV Magnesium stearate 1.99% 1.99%
Total 100.00% 100.00% 100.00%
* In this composition the colloidal silicon dioxide used was AEROSIL R 972.
All other
compositions in Tables 3a to 3d contained AEROSIL 200.
[0055] Part III ingredients were combined and mixed. Naproxen granulate was
added
and mixed for 5 minutes. Sumatriptan granulate was added and mixed for 5
minutes.
Magnesium stearate was added and mixed for 2 minutes. Compositions were
tabletted using a
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Kilian SP300 tabletting machine, with a mean hardness of about 20-24 SCU (high
hardness,
HH). Compositions 8 and 9 were tabletted to a mean hardness of about 13-15 SCU
(low
hardness, LH).
[0056] Tablets from composition 5 were then placed in a vacuum oven heated to
about 35 C for about 5 hours.
Example 4: Preparation of a comparative composition containing sumatriptan
[0057] The granulation of Example 1 was used in a composition according to
Table 4.
About 15 tablets were prepared.
Table 4. Composition containing sumatriptan succinate
Ingredient Composition 10
Part I Sumatriptan 80.00%
granulate
Part II Microcrystalline 7.55%
cellulose
Lactose anhydrous 7.55%
Croscarmellose 3.77%
sodium
Part III Magnesium stearate 1.13%
Total 100.00%
[0058] Ingredients of Part II were combined and mixed for 5 minutes. The
resulting
sumatriptan granulation was then added and blended for 5 minutes. Magnesium
stearate was
finally added to the sumatriptan granulation, and blended for 2 minutes.
Tablets were
prepared using a Kilian SP300 tabletting machine, to a mean hardness of about
20 SCU.
Example 5: Preparation of a comparative composition containing naproxen
[0059] The granulation of Example 2 was used in a composition according to
Table 5.
About 15 tablets were prepared.
Table 5. Composition containing naproxen
Ingredient Composition 11
Part I Naproxen granulate 91.13%
Part II Microcrystalline 3.17%
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cellulose
Lactose anhydrous 3.17%
Croscarmellose 1.58%
sodium
Part III Magnesium stearate 0.95%
Total 100.00%
[0060] Ingredients of Part II were combined and mixed for 5 minutes. Naproxen
granulation was then added and blended for 5 minutes. Magnesium stearate was
finally added
to the naproxen granulation, and blended for 2 minutes. Tablets were prepared
using a Killian
SP300 tabletting machine, to a mean hardness of about 20 scu.
Example 6: Preparation of a bi-layer tablet containing sumatriptan and
naproxen
[0061] The granulations from examples 1-2 were used in a composition according
to
Table 6. About 6 tablets were prepared.
Table 6. Bi-layer tablet containing sumatriptari and naproxen
Ingredient Composition 13
Part I Naproxen granulate 67.97%
Part II Sumatriptan granulate 25.06%
Part III Microcrystalline 2.36%
cellulose
Lactose anhydrous 2.36%
Croscarmellose 1.18%
sodium
Part IIV Magnesium stearate 1.07%
Total 100.00%
[0062] Ingredients of Part III were combined and mixed. 2/3 of the total
weight were
mixed for 5 minutes with granulate of Part I, 6 mg of magnesium stearate were
added, and
the combined mixture mixed for 2 minutes. The resulting first admixture was
poured into the
matrix of a manual press, and lightly pressed. The remainder of the Part III
mix were mixed
for 5 minutes with the granulate of Part II, and then 3 mg of magnesium
stearate were added,
and the admixture was mixed for 2 minutes. The resulting second admixture was
poured on
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top of the first admixture inside the matrix. The total composition was
pressed using a manual
press. The hardness of the resulting tablets was not determined.
