Note: Descriptions are shown in the official language in which they were submitted.
36~'~
1059-81
ANTACID CO~POSITIOMS
Field of the Invention
This invention relates to improvements in antacid
compositions and is particularly concerned with new
hydrotalci~es which have been found to have desirable antacid
properties that are eminently suitable for medicinal use for
the treatment of gastric hyperacidity.
Back~round of the Invention
Antacid preparations are now quite generally employed
for the t~eatment of peptic ulcers, gastric hyperacidity and
dyspepsia. Gwilt, Livingstone, and Robertson in the Journal of
Pharmacy and Pharmacology, X No. 12,7iO,775 (1958), describe
the characteristics of an-ideal antacid. They point out that
it should show its maximum neu~ralizing effect in the shortest
possible time, that it should neutralize an adequate amount of
gastric hydrochloric acid and maintain its action during the
no~mal period of gastric digestion, ~hat any excess however
great beyond the amount required to neutralize free gastric-
acid should not cause alkalization, that it should raise the pH
of the gastric contents to a level at which pepsin activity is
reduced signi~icantly but not totally inhibited, tha-t adequate
2~ and repeated doses should be palatable to the hyperacid
patient 9 and that its use should not lead to laxative,
constipating or other side efects such as gastric irritation.
In addition to these factors 9 the antacid composition should be
inexpensive and it should not deteriorate significantly in any
25 - respect on aging. These workers summariæe the various
_ I ~
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statements in th~ literatures to the pH ranges desirable for
the ideal antacid, and conclude th~t p~l within the range from
about 3 to 5 is apparently the optimum to ensure adequate
relief from hyperacidity, partictllarly if an ~t]c~r s,ite is
present, and at the same time permits sufficient residual
pepsin activity to avoid secondary digestive disturb~nce~s.
U.S. Patents Mos. 3,65~,704 and 3,539,306 o~ nlur~
et al disclose a synthetic hydro~alcite of the formula:
~1203 6MgO C02 12ll20
1~ which is use~ul as an antacid.
U. S. Patent No. 2,958,626 of Schencl; et al discloses
an aluminum magnesium carbonate of the composition:
~ OH)2A12 Mg(C03)2nll2
for controlling gastric acidity.
Summary of the Invention
The present invention relates to novel antacid
compositions ~hich contain as the active ingredient a
hydrotalcite of the general formula:
g6 12(OH)16(C03)1_X(A )x n~l20 (I)
2~ wherein A2 represents SO or ~IPO , n is an integer of l 5 to
12 and 0< x< 1.
Accor~ing to a feature of the inven~ion, the comple~
of Formula I is produced by a modification of the process
described in U.S. Patent No. 3,650,704 which comprises mixing
an aluminum component with a magnesium component in an aqueous
medium in the presence o~ chloride ion and followed ~y either
sulfate or phosphate ion and carbonate ion at a p~l of at least
8 and thereafter, recovering the res~ltant precipitate. The
said aluminum component being selected from the group
consisting of aluminum hydroxide, aluminum amino aci~ sa]ts,
-- 2--
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alu~inum alcoholates water-soluble aluminum salts and
water-soluble aluminates, and ~hc said magnesium cc)lnpot-cllt
béing selected from the group consisting of magnesi~lm ox;de
magnesium hydroxicle and water-soluble salts. As tl~e
water-soluble aluminum salt aluminum salts o~ aci~l~s such as
aluminum sulphate aluminum chloride aluminlml nitr~te and
aluminum acetate and their com~lex s~lts such as al~m~ ~-.ln be
used. As the water-soluble aluminate there m~y be used an
alkali aluminate such as sodium aluminate. Obvious]y in
1~ conducting the above process it is permissible to form
aluminum hydroxide or aluminum amino acid salt in situ
preceding the described reaction.
As the magnesium component which is the other
reactant any member of ~he group consisting of magnesium
oxide magnesium hydroxide and water-soluble magnesium salts
may be used. As the water-soluble magnesium salt there can be
mentioned mineral acid salts of magnesium such as magnesium
chloride magnesium nitrate magnesium sulphate and bittern.
