Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~.c98~3A~
ANALGESIC TABL~T OF ASPIRIN,
ACETAMINOPHE~ AND CAFFEINE CONTAINING
LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE
This invention relates to t~blets contsining, in combination,
~spirin, acetaminophen and caffeine. More particularly it concerns
tablets of this charscter having improved di6solution rates.
The combin~tion of a6pirin, acetaminophen and caffeine i6
popular in analgesic preparations nnd finds widespread use,
particularly in over-the-counter (O.T.C) products. Moreover, a
~idely used dosage form for delivering this combination drug i6 still
the tablet. Since these products are also likely to be subjected to
elevated temperatures while in storage in warehouses and in homes, it
has become customary in course of manufacturing such tablets to store
them ut elevated temperatures for extended periods of time to test
their, stability and the in-vitro availability of the active
ingredients; i.e., aspirin, acetaminophen and caffeine for
pharmaceutical action. One method for measuring the latter has been
to measure the dissolution rates of the tablets. If the tablets
meet a certain standard for dissolution rate, the active ingredients
should be available for absorption into the blood stream within an
acceptable period of time after ingestion.
TM
Aspir~n, acetaminophen, or caffeine when used separately in
tablets or the combination of aspirin and acetaminophen in tablets
have not presented any partic~lar problem with respect to the
acceptability of their dissolution rates. However, when all three
are combined in a tablet, serious problems do arise. Such tablets
have proven to have dissolution rates which do not meet the standards
set. The reason for this is not clearly understood. Nevertheless,
it is known that the three ingredients react physically to form a
eutectic mixture. This is manifested by a slowdown in the
dissolution rate of aspirin accompanied by a high free salycilic acid
(FSA) level resulting from the hydrolysis of the aspirin.
It has now been found, quite unexpectedly, that the dissolution
rates of tablets conlaining aspirin, acetaminophen and caffeine that
have been stability tested under various conditions can be
dramatically improved by incorporating in said tablet a
low-substituted hydroxypropylcellulose ~hereinafter referred to as
L-HPC) in sufficient amount to serve as a secondary disintegrant.
.~, ,~;,
~.~.28~34g
C. Car~nell~, ~t al, in their Articlo, "~he Role of Swelling ln
the Disintegr~tion Proce66", Int. J. Phs~n. ~ech. 6 Prod. Mfr. 5~2)
l-S, 1984, studied the di~integrating proces6 of certain ~pecific
t~blet~ and the rel~tionship of the character of certain
disintegrant~ to the di~integration proces~. The tsblets employed in
these studies were a series of t~blets containing 500 mg of ~spirin,
2% talc and 4~ di~integrant. Among the several disin~egrant6 tested,
the author~ mention L-HPC and Polyplasdone XL. The authors conclude
that di~integration efficiency is related to what is referred to ~s
the swelling force and particularly the "disintegrating force
development rate". In T~ble 3 of this article at the top of page 4
the authors summarize certain of their results. Thus they note that
the disintegrating force developed in the tablet containing
Polyplasdone XL is 4.3 + .1 in both isotonic saline and O.lN HCl, but
for L-HPC the values were 2.2 + .1 and 2.0 + .2. Similarly, for the
disintegration time in the tablet containing Polyplasdone XL, the
value was 10 ~ .2 and 9 + .2 sec.; whereas, for the aspirin tablet
containing L-HPC, the values were 18 ~ 3 and 19 4 3 sec. On the
basis of this study, one skilled in the art might expect that if
L-HPC were incorporated in a tablet containing aspirin, acetaminophen
and caffeine that the dissolution rate would be lower
than that obtained with the use of Polyplasdone XL. As wili be shown
in more detail below, unexpectedly, the reverse has been found to be
the case and the dissolution rates were higher with the use of L-HPC
than with the Polyplasdone XL. This dissolution rate was measured as
tne time in minutes that it takes to dissolve 75% of the active
ingredients in the tablet. Accordingly, the lower the value, the
greater the dissolution rate.
-
In their search for a suitable disintegrant that would give thedesired results, applicants have tested a number of ~aterials all of
which proved to bq~e1unsatisfactory. Thus, other cellulose material
such as Ac-Di-Sol (internally cross-linked form of sodium
carboxymethylcellulose) was tried without succass. It produced only
a marginal benefit in dissolution rate while affecting the stability
of the aspirin negatively generating high values of FSA. Similarl~
such commercially available disintegrants as Explotab and Primogel
were tried and also found unacceptable.
-2-
8~334!~
The L HPC's that are useful for the practice o~ the present are
available in a variety of grades that are classified on the basis of
their ~ hydroxypropyl content. These extend over the range of from
~bout 10~ to about 16~ hydroxypropyl. Of special utility in the
present inventi~n are the L-HPC's that contain a hydroxypropyl
content of from about 10~ to about 13~. Such products are cold on
the market by the Shin-Etsu Chemical Company under the tr~de
designation low-substituted hydroxypropylcellulose Grade LH-21 or
LH-ll. These differ from each other in particle size.
.
These materi~ls conform to the general formula,
' -- ~- OH CH2c)c~acH~oH)cH3 1
_ ~ H ~ O
H ~ ~ ~ ~ H J
CHlOH H OH ~
wherein n is the degree of polymerization. They are non-ionic type
cellulose ethers with a neutral p~ range (5.0 - 7.5) that do not
react with amines or other ionic ingredients. The particle size of
these materials may vary somewhat. However, in the preferred grade
(LH-21) the particle 6izes are as follow:
74 um pass: not less than 90
105 um on: less than 1%
The quantity of L-HPC that will be contained in the tablets of
the present invention may vary somewhat. However, again qui~e
unexpectedly, it has been found as little as 1~ or less of the L-HPC,
based on the total weight of the tablets, have given excellent
results. This is to be contrasted with the concentrations of from 3%
- 15% which have been recommended for these materials when used as a
binder/disintegrant for tablets. Generally, in accordance with this
invention, the L-HPC will constitute from about 0.5~ to about 5% by
weight based on the total weight of the tablet. However, the
preferred range for the L-HPC is from about 0.8~ to about 2.0% on the
same weight basis.
The aspirin, acetaminophen and caffeine will be contained in the
present tablets at concentrations at which these ingredients are
generally employed in analgesic tablets. That is to say that they
~l2~3~334~
will be contained in analgesic quantities. However, th~ general
ranges and the preferred ranges for these ingredient6 are those that
are given in the tabl~ below expres6ed in terms of percent by weight
based on the total weight of the tablet.
Table I
~ W/W of Tablet
In~redient General Ranqe Preferred Range
Aspirln from about 22% to from about 30 % to
about 75% about 45 ~
Acetaminophen from about 22% to from about 30% to
,~bout 75% about 45%
Caffeine from about 4~ to from about 9~ to
abou~ 19% about 11~
The products of the present invention will be made up into
tablets that may be taken comfortably by oral administration. Again,
the quantity of ingredients that will be contained in each tablet may
vary over a range. Table II below gives the general and preferred
quantity range of the ingredients contained in each tablet expressed
in terms of mg/tablet.
~able II
mq/Tablet
Ingredient General Ranqe Preferred Ranqe
L-HPC about 5 mg to about 5 mg to
about 35 mg about 10 mg
Aspirin about 150 mg to about 200 mg to
about 500 mg about 300 mg
Acetaminophen about 150 mg to about 200 mg to
about 500 mg about 300 mg
Caffeine about 30 mg to about 60 mg to
about 130 mg about 70 mg
In addition to the L-HPC, aspirin, acetaminophen and caffeine,
the tablets of the present invention may also contain other tablet
adjuvants that are well known to those skilled in this art. These
1.2~383~9
are added for a number of purpo6e6, .9. ~cilltate tabl~ting,
improve the orgAnol~ptics of th~ tabl~t, improve ~tability of the
tablet, improve the e~se of administration of thQ tablot6, otc. By
way of example, tablet adjuvants that may b~ incorporated in the
present tablet include lubricants (e.g. ctearic acid, zinc ctear~te),
flow agents (e.g. fumed silica, precipitated silica), and wetting
agents (Tween 80, sodium lauryl sulfat2).
