JP2001516328A - Basic magnesium aluminum carbonate, method for its preparation and its use as a pharmaceutical composition for treating gastric acidity - Google Patents

Abstract

(57) [Summary] The present invention relates to a compound of the formula (I): Al ₂ Mg ₄ (OH) ₁₂ CO ₃ . A novel basic magnesium aluminum carbonate of 3H ₂ O and rhombohedral crystals, the network parameters of which are a = b = 3.046 °; c = 22.79 °; α = β = 90 °; is the volume = 183Å ^3, shows a d (Å) value of the X-ray diffraction spectrum follows: 7.597; 3.798; 2.6202; 2.5698; 2.5322; 2.2830; 1.93545 1.72447; 1.62930; 1.52289; 1.49318; 1.60002; 1.41351; 1.38528; and 1.31011, whose infrared spectra are characteristic bands at 1361 and 449 cm ^-1 (FIG. The present invention relates to the novel basic magnesium aluminum carbonate, which shows 1) and whose differential operating calorimetry (DSC) is illustrated in FIG. This compound is used in therapy as an antacid and a gastroprotectant.

Description

DETAILED DESCRIPTION OF THE INVENTION          Basic magnesium aluminum carbonate, method for producing the same, and          Use thereof as a pharmaceutical composition for treating gastric acidity   The present invention relates to the formula Al_TwoMg_Four(OH)₁₂CO_Three. 3H_TwoO (I) and rhombohedral (rhombic New basic magnesium aluminum carbonate in the form of Meters a = b = 3.046 °; c = 22.79 °; α = β = 90 °; γ = 1 20 ° and cell volume = 183 °^ThreeAnd its X-ray diffraction spectrum is d (Å) Indicates values: 7.597; 3.798; 2.6202; 2.5698; 5322; 2.2830; 1.93545; 1.72447; 1.62930; 1.52289; 1.49318; 1,46002; 1.41351; 1.38 528; and 1.31011, whose infrared spectra are 1361, 785 and 449cm^-1(FIG. 1) and its differential scanning calorimetry (DS) C) is illustrated in FIG.   The compounds of this invention can be used in aqueous media at the boiling temperature of the mixture, By reacting with magnesium hydroxide and sodium acid carbonate You. The stoichiometric ratio of aluminum hydroxide to magnesium hydroxide should be 1: 2. It is. The acidic sodium carbonate is in molar excess so that the pH of the medium is 9-11. Used. Once the system has cooled, the product is separated by filtration. Warmed to 50-70 ° C. until it becomes a sign of weight that is washed with water and provides a solid. The solid is resuspended in water and heated to reflux. Filter the solid Filter, wash with water and vacuum dry at a temperature of 50-70 ° C. ) As a crystal, magnesium aluminum hydroxide carbonate trihydrate (Al_Two Mg_Four(OH)₁₂CO_Three. 3H_TwoO) (I) is obtained. The net parameters are a = b = 3.046 °; c = 22.79 °; α = β = 90 °; γ = 120 °. Conclusion Crystal cell volume is 183Å^ThreeAnd the X-ray diffraction spectrum is the following d (Å) Values are shown: 7.597; 3.798; 2.6202; 2.5698; 5322; 2.2830; 1.93545; 1.72447; 1.6 2930; 1.52289; 1.49318; 1.60002; 1.41351. 1.38528 and 1.31011 (Table 1). (1): observed value, (2): calculated value, (3): intensityDescription of the columns in the table: H. K. L : Indices for each line of diffraction or integer triplet (Elemental cell) which makes it possible to give (triplet) (HKL) (Elemental cell)).2-θ : Variable angle number indicating the angular position where the diffraction line (HKL) appears on the figure. If book If the element cell and triplet (HKL) of the compound are known, the observation position and The theoretical positions that should match can be calculated (obs .: observations, ca l. :Calculated value).Strength: It is a characteristic of the dimensions of the crystal cell, that It provides the height of the diffraction line, which is a characteristic of the position of the atoms in the beam.d: Atomic spacing. It is also characteristic of the elemental cell of the compound and unlike 2-β As such, it is independent of the wavelength of the radiation used.Rhombohedral (rhombohedral) system: Reticulated parameters: a = b = 3.046 °; c = 22.79 °; α = β = 90 °; γ = 120 °. Crystal cell volume = 183Å^Three.   Similarly, the infrared spectrum is 3500-3400 (width) (FIG. 1 '), 1361, 785 and 449 cm^-1The bands in FIG. 1 are shown and the last three bands are only This is one of the features. Differential scanning calorimetry (DSC) is illustrated in FIG.   Some magnesium aluminum carbonates are used as antacids in treatment Is already known. U.S. Pat. Nos. 3,539,306 and 3,650,704 (Formula Al_TwoMg₆(O H)₁₆CO_Three. 4H_TwoO hydrotalcite [Ta lcid^TM]), U.S. Patent Nos. 4,447,417 and 4,560,545. No. (Formula Al_TwoMg₆(OH)₁₄(CO_Three)_Two. 4H_TwoAlmagate of O (almag ate) [Almax^TMAnd Almax^TMForte]) and U.S. Pat. No. 539,195 (formula Al_TwoMg₆(OH)₁₂(CO_Three)_Three. xH_TwoO compound) Thus, the prepared compounds can be used.   Compound (I) of the present invention differs from the compounds disclosed in the above patents and Despite the similarities between the chemical formulas, they are not obvious. Book in fact Compound (I) was prepared as clearly shown by its X-ray diffraction spectrum (Table 1). It has a unique crystal structure. Similarly, the DSC autograph thermogram has an appropriate structure. The presence of the obtained unique compound is shown (FIG. 2). The compounds of the present invention And also show advantageous and superior gastroprotective activity over known compounds.   