Note: Descriptions are shown in the official language in which they were submitted.
APAP Antacid Composition
_
This invention relates to analgesic compositions con-
taining N-acetyl-p-aminophenol (hereinafter referxed to as
APAP) and to processes involving the administration of
such compositions ~o subjec~s and especially human subjects.
More particularly~ it concerns compositions of this above
character that have relatively high absorption rates
as measured by the time it takes after ingestion for the
level of APAP to reach its maximum in the blood plasma of
the subject (t max.).
APAP has long been known in the pharmaceutical and
medical arts to be useful as an analgesic and/or antipyretic
agent and has found its way into several commercially avail-
able products including tablets, capsules, and liquids.
Subsequent to ingestion of APAP, the rate o~ onset of the
intended pharmacologic action is often slower than desired
and also quite variable from subject-to-subject. Such
slowness ànd variability apparently result from the fact
that absorption of AP~P from the gastrointestinal tract
into the bloodstream is inhibited 21S a consequence of the
proces5 usually used in making the~e products.
It has now been found that the rate of absorption
of ~P~P into the bloodstream as measured by the t max, can
be increased if the APAP is coadministered with a dose
of an antacid that falls in the range of from about 60 mg
to about 1200 mg with the preferred range being from about
400 mg to about 1000 mg and the optimum range being from
about 450 mg to 880 mg. The weight of antacid used will
depend on its milliequivalent weight.
It is accordingly an object of the present in~ention
to provide an analgesic composition containing APAP that has
a relatively high absorption rate.
- 2 --
It is also an object of the present invention to
provide processes which entail administering the composi-
tions of the aforesaid object to subjects and particularly
human subjects.
Other and more detailed objects of this invention will
be apparent from the following description and claims.
The increase in ~PAP absorption rate with the composi-
tions of this invention has been most readily demonstrated
on so-called slow APAP absorbers. For the purposes of this
invention, those subjects who had less than 2/~g/ml of
plasma APAP at 10 minutes after they were given APAP alone
at the recommended dose i.e. 650 mq. without an antacid
were considered as slow absorbers.
It has been suggested in the prior art to simultaneously
administer as a single oral dose 4.0 g (i.eO 4000 mg) of
calcium carbonate with paracetamol tablets (i.e. 1 gm of
APAP) (J. Wojcicki et al, Zbl, Pharm, 118 (1979) Vol 2-3).
These were administered by Wojcicki et al to investigate
the phaxmacokinetics of paracetamol. It was found in this
study that when 4 grams of CaC03 were administered wi.th
1 gm of ~PAP that in fact there was a significant decrease
i7.1 the rate o~ absorption as measured by the t max. As
shown ln Table 5, (p. 289 o the WG jcicki et al article)
the t max for APAP alone was 1.4 hours; whereas, the t max
for CaC03 and APAP was l.9 hours. In other words, the t~me
it took for the plasma level of APAP to reach its maximum
was 1/2 houx longer when the APAP was coadministered with
4 gm (4000 mg) of CaCO3 as compared with the case when the
APAP was administered without the CaC03.
As will be shown in more detail below, when the antacids
are administered at the le~els prescribed in the pxesent
invention along with the APAP, the results are reversed.
The t max values are lower in the case where the antacid
at the levels prescribed in the present invention is admini-
stered along with the APAP as compared with the case where
the antacid is eliminated.
The APAP and antacid may be administered in a variety
of fashions according to the present invention. They may,
for example, be administered as two separate tablets; that
is, as an APAP tablet and a separate antacid tablet which
can be taken simultaneously or serially. They may also be
administexed in the form of a novel single layer or two
layered tablet~ In the latter case, the antacid will ordin-
arily be contained in one layer and the APAP will be con-
tained in the other layer.
They may also be administered in the form o novel
capsules in which the powdered or granular APAP is intimately
mixed with the powdered or granular: antacid. In a modifica-
tion o the capsule product, one of the components may be
present in the capsule as one or more small tablets and
the other as a ~owder or granular preparation.
The APAP and antacid can also be taken in liquid form
a~ solution or suspension of one or more of the active
inyredient~. In thls aase, suitable stabilizers, emulsi-
~ier~, and/or suspending agents may be used to maintain
the ànkacid or APAP in suspension or solution.
Any antacid or combinations thereof commonly used
to neutralize stomach acids may be used in the compositions
or proces~es of the present in~ention. Such antacids are
listed in the Handbook of Non-Prescxiption Drugs, 6th
Edition, 1979, p. 1-19 or the OTC Antacid ~onograph. By
way of example, mention may be made of calcium carbonate,
magnesium carbonate r sodium bicarbonate, sodium carbonàte,
potassium bicarbonate, aluminum hydroxide, aluminum oxide,
magnesium oxide, magnesium hydroxide, magnesium ~risilicate,
aluminum glycinate, dihydroxyaluminum acetate and mixtures
thereof. Of special interest are calcium carbonate,
magnesium carbonate, a combination of calcium carbonate and
magnesium carbonate, sodium bicarbonate and magnesium
hydroxide. When calcium carbonate and magnesium carbonate
are employed together, they may be used in the weight ratio
of ~rom about 5:1 to 1:5 and pxeferably in the ratio of 2:1.
As indicated previously, the level of antacid that
will be coadministered with the ~PAP or contained in the
dosage fo~ms o:E this invention may vary from 60 mg to
about 1200 mg. However, the preferred range is from about
400 mg to 1000 mg with the optimum range being from about
450 mg to 880 mg.
The quantity of AP~P which will be administered with
t.he antacid or contained in the dosage forms o~ this inven-
tion may al~o ~ary. Usually, it will fall in the range of
rom about 150 mg to 2000 mg with thle preferred range being
2Q ~rom about ~S0 mg to 1000 mg.
In addition to the antacid and APAP contained in the
compositions o~ this in~enkion, they may alsG include other
pharmaceutically active ingredie.nt~. These may be other
analgesic~, antihistamines, decongestants, cough suppressants,
etc. ~y way of more specific illustration o~ the other
pharmaceutically active ingredients that may be employed,
mention may be made of aspirin, phenylpropanolamine hydro-
chloride, chlorpheniramine maleate, dextromethorphan
hydrobromide~ etc.
f`~
~8~
-- 4a --
Thus in a broad aspect the present invention provides a
therapeutic dose i.n the f~rm of one or more of tablets, powder,
granulation or a combination of these forms, comprising from
about 400 mg to about 10~0 mg o~ an antacid component selected
~rom the group consistin~ of calcium carbonate, magnesium
carbonate, sodium bicarbonate, sodium carbonate, potassium
bicarbonate, magnesium hydroxide, magnesium oxide, magnesium
trisilicate, aluminum glycinate, dihydroxyaluminum acetate
and mixtures thereof, and from about 150 mg to about 2 g of
N-acetyl-p~aminophenol.
When the compositions of the present invention take
the form of tablets, they may also con~ain adjuvan~s conven-
tionally included in composi~ions of this general character.
_ 5 _
Thus, for example, they may contain a binder which is exem-
plified by such materials as: lactose, dextrose, starch,
polyvinylpyrrolidone (PVP), sucrose, gelatin; natuxal
gums such as acacia, trasacanth, pectin, guar, karaya;
cellulose derivatives such as methyl cellulose USP,
sodium carboxymethyl cellulose USP, hydroxypropylmethyl
cellulose USP (Methocel*HG), hydroxypropyl cellulose
(Klucel~, ethyl cellulose NF, or avicel microcrystalline
cellulose NF. The quantity of binder included in these
compositions may vary somewhat~ Generally, it will be
no greater than the amount of APAP in the tablet and prefer-
ably no greatex than one hal~ of the amount of APAP contained
in the tablet. Usually, each tablet will contain from about
10 to about 300 mg of binder.
Another tablet adjuvant that may be added to the
tablets of the present invention is a disintegrant.
Typical disintegrants include starches; modified staxches
such as sodium caxboxymethyl starch, microcrystalline
cellulose; water soluble cellulose derivati~es such as
methyl cellulose or sodium carboxyme!thyl cellulose or clays.
The ~uantity of disintegrant in the present tablet may also
vary bu~ usually will be in the range of ~rom 10 to 500
mg pe~ tablet.
When the composition o~ this invention take the dosage
orm o~ a capsule, it may also contain additives that are
conventionally included in this type of dosage forms. Thus,
it may include such things as flow aids (e.g. silicone fluid,
Cab-O-Sil* talc, metallic stearates, stearic acid),
wettlng agents (e.g. SLS). Usually, the total quantity of
capsule adjuvants may vary and may be related to the amount
of APAP contained in the capsuleO Typically~ this will amount
*Trademark
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. ~
-- 6
to from about 0.1% to 15~ by weight based on the weight
of the APAP in the capsule.
The compositions o the present invention may be
administered in unit dosage forms that contain ~arying
amounts of the active ingredients (i.e. AP~P and antacid).
Furthermore, to administer the required dose of active
ingredients, it is possible to give the subject one or more
of the unit dosage forms. It is to be understood that when
the term dose is used herein and in the appended claims,
it is intended to cover the quantity of active ingredients
administered at a single administration of the composition
irrespective of whether one or more unit dosage forms
are given as tablets, capsules, teaspoonfuls, etc. It is
al30 intended to cover the sit~ation in which some or all
of one active ingredient (i.e. APAP or antacid) is contained
in one unit dosage form and some or all of the acti.ve
ingredient is contained in another unit dosage form.
The following Examples are given to ~urther illustrate
th~ present invention. It is to be understood, however,
that the invention i-q not limited thereto.
EXAMPLE 1
Two-~ayered Table~
Inyredients m
LAYER I: APAP Layer
Acetaminophen, powder 325.000
Cellulo~e, microcrystalline147.500
Sodium carboxymethyl starch55.000
Colloidal silicon dioxide M-52.500
Deionized water 12.500
Stearic acid, powdered 2.500
Methylparaben 0.545
Propylparaben 0.218
545.763
-- 7 ~
Dry blend the above ingredients.
LAYER II: Alkaline Layer
Calcium carbonate 200.000
Magnesium caxbonate lO0.000
Corn starch as aqueous starch
paste (10%) 20.000
Corn starch 40~000
360.000
Moisture: 2.0% Gran~ total 905.763
Blend CaCO3, MgCO3 and corn starch, and granulate with 10%
starch paste in a pony mixer pot. Screen wet granulation
through 4 mesh screen and dry in a Glatt, and screen through
8 mesh and 12 mesh screen.
The mixture described above under "Layer I" is
charged into a tablet punch and preferably tamped down
lightly. The mixture described uncler "Layer II" i5 then
fed into the tablet p~mch and top o~ "Layer I" and the com-
bination is compressed to form a two layered tablet.
E~AMPLE 2
~ __s Tablet: Formula #1428
___
Item No. Ingredients mg/tab
Part I
1 Acetaminophen, powd. 500.00
2 Starch, corn 44.25
3 Stearic acid, powder 4~75
4 Methylparaben 0.55
Propylparaben 0.20
6 Povidone K 29-32 (polyvinyl-
pyrrolidone) 0.25
7 Water~ deionized
550.00
~ 8 --
Cont'd
Part II
8 Sodium bicarbonate, ~5 gran. _25.00
Procedure: 775.00
Part I
A. In a mixer, place half of 1, and all o~ 2, 3, 4 and 5,
and mix.
B. Dissolve 6 in 7 which has been heated to 100C.
C. Immediately add 3/4 of B to mixture A, mix well, add
the remaining half of 1, and mix well again.
D. Add remaining 1/4 of B, mix for 5 minutes.
E. Pass damp granulation D through Oscillator, 6 mesh screen.
F. Dry in Fluid Bed Dryer, inlet temp. 55C~ until
outlet temp. reaches 40-44OC (moisture content 3%, see below).
G. Pass through Oscillator, 20 mesh screen, (.027"
opening).
Part II
A. Dry 8 in Fluid Bed Dryer for 2 minutes at 35C
(i~ caked).
2a B. Blend Part I with 8 ~or 5 minutes.
C. Compre~s to the speciications below.
Appearance: White tablet
Moisture: Part I gran. 3% (180F oven~ 30 min.)
Punch: 15/32"SCU
Weight: 775 mg.
Thickness: .255" ~ .005"
EIard~ess: 10-14 SCU
Disintegration: 30 Sec., USP Basket App. 37C
g
EX~IPLE 3
Homogeneous Tablet - Sodium Bicarbonate Formula -
Formula ~ 1455
Item No. Ingredl_ ts m~tab
Part I
1 Acetaminophen, spec. podw. 325.0000
2 Starch, corn 28.7625
3 Methylparaben 0~3575
4 Propylparaben 0.1300
Povidone (K-29-32) (PVP)0.1625
6 Stearic acid, powd.3.0875
7 Water, deionized
357.5000
Part II
lS 8 Sodium bicarbonate #5
granular 2?5.0000
582.5000
Procedure:
Part I
Z0 Same a~ for Part I :in Example 2 above, but pass through 12
mesh screen Oscillator.
Part II
A. If caked, 8 may be dried ~or 2 minutes at 35C in Fluid
Bed Dryer.
B. Blend 8 and Part I for 5 minutes.
C. Compress to specifi.cations below.
Appearance: White tablet
Moisture: Part I gran. 3-4~ (180F o~en, 30 min)
Punch: 7/16" SC
Weight: 582.5 mg ~ 5~
Thickness: 0.210" ~ .005"
Hardness: 7-9 SCU (Heberlein~
Disintegration: USP Basket 3~C water, 30 sec. 25C water
1 min.
-- 10--
To compare the absorption rate for APAP, as measured
by the t max when APAP is administered with and without
the coadministra~ion of antacids, the following tests were
carried out:
A contemporaneous cross-over study comparing the free
n-acetyl para-aminophenol (FAPAP) plasma concentrations
produced in a panel consisting of between 15 and 50 healthy
volunteers was conducted.
