CA1198675A - Antacid compositions - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Antacid compositions which contain as the active ingredient a hydrotalcite-like complex of the general formula:
Mg6Al2(OH)14(A2-)2?1.5-12 H2O
wherein A2- represents SO? or HPO?.

Description

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~ITACID COMPOSITIONS

~ield of the Invention This invention relates to improvemcnts in antacid compositions and is par~icularly concerned with new hydrotalcite~like magnesium aluminate compositions which have been found to have desirable antacid properties that are eminently suitable for medicinal use for the treatment o~ gastric hyperacidity.

Background of the Invention Antacid preparations are now quite generally employed for the treatment of peptic ulcers, gastric l~ hyperacidity and dyspepsia. Gwilt, Livingstone, and Robertson in the Journal of Pharmacy and Pharmacology, X No, 12,770,775 (1958), describe the characteristics of an ideal antacid. They point out that it should show its maximum neutralizing ef~ect in the shortest possible time, that it ; 15 should neutralize an adequate amount of gastric hydrochloric acid and malntain lts action during the normal period of gastric digestion, that 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 2n gastric con~ents to a level at which pepsin activity is reduced significantly but not totally inhibited, that ad quate and repeated doses should be palatable to the hyperacid pa~ient, and that its use should not lead to laxati.ve, constipating or other side effects such as gastric irritation.

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In addition to these factors, the antacid composition should be inexpensive and it should not deteriorate significantly in any respec~ on aging. These workers summarize the various statements in the literatures to the pH ranges desirable for the ideal antacid, and conclude tha~ pH within the range from about 3 to 5 is apparently the optium to ensure adequate relief from hyperacidity particularly if an ulcer site is present, and at the same time permits sufficient residual pepsin activity to avoid seco~dary digestive disturbances.
U.S. Patents Nos. 3,650,704 and 3,539,306 of Kumura et al disclo~e a synthetic hydrotalcite of the formula:
A12O3~6MgO CO212H2O
which is useful as an antacid. "
U. S. Patent No. 2,958,626 of Schenck et al discloses an aluminum magnesium carbonate of the composition:
(OH)4 A12 Mg(C3)2 nH2 for controlling gastric acidity.

Summary of the Invention The present invention relates to novel antacid compositions which contain as the active ingredient a hydrotalcite-like complex of the general formula:
~g6~12(oH)l4(A )2 nH~O
whereln A2 represents SO4 or ~PO4 and n is an integer o~ 1.5 - 12.

According to a feature of the invention, the complex of Formula I is produced by a modifica~ion of the 3~ process described in German Offenlegunschrift No. 2905256 of Anphar S.A., which comprises heating a mixture of aluminum hydroxide and magnesium hyclroxide in suit~ble molar ratios in an aqueous medium containing ammonia or a water soluble organic nitrogen-containing base plus an alkali halide at a temperture of 70 - 100C under atmospheric pressure. After cooling, an alkali sulfate or phosphate is added and mixing is continued. The amount of ammonia or water soluble organic base used is critical, and quantities of over 6 moles per mole of A12O3 present in the reaction mixture are needed to guarantee a complete reaction. The progress of the reaction can be evaluated by the conversion of the crystalline raw materials to a gel. When the reaction is completed, the product is reco~ered by filtration, washed with water and dried to form a complex of Formula I.
Suitable water-soluble organic nitrogen-containing bases for use in the reaction mixture are mono-, di- and trialkylamine containing up to 4 carbon atoms in the alkyl radical or radicals, such as methyl-, ethyl-, propyl- or butylamine, pyridine or piperidine and, particularly triethylamine.
Suitable aluminum compounds utilized in the reaction mixture include aluminum hydroxide, aluminum amino-acid salts, aluminum alcoholate, aluminum nitrate, aluminum chloride 9 water-soluble aluminates, and the like.
The magnesium component may include magnesium oxide, magnesium hydroxide, and certain water-soluble magnesium salts.
Description of the Preferred Embodi~ents The present in~ention relates to an antacld composition which cGntains a synthetic hydrotalcite-like 7~

complex tha~ can be industrially produced from readily available starting materials without a specially complicated operation.
More specifically, the present invention relates to an antacid composition which contains as the active ingredient a synthetic hydrotalcite-like complex of the formula:
Mg6A12 (OH)14(A )2 nH2 (I) Wherein A2 represents SO4 or HPO4 and n is an integer o~
1~ 1.5 - 12.
In accordance with the present invention, it has been discovered that the hydrotalcite-like complex utilized in the present invention eliminates certain disadvantages and difficulties which are associated with convention~l antacids. The synthetic hydrotalcite-like compJex of the present invention has a specifically defined X-ray diffraction pattern. The complex o~ this invention has been surprisingly discovered to maintain the pH of the gastric juice in a range of about 3 - 5 despite the fact