The safety and efficacy of the compounds of the invention obtained according to Example 1 were determined by the Irwin test (Safety) and by measuring its antacid activity and gastroprotective activity (efficacy) Was done. Irwin test: (Academic, New York and London, 1965)   Press issuance Screening Methods in Pharmacology, pp. 27-34). A. Described by Turner Technology was used. In this comparative test, the compound of Example 1 and almagate (Algamate) at a volume of 30 ml / kg, 0.3, 1 and 3 g / kg Dosage was administered orally to either male or female Swiss rats. Which guru Parameters (consciousness and mood, reflexes, motor activity, central deity) Trans (CNS) agitation, muscle tone, optical signs, secretory-excretion signs, systemic signs, acute mortality And delayed mortality), the three doses tested did not induce a change and It should be emphasized that there is no change in defecation and mortality. Therefore Ir Win test shows safety of compound of Example 1 and almagate did.   Antacid activity: The measurement of antacid activity is based on a female Wistar weighing 140-160 g. Made in the mouse. Place the animals in metabolic cages and at 24 hours of the experiment Fasted until one hour before the start of the experiment, but water was allowed ad libitum. Animals Ketoral (91 mg / kg) and thiazine ) (3.6 mg / kg) and then laparotomy was performed: inject pylorus The ligature was carefully ligated and the abdominal cavity was closed using a disinfecting suture (H. Shay et al., "Gast roenterology "1954,5  43-61). 3 hours of pyloric ligation The conscious animals were later given the test medication orally. One glue of ten animals Example 1 in a 0.25% Bacto-agar suspension at a dose of 125 mg / kg And another group of 10 at a dose of 62.5 mg / kg Receipt: 10 animals dosed at 10 ml / kg of 0.25% Bacto-agar Control groups were used. Similarly, almagate (almag) at the same dose ate) and using the same number of animals, the experiment was repeated: 10 animals A new control group of the same dose of Bacto as in the experiment with the compound of Example 1 -Agar was given. Sixty minutes after dosing, the animals are sacrificed, the stomach contents are collected and The capacity was measured. The test sample was centrifuged at 3000 rpm for 10 minutes, and the supernatant was separated. Release and titration of the pH and concentration of hydrochloric acid in the test article (Titrilab, R adiomater). Table 2 shows the obtained results.[1] mg / kg, [2] gastric volume (ml), [3] acid secretion (m equivalent / 1), [ 4] acid secretion (inhibition rate), (*) 10 ml / kg   From the above results, a dose of 125 mg / kg of the compound of this invention is the same Acid neutralization similar to that of almagate at room temperature However, at a dose of 62.5 mg / kg, its acid-neutralizing activity was It can be concluded that it is superior to the acid neutralizing activity of the gate. Gastroprotective activity: To determine gastroprotective activity, A. Robert et al. Experimental method for ethanol-induced gastric necrosis (Gastroenterology, 1). 979,77(3) 433-443) were used. The experiment is 2 Female Sprague-D weighing 180-200 g fasted for 4 hours performed in the awley rat. This is done in the same way as in the test described above. The compounds of the invention were compared to almagate. Compound of Example 1 , 0.25% Bacto-agar suspension. 100 m for both test products It was administered orally at doses of g / kg and 50 mg / kg. At the same time, contrast The group received 0.25% Bacto-agar. 30 minutes later, 1ml / ne Animals received a dose of absolute ethanol. 60 doses of ethanol After minutes, the animals were sacrificed and the length of the lesion in the gastric mucosa was measured. Table 3 shows the obtained results. [1] Number of animals, [2] mm   These results indicate that the present invention was used as a gastroprotector. Myo Compound at 50 mg / mouse dose from Almagate A little better, but at a dose of 100 mg / mouse It shows that it is excellent.Duration of gastroprotective activity:   Female Sprague-Daw weighing 180-200 g for this experiment A rey mouse was used and maintained under the same conditions as the experiments shown above. This Was compared with almagate. 0.25% B A suspension of the compound of Example 1 in acto-agar was made. 250 test products mg / mouse in a single dose, given orally, 90 minutes and 180 minutes later Absolute ethanol was administered at a dose of 1 ml / mouse. 60 minutes of ethanol administration Later, the animals were sacrificed and the length of the lesion in the gastric mucosa was measured. Get The results obtained are shown in Table 4 (90 minutes) and Table 5 (180 minutes). [1] Number of animals, [2] mm [1] Number of animals, [2] mm   The results show that the compounds of the invention have an advantage over almagate And has a surprisingly long duration of gastroprotection and The difference increases preferentially over time with the compound of Example 1.   From the pharmacology studies performed here, the compounds of the invention inhibit gastric acid secretion. Control gastrointestinal mucosal invasive factors and also provide a surprising gastroprotective effect It can be concluded that it is characterized by showing. According to the compound of the present invention The gastroprotection provided is more potent and longer than almagate Which has the advantage of improving the defense mechanisms of the gastric mucosa more effectively. Occurs. Finally, the therapeutic application of the compounds of this invention is with antacids and gastroprotectors. And hyperchlorhydria, gastritis, gastroduodenum, dyspepsia, esophