Note: Descriptions are shown in the official language in which they were submitted.
1 336687
INTRODUCTION
This invention relates to analgesic tablets, and particularly
to analgesic tablets that contain a combination of ibuprofen,
acetaminophen (APAP) and caffeine.
BACKGROUND OF lNV~:NTlON
The use of the combination of acetylsalicylic acid, APAP and
caffeine in analgesic tablets has been known for a long time. One
such product is marketed by the Bristol-Myers Company under the
trademark EXCEDRIN (See "Handbook of Non-PrescriPtion Drugs" 1969
Edition P.34 published by The American Pharmaceutical Association).
More recently, ibuprofen has been approved to some extent by
the Food and Drug Administration for over-the-counter sale and has
been marketed widely as such. It was thought that a useful
combination analgesic product could be made available if ibuprofen
was combined with APAP and caffeine in a tablet dosage form.
While investigating the pharmacological availability of the
three-active-component analgesic tablet containing ibuprofen, APAP
and caffeine as measured by the dissolution rates of these active
1 336687
in~redients, it soon became obvious that the problem of formulating
such a dosage form was much more complicated than was originally
anticipated. It was found, for example, that if the three
component analgesic tablet product containing ibuprofen, APAP and
caffeine was prepared by the direct compression of these actives
that the dissolution rates for the active ingredients in these
tables left something to be desired.
Another phenomenon was discovered which appeared to portend
still more difficulty in preparing analgesic tablets containing
ibuprofen, APAP and caffeine as actives that had suitable
dissolution rates for the three active ingredients. The disso-
lution rates of APAP, acetylsalicylic acid and caffeine in tablets
containing these three actives, prepared by direct compression and
stored under stressed conditions were compared with tablets
containing two active ingredients, (i.e. APAP/caffeine and
acetylsalicylic acid/caffeine, respectively) also prepared by
direct compression and stored under stressed conditions. It was
found that for each of the actives, i.e. APAP, caffeine and
acetylsalicylic acid the time it took for 80% of each active to
dissolve from the direct compression, three-actives tablet was
dramatically increased when compared with that found for
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t~e case of the two-actives tablets. In the case for caffeine and
APAP, this amounted to about a sixfold increase. In the case of
acetylsalicylic acid, it took about 22 minutes for 80% of the
acetylsalicylic acid to dissolve in the two actives tablet. But
for the three-actives tablet even after 60 minutes, the level of
dissolution for acetylsalicylic acid had not reached 80%. These
data suggested that when the three active ingredients are pressed
into a tablet some sort of interaction takes place among the three
ingredients which is some fashion deleteriously effects the
dissolution rat~ uf the active ingredients. This raised serious
doubts as to whether a suitable analgesic tablet having
satisfactory dissolution rates for the active ingredients could be
prepared with ibuprofen, APAP and caffeine as active ingredients.
THE lNVhNllON
It has now been unexpectedly found that the dissolution rates
of the active ingredients in an analgesic tablet containing
ibuprofen, APAP and caffeine as active ingredients can be
maintained at a satisfactory level if each of these ingredients is
formed into a separate granulation before mixing them together for
1 336687
compression into a tablet. These active ingredients are each
separately granulated using a wet granulation process and the
granulations so prepared are then mixed together, usually with
other tablet adjuvants, and then tabletted in conventional
punchpress type machines.
Thus the present invention provides a process for
preparing a tablet containing ibuprofen, acetaminophen
and caffeine as pharmaceutically active ingredients
comprising:
claim 1
(a) preparing separate wet granulations of each of ibupro-
fen, acetaminophen and caffeine suitable for tabletting;
(b) forming a mixture suitable for tabletting containing
said ibuprofen granulation, said acetaminophen granulation
and said caffeine granulation prepared in 6tep ~a) and
- (c) tabletting the mixture prepared by step (b)
The invention also provides in certain aspects
tablets prepared in accordance with such process and the
use of such tablets for alleviating pain and/or reducing
fever and/or reducing an inflammatory process in a
subject.
