Note: Descriptions are shown in the official language in which they were submitted.
8254
L7~i
This invention relates to a controlled antacid
delivery form and to a method for the controlled adminis-kra-
tion of antacid. More particularly, a slowly dissolving
antacid dosage form is obtained from an acid neutralization
component in a matrix including a sugar or a sugar alcohol,
a gel-forming, swelling agent and a water insoluble lipid
material. When these materials are mixed with the antacid
component, together with conventional tabletin~ binders, lubri-
cants and other excipients, and eompressed at high pressure,
they yield an antacid 1O2enge whieh dissolves very slowly in
the mouth. When the sweet excipient is a sugar alcohol, the
lozenge is ~Isugarless~ and desirably noncariogenic.
As the controlled dosage form is slowly dissolved in
the mouth, a sustained release of antaeid is obtained whieh
unexpeetedly neutralized the stomaeh acid over a long period
of time with surprisingly little antaeid. When the lozenge
includes a mixture of antaeids with different reactivities
such as the magnesium and aluminum salts, this invention also
involves the discovery that sueh dosage form provides for
more complete utilization of the antaeid than i5 possible
with eonventional antaeids. Administration oE the present
dosage form also provides for more effeetive treatment sinee
the gradual release of antaeid off-sets the effeet of stomaeh
emptying and eontinuous seeretion of aeid. It also contin-
~25 uously bathes the lining of the esophagus and provides relieffor tissues inflamed by yastric reflux.
With eonventional antaeids, whether in liquid,
powder or tablet form, the entire dose is ingested at one
time. They, therefore, have only brief therapeutie effect
30~ because the stomach is constan-tly emptying and seeretiny
more hydrochloric ac-d. The amount~of antacid actually
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8254
utili~ed can be as small as 10 to 15 percent and is gen- -
erally no greater than 50 to 60 percent. The exact amount
depends UpQn the amount of the antacid, its dosage form,
the individual patient and the time he ingests the medica-
tion.
Many commercially available antacids contain a
mixture of magnesium and aluminum salts. It has now been
discovered and is disclosed herein that when there is an
excess of antacld~ the acid preferentially reacts with the
magnesium component and the beneficial effect expected
from the admixture is thus subverted. More partlcularly,
when 20 to 40 percent of the antacid is consumed, only the
magnesium component reacts with the acid while the aluminum
shows almost no reactivity. Since no more than 50 to 60
percent of a conventional antacid is actually utilized in
the stomach, there is substantially no benefit gained from
the combination of such metal salts where the entire dose
is ingested at one time. This is wasteful of the aluminum salts
and may cause undesirable side effects through phosphate
binding in the intestines.
The standard recommended dose for most commer-
cially available antacids is "1 to 2 teaspoonfuls" or "1
to 2 tablets" three times daily, after meals and at bedtime.
Such recom~nendation is given scant attention by laymen and
physicians. For example, some gastroenterologists prescribe
3 to 6 teaspoonfuls every waking hour for peptic ulcer
patients.
It has also been discovered and is disclosed here-
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6~
in that there is substan-tially no benefit gainecl Erom
such overdosing. On the contrary, massive overdoses
can produce undesirable side effects. For ~xample, ex-
cessive amounts of magnesium can cause hypermagnesia
5 and diarrhea. ~s mentioned above, excessive amounts of
aluminum can cause phosphate binding, which in extreme
cases can result in electrolytic imbalance, home el~rit- ~'
tlement, lethargy and labored gait. Too much calcium
can cause hypercalcemia, milk-alkali syndrome and
Burnett's syndrome. The effect of borderline overdosaye,
particularly if chronic, is less well documented but is
suspected to be a serious medical problem.
In view of the above, it is an object of the pres-
ent invention to provide a controlled antacid dosage form, as
well as to provide for the controlled administration of a mix-
ture of antacids such that all components neutrali~e the acid
and the benefits of the combination are thus obtained. In its
pxefexred form, a slowly dissolving lozenge is provided
of a size and shape so that it can be comfortably retained
in the mouth for extended periods of time. It is a fur-
ther object to provide a controlled dosage form which when
administered in accordance with the present invention
provides better antacid therapy with surprisingly little ant-
acid than obtained even with a massive overdoes of a conven-
tional antacid and which off-sets the effect of stomach emp-
tying and continuous secretion of acid. It is a s-till further
object to provide a dosage form which provides relief to pat-
~ients suffering from esophageal inflammation caused by gastric
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reflux. Other objects and Eea-tures will be in part ap- -
parent and in part pointed out hereinafter.