No special technique i5 required to prepare the tablets of this
invention. Generally, the ingredients will be dry blended (e.g. Twin
Shell Blender) and the ~ixture i8 then filled into a tablet press and
then compressed into a tablet. Alternatively, the L-HPC can be
incorporated into wet granulations of the other ingredients and the
mixture then compressed into tablets.
The regimen for administering the tablets of this invention may
vary somewhat depending on the size of the tablet~, the racommended
daily dose for the ingredient, and the condition being treated with
these tablets. Generally, this will amount to about 1 to 2 tablets
with each dose about 4 times a day and preferably 1 to 2 tablets 3 or
4 times a day.
The following e~amples are given to further
illustrate the present invention. It i5 to be understood, however,
that the invention is not limited thereto.
Exam~le 1
Formula CW 3446-58
3Osage Unit Amt Item
mqlTablet _ No. Inqredients ~ WLW
75.00 1 Aspirin 40 mesh 11.12760
175.00 2 Aspirin 80 mesh 25.96439
250.00 3 Acetaminophen Granular37.09199
65 00 4 Caffeine, Anhydrous Powder 9.64392
100 00 5 Cellulose, Microcrystalline 14.83679
5.00 6 Low-substituted Hydroxypropyl
Cellulose Grade LH-21 (Shin-
Etsu Chemical Co.) 0.74184
4.00 7 Stearic Acid, Powdered C.59347
674.00 100.00000
5-
~ X~83~9
Procedure:
A. Screen caffeine through n ~20 mesh 6creen.
B. Screen ~tearic acid through a ~50 mesh 6creen.
C. Mix all ingredients except stearic acid for 15
minutes in a Twin Shell Blender.
D. Add stearic scid to (C) and mix for five
minutes.
E. Compress to specifications shown below.
Appearance: White Tablets
Punch: 7/16"
Tablet Weight: 674.0 mg.
Thickness: 0.245" + 0.005"
Hardness: 15-20 SCU (Heberlein)
Disintegration: water, 37C/l min.
USP basket apparatus
~ - `~
~1 28~3349
Example_2
Formula CW 3446-38
Dosage Unit Amt Item
mgLTablet _ Ingredient6
75.00 1 Aspirin 40 me~h
175.00 2 Aspirin 80 mesh
250.00 3 Acetaminophen Granular U.S.P.
Mallinckrodt, Grade 0057
65.00 4 Caffeine, Anhydrous Powder
100.00 5 Cellulose, Microcrystalline
2.50 6 Stearic Acid
5.00 7 L-HPC LH-21
-
672.50
ExamPle 3
Formula CW 3589-9 (8 mq L-HPC Formula?
Dosage Unit Amt Item
mqlTable~ No. In~redients
75.00 1 Aspirin 40 mesh
175.00 2 Aspirin 80 mesh
250.00 3 Acetaminophen Granular U.S.P.
65.00 4 Caffeine, Anhydrous Powder
100.00 5 Cellulose, Microcrystalline
2.50 6 Stearic Acid
8.00 7 L-HPC LH-21
67 5 ~ 50
F.xamPle 4
Formula CW 3446-94 (10 mq L-HPC Formula~
Dosage Unit Amt Item
mq/Tablet No. Inqredients ~
75.00 l Aspirin 40 mesh `
175.00 2 Aspirin 80 mesh
250.00 3 Acetaminophen Granular ~.S.P.
65.00 4 Caffeine, Anhydrous Powder
100.00 5 Cellulose, Microcrystalline
2.S0 6 Stearic Acid
10.00 7 L-HPC LH-21
67i . SO
The procedure for Examples 2, 3 and 4 are similar to that `~
de!scribed in Example 1.