6 --
1 336687
In the attached drawings:
Fig. 1 is a graph showing the initial dissolution rates and the
dissolution rates after storage for 1 month at 40C and 75%
relative humidity (designated by the expression H/H) for the active
ingredients, i.e. ibuprofen (IBU), acetaminophen (APAP) and
caffeine contained in tablets prepared by first preparing separate
wet granulations of the actives and then mixing and compressing
them into tablets in accordance with the present invention (Formula
CW 4708-29B);
Fig. 2 is a graph similar to that shown in Fig. 1 except that
the tablets tested were prepared by direct compression of IBU, APAP
and caffeine, that is to say that the IBU, APAP and caffeine were
used in the form of powders or granules as distinguished from a
granulation form (Formula CW 3708-28B).
- 6A -
~............................................. ,
1 336687
In the pharmaceutical tabletting art, a distinction is made
between a granulation form and a granular form of an ingredient
that is to be compressed into a tablet. The granulation form of
an ingredient (e.g. ibuprofen) is prepared by a wet granulation
process that begins with the ingredient in powder or granular
size. Either or a combination of the latter two are wetted with a
granulation solution, usually containing a binder to form a
crumbly mass which is then ground and sized. Such a product is
referred to as a granulation product and in the case of ibuprofen
it can be referred to as an ibuprofen granulation. By contrast,
granular ibuprofen, although not available commercially, could
theoretically be used to refer to ibuprofen which has not been
processed in this fashion. In this case, the term granular is an
expression of the particle size of the ibuprofen rather than the
manner in which the ibuprofen was processed and is often used to
distinguish the material from its finely divided or powder form.
By an extension of this nomenclature, we can and do refer to APAP
granulation and caffeine granulation on the one hand and to
granular APAP and granular caffeine on the other hand.
A further way of distinguishing between the granulation form
and the granular form of material is by way of the bulk density
and the particle size of the substance. The particles of the
1 336687
gra~ulatio~ form of a drug generally have a lower bulk density and
larger particle size (e.g. No. 8 mesh to No. 20 mesh) whereas the
particles of the granular form of a drug have a higher bulk
density than the granulation form of the drug and a smaller
particle size (e.g. No. 8 mesh to No. 80 mesh).
Still a further way of distinguishing between the granulation
form and the granular form of a material takes advantage of the
fact that in preparing the former a granulating solution is
employed which usually contains a binder (e.g. starch) that
becomes incorporated in the granulation. The binder generally
comprises from about 0.5% to about 6% by weight of the granulation
based on the total weight of the granulation with the preferred
range being from about 1% to about 4 or 5% on the same weight
basis.
The quantity of ibuprofen that will be contained in the
tablets of this invention might vary depending, among other
things, on the number of tablets that are to be used to deliver an
effective analgesic dose. Generally, however, each tablet will
contain from about 50 mg. to about 400 mg. of ibuprofen. In the
preferred case, the effective analgesic dose will be delivered
with two tablets each of which will contain about 50 mg. to about
400 mg. of ibuprofen.
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Similar considera~ions obtain with respect to ~uantity of APAP
and caffeine contained in each tablet of this invention. Thus,
generally each tablet will contain from about 150 mg. to about 500
mg. of APAP and from about 30 mg. to about 130 mg. of caffeine.
In the preferred cases, two tablets are used to delivery an
effective dose, each tablet will contain from about 150 mg. to
about 500 mg. of APAP and from about 30 mg. to about 130 mg. of
caffeine.