The invention accordingly comprises the products
and methods hereinafter described, the scope of the inven-
tion being indicated in the subjoined claims.
In dosage forms according to the present invention,
the antacid component, or acid neutralizing substance, can be
any of various nontoxic sodium, calcium, magnesium or aluminum
salts used to neutralize gastric Eluids. Illustrative antacids
are sodium bicarbonate, sodium citrate, calcium carbonate,
calcium phosphate, magnesium oxide, magnesium hydroxide, mag-
nesium carbonate, magnesium trisilicate, aluminum aarbonate
and aluminum hydroxide. Other suitable antacids include
dihydroxy aluminum sodium carbonate, dihydroxy aluminum
aminoacetate and magnesium hydroxy aluminates. Various
other coprecipitates of aluminum hydroxides or carbonates
with magnesium hydroxides or carbonates t hexitols, amino- -
acetic acid or the like can be used. As ln the most fre-
quently prescribed antacides, it is preferred that the neutral-
izing substance in thé present dosage form be a com-
bination of magnesium and aluminum salts. This combina-
I
tion is preferred because it provides an antacid with thecharacteristics of both metals.
The gel-forming, swelling agents used with the
above-mentioned antacids are those pharmaceutically accept-
able high molecular weight substances which swell and form
a gel upon contact with water. Such gel-forming, swelling
agents include various gums, polysaccharides, cellulose
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~7~ 6 8254
derivatives and the like. Specific examples of gums are
gum acacia, gum tragacanth, guar gum and xanthan gum.
Exemplary polysaccharides include the carageenans and al-
ginic acid and its derivatives such as sodium alginate
S and propylane glycol alyinate. Suitable cellulose de-
rivatives include methyl cellulose, hydroxyethyl cellu
lose, hydroxypropyl cellulose, hydroxypropylmethyl cellu-
lose and sodium carboxymethyl cellulose. Of those materials
listed above, sodium carboxymethyl cellulose is particularly
preferred for use herein.
The water insoluble lipid material for use in
combination with the gel-forming, swelllng agents is a
hydrophobic metal salt of a fatty acid such as stearic
acid, palmetic acid, oleic acid and lauric acid. Appli-
cable metals for formation of the above sal-~s include
magnesium, calcium and aluminim. Of these materials, mag-
nesium and calcium stearate are preferred:
Dosage forms according to this invention are
~` preferably formulated from a granulation containing the
antacid and a sweet tasting excipientO To this granulation,
which may contain additional materials such as gelatin or
starch, is added the gel-forming, swelling agent and the water
insoluble lipid material. If desired, part of the yel-form-
ing, swelling agent may be dissolved and incorporated in the
~5 granulationO Other materials such as talc, flavorants, dyes
or the like may b~ added to the granulation before the mix-
ture is compressed into lo~enges.
Since the pr~duct is intended to be slowly dissolved
in~the mouth, it i5 impoxtant that the lozenge contain a
: 30 large amount of a good tasting excîpient. Suitable good tast-
:
ing, sweet excipients include the sugar alcohols mannitol,
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sorbitol and xylitol~ Sugar alcohols are particularly
preferred for use herein because they provide lozenges
which are "sugarless" and, hence, noncariogenic. Of the
sugar alcohols mentloned above, mannitol is best suited because
it is less soluble than sorbitol. It provides a slightly sweet
product with a particularly refreshing taste because of its
negative heat of solution. Moreover, products formed
therewith have better shelf life because mannitol, un-
like sorbitol, is not hygroscopic.
When the sweet excipient is an alcohol sugar,
it may be necessary to add an artificial sweetener to
provide a lozenge with an acceptable taste. While manni-
tol is preferred, it may be substituted by or used in
combination with other sugar alcohols. If a candy like
lozenge is wanted, sucrose, dextrose or the like may be
used in place of the sugar alcoholO Since these sugars
are more soluble than mannitol, the amount of the gel-
; -Eorming, swelling agent and the amount of the water in-
soluble lipid material must be increased to provide loz~
enges with comparable dissolving times.
The antacid is provided in a sufficient quan-
tity to effect neutralization of the acid over the sel-
ected period. For use in accordance with this invention,
that period is from 15 to 60 minutes, preferably from
; 25 30 to 60 minutes. To that end each lozenge has from 15
.
to 40 meq. of antacid, preferably from 20 to 30 meq.
The amount of sweet excipient is selected to
give the lozenge a pleasantly sweet tasteO For that pur-
pose, the sweet excipient makes up 25 to 60 percent by
weight of the lozenge, preferably from 35 to 50. When
: the excipienl is mannitol, it is most preferably present
7 ~
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in an amount from about 30 to 55 percent.
The amount of the gel-forming, swelling agent
and the amount of the water insoluble lipid material
varies with the particular agents selected. They should
be present, however, in combination in a sufficient
amount so that the lozenge will slowly dissolve and ad-
minister the antacid in the requisite time. Since the
patient usually works the lozenge with his tongue and
teeth, there is a continuous erosion of the lozenge so
that the dissolution time in vivo is usually much shorter
than in vitro even with good agitation.
The gel-forming, swelling agent when hydrated
forms a film barrier through which the antacid is slowly
diffused. If no water insoluble lipid material is added,
a satisfactory lozenge cannot be formed. That is, when
sufficient gel-forming, swelling agent is added to control
the release time, the lozenge has a slimy~ unpalatable
mouth feel. On the other hand, if no gel-forming, swell-
ing agent is added, the gritty feel and astringent taste
of the antacid is exposed. By providing a proper balance
of said agents, it is possible to provide a controlled ant-
acid delivery form which is palatable.
When the gel-forming, swelling agent is medium
visc03ity grade sodium carboxymethyl cellulose, it is pre
ferably present in an ~nount from about 3 to 10 percent by
weight. If larger amounts are used, for example 15 to 20
percent, the lozenge has an unacceptable gummy texture.
` ~ ~ Amounts less than 3 pe~cent do~not sufficiently slow dis-
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~ 6 8254
solution and amounts over 10 percent produce a slimy
feeling.
When the water insoluble lipid material is
calcium or magnesium stearate/ it is preferably present
in an amount from about 1 to 5 percent by weight.
Amounts less than 1 percent do not sufficiently slow
dissolution and amounts over 5 percent are likely to
interfere with the antacid activity in the stomach.
The compressive force with which the lozenges
are formed, as well as the surface area and hence the
shape, also has an important effect on dissolution times.
Mass of the tablet is also important. Lozenges in accordance
with the present invention have a hardness of at least 15 kg/in.2
as determined with a modified Herberlein hardness tester. As
modified, one of the testing jaws has a V-shaped inden-
tation for registry with a correspondingly V-shaped
protrusion on the other jaw. Such lozenges can be
formed on a Stokes tableting machine at approximately
7 tons pressure into pieces weighing between 1 and 3 g. with
5/8 in. punches having deep concave faces. Similar tablets
can~be made with a Carver laboratory press at a pressure of
3,600 psiO Although the above-described methods of manu-
facture are efficacious, they are merely illustrative.
~ j
The controlled antacid delivery form of this in-
vent`ion can also contain other excipients or therapeuticsubstances.
The preparations of this invention are particu-
larly useful in antacid therapy since the gradual release
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l~liL766 8254
of antacid off-sets the effect of stomach emptying and
constant secretion of acid. When the lozenge contains
a mixture of antacids having different reactivities,
the present invention provides for substantially com-
plete utilization of all of the antacid components. Itis also useful in the treatment of reflux esophagitis
and heartburn.
The following examples il:Lustrate the inven-
tion:
Example 1
A wet granulation having the composition shown
in Table 1 was prepared as follows: The mannito:L, alumi-
num hydroxide-magnesium carbonate coprecipitate and mag-
nesium carbonate were mixed in a twin shell blender for 5
; 15 minutes. The gelatin was dissolved in water and heated to
; 60C. The gelatin solution was mixed with the above-de-
s~ribed blend in a Simpson mixmuller to form a wet granu-
lation. The wet granulation was spread on a tray and
dried at 60C for 8 hours. The dried granulation was then
passed through a Erweka granulator to reduce the dried
material to an 18 mesh or finer particle size. This dried
material is called the raw granulation.
i
Table 1
~ ~:
Raw Granulation
` ; ~ In~_edient Percent
Mannitol Powder 48~17
Aluminum H~droxide-Magnesium Carbonate
Copxecipitate . 25.74
` ~ Magnesium Carbonate 21.76
Gelatin Solution, 10% weightJweight ~ 4~33
3n~ lOO.OO
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~ 766 8254
Loæenges having the composition shown in Table
2 were prepared as follows: The raw granulation, sodium
carboxymeth~l cellulose, calcium stearate, talc and flav-
oran~ were mixed for 15 minutes in a twin shell blenderO
This mlxture was then made into lozenges on a Stokes RD-3
tablet press with 5/8 in. die and deep concave punches at
a pressure of 7 tons.
Table 2
Lozenge Formula
Ingredient Percent
Raw Granulation 91.33
Sodium Carboxymethyl Cellulose(l) 5.00
Calcium Stearate 1.00
Talc 1.00
Flavorant _ 1.67
100.00
(l)medium viscosity grade
:, .
The lozenges formed in accordance with this exam-
ple were very hard, beyond the normal scale range ~or a Pfizer,
:
Erweka or ~eberlein tablet hardness tester. The average
time to dissolve the lozenge in the mouth was approximately
50 minutes. They had a sweet, pleasant taste wi-th no unpala-
table slimy or gritty mouth feel. These lozenges had 18
~ .
; meq. of antacid neutralizing capacity.
Example 2
A raw granulation having the composition shown in
~ ~ :
Table 3 was prepared according to the procedure o~ Example 1
, ~ '
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except that calcium carbonate was used as the antacid
component and starch paste ~as used as the auxiliary
binder. The wet granulation was dri.ed a-t 60C for 24
hours.
Table 3
Raw Granulation
In~redient Percent
Mannitol Powder 19.63
Calcium Carbonate 76.45
Starch Paste~ 10% weight/weight3.92
100.00
Lozenges having a slow dissolving layer and a
fast dissolving layer with the composition shown in Tables
4 and 5, respectively, were prepared as in example 1 ex-
cept that the slow and fast mixtures were loaded into a
Manesty double-layer tablet press with 5/8 in. die and deep
concave punches. The machine was adjusted so tha~ the
slow dissolving layer weighed 1.8 g. and the fas-t dissolv-
ing layer weighed 0.8 g.
Il ~
}
; Table 4
Slow Dissolvin~ Layer
Ingr~edient~ Percent
Raw Granulation 54.5
Sodium Car~oxymethyl Cellulose 4.0
Calcium Stearate 1~1
Gxanular Sorbitol 39.6
Fla~orant ~ 0.~
100.00
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8254
Table 5
Fast Dissolvin~ Layer
In~redient Percent
.
Raw Granulation 42.00
Sorbitol Granular 52.66
5 Calcium Stearate 0.10
Talc 0~40
Colorant 0.30
Primogel 4
Flavorant 0-54
100 . 00
10 The lozenges formed in accordance with this exam-
ple were very hard. The slow dissolving layer is in accord-
ance with the invention, the fast dissolving layer is not.
The fast dissolving layer dissolved in less than 5 minutes.
The dissolution time for the entire double-layer lozenge in
the mouth was approximately 20 minutes. The lozenge had a
pleasant taste with no unpalatable slimy or gritty mouth feel.
.
Example 3
A raw granulation having the compos.ition shown in
: 20 Table 6 was prepared according to the procedure of Example 1
except that calcium carbonate was included as part of the
antacid component and starch paste was used as the auxiliary
binder.
2:5 ~able 6
Raw Granulation
Ingredient Percent
Mannitol Powder 53.87
~Aluminum ~ydroxide-Magnesium Carbonate
Coprecipitate 9.43
~: Magnesium Car~onatP 13.47
~: 30 Calcium Carbonate 18.52
S~tarch Paste, 10% weight/weight4.71
~: :
100.00
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Lozenges having the composition shown in Table 7
were prepaxed following the procedure of Example 1.
T ble 7
Lozeng _Formula
In redient Percent
Raw Granulation 93.34
Sodium Carboxymethyl Cellulose 3.00
Calcium Stearate 1.00
Talc 1.00
Flavorant _1.66
100. 00
The lozenges were hard, slow dissolving and had
24 meq. of antacid neutralizing capacity. They had a
sweet, pleasant taste with no unpalatable slimy or yritty
mouth feel. They weighed 2 g. and had a dissolution time of
47 minutes.
