CA1198674A

CA1198674A - Antacid compositions

Info

Publication number: CA1198674A
Application number: CA000415687A
Authority: CA
Inventors: Wayne M. Grim; John D. Buehler
Original assignee: Rorer International Holdings Inc
Current assignee: Rorer International Holdings Inc
Priority date: 1981-11-23
Filing date: 1982-11-16
Publication date: 1985-12-31

Abstract

ABSTRACT OF THE DISCLOSURE

Antacid compositions which contain as the active ingredient a hydrotalcite of the general formula:
Mg6Al2O (OH) 16 (CO3)1 -x (A2-)x?nH2O
wherein A2 represents SO? or HPO?, n is an integer of 1.5 to 12 and 0< x< 1.

Description

36~'~

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 ~
~;

-1059-~1 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, 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 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,~
~ - 4 -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 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 6i d 4 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'f~

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 7~

1059-~1 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 _ g_ tjJ9~

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 .

1059-~1 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.

Claims

We claim:

1. A process for the preparation of a compound of the formula Mg6 Al2 (OH)16 (CO3)1-x (A2-)x?nH2O

wherein: A2- is SO4= or HPO4=;
x is about 0.2 to about 0.8;
n is an integer from 2 to 12;
comprising:
A) mixing in an aqueous medium an aluminum and magnesium compound in the presence of chloride ion at a pH of at least about 8;
B) adding sulfate or phosphate ion and carbonate ion to said aqueous mixture; and C) recovering the resulting precipitate.

2. A process according to Claim 1, wherein:
the atom ratio of aluminum in said aluminum compound to magnesium in said magnesium compound is about one to about three;
the atom ratio of said chloride ion to said aluminum is at least about one to one;
the atom ratio of said sulfate or said phosphate ion to said aluminum is about one to about four; and the atom ratio of said carbonate ion to said aluminum is about one to about four.

3. A process according to Claim 2 where the pH of said aqueous medium is about 9.5.

4. A process according to Claim 3 where the mole ratio of said carbonate ion to either said sulfate or phosphate ion is about 0.25 to about 4.

5. A process according to Claim 1, wherein phosphate ions are used in Step B.

6. A process according to Claim 1, wherein sulfate ions are used in Step B.

7. A compound of Claim 1, when prepared by the process defined in Claims 1, 2 or 3 or by an obvious chemical equivalent.

8. A compound which is Mg6 Al2 (OH)16 (CO3)1-x (HPO4)x?nH2O wherein: x is 0.2 to 0.8; and n is 2 to 12, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

9. A compound which is Mg6 Al2 (OH)16 (CO3)1-x (SO4)x?nH2O wherein: x is 0.2 to 0.8; and n is 2 to 12, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.