In addition to the above mentioned ingredients, the tablets of
this invention may also contain adjuvants that are commonly added
in tablet manufacturing to form more elegant tablets or to
facilitate the tabletting process. These may include such agents
as fillers, disintegrants, lubricants, binders, etc. By way of
illustrating particular adjuvants that may be employed in
preparing the present tablets, mention may be made of the
following:
fillers; lactose, microcrystalline cellulose, etc.
disintergrants; starch, Ac-Di-Sol , CROSPOVIDONE XL-10, etc.
lubricants, stearic acid, Mg-Stearate, etc.
flow agents; Cab-0-Sil (Silicone Dioxide), etc.
Trademark
1 336687
As indicated above, it ~ a feature of the present invention
that each of the active ingredients be prepared as a granulation
before it is mixed with the other ingredients to be pressed into a
tablet. A variety of wet granulation procedures, known to those
skilled in the tabletting art, may be used in preparing the
individual granulations that are useful for the purposes of the
present invention. Generally, the wet granulation process will
involve moisturizing the powdered active ingredient with a
solution of a bonding agent to cause a certain amount of
agglomeration to bring the powder to the consistency of a crumbly
mass. This mass will then be sized and dried and the resulting
dried mass will be broken up to give granulation particles of the
desired size.
A preferred wet granulation procedure useful for preparing the
granulations of active ingredients useful for the purposes of the
present invention may be described in the following terms. The
first step in the wet granulation process consists of uniformly
mixing the powdered active agents with the diluent. The mixture
is passed through a No. 10 to No. 30 mesh screen and subjected to
additional blending. This is followed by careful moistening with
the proper binding solution until the mixture has the consistency
-- 10 --
1 336087
of a crumbly mass. The wet mass i6 ~_n screened through a No. 6
mesh to a No. 20 mesh screen using an oscillator. The wet
particles are then dried in an Fluid Bed Dryer at about 50C.
After drying, the particles are broken up and passed through the
proper screen to obtain the desired particles size.
The tablets of the present invention may be used in the
treatment of those conditions for which over-the-counter anal-
gesics are generally recommended. These include the treatment of
pain from neural and muscular sources, fevers, inflammation of the
kind that responds salicylate therapy.
It has also been found advantageous in this invention to
sometimes apply a film coating to the tablets. This provides
tablets that have satisfactory chemical and physical stability
characteristics. A variety of film forming polymers are known in
this art that are useful for this purpose. These include such
polymers as polyvinylpyrrolidone (PVP), hydroxypropylmethyl
cellulose, hydroxyethyl methyl cellulose, ethyl cellulose,
hydroxypropyl cellulose, sodium carboxymethyl cellulose,
polyethylene glycols and mixtures thereof. These film forming
polymers will generally be applied from a liquid composition
-- 11 --
1 336687
containing them. Such liquid compositions, ~- de from the film
forming polymer or polymers may also contain surface active
agents, plasticizers, film smoothing agents, coloring agents and
antifoaming agents. The vehicle for the liquid coating composi-
tion will generally be an aqueous vehicle in which the film
forming polymers are suspended. The older solvent systems can
~ -
also be used as the vehicle.
The film coating may be applied to the tablets of this
invention in any suitable manner known to those skilled in this
art. One highly satisfactory procedure may be described as
follows:
1. Place the tablet cores into a 24" Accela Cota pan
(perfc.^ated pan) and turn on the exhaust and heater.
Pre-heat the tablets to 42C while jogging the pan.
2. The film coating solution is sprayed through spray guns
using the following parameters.
pan speed: 10-16 rpm
spray rate: 3Oml-4Oml/min.
No. of spray guns: 2
Inlet temperature: 40-42C
Outlet temperature: 38-40C
Atomization air pressure: 20 psi
Amount of film (as solid): 2%-3% (w/w) of tablets
1 336687
3. At the completion of the coating, the film coated tablets
are dried while jogging the coating pan until outlet
temperature reaches 42-C.
The following examples are given to further illustrate this
invention. It is to be understood, however, that this invention
is not limited thereto.