Two criteria are important in determining the acceptability of
tablets containing aspirin, acetaminophen and caffeine. One is the
~2~l83~9
di6solutioo rAte of the t~blet after storage for a period of time ~nd
the second is the ~SA (free salicylic acid) analysis. The first is
important in that it is an in-vitro indication of the avail~bility of
the active ingredients for absorption into the blood etream. The
second is important since it is a measure of the ~tability of the
tablet. High FSA values indicate that significant aspirin hydrolysis
has taken place with the release of free salicylic acid.
.
Tests were carried out comparing the dissolution rates and/or
the FSA values of tablets of the present invention with essentially
two different types of tablets. The first category of tablets are
essentially the sarne as those of the present invention excepting that
they do not contain the L-HPC. The second category of tablet are
those in which a different disintegrating agen~ is employed.
The tablets of this invention were tested after storage at
various coDditions of time and temperature and in various types of
containers and found to give acceptable dissolution rates and FSA
values. Tb insure that the tablets would perform acceptably under
all the reasonably anticipated field conditions' in their tests
applicants also stored the tablets under stressed conditions and
measured their performance after such treatment. These stress
conditions are described in more detail below. For purposes of
comparison other tablets were also subjecled to these stress
conditions and their dissolution rate and FSA values were determined.
Test Procedure
A. Stress Testinq:
Test Tablets stored at room temperature in glass bottles; this
was the u~stressed storage condition. Other samples of the same
tablet were stored at 60C and 60~ relative humidity in an opan
petri dish for 6 days. The latter are considered stress conditions.
FSA values were determined on test tablets that were stress tested;
i.e., stored at 60C and 60% relative humidity in an open petri
dish for 6 days.
B. Dissolution Rate Test:
The dissolution method used to evaluate these tablets employs
the dissolution test described in the USPXXI p. 14. The dissolution
-- 8 --
~l28~
test c~lls for the use o ~00 ml. water maintnined at 37~ and the
USP paddle, known as Apparatus 2, rotated at 50 rpm.
The tablet is placed in the beaker of water nnd after 45 minutes
of paddle rotation at 50 rpm, ~n eliquot of solution is analyzed for
aspirin, acetaminophen an~ caffeine content.
The analysis can be done via high pressure chromatography or via
spectrophometric analy6is using a multi-component analysic on HP8450
or HP8451 ~pectrophotometer.
As a criteria for acceptability, applicants have adapted a
dissolution rate such that at least 75~ of the tablet dissolves in
under 45 minutes.
Table III below gives the formulas for each of the tablets which
were tested. The quantities of the various ingredients are given in
terms of mg/tablet.
Table III
*CW-3446-*CW~3446- *CW-3446- ~CW-3446- CY3513-
Ingredient 38B 38A 54B 58
Aspirin, 40
mesh 75 75 75 75 __
Aspirin, 80
mesh 175 175 175 175 --
Acetaminophen 250 250 250 250 --
Caffeine, Anhy.
Powder 65 65 65 65 --
Microcrystalline
Cellulose 100 100 100 100 --
Stearic Acid2.5 2.5 2.5 4 3
L-HPC ~LH21 5 -- -- 5 --
Crospovidone XL-10
(Polyplasdone
XL-10) -- -- 5 -- --
Caffeine Starch
Granulation
(Eq. to 65 mg.
Caffeine) -- -- -- -- 100
_ g _
~1 28~3349
'
Aspirin 12/50 Granul~tlon
(Eq. to 250 mg. I
Asplrin) ~ -- -- 277.8
APAP 10~ Starch 145
(Eq. to 250 mg
APAP) -- -- -- -- 277.8
TOTAL 672.5 667.50672.5 674.0 658.6
Subjected to stxess test.