The s~udy usually begins between 7:00 and 8:00 a.m.
Subjects are instructed to fast after their evening meal the
night before. After the subjects assemble in the morning,
the test product is administered along with 100 ml of water.
Blood samples are taken precisely 10, 20, 40 and 60 minutes
po~t administration.
Plasma is separated ~rom the blood samples, and the
FAPAP concentration is determined using a high pressure
liquid chromatography procedure. Administration of different
products in the cross-over study is at least one week apart.
Four studies were run identi~ied as studies BC 5-75,
BC 9-76, ~C 24-77 and BC 1-81 respectively. In study BC 5-75
two tablets of a commercial AP~P tablet (Tablet D) each con-
taining 325 mg of APAP were administered to the test subjects
and t max was measured. This was compared with the results
obtained when 2 Tablets D each containing 325 mg of APAP were
coadministered with 2 chewable CaC03 tablets each containing
440 mg o CaCO3. The composition of each of these tablets
is given below:
TRBLET D
Ingredients mg/tab
Acetaminophen, powder 325.0
Cellulose, microcrystalline 75.0
Starch, corn 75.0
Sodium lauryl sulfate, phosphate
buffered l.0
Povidone (K-29-32) 5.0
Water, deionized
Polyethylene glycol 6000 (fine powd.) l.25
48Z.25
CaC03 TABLET
In ~ ts mg/t _
Calcium carbonate 440.0
Corn starch as aqueous paste ~lO~)20.0
~extrose monohydrate 540.0
St~axia acld, powder lO.0
lOlO.0 mg
In study BC 9-76 two Tablets D (each containing 325 mg
of APAP) were administered to.the test subjects and the t max
was measured. This was compared with the re~ults obtained
when two tablets o Example l above (i.e. the two layered
tablet) each containing 325 mg of APAP, 200 mg calcium carbonate
and lO0 mg magnesium carbonate were administered to the subjects.
In study BC 24~77 two tablets of an extra strength commer-
cial APAP tablet (Tablet T) each containing 500 mg of APAP
were administered to the test subjects and the t max was measured.
12 -
The formula for Tablet T is given below:
TABLET T
~E~ mg/tab
APAP 500 ~
Inert insredients 165.0
This was compared with the results obtained when two
tablets of Example 2 Formula 1428 ~i.e. the single layer homogeneous
tablet) each containing 500 ~g of APAP and 225 mg of sodium
bicarbonate was administered to the subjects.
In Study BC 1-81, two tablets of a commercial 3~5 mg
~PAP tablet (Tablet t) were administered to test subjects
and the t max was measured. The formula for tablet t is
given below:
TABLE~ t
; ~ mg/tab
AP~P 325.0
Inext ingredients 228.0
This was compared with the results obtained when two
tablets of Tablet t were administered alo~g with a chewable
ta~let containing 400 mg o~ CaC03 (Tablet C). The formula
~ox Tablet C is given below:
TABLET C
In~redients m~/tab
Calcium carbonate (Sturcal*"H") 440.0
Corn starch (as 10% starch paste)20.0
Dextrosa monohydrate 540.0
Stearic acid, powder 20.G
Cellulose microcrystalline (~vicel P~ 105) 20.0
1040.0
*Trademarlc
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, ~
... .
- 13 -
Two tablets of Example 1 were also gi~en in this
study, as well as two tablets containing 325 mgO cf APAP
and 225 mg. of NaHCO3 (Tablet B - Formula 1455). The
formula for Tablet B is given in Example 3 above.
The results of these tests are summarized in the Table
below:
TABLE I
Av. of the Individual
Study Product Peak Time in Min. (t max)
BC 5-75 Tablet D (325 mg APAP) 43
2 tab.
Tablet D (325 mg APAP)
2 tab. + CaCO3 2 tab. 32
BC 9-76 Tablet D (325 mg APAP)
2 tab. 36
Tablet of Example 1
(325 mg AP~P, 200 mg
calcium carbonate & 100 mg
magnesium carbonate) 2 tab. 30
BC 24 77 Tablet T (500 mg APAP)
2 tab. 42
Tablek of Example 2
(500 mg Al~AP and 200 mg
NaHCO3) 2 tab. 29
BC 1-81 Tablet t (325 mg APAP)
2 tab. 38
Tablet t (325 mg ~P~P)
2 tab. -~ Tablet C
(440 mg CaCO3) 36
30Tablet D (325 mg APAP ~
225 mg NaHCO3) 2 tab. 30
Tablet of Example 1 33
As will be clear from the above Table, each study demon-
strated a significant increase in absorption rate as measured b~
the t max value, that accompanied the administration of the
compositions of this invention. These increases are in the range
of from about 7% to about 31%.