The trade designations for materials listed below appear in
this specification and are identified chemically by the definition
following each trade designation:
DC APAP 90 = 90% acetaminophen granulation,
Crospovidone XL-10 = cross linked, insoluble homopolymers of
N-vinyl-2-pyrrolidone,
Povidone (K29-32) = Polyvinylpyrrolidone,
ydroxypropylmethyl cellulose = glycol ether of hydroxymethyl
cellulose,
Arlacel 20 = sorbitan laurate,
Tween 20 = polysorbate 20,
Color White = Titanium dioxide in aqueous propyleneglycol base,
Antifoam = Simethicone NF (polymethylsiloxane)
In the Examples given below, the ibuprofen, ASA, APAP and
caffeine are employed as particles made by a wet granulation
process. The details for the preparation of each granulation
active ingredient or the physical data that characterize these
granulations are as follows:
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1 336687
A. Pre~aration of IbuProfen Granulation
1. Mix a formula amount of ibuprofen and a formula
amount of corn starch in a Ribon type blender.
2. Dissolve a formula amount Povidone in hot water
(granulating solution: 3.2%)
3. Granulate the mixture of ibuprofen and corn starch
with the Povidone solution, and add a formula amount
of microcrystalline cellulose and Crospovidone
XL-10, and mix well.
4. Pass wet granulation through a Tornado mill with
1/2" plate and dry it in a Fluid Bed Dryer.
5. Oscillate dry granulation through a No. 10 mesh
s~reen.
B. Preparation of DC APAP 90 Granulation
Ingredients:
Acetaminophen fine powder
Corn starch
Croscarmellose Sodium
Povidone
Stearic Acid
Process:
Refer to U.K. Patent GB 2090739A (Applicants;
Monsanto, Inventors: Stephen H. Vogel)
Particle size:
On 30 mesh : 10.0% maximum
on 30 + 40 mesh : 30.0% maximum
on 30 + 40 + 80 mesh : 60.0% minimum
C. Preparation of Caffeine Granulation
1. Mix a formula amount of caffeine and 1/7 of a
formula amount of corn starch in a Hobart mixer.
2. Add hot water and the remaining amount of corn
starch, and granulate.
3. Pass wet granulation through a Tornado mill with
1/2" plate.
1 336~87
4. Dry wet granulation in a Fluid Bed Dryer.
5. Oscillate dry granulation through a No. 14 mesh
screen.
D. AcetYlsalicylic Acid Starch Granulation ~12/50
Process: Dry Compaction Method.
Particle size:
On 12 mesh : 0.4% maximum
On 14 mesh : 3.0% to 15.0%
On 40 mesh : 75.0% minimum
On Pan : 10.0% maximum
E. APAP Starch Granulation 145
Ingredients:
Acetaminophen fine powder
Corn starch
Erythrobic Acid
Polysorbate 80
Povidone
Process:
Refer to U.K. Patent GB 2090739A (Applicants;
Monsanto, Inventors; Stephen H. Vogel)
Particle size:
On 30 mesh : 10.0% maximum
On 30 + 40 mesh : 30.0% maximum
On 30 + 40 + 80 mesh: 60.0% minimum
Exam~le 1
Formula CW-3589-71
Core Tablets: Ingredients mq/tablet
DC APAP 90 (granulation) 361.0 (equiv. to
325 mg of APAP)
Ibuprofen (granulation) 100.0
Caffeine (granulation) 50.0
Corn Starch 52.0
Microcrystalline Cellulose 21.0
Crospovidone XL-10 1.0
Povidone (K29-32) 3.0
Stearic Acid 3.0
591.0
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I~ Film Coating: Ingredients mg/tablet
Povidone (K29-32) 0.95
Hydroxypropylmethyl Cellulose 5.05
Propylene Glycol 1.13
Arlacel 20 0.71
-- Tween 20 0.47
~--- Mineral Oil Light 0.19
Color White 3.31
Antifoam 0.01
11.82
Preparation of the Core Tablets
1. Mix DC APAP 90, Ibuprofen granulation (ibuprofen, corn
starch, microcrystalline cellulose, Crospovidone XL-10 and
Povidone (K29-32)) and caffeine granulation (caffeine and
starch) in a Twin Shell Blender for 15 minutes.
2. Screen stearic acid through a No. 30 mesh screen and mix it
with the above mixture in a Twin Shell Blender for 5
minutes.
3. Compress Tablets on a rotary press using 7/16" standard
concave punches.
Coatinq Procedure
A coating composition is prepared having the following formula:
% (w/w)
Water 84.00
Povidone (K29-32) 1.00
Hydroxypropylmethyl Cellulose5.34
Propylene Glycol 1.20
Arlacel 20 0.75
Tween 20 0.50
Mineral Oil Light 0.20
Color White T-510W 7.00
Antifoam 0.01
100 . 00
This coating was applied to the core tablets described above
using the following procedure:
1. Place the 6 KG compressed tablets into 24" Accela Cota pan
and turn on the exhaust and heater. Pre-heat the tablets
to 42-C while jogging the pan.
- t 336687
2. 0.132 Kg of the film coating 601ution is sprayed through
spray gums using the following parameters:
Pan Speed: 14 rmp, Spray rate: 30 ml/min.
No. of Spray Gums: 2 Inlet Temperature: 40C
Outlet Temperature: 38C Atomization Air Pressure:
20 psi.
3. At the completion of the coating, the film coated tablets
are dried while jogging the coating pan until outlet
temperature reaches 42C..
Example 2
Formula CW 3708-29B
Formula mq/tablet
Ibuprofen (granulation) 150.0 (100 as ibuprofen)
DC APAP 90 (granulation) 277.8 (250 as APAP)
Caffeine ~granulation) 100.0 (65 as caffeine)
Stearic Acid 3.0
530.8
Procedure for tablet preparation:
1. Mix DC APAP 90 granulation, ibuprofen granulation
(ibuprofen, corn starch, microcrystalline cellulose,
Crosspovidone XL-10 and Povidone (K29-32)) and caffeine
granulation (caffeine and starch) in a Twin Shell Blender
for 15 minutes.
2. Screen stearic acid through a No. 30 mesh screen and mix it
with the above mixture in a Twin Shell Blender for 5
minutes.
3. Compress tablets on a rotary press using 7/16" standard
concave punches.
. . .
1 336~87
For the purposes of comparison, tablets of the following
formulations were prepared:
Formula CY 3513-1
Formula mq/tablet
Caffeine starch granulation 100.0 (65 as caffeine)
- Acetylsalicylic acid starch granulation (12/50) 277 . 8 (250 as ace~lsalicylic acid)
APAP 6tarch granulation 145 277 . 8 (250 as APAP)
Stearic Acid 3.0
658.6
Process for preparing tablets:
1. Mix caffeine starch granulation, acetylsalicylic acid starch
granulation and APAP starch granulation in a Twin Shell Blender
for 15 minutes.
2 . Screen stearic acid through a No. 30 mesh screen and mix it
with the above mixture in a Twin Shell Blender for 5
minutes.
3. Compress tablets on a press using 7/16" standard concave
punches.
Formula CW 3708-30
Formula mq/tablet
Acetylsalicylic Acid 250.0
APAP 250.0
Caffeine 65.0
Microcrystalline cellulose 100.0
Stearic Acid 3.0
667.5
- 18 -
Process for preparing tablets: 1 336687
1. Mix acetylsalicylic acid, caffeine and microcrystalline
cellulose in a Twin Shell blender for 15 minutes.
2. Screen stearic acid through a No. 30 mesh screen and mix it
with the above mixture in a Twin Shell Blender for 5
minutes.
3. Compress tablets on a press using 7/16" standard concave
punches.