The sulfa~e, hypophosphate chlorid~ and carbon~te
2~ component may be introduced as an alkali salt.
In accordance wi~h the above process ~hc saicl
aluminum component is mixed with the magnesium component in
basic aqueous medium in the presence of chloride ion. It i~
preferable to mix the aluminum component wi~h the magnesium
component so that the atom ratio of Al to Mg may be about
one-third and to cause the chloride ion to be present in a
ratio of at least one-one in each aluminum atom. This is
followed by the addition of sulfate or phosphate ion and
carbonate ion in a ratio of carbonate to aluminum of one to
four and a ratio of phosphate or sulate to aluminum is 1 to 4.
According to a preferred embodiment of the above
processj the mixing is preferred to make ~he p~l of the entire
-- 3--
system composed of the aluminum componen-t, magnesium com-
ponent, chloride component, and aqueous medium at least 8,
particularly above 9.5. In order to maintain the pH of the
entire system at said level during the reaction, alkaline
substances such as an alkali hydroxide may be suitably added
to the aqueous medium, when a water-soluble aluminum salt
and/or a water-soluble magnesium salt is used.
The critical feature of the above process resides
in that ~he initial reaction of the aluminum component~ mag-
nesium component, and chloride component, followed by theaddition of the carbonate and either the phosphate or sulfate
component is performed in water and under a basic condition.
Because the reaction of the components is performed in water,
mild reaction condition with respect to pressure and tempera-
ture become feasible.
The temperature conditions for the reaction varyconsiderably depending on the types of the aluminum component
and magnesium component employed, but normally tne range of
0C 150C is preferred. Also the reaction time is to some
extend a dependent factor on the reaction temperature and the
types of the starting materials.
As in accordance with the above process the hydro-
talcite is obtained in the form of precipitate, the product
is filtered and washed with water if desired, and thereafter
the solid is separated by known solid liquid separation means
such as centrifuge, followed by drying to serve as the dry
product.
In another embodiment of the above process in which
aluminum hydroxide is used as the aluminum component, an
aqueous slurry of aluminum hydroxide is added with neutral
magnesium chloride and the pH adjusted to 9.5 with alkali
.,~p,~
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1059-81
hydroxide. The system is heated at such temperature for such
time as su~ficient to cause disappearance of the alunlinum
hydroxide. Then the alkali carbonate and either alkali
phosphate or sulfate is `added. Thus, the desired hydrotalcite
is formed.
Description of the Preferred Embodiments
The present invention relates to an antacid
composi~ion which con~ains a synthetic hydrotalcite that can be
industrially produced from readil,y available s~arting materials
1~ without a specially complicated operation.
More specifically, the present invention relates to
an antacid composition which con~ains as the active ingredient
a synthetic hydrotalcite of the formula:
~g6A12(O~)16(co3)(l-~)(A x nH2O
Wherein A2 represents SO or HPO , n is an integer o~ 1.5 to
12 and O< x~l.
In accordançe with the present invention, it has been
discovered that the hydrotalcite utilized in the prcsetlt
invention eliminates certain disadvantages and difficulties
2~ which are associated with conventional antacids. Thc synthetic
hydrotalcite of the present invention has a specifically
deined X~ray diffraction profile. It is ?ble to maintain tlle
pH of the gastric juice in,a range of ~bout l~ - 5.0 despite the
fact ~hat there is present a high magnesium content'.
Furthermore, due to thc low aluminum content of the
hydrotalcite, the problem of constipation which is normally
associated with conventional antacid compositions is
eliminated. Also there is little laxation which often
accompanies high magnesium content. Accordingly, pursuant to
3~ the present invention there has been discovered an ideal
antacid composition which eliminates both the problems
associated with high aluminum content and high magnesium
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content. In accordance with a preferred embodimen~ of the
invention, there is provided a synthe~ic hydrotalcite complex
which contains therein a phosphate component that reduces the
' proble~ of the depletion of body phosphate which is associated
with the use of conventional aluminum hydroxide containing
antacid compositions.
The preerred hydrotalcite complexes which m~y ~e
used in the practice of this inverltion include:
Mg6A12(OH)16(CO3)1_X (~IPO4)x 2
6A12(O~ 6(Co3)1_X (SO4)x
wherein x and n are as h~reinbefore described.