2~ that there is present a high m~gnesium content.
Furthermore, in spite of the high magnesium content of the present complex , the problem of laxation which is normally associated with conventional antacid compositions is eliminated. Accordingly, pursuant to the present invention z~ there has been discovered an ideal antacid composition which elimina~.es both the problems associated with high aluminum content and high magnesium content. In accordance with a preferred embodiment of the invention, there is provided a hydrotalcite-like complex which contains therein a

3~ phosphate component that reduces the problem of the depletion of phosphate from the body which is associated 1060-~1 with the use of conventional aluminum hydroxide containing antacid compositions.
The preferred hydrotalci~e-like complexes which may be used in the practice of this invention include:
g6A12(O~ 4(~1PO4)2 4~12O (I)a -and-Mg6~12(OH)14(So4)2 4~l2 (I)b The complex of the present invention can provide an antacid which is excellent in its prompt but ].asting 1~ neutralizing action and is never impaired by a long term storage. The synthetic hydrotalcite-like complex of the present invention may be utilized alone or together with a suitable pharmaceutical vehicle. The compounds may be prepared in a suitable form for oral ad~inistration and can be in a form of tablets, capsules, suspensions ~r powders;
such preparations being prepared by conventional methods.
The antacid formulation of the invention may suitably include aluminum hydroxide, magnesium carbonate, calcium carbonate, magnesium hydroxide, aluminum 2~ hydroxide-alkali carbonate complex, silicate and the like.
Such antacid f~rmulation comprising hydrotalcite-l-ke eomple~. and the foregoing subs~ances can be prepared by mixing the latter with hydrotalcite-like complex or coprecipitating hydrotalcite-like complex with the substance or substances by reacting the starting material for the hydrotalcite-like complex in the presence of a suitable amount of the foregoing substances or of the starting materials for such substances.
The antacid effectiveness of the antacids of the invention may be determined by the method of Rossett-Rice, Gastroen~erology 26, 490 ~1954). In this method, a test sample of antacid is added to 70 ml of O-lN HCl and 30 ml of . ~ ~

1060-~1 water. This solution approximates the acidity o~ the gastric contents. The artificial gastric juice is maintained at a tempera~ure of 37C. The test procedure is carried out by continuously introducing 0.1~ ~ICl at a rate of 4 ml/min. This rate simulates the normal acid secretion rate. The antacid effect is determined by I~easuring the time during which the pH is maintained between pH 3 - 5.
The complexes of the present invention have been Eound to be especially advantageous for use as buffers in 1~ formulations containing aspirin and aspirin-like compounds because of high neutralizing activity and enhancement of the dissolution rate of the aspirin.
The following Examples serve to demonstrate the preparation of the hydrotalcite-like complexes of the present invention.
EXAMPLE I
A suspension of aluminum hydroxide (9.57 g, or 5.09 g A12O3; 0.05 mole), 18.87 g (0.3 mole~ of magnesium hydroxide with a purity of 92.09%, 44.2 g (0.6 moles) of 2q KCl, 33.4 g (0.33 mole) of triethylamine and 500 ml of water were heated to boiling under reflux for 8 hours. After cooling1 52.2 g (0.3 moles) of K2HPO4 was added and mixing continued for 1 hour. The the insoluble compound was filtered off, washed several times with water and then dried under reduced pressure at 60C. 30.8 g of basic aluminum magnesium phosphate complex of Formula Ia was obtained.
EX~IPLE II
A suspension of aluminum hydroxide (9.57 g, or 3~ 5.09 g A1~03; 0.05 mole~, 18.87 g (0.3 mole) 92.09% pure magnesium hydroxide, 35.1 g (.6 mole) of NaCl, 4.89 ml (0.33 mole) concentrated ammonium hydroxlde and 500 ml of water 1060~~31 were heated for 6 hours to boiling under reflux. The reaction mixture was cooled, and 36.0 g (.3 mole) l~a~lSO4 was added. Mixing was continued for one hour then the insoluble compound was ~iltered off, washed sever~l times with water and then dried in a vacuum at a temperature of 60C. The basic aluminum magnesium su]fate com~]ex of Formula Ib was obtained.
The method of preparation of formulations containing the hydrotalcite-like complexes of the present invention is illustrated in the following Examples. They are not intended as limitations ~hereof.

EXAMPLE III
10,000 units of an antacid suspension, where each unit contains 500 mg of Mg6A12(OH)14(HPO4)2 4H2O~ p 5 of suspension, were prepared as follows:

Mg6A12(O~)l4(HPO4)2 4H2O
70% aqueous sorbltol solution 5000 g Sodium carboxymethyl cellulose, 400 cp/2% 650 g Sodium salt of methyl-p-hydroxybenzoate 112.5 g 2n Sodium salt of propyl-p-hydroxybenzoate 12.5 g Sodium salt of saccharin 50 g Aneth~le 20 g Water q.s. 50 1 Sodium carboxymethyl cellulose, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate and the sodium salt of saccharin were dissolved with stirring in 35 liters of distilled water. The sorbitol solution was added and the hydrotalcite-like complex was dispersed in the solut:ion. Subsequently, anethole was added, and the mixture 3~ wa~ diluted to 50 liters with water. The resulting - ~ ~
t~

1060-~1 suspension was made to pass through a colloid mill and then packaged as single doses in containers~ with each container holding 5 ml of suspension.
~XAMPLE IV

10,000 antacid tablets were prepared, each containing 500 mg of a complex of the present invention:
Mg6A12(OH)l4(Hpo4)2 4H2O
Mannitol6000 g Cornstarch195 g 1~ Soluble starch 325 g Fructose 20 g Flavor (dry powder) 10 g Magnesium stearate 100 g The complex and mannitol were mixed,.and granula-ted with a solution of the fructose and the soluble starch in 6 liters of water. The granulate was dried and subsequently screened through a screen with a mesh size of O.5 mm. The granulate was then mixed with the remainder of the compounds, and the mixture was pressed to tablets of i.165 g using a 15 mm disk and a flat bevel-edged die.
EXAMPLE V
10,000 swallow tablets were prepared, each -containing 500 mg o~ a complex per tablet:
Mg6A12tOH)l~(So4)2 4H2O
Cornstarch195 g Soluble starch 325 g Magnesium stearate 100 g The complex and starch were mixed and granulated with a solution of soluble starch in 6 liters of water. The 3~ 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 0.56? g using a 10 mm disk and ~ flat be~el-edged die.
EXAMPLE VI

5,000 powder units were prepared, each containing 500 mg of a mix~ure of hydrotalcite-like complex per 3 g of powder:
Mg6A12(OH)l~(so4~2 4H2O 125 g Mg6A12(OH)14(HPO4)2 4H2O 125 g 1~ Mannitol 12,175 g Co~loidal silicon dioxide 150 g Fructose 50 g Flavor (dry powder) 125 g The two hydrotalcite-like complexes were micronized in a jet mill and then mixed with the remaining ingredients. The resulting powder was place~ in single-dose containers holding 3 g each.
The formulation can be used for treatment of disturbances of the upper gastrointestinal tract that zo involve excess acid and pepsin secretion and a reflux of bile.
EXAMPLE VII
A lot of two-layered tablets containing aspirin are prepared as follows:
A. Aspirin with 10% starch 36.1 g Talc 0.67 g Bo Mg6A125OH)l4(so4)2 2 30.0 g Starch 10.0 g Soluble starch 2.0 g The ingredients of Part A were mixe~ together and placed in the mold of a tableting machine. The hydrotalcite _9_ -3~L98~75 and starch were mixed together and granulated with soluble starch dissolved in water. The g~anulate was dried and subsequently screened through a suitable screen. The granulate was then mixed with the magnesium stearate. The mixture of Part B was then added to the mold to cover the Part A ingredients. The ingredients were then compressed to form tablets of buffered aspirin.
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Claims (10)

We claim:

1. A process for preparing a compound of the formula Mg6 Al2 (OH)14 (A2-)2?nH2O

wherein A2- is SO4= or HPO4= and n is integer of about 2 to about 12, comprising.
(A) stirring a mixture of a magnesium compound, an aluminum compound, a water soluble nitrogen-containing base and an alkali halide in water at a temperature of about 70 to about 100°C at about atmospheric pressure;
(B) cooling said mixture to room temperature and adding thereto an alkali sulfate or an alkali phosphate;
(C) stirring the reaction mixture until a gel is formed;
(D) recovering the solid from the gel and drying the solid;
wherein the mole ratio of magnesium in said magnesium compound to aluminum in said aluminum compound and to said sulfate or phosphate is about six to about two and the mole ratio of said magnesium to said nitrogen-containing base is about equal to or greater than six.

2. A process according to Claim 1, where said mixture of Step (A) is stirred for about six to about eight hours.

3. A process according to Claim 2 wherein said nitrogen containing base is selected from the group consisting of ammonia, pyridine, piperidine, or a mono-, di- or trialkylamine wherein alkyl includes about one to about four carbon atoms.

4. A process according to Claim 3, wherein said aluminum compound is selected from the group including aluminum hydroxide, aluminum nitrate or aluminum chloride.

5. A process according to Claim 4, wherein said magnesium compound is selected from the group including magnesium oxide and magnesium hydroxide.

6. A process according to Claim 1, wherein an alkali phosphate is used in Step (B).

7. A process according to Claim 1, wherein an alkali sulfate is used in Step (B).

8. A compound which is Mg6 Al2 (OH)14 (A2-)?nH2O, when prepared by the process defined in Claims 1, 2 or 3 or by an obvious chemical equivalent.

9. A compound which is Mg6 Al2 (OH)14 (HPO4)2?
4H2O, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.

10. A compound which is Mg6 Al2 (OH)14 (SO4)2?
4H2O, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.