Example 4
A raw granulation having the composition shown in
Table 8 was prepared according to the pxocedure of Example 1
~ except that magnesium hydroxide was substituted for the mag-
; 20 nesium carbonate and sorbitol was substituted for part o~ the
mannitol.
:
:
Table 8
Raw Granulation
~ Percent
Mannitol Powder (1)31O53
Sor~ito- Solution~ 10~ weight/weight 4.74
Aluminum Hydroxide-Magnesium Carbonate
Coprecipitate 14.24
Magnesium Hydroxide 42.37
~ Gelatin Solution, 15% weight/weight(l) 7.12
i ~ ~ I00.00
30~ (l)Added as a sorbitol and ~elatin solution
whîch was 10~ weight/weisht in sorbitol
and 15~ welght/weight in gelatin~ `
.~
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~ 76~ 8254
Lozenges having the composition shown in Table 9
were prepared following the procedure of Example 1.
Table 9
Lozenge Formula
Ingredient Percent
Raw Granulation 90~34
Sodium Carboxymethyl Cellulose 5.00
Calcium Stearate 2.00
Talc 1.00
Flavorant 1.66_
100. 00
;~ .
The lozenges had 33 meq. of acid neutralizing
capacity and took an average ti~e of 50 minutes to dissolve
in the mouth.
Example 5
.A raw granulation having the composition shown
in:Table :lO:was prepared according to the procedure of
xample l except that powdered sugar was substituted for
io ~ the:mannitoI~powder.
: Table 10
, : ~
~ Raw Granulation
t~ Ingredient : Percent
2~5~:~ Powdered Sugar ~ :: 49.17
:Aluminum H~droxide-Magnesium Carbonate
Coprecipitate 26.26
Magnes:ium~Ca.rbonate 22~19
Gelatin~S~}~tion, 10% weight/welght 2.38
. ~
8254
.7~
Lo~enges having the composition shown i.n Table 11
were prepared following the procedu:re of Example 1. These
lozenges weighed 2 g. and dissolved in approximately 30 mi.nutes.
Table 11
Lozenge Formula
Ingredient Percent
Raw Gr~nulation 91.49
Sodium Carboxymethyl Cellulose 5.00
Calcium Stearate 1.00
Talc 1.00
10 Flavorant 1.51
i00 . 00
Example 6
.
A raw granulation having the composition shown in
Table 12 was prepared according to the procedure of Example 4
except that sorbitol was subs-tituted for part o~ the manni-
tol.
.,
Table 12
; Raw Granulation
~` : 20 Ingredient Percent
Manni~ol Powder 47.88
Sorbitol Solution, 10~ wei.ght/weight 4.40
Aluminum Hydroxide-Magnesium Carbonate
Coprecipitate 13.57
` Magnesium Carbonate 27~55
j Gelatin Solutionr 15~ weight/weight 6.60
' 100 . 00
~; ~ 25
Lozenges having the composition shown in Table 13
~ were prepared following the procedure of Example 1 except
':
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~ 7~ 8254
that xanthan gum was substltuted for the sodium carboxy-
methyl cellulose.
Table 13
Lozenge Formula
In~redient Percent
Raw Granulation 93.59
Xanthan Gum 3~00
Calcium Stearate l.00
Talc l.00
Flavorant _ 1.41
100 . 00
The lozenges had a sweet, pleasant taste, as in
all of the previous examples, with no unpalatable slimy
or gritty mouth feel. They dissolved in approximately 33
minutes in the mouth.
Example 7
A raw granulation having the composition shown in
Table 14 was prepared according to the procedure of Example
; .
l except that calcium carbonate was used as the antacid com-
~, ponent.
`
Table 14
l ~ .
¦ Raw Granulation
Ingredient Percent
Mannitol Powder 51.80
Calcium ~arbonate 46.04
;~ Gelatin Solution, 10% weighk/weight 2.16
10 0 . 0 0
17
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~ 8254
Lozenges having a slow dissolving layer and a
~ast dissolving layer with the composition shown in Tables
15 and 16, respectively, were p.repaxed according to the pro-
cedure o~ Example 2.