The hydrotalcite of the present invention c~n provi~e
an antacid which is excellent in its prompt but lasting
neutralizing action and is never impaired by a long term
storage. The synthetic hydrotalcite of the present invention
may be utilized alone or together with a suitable
pharmaceutical vehicle. The co~pounds m~y be prepared in a
suitable fGrm for oral administration and can be in a form of
tablets,capsules, suspen~ions or powders; such preparations
being prepared by conventional methods.
The antacid of ~he present invention may suit~bly
contain, besides the hydrotalcite, aluminum hydroxide,
magnesium carbonate,' calcium carbonate, magnesium hyclroxide,
' aluminum hydroxide-alkali carbonate complex, silicate and the
like. Such antacid comprisi.ng hydrotalcite and the foregoing
substances can be prepared by mixing the latter with
hydro~alci~e or coprecipitating hydrotalci~,e with the substance
or substances by reacting the starting materials for such
sub8tances.
The antacid efeetiveness of the antacids of the
invention may be determied by the method of Rossett-Rice,
Ga~troenterology 26, 490 (1954~. In this method, a test sample
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of antacid is added ~o 70 ml. of 0.1 I~ ~ICl and 30 ml. of water.
This solution approximates the acidi~y of the gastric contents.
The artificial gastric juice is maintained at a temperature of
37C. The tect procedure is carried out by continuously
introducing 0.1 N HCl at a rate of 4 ml./min. This rate
simulates the normal acid secretion rate. The antacid effect
is determined by measuring the time during which the pH is
maintained between 3 - 5.
The hydrotalcites of the present invention have been
ound to be especially advantageous for use as buffers in
~ormulations containing aspirin and aspirin-like compounds
because of high neutralizing activity and enhancement of the
dissolution rate of the aspirin.
The following Examples serv~ to demonstrate the
prepara~ion of the hydrotalcites of the present invention.
EXAMPLE I
33.3 g of aluminum chloride and 152.5 g of magnesium
chloride hexahydrate are dissolved in one liter of water. This
solution is pumped into a reaction flask and sodium hydroxide
solution is added to maintain a pH of 10. After the entire
- aluminurn-magnesium solution is added to the reaction vessel,
6.6 g of sodium carbonate and 17.0 g of dibasic sodium
phosphate heptahydrate are added. Mixing was continued for one
hour while maintaining the pH at 10 by the addition of sodium
hydroxide. The the mixture was fil~ered and washed until no
sodium or chloride ion was detected. The product was dried at
60C to obtain:
Mg~Al2(0~)16 (Co3)o~5(HPO4)o~5 4~I20
EXAMPLE II
An amount o aluminum hydroxide equal to 102 g of
A12O3 was mixed with 350 g of magnesium hydroxide in 5 liters
of water. After a uniorm sIlspension was obtained, 150 g of
-- 7--
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1059-~1
potassium chloride was added. The mixture was heated to S5C
and mixed for 5 hours. Then 26.5 g of so~ium carbonate and
106.5 g of sodium sulfate were added. The suspension was
stirred for one hour. The mixture was filtered and washed
until no chloride or sodium was deLec~ed. The product was
dried at 60C to yield:
g6A12(OH)16 (Co3)0 25 (So4)0 75-4H2O
EXAMPLE III
267 g of alu~inum chloride and 350 g of magnesium
1~ hydroxide were mixed in 5 liters of water. The solution was
then adjusted to pH 10 with sodium hydroxide. The suspension
was heated to 70C for 4 hours with mixing. Then 21 g of
sodium bicarbonate and 107 g of dibasic sodium phosphate were
added to the mixture and stirring continued for one hour. The
lS mixture was filtered and the product was washed until no sodium
or chloride ion was detected. It was then dried a~ 60C to
yield the product which was:
g6~12~OH)16 (Co3)0 25 (HPO4)0 75-4H2O
EXAMPLE IV
10,000 units of an antacid suspension, where each
unit contains 500 mg of Mg~A12(OEl~l6 (CO3) 5(HPO4) 5 4H2O per 5
ml of suspension, were prepared as follows:
Mg6Al2(~ 6 (CO3) 5(HPO4) 5-4H2O 5000 g
70~ aqueous sorbitol solution 5000 g
~5 Sodium carboxymethyl cellulose, 400 cp/2% 650 g
Sodium salt of methyl-p hydroxybenzoate 112.5 g
So~ium salt of propyl~p hydroxybenzoate 12.5 g
Sodium salt of saccharin 50 g
Aneth31e 20 g
3~ Water q.s. 50 1
Sodium carboxymethyl cellulose, sodium methyl
hydroxybenzoate, sodlum propyl hydroxybenzoate and the sodium
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salt of saccharin were dissolved with stirring in 35 liters of
distilled water. The sorbitol solution was added, and the
hydrotalcite was dispersed in the solution. Subsequently,
anethole was added, and the mixture was dîluted to 50 liters
with water. The resulting suspension was r.lade to pass through
a colloid mill and then packaged as single doses in containers,
with each container holding $ ml of suspension.