Example 7: Dissolution of tablets
[0063] Dissolution of the sumatriptan in tablets prepared in Example 3 was
studied
using a USP Apparatus 2(paddles), rotation speed of 40 rpm, at a temperature
of 37 C. See
U.S. PHARMACOPEIA, 2413-2414 (28th ed. 2005), hereby incorporated by
reference. The
medium used was 0.O1N HCl or a buffered solution at pH 6 with 0.15% sodium
dodecyl
sulfate. In some cases, 0.O1N HCl was used for 30 minutes, neutralized with a
sodium
phosphate and sodium hydroxide solution, buffered to pH 6 and 0.15% sodium
dodecyl
sulfate added. The dissolution profile of the sumatriptan in these
compositions was compared
with the dissolution of sumatriptan in a tablet of sumatriptan prepared
according to Example
4 in the presence of a separate tablet of naproxen prepared according to
Example 5, as well as
the dissolution of sumatriptan in a bilayer tablet of sumatriptan and naproxen
prepared
according to Example 6. The results are summarized in Table 7 below.
Table 7. Dissolution of sumatriptan following exposure to 0.O1N HCl for 30
minutes
Formulation Hardness %
(total % carbonate, bicarbonate (SCU) Dissolved
and superdisintegrant)
Sumatriptan and naproxen Composition 1 22-25 10**
without a carbonate,
bicarbonate or the Composition 2 22-25 24
superdisintegrant
crospovidone Composition 12 15-17 16
Sumatriptan and naproxen Composition 3 (9.92%) 22-25 48
with sodium bicarbonate or
the effervescent couple Composition 4 (11.94%) 22-25 77
sodium bicarbonate and
tartaric acid
Sumatriptan and naproxen Composition 5(2.21%) 22-25 13
with the superdisintegrant
crospovidone Composition 7(13.90%) 13-17 75
Sumatriptan and naproxen Composition 6 (14.19%) 13-17 85**
with sodium bicarbonate
and the superdisintegrant Composition 8 LH (13.90%) 13-17 95*
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erospovidone Composition 8 HH (13.90%) 22-25 89**
Composition 9 LH (13.90%) 13-15 102
Composition 9 HH (13.90%) 22-25 88
Sumatriptan and naproxen Composition 10 (in the -- 89*
in separate tablets presence of composition 11)
Bi-layer tablet of Composition 13 -- 68
sumatriptan and naproxen
* average of 3 experiments; ** average of 2 experiments; LH = low hardness; HH
= high
hardness
[0064] As illustrated in Table 7 above, compositions having less than 10% of
carbonate, bicarbonate, or superdisintegrant release about 25% or less of the
sumatriptan
following exposure to 0.01N HCl for 30 minutes. Compositions having more than
10% of
carbonate, bicarbonate, or superdisintegrant, however, release about 50% to
100% of the
sumatriptan following exposure to 0.01N HCl for 30 minutes. The dissolution
profile of
sumatriptan in the compositions having more than 10% of carbonate,
bicarbonate, or
superdisintegrant is comparable to the dissolution profile of sumatriptan when
it is
administered separately from naproxen, either in a separate tablet or in a bi-
layer tablet
wherein the naproxen and the sumatriptan are in separate layers.
Example 8: Dissolution of Tablets
[0065] Comparative dissolution of 2 separate tablets of sumatriptan and
naproxen
(Compositions 10 and 11), homogeneous compositions of sumatriptan and naproxen
with
sodium bicarbonate and the superdisintegrant crospovidone (Compositions 6 and
8), and a bi-
layer tablet of sumatriptan and naproxen (Composition 13) was carried out
using a USP
Apparatus II (paddles), rotation speed 40 r.p.m, at a temperature of 37 C.
Tablets were
initially placed in 200 mL 0.01N HCl solution for 30 minutes. The solution was
then
neutralized using 10 mL of phosphate neutralizing buffer (60 g/L sodium
dihydrogen
phosphate, titrated to pH 6 with sodium hydroxide, and sodium hydroxide added
until a pH of
is reached). This was followed by addition of 700 mL phosphate buffer (6 g/L
sodium
dihydrogen phosphate, pH adjusted to 6 with sodium hydroxide, and 0.15% (w/v)
sodium
lauryl sulfate added). Samples were drawn 15, 30, 45, 60, 90, and 120 minutes
after the
experiment was started. Results are shown in Figure 2.
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