MXPA99007945A - Basic aluminum magnesium carbonate, method for the preparation thereof and its use as a pharmaceutical composition for treating stomach acidity - Google Patents

Abstract

The present invention relates to a new basic aluminum magnesium carbonate of the formula (I):Al2Mg4(OH)12CO3.3H2O and rhombohedral crystallization, whose reticular parameters are a=b=3,046Å;c=22.79Å;&agr;=&bgr;=90°;&ggr;=120°and cell volume=183 A3, whose X-ray diffraction spectrum shows the following d(Å) values:7.597;3.798;2.6202;2.5698;2.5322;2.2830;1.93545;1.72447;1. 62930;1.52289;1.49318;1.46002;1.41351;1.38528 and 1.31011;whose infrared spectrum shows characteristic bands at 1361 and 449 cm-1 (Figure 1) and whose differential scanning calorimetry (DSC) is illustrated in Figure 2. This compound is used in therapeutics as an antacid and gastroprotector.

Description

BASIC CARBONATE OF ALUMINUM AND MAGNESIUM DESCRIPTION The present invention relates to a new aluminum-magnesium basic carbonate of formula Al2Mg4 (OH) 12C03.3H20 (I) and rhombohedral crystallization, whose lattice parameters are a = b = 3.046 A; c = 22.79 A; a = ß = 90 °; ? = 120 ° and cell volume = 1S3 A3, whose X-ray diffraction spectrum presents the following d (Á) values: 7,597; 3,798; 2.6202; 2,5698; 2.5322; 2.2830; 1.93545; 1,72447; 1,62930; 1.52289; 1,49318; 1.46002; 1,41351; 1,38528 and 1,31011; whose infrared spectrum has characteristic bands at 1361, 785 and 449 cm "1 (Figure 1) and whose DSC (Differential Scanning Calorimetry) is represented in Figure 2.

The compound of the present invention is obtained by reaction of the aluminum hydroxide with magnesium hydroxide and sodium acid carbonate in aqueous medium and at the boiling temperature of the mixture. The stoichiometric ratio of aluminum hydroxide to magnesium hydroxide should be 1 to 2. Sodium carbonate acid is used in molar excess, so that the pH of the medium is between 9 and 11. The material separated by filtration Once the system has cooled, it is washed with water and dried under vacuum at a temperature between 50 and 70 ° C. The solid obtained is suspended again in water and it is heated to reflux. The solid is filtered, washed with water and dried under vacuum at the same temperature as before. The product thus obtained corresponds to the hydroxide aluminum magnesium carbonate trihydrate of formula Al2Mg4 (OH) 1CO, .3HO (I). It is presented in rhombohedral crystals or o and its reticular parameters are a = b = 3,046 A; c = 22.79 A; a = ß = 90 °; ? = 120 °. The volume of the crystalline cell is 183 A 'and the X-ray diffraction spectrum presents the following d (Á) values: 7,597; 3,798; 2.6202; 2,5698; 2.5322; 2.2830; 1.93545; 1,72447; 1,62930; 1.52289; 1,49318; 1.46002; 1,41351; 1,38528 and 1,31011 (Table 1). Table 1 Observed Calculated [3] Intensity Explanation of the columns: H, K, L: Location of the reticular parameters of the compound (elementary cell) that allow assigning a triplet of indices or integers (H, K, L) _ to each diffraction line. 2 -? : An angular variable that denotes the angular position where the diffraction line (H, K, L) appears in the diagram. If we know the elementary cell of the compound and the triplet (H, K, L), we can calculate the theoretical position that must coincide with the observed one (obs .: observed, cal .: calculated). Intensity: It gives the height of the diffraction line that is characteristic of the atomic positions in the crystalline cell, unlike the angular position that is characteristic of the dimensions of the crystalline cell, d .: atomic spacing. It is also characteristic of the elementary cell of the compound and unlike 2-? it is independent of the wavelength of the radiation used. Rhombohedral system. Reticular parameters: a = b = 3,046 Á; c = 22.79 A; a = ß = 90 °; ? = 120 °. Volume of the crystalline cell = -18-3 A3.