EXAMPLE V
10,000 antacid tablets were prepared, each containing
500 mg of a hydrotalcite of the present invention:
Mg6Al2(oH)l6 sC3).5(~P4~,5 4 2
Mannitol 6000 g
Cornstarch 195 g
Soluble starch 325 g
Fructose 20 g
Flavor (dry powder) 10 g
Magnesium stearate 10Q g
The hydrotaleite and mannitol were mixed and
granulated with a so].ution of the fructose and the soluble
2~ starch in 6 liters of water. The granulate was dried and
subsequently screened ~hrough a sereen with a mesh size of 0.5
mm~ The granulate was then mixed with the remainder of the
compounds, and the mixture was pressed to tablets of 1.165 g
using a 15 ~ disk and 2 flat bevel-edged die.
EX~MPLE VI
10,000 swallow tablets were prepared, each containing
500 mg of a complex per tablet:
Mg6A12(~ 6(C3)o 2~(SO4)0 75-4H2O 5000
Cornstarch 195 g
Soluble starch 325 g
Magnesium stearate 100 g
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059-81
The hydrotalcite and starch were mixed and
granulated with a solution of the soluble starch in 6 li~ers
of water. The granulate was dried and subsequently screened
through a screen with a mesh size of 0.5 mm. The granulate was
then mixed with the magnesium stearate, and the mixture was
pressed to tablets of 0.562 g using a 10 mm disk and a flRt
bevel-edged die.
Similarly there can be prepared swallow tablets
utilizing other hydrotalcites of this invention.
1~ EXAMPLE VII
5,000 powder units were prepared, each containing 500
mg of a mixture of hydrotalcites per 3 g of powder:
~Ig6Al2(oH)l6 (cO3).s~HPo4).5 4H2 125 g
Mg6A12(H)16 tC~3).5(S~4).5 4H2O 125 g
Mannitol 12,175 g
Colloidal silicon dioxide 1~0 g
Fructose 50 g
Fl~vor (dry powder) 125 g
The hydrotalcites were micronized in a jet mill and
2~ th~n mixed with the remaining ingredients. The resulting
; powder was placed in single-dose containérs holding 3 g eachA
The formulation can be used for treatment of
disturbances of the upper gastrointestinal tract that involve
exc~ss acid and pepsin secretion and a reflux of bile.
EXAMPLE VIII
A lot of two-layered tablet~ containing aspirin are
prepared as follows:
A, Aspirin wi~h 10~ starch 36.1 g
Talc 0.67 g
B- Mg6Al2loH)l6(co3)o.5(Hpo4)oo5 4H2Og
- 10-
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Starch 10.0 g
Soluble Starch 2.0 g
Magnesium stearate 1.0 g
The ingredients of Part A are mixed together and
placed in the mold of a tableting machine. The hydrotalcite
and starch are mixed together and granulated with soluble
starch dissolved in water. The granulate was dried and
subsequently screened through a suitable screen. The granulate
was then mixed with the magnesium stearate. The mixtures of
Part B are then added to the mold to cover the Part A
ingredients. The ingredients are ~hen compressed to form
tablets of buffered aspirin.