The results of these tests are summarized in Table IV below. It
will be noted that the tablets CW 3446-38A do not meet the criteria
of a dissolution of 75~ of the tablet in under 45 minutes, whereas,
tablets CW 3446-38B do so readily. As is clear from Table
III,tablets CW-3446-38A differ from CW-3446-38B in that the latter
also contain 5mg of L-HPC #LH21. Similarly it is to be noted that
tablets CW 3446-54B also do not meet the criteria of a dissolution of
75~ of the tablet in under 45 minutes. Tablets CW 3446-54B, as Table
III shows, contain 5mg of Polyplasdone XL-10 as a disintegrant,
whereas, tablets CW 3446-38B of this invention contain 5mg of L-HPC
~lH21 as the disintegrant. In addition, the product containing the
Polyplasdone XL-10 (CW 3446-54B) is less stable after stress testing
than the product of this invention (CW 3446-38B?. The amount of
salicylic acid produced by degeneration of aspirin .in the former is
2.2 mg/tab, whereas, in the latter it is 0.57mg/tab. This is about 4
times as much.
- ln -
2~38349
T~ble IV
~issOlution R~tes
1/900 ml H20/37/P~ddlo 50 rpm
T _e ~minutesL
T~blet T25 _ ~AP CAr~ ASA APAP CAFF ASA APAP CAFF
CW3446-38A23 7 428 15 8 44 27 14 4529 18
60C~60% ~H
6 days 20 15 945 29 18 45 45 31 4545 36
CW3446-38B 2 15 4 3 19 7 8 138 7
60C/60% RH8 4 39 7 8 16 11 11 1813 12
6 days
C~-3446-548
RT 2 2 14 3 2 9 6 4 106 5
60C/60% RH27 11 845 27 16 45 45 27 4545 30
6 days (2 tab) (2 tab)(2 tab)
Stability: 60Ct60~ R.H. in open petri dish 6 days.
Salicylic Acid mq/tab
Cw 3446-38A 0.46
CW 3446-38B 0.57
CW 3446-54B 2.2
11
.
~ .
.' ' `' '
,
~1 2~8349
.
T~blets CW 3446-56 involved in this invention were also compared
to ~ comparable product that doe~ not contain the L-HPC LH21
disintegrant; i.e., tablets CY 3513-1 (see Table III), as to their
dissolution rate at various conditions of storage and in different
types of containers. In addition, they were al60 compared AS to
their st~bility as measured by the FSA values. These measurement6
were made after 2 months storage. The results of these studies are
summarized in Table Y below.
~2~1~3349
~ T~ble V
! Dissolution Rates
1/900 ~l H20/37C/Paddle 50 rpm
-- - .
T25 T50 _ ~75
TabletASA APAP CAFF ASA APAP CAFF ASA APAP CAFF
CW 3446-58
Initial 2 2 1 4 3 2 7 5 4
Two Months
Poly~tyrene/
Safety Ca~e_
RT 3 2 1 5 4 3 9 7 6
125/F 5 2 2 11 5 4 26 12 11
H/H 12 8 7 20 15 lZ 32 24 20
Polyethylene/ :~
Safetv Cap `
125/F 11 7 6 18 12 10 26 20 16
H/H 4 3 2 8 6 5 13 10 9
Slide Box `
H/H 10 7 6 16 12 10 24 19 18
CY 3513-1
Initial 3 2 2 6 4 3 14 6 6
Two Months
Polystyrene/
Safety CaP
RT 3 3 3 7 5 5 14 lO 9
125/F 3 2 2 6 4 3 12 7 7
H/H 19 6 8 36 15 17 45 (3) 30 31
Polyethylene/
Safety Cap
125/F 23 7 10 41 17 24 45 (4) 36 45 (1)
H/H 8 5 5 14 8 9 27 12 12
Slide Box
H/H 7 3 4 13 6 7 25 lO ll
Stability:
~l288349
Salicyllc Acidl _g¦Tab., 1 Month
__ _~04F!7 5% RH
125/~ _
P/S S. Ca~ HD/PE S. Cax PIS Slide Box HD/PE S. Ca~
CW 34~6-56 1.7 0.7 2.2 3.0
CY 3513-1 0.6 0.5 1.1 3.4
As i~ clear from Table V, tablets CY 3513-1 are acceptable only
when packaged in a 61ide box. Tablets CW 3446-58, however, were
acceptable under all the storage conditions; that is to say, they had
an acceptable dissolution rate. As to st~bility, these respective
products are quite comparable.