Analogously, the infrared spectrum has bands at 3500-3400 (wide) (Figure 11), 1361, 785 and 449 cm "1 (Figure 1), with only the last three being characteristic, and its DSC (Differential Scanning Calorimetry) -se Represents in 1-a Figure Some aluminum and magnesium carbonates are already known in chemistry and are used as antacids in therapeutics. Some examples are Hydrotalcite (Talcid), of formula Al..Mg? (OH) lriCO .4H, 0 and which is obtained according to patents US 3,539,306 and US 3,650,704; the Almagato (marketed as Almax and Almax Forte), of formula Al2Mg6 (OH) 14 (C03) 2, 4H20 and obtained according to patents US 4,447,417 and 4,560,545; or the compound of the formula Al2Mg6 (OH) 12 (C03) 3.xH20 of the patent US 4,539,195.

The compound object of the present invention (I) is different from the compounds of the aforesaid patents and it is not obvious in spite of the similarity of its chemical formulas. Indeed, the compound (I) has a unique crystalline structure, as demonstrated by X-ray diffraction (Table 1). Likewise, the DSC thermogram demonstrates the existence of a unique compound with its own structure (Figure 2). The compound of the present invention possesses antacid properties and, moreover, advantageously, it has a superior gastroprotective activity against the already known compounds.

The safety and efficacy of the compound of the present invention, obtained in Example 1, has been demonstrated by the Irwin test (safety) and the determination of its antacid and gastroprotective activity (efficacy).

Test, by Irrwin: It has been carried out according to the technique described by R.A. Turner (Screening-Methods in Pharmacology, 1965, pp. 27-34, Academic Press, New York and London). In this test, the compound of Example 1 and the Almagato preparation were administered comparatively orally to Swiss mice of both sexes at doses of 0.3, 1 and 3 g / Kg in a volume of administration of 30 mL / Kg. None of the three tested doses have been modified the parameters evaluated in the test (knowledge and disposition, reflexes, locomotor coordination, excitation of the CNS, muscle tone, ocular parameters, secretion and excretion, general registry, acute mortality and delayed mortality) in none of the groups, highlighting the absence of changes in defecation and mortality. The Irwin test thus demonstrates the safety of the compound of Example 1 and the preparation of Almagato.

Antacid activity: The determination of the antacid activity was carried out in female Wistar rats weighing 140-160 g, placed fasting in metabolism cages from 24 h before the experiment, with free access to drinking water up to 1 h before of the beginning of the experience. The animals were anesthetized with a mixture of Ketolar (91 mg / Kg) and Thiazine (3.6 mg / Kg) and they were "practiced a laparotomy, carefully ligating the pylorus" (H. Shay et al., "Gastroenterology" , 1954, 5_, 43-61) and closing the abdominal cavity by sterile suture, after 3 h of having ligated the pylorus, and the animals being conscious -, - They administered the products orally. A group of 10 animals received the compound of Example 1, in suspension of 0.25% Bacto-agar, at a dose of 125 mg / kg and another group of 10 animals at a dose of 62.5 mg / kg, all in front of to a control group of 10 animals that received 10 mL / Kg of 0.25% Bacto-agar. In the same way the experience with the Almagato preparation was repeated at the same doses and using equal numbers of animals, using another new control group of 10 animals that received Bacto-agar at the same dose as in the experience with the compound of Example 1 60 minutes after the administration of the products, the animals were sacrificed and the gastric content was collected. After determining the volume of each sample, they were centrifuged at 3000 rpm for 10 minutes, the supernatant was separated and the pH and concentration of hydrochloric acid were determined in the samples obtained by titration (Titrilab, Radiometer). The results obtained are shown in Table 2.

Table 2 [1] mg / Kg; [2] Gastric volume (mL); [3] Acid secretion (mEq / L) [4] Acid secretion (Percentage of Inhibition) (*) 10 mL / Kg These results allow to conclude that if the compound of the present invention at a dose of 125 mg / Kg exhibits an acid neutralizing activity similar to that obtained with the same dose of Almagato preparation, advantageously, at a dose of 62.5 mg / Kg, its neutralizing activity- is much higher than that obtained with the same dose of Almagato preparation.

Gastroprotective activity: It has been carried out following the experimental method described by A. Robert et al. (Gastroenterology, 1979, 77. (3), 433-443). The determination of the gastroprotective activity was carried out by studying gastric necrosis induced by ethanol. The experiment was carried out with female Sprague-Dawley rats weighing 180-200 g, maintained fasting for 24 h before the start of the test. Analogously to the previous study, the compound of the present invention was compared with the Almagato preparation The compound of Example 1 was administered in a suspension of 0.25% Bacto-agar The two products to be studied were administered via orally at doses of 100 and 50 mg / rat In parallel, a control group received 0.25% Bacto-agar.At 30 minutes absolute ethanol was administered to the animals at a dose of 1 mL / r & 60 minutes after the ethanol was administered, they were sacrificed and the length of the lesions present in the gastric mucosa was evaluated.The results obtained are shown in Table 3.

Table 3 [1] number of animals; [2] mm These results demonstrate that the compound of the present invention is slightly superior to the preparation of Almagato as gastroprotector a. the dose of 50 mg / rat, but notably higher than the dose of 100 mg / rat.

Duration of the gastroprotective activity: Sprague-Dawley rats of female sex and 180-200 g of weight maintained in the same conditions as in the previous experiment have been used for this test. In the test the compound object of the present invention was compared with the Almagato preparation. For this, a suspension of the compound of Example 1 was prepared in 0.25% Bacto-agar. The products studied were administered orally at a single dose of 250 mg / rat at 90 and 180 minutes before the administration of absolute ethanol at a dose of 1 mL / rat. The animals were sacrificed 60 minutes after the administration of ethanol and the length of the lesions present in the gastric mucosa was evaluated. The results obtained are shown in Tables 4 (90 minutes) and 5 (180 minutes). Table 4 [1] number of animals; [2] mm Table 5 [1] number of animals; [2] mm The results obtained show that the compound of the present invention shows, advantageously and surprisingly, a more prolonged gastroprotective action than the preparation of Almagato, increasing the difference in favor of the compound of Example 1 with the passage of time.

From all the pharmacological experiences that the applicants have made, it can be stated that the compound of the present invention is characterized by inhibiting the acid secretion of the stomach, thereby decreasing the aggressive factors acting on the gastric mucosa and, moreover, surprisingly , has a superior gastroprotective action in potency and duration at prepares or e maga or, or that is sold salemente in a much more effective improvement of the defense mechanisms of the gastric mucosa. In conclusion, the compound object of the present invention has therapeutic application as an antacid and gastroprotector. It can be administered in cases of hyperchlorhydria, gastritis, gastroduodenitis, dyspepsia, esophagitis, diverticulitis, hiatus hernia, gastric ulcer, duodenal ulcer, post-gastric patients, vaguectomized patients, and in general as a relief of all those conditions or situations that produce a increase in heartburn.

The compound object of the present invention can be administered orally, mixed with suitable excipients in the form of suspensions, granules, tablets, capsules, powders, dragees and the like, at daily doses between 250 mg and 10 g, preferably between 1 and and 6 g.