Table 15
Slow Dissolvin~ Layer
Ingredient Percent
Raw Granulation 90.82
Sodium Carboxymethyl Cellulose 6.00
. 10 Calcium Stearate 1.00
Talc 1.00
Sodium Hexametaphosphate 0.52
Flavorant 0 56
100 . 00
Table 16
, 15
Fast Dissolving Layer
Ingredient Percent
Raw Granulation 96.60
Calcium Stearate 1.00
. : Talc 1.00
: Sodium Hexame~aphosphate. 0.52
Flavorant 0.58
20 Colorant _ 0.30
100. 00
The slow dissolving layer is in accordance with
: the~present invention, the fast dissolving layer is not.
The lozenges had a pleasant taste with no unpalatable slimy
or ~xitty mouth feel.
,- 18 - :
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IL766
8254
_X~
In order to compare the lozenge of this invention
prepared in Examples 1 and 7 with a conventional antacid, a
cross-over stud~ was made as follows: Ten human s~bjects par-
ticipated in each of four groups. Group I subjects received
30 cc. of MAALOX~72 meqO), Group II 60 cc. of MAALOX (144 meq.),
Group III one lozenge prepared according to Example 1 (18 meq.)
and Group IV one lozenge prepared according to Example 7 (20 meq.).
Before the antacid was administered, a sillcon-
ized nasogastric tube was inserted into the gastric puddle.
Once the tube was in position, a sample of gastric juice
was taken and then returned after the pH has been recorded.
; This was done 30 minutes, 15 minutes and immediately before
the antacid was given to provide three reference points.
The subjects in Groups I and II then ingested the
1 above-indicated amount of M~ALOX and the subjects in Groups
:. .
III and IV sucked on the lozenges o~ Examples 1 and 7, re-
.spectively. The p~ of 2 ml. gastric samples was read from
` ~ time to time and then returned to the stomach. When the pH
fell below 3.5, ths effect of the antacid was conside~ed over.
,~ :
The results are shown in Fig. 1, Group I being represented
by closed trlangles, Group II by open circles, Group III by
open squares and Group IV by open triangles. Referring to
Table 17, it is seen that the new antacid d~livery form of the
. . .
2S~ present invention unexpectedly maintains the gastric contents
over pH 3.5 twice as long as MAALOX with as Iittle as one-
eighth~ the acld ne~trallzing oapacity.
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Table 17
Time Over
Dosa~e Form Meq. pH 3. _
30 cc. MAALOX 72 40.6
60 cc. MAALOX 144 45.3
Example 1 Lozenge 18 82.8
Example 7 Lozenge 20 77~3
From the above it is seen that the present
dosage *orm neutralizes the stomach acid over a con-
siderably longer period of time as compared to conven-
tional antacids with a much smaller amount of antacid.
In this example it is shown that the magnesium
component of an antacid containing a combination of mag-
nesium and aluminum reacts first. When the antacid is in
excess, as shown in Table 17, substantially none of the
aluminum is reacted. When the antacid is gradually ad-
ministered in accordance with the present invention, how-
ever, both metal components are utilized.
In Test Nos. 1-4, a MAALOX tablet was yround into
a powder passing through a 30 mesh screen. The powder
was suspended in water and the amount of acid shown in
Table 17 added. The solution was filtered and the ~iltrate,
which contained the reacted antacid, was analyzed for mag-
nesium and aluminum content. As shown in Table 17, sub-
stantially none of khe aluminum was reacted.
Tests Nos. 5-10 were conducted similarly except
that in Test ~, 5 ml. of MAALOX liquid was used in place
of the powdered MAAhOX tablet. In Tests 6-10, a MYLANrrAO
tablet was used in place v the MAALOX tablet.
~ - 20 -
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~ 825~
In Tests Nos. 11-14, a lozenge made in accord-
ance with Example 1 was ground into a powder which passed
through a 35 mesh screen. In Tests Nos. 11-12, the pow-
dered lozenge was dissolved in water and the amount of
acid shown in I'able 17 added, whereas in Tests Nos. 13-1
the antacid was suspended in a small amount of water and
added concurrently with the acid. As ls shown in Table 17,
in Tests Nos. 13-14 both the magnesium and aluminum com-
ponents of the antacid are utilized. These tests simulate
the in vivo benefits obtained with the controllecL antacid
delivery form of this invention.
In view of the above, it will be seen that the
several objects of the invention are achieved and other ad-
vantageous results attained. As various changes could be
made in the above methods and products without departing
fr~m the scope of the invention, it is intended that all
matter contained in the above description shall be inter-
preeed as illustrative and not in a limiting sense.
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