The active ingredients were used in the Formula CW 3708-30 in
the following forms:
Acetylsalicylic acid - crystals from 20 mesh to lO0 mesh
Caffeine - powder or granular: 20 mesh to 100 mesh
APAP - ~owder or granular: 12 mesh to 100 mesh
Under actual use conditions tablets are likely to be exposed to
stress conditions, such as high humidity, which can have an effect
on the dissolution rate of the actives in a tablet. With this in
mind, the tablets tested were first subjected to stress which took
one of two forms. One form entailed storing the tablets in a petri
dish for 4 weeks at high humidity. The other form was to store the
tablets in a slide box at high humidity for 4 weeks. Slide boxes
are not well sealed from the atmosphere and consequently their
contents can be effected by a high humidity environment.
-- 19 --
--~ 1 336687
To com~ar.e the release rates of active ingredients of tablets
embodied in the present invention ~Formula CW 3708-29B,) with
comparable tablets containing acetylsalicylic acid rather than
ibuprofen (CY 3513-1, and CW 3708-30,) the following tests were
carried out:
(a) the acetylsalicylic acid containing tablets Formula CY
3513-1, were stressed by storing the tablets in a slide
box at high humidity for 4 weeks before measuring the
release rates of the active ingredients;
(b) the acetylsalicylic acid containing tablets Formula CW
3708-30 and the ibuprofen containing tablets of this
invention, Formula CW 3707-29B, were both stressed by
storing 'hese tablets at high humidity in a petri dish
for 4 weeks before measuring the release rate of the
active ingredients;
(c) The protocol for testing the dissolution rates for the
active ingredients in each species of tablet was the same
and was as follows:
Dissolution Rate Test:
The dissolution method used to evaluate these tablets employs
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1 336087
the di6solution te~ iescribed in the USPXXI p. 14. The dissolu-
tion test calls for the use of 900 ml. water maintained at 37C and
the USP paddle, known as Apparatus 2, rotated at 50 rpm.
The tablet is placed in the beaker of water or buffer solution
(pH 7.2) and after 45 minutes of paddle rotation at 50 rpm, an
aliquot of solution is analyzed for acetylsalicylic acid,
acetaminophen, caffeine and ibuprofen content.
The analysis can be done via high pressure chromatography or
via spectrophometric analysis using a multi-component analysis on
HP~450 or HP8451 spectrophotometer.
As a criteria for acceptability, applicants have adapted a
dissolution rate such that at least 75% of the tablet dissolves in
under 45 minutes.
The results of these tests are summarized in Table I below.
The release of acetylsalicylic acid was measured as acetylsalicylic
acid (ASA).
The entries in this Table under the heading T25, T50,
T75, T80, T85 represents the time in minutes it took for 25%,
50%, 75%, 80% or 85%, respectively of the active ingredient in
question contained in the tablet to be released.
1 336687
An appreciation for the ~erits of the tablets of this invention
can be seen by comparing the dissolution values under the heading
"T75" for each of the active ingredients. Thus, with the
tablets of the present invention (CW3707-29B) it took 7.7+.6
minutes for 75~ of the ibuprofen to be released from these
tablets. This is to be compared with the ASA release rates for
formulas CW3708-30 and CY 3513-1. For tablets CW-3708-30, and
tablets CY 3513-l, the values were more than 60 minutes, and from
24 to more than 48 minutes, respectively to reach a level of a 75%
release of ASA from the respective tablets. Similar results hold
for the other active ingredients, that is APAP and caffeine, as
the data also demonstrate.
To demonstrate the effect of the wet granulation of actives
(i.e. ibuprofen, APAP and caffeine) on the dissolution rates of
these materials when they are compressed into tablets and to
compare these dissolution rates for the same materials in tablets
prepared by the direct compression of these actives in particle
forms other than granulations as understood herein an additional
formulation (identified as CW 3708-28B) of tablets prepared from
direct compression of said non-qranulation actives was made. The
formula for these tablets and its process for preparation is given
below:
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1 336687
~10 ` 'I
~ o ~ ~ o ~
o~ oo o ,,
.
~. ~
~ C
0
o
~ o~
,,. + +, +, ~o ~
t` X ~ +l a
r~ o
~r er
Co~ ~ + o I +
~D U' r~
o+~ +
'` ~ ~ X ~ r~
13
~1 ; r+ o ~ +1 +
r~ ~ ~
+ ~ +, ~ +, ~ ~ 6
o~ o _____ U ~
~ r ~' , t~
1 336~87
Formula CW 37~-288
Direct Compresslon 3 Actives
(IBU/APAP/Caff.)
Formula mg/tablet
Ibuprofen 100.0
APAP 250.0
Caffeine 65.0
Microcrystalline cellulose 100.0
Stearic acid 2.5
517.5
Process for preparing tablets:
1. Mix ibuprofen, APAP, Caffeine and microcrystalline
cellulose in a Twin Shell Blender for 15 minutes.
2. Screen streaic acid through a No. 30 mesh screen and mix
it with the above mixture in a Twin Shell Blender for 5
minutes.
3. Compress tablets on a press using 7/16" standard concave
punches.
The form of the ibuprofen, APAP and caffeine used in this
formulation is as follows:
Ibuprofen - fine powder from 25 microns to 60 microns
APAP - powder or granular
particle size : 12 mesh to 100 mesh
Caffeine - powder or granular
particle size : 20 mesh to 100 mesh
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1 336687
The dlssolution rate of tablets of this for~la CW 3708-28B and
those of this invention [CW-3708-29B, see Example 2] was measured
for each of the active ingredients (i.e. IBU, APAP and caffeine)
using the protocol of the "Dissolution Rate Test" also described
above. The results of test are summarized in the attached
drawings.
Fig. 1 summarizes that dissolution rate data for ibuprofen/
APAP/caffeine tablets prepared in accordance with the present
invention (Formula CW 3709-29B) from three separate wet granu-
lations of ibuprofen (IBU), APA and caffeine. These dissolution
rates were measured for each of the actives from tablets which were
unstressed and those which were stressed, (i.e. stored for one
month at 40C and 75% relative humidity). The dissolution rate for
a particular active from an unstressed tablet is designated in the
graph by the legend "Initial". Thus, for example, the curve
identified by the legend "APAP, Initial" summarizes the dissolution
rate data for APAP obtain from unstressed tablets containing
ibuprofen, APAP and caffeine. In an analogous manner, the disso-
lution rate for a particular active ingredient from a stressed
tablet (i.e. a tablet stored for one month of 40C and 75% relative
humidity) is designated by the legend "H/H", Similarly, for
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1 336~87
e~ample, the curve identified by the legend "AP~P at H/H"
summarizes the dissolution rate data for APAP obtained from
stressed tablets containing ibuprofen, APAP and caffeine. These
designations are carried over to the data for the other active
ingredients as well as into the data summarized in the graph of
Fig. 2.
A study of Fig. 1 will reveal that for the tablets of this
invention in their unstressed condition, 80% of each of the actlve
ingredients dissolved in under 5 minutes. The same was true for
the tablets in the stressed condition except for ibuprofen for
which it took about 10 minutes for 80% of the ibuprofen to
dissolve.
These data are to be compared with the similar data obtained
from tablets of IBU/APAP/caffeine prepared by direct compression as
understood herein. The data of the latter are summarized in Fig.
2. With the unstressed tablets of this type, none of the active
ingredients dissolved to a level of 80% in less than 5 minutes as
was the case with the tablets of this invention. (See curves
captioned "Caffeine, Initial", "APAP, Initial" and "Ibuprofen,
Initial"). As a matter of fact it took more than 10 minutes for
the APAP and about 25 minutes for ibuprofen to reach this level of
dissolution.
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1 336687
The difference in dissolution rate for the actives between that
obtained from the tablets of the present invention and that
obtained from direct compression tablets, as understood herein, is
even more dramatic when the tablets compared are those that have
been stressed (i.e. stored for 1 month at 40-C and 75% relative
humidity). Thus it took just under about 5 minutes for 80% of the
caffeine to dissolve from the stressed tablets of this invention.
(See curve "Caffeine at H/H" in Fig. 1.) This is to be compared
with the curve "Caffeine at H/H" in Fig. 2 for the direct
compression tablets from which it took as much as about 35 minutes
for 80% of the caffeine to dissolve from these stress tablets.
These differences are still more remarkable for APAP and
ibuprofen. For the stressed tablets of the present invention it
took about 4 minutes for 80% of the APAP to dissolve (See curve
"APAP at H/H, FIg. 1 ). This is to be compared with curve "APAP at
H/H" in Fig. 2 which indicates that it took 60 minutes or more for
80% of the APAP to dissolve from the stressed direct compression
tablets. Even more dramatic differences in dissolution rate between
the respective tablets is to be seen with respect to ibuprofen. In
the stressed tablets of this invention, it took about 10 minutes
for 80% of the ibuprofen to dissolve (See Curve "Ibuprofen at H/H
in Fig. 1). In the case of the stressed direct compression tablet,
even after 60 minutes the level of ibuprofen dissolution had only
reached about 50% (See curve "Ibuprofen at H/H" in Fig. 2).
- 26 -
- 1 336~87
Another unexpected feature of the tablets of the present
invention i6 the surprisingly good stability characteristics that
they exhibited. No evidence of physical incompatibilities was
noted such as eutectic formations. Chemical stability is satis-
factory in high density polyethylene and polystyrene bottles with
safety and non-safety caps at high humidity and 125-F after three
months of storage.
Physical stability of the tablets of this invention is
satisfactory with regard to appearance and disintegration time in
all packages at all conditions except 125F after three months
storage. A temperature of 125F is an extreme condition for
ibuprofen containing tablets.
Table II summarizes the data collected in the stability
testing. The tablets used in these stability tests were those of
formula CW-3589-71 (See Example 1 above). The characteristics
tested were disintegration time measured in minutes (see upper half
of Table II) and appearance (See lower half of Table II). The
shorthand terms appeared in the headings of the columns in Table II
have the following meaning:
HD/PE = high density polyethylene;
P/S = polystyrene.
- 27 -
t 336687
~E II
Fhysical StabllltY of Tablets CW-3589-71 with IbuProfen
p~r~ q HD/PE Eot*le HD/PE Eottle HD/PE Eottle P/S Bottle P/S Eottie
Tests SafetY caP Non-safety cap Screw-caP SafetY CaP NoQ-safety c~
Disinteqration (in ~un.~
1 Mbnth R~ 2 2 2 2 2
104-F 2 2 2 2 2
H 2 2 2 2 2
125-F 3-11 3- ~10 3-8 3-7 3-7
2 Month RT 2 2 2 2 2
104-F 2-3 2-3 2-3 2-3 2-3
HVH 2-3 2-3 2-3 2 2
125'F 4-7 9- >20 4-14 4-11 4-8
3 Mbnth R~ 2 2 2 2 2
104-F 2-3 2-3 3 2-3 2-3
HvH 2-3 2-3 3-7 2-3 2-3
125-F 4-7 5- >10 5-7 4- >10 7-8
A~
1 Mbnth RT CK CK QK OR oR
104-F OK ox oK oR oK
~VH aK * * * *
125-F **** **** **** ~*** ****
2 Mbnth RT oK oR oR oK o~
104-F OK OK CR OK OR
H~H ** ** ** ~* **
125-F **** **** **** **** ~***
3 Mcnth RT QK oR CK OR OR
104-F ** ** ** ** **
HVH *** *** *** ~** ***
125-F **** **** **** **** ****
Note: * - very very slight color change; ** - very slight color change
*** - sl~ght color c~ange; ~**- c~ange in color
27A