Example 1: Aluminum magnesium carbonate hydroxide trihydrate.de (Al.Mg., (OH) 12CO, .3HO) (I) In a 1 L balloon are suspended 9.44 g of aluminum hydroxide (corresponding to 5.4 g of A1.0, 53 mmol), 12.37 g of Mg (OH) 2 (212 mmol) and 34, 4 g of NaHCO., (409 mmol) in 400 L of water. Heat to reflux for 3 hours. Allow to cool, filter and wash the solid with water (2 x 300 mL). The pH of the water should be 10. The solid is dried under vacuum at 60 ° C for 20 hours. The solid obtained is again suspended in 400 mL of water and heated to reflux for 24 hours. The solid is filtered, washed with water and dried under vacuum at 60 ° C. The yield is 90%. IR (KBr): 3500-3400 (non-specific band) (Figure 11), 1361, 785 and 449 cm "1 (Figure 1) DSC (Differential Scanning Calorimetry): Figure 2.

Crystallographic analysis by X-ray diffraction: It has been carried out with a Siemens D5000 diffractometer. In the course of the experience, the following parameters have been set: Measurement interval in 2? ** 5-105 ° Angular increase: 0.02 Time per step: 2.5 seconds Radiation A = 1.54056 A Power: 1.8 kW Receiving sliver: 0.2 ° Divergence divergence: Io The values of the d (A) found have already been indicated previously in Table 1.

Example 2: Preparation of a suspension of aluminum hydroxide carbonate magnesium trihydrate Formula for 100 mL of suspension: Hydroxide magnesium aluminum carbonate trihydrate .- 10.00 g methyl p-hydroxybenzoate 0.16 g Propyl p-hydroxybenzoate 0.04 g Methylcellulose 400 cps 1, 03 g Sorbitol 70% 24.00 g Saccharin sodium 0.10 g Dimethicone 0.20 g Peppermint essence 0.05 g Distilled water csp 100.00 mL This suspension can be presented in 100 mL containers or in single-dose sachets of 15 mL with an active substance content of 1.5 g.

E-i emplo 3: Preparation of a dispersible granulate of Hydroxide aluminum magnesium carbonate trihydrate Formula for 5 g of granulated hydroxide aluminum magnesium carbonate trihydrate "" 1, 50 g Dimethylpolysiloxane. ' 0.20 g Sorbitol powder _. 1, 00 g Saccharin sodium 0,? R__ g Polyvinyl pyrrolidone K-25 - 0,03 g Butylhydroxytoluene 0.0005 g Lemon aroma 0.0050 g Powdered skim milk csh 5, .0000 g This granulate is packaged in single-dose sachets for dispersion in water.

Example 4: Preparation of chewable tablets of Hydroxide aluminum magnesium carbonate trihydrate Formula per 500 mg tablet Hydroxide aluminum magnesium carbonate trihydrate 500 mg Microcrystalline cellulose 120 mg Polyvinylpyrrolidone 50 mg Talc ...... 20mg Magnesium stearate .. ~. 10 mg Mint aroma 5 mg Mannitol csh 1200 mg These tablets are packed in aluminum tube or in blister and are for desleír in the mouth or mas_ticar.

Claims (2)

1) - A basic carbonate of aluminum and magnesium of formula AlMg4 (OH) 1CO, .3H20 (I) and rhombohedral crystallization, which is used in Therapeutic as an antacid and gastroprotective, whose reticular parameters are a = b = 3,046 A; c = 22.79 A; a = ß = 90 °; ? = 120 ° and cell volume = 183 A3, whose X-ray diffraction spectrum presents the following d (Á) values: 7,597; 3,798; 2.6202; 2,5698; 2.5322; 2.2830; 1.93545; 1,72447; 1,62930; 1.52289; 1,49318; 1.46002; 1,41351; 1,38528 and 1,31011; whose infrared spectrum has characteristic bands at 1361, 785 and 449 cm "1 (Figure 1 ') and whose DSC (Differential Scanning Calorimetry) is represented in Figure 2.

2) - A process for obtaining the compound of claim 1, characterized by reacting the aluminum hydroxide with magnesium hydroxide, in a molar ratio of 1 to 2 respectively, and an excess of sodium acid carbonate in aqueous medium and at a temperature of boiling the mixture, followed by the proper operations of isolation and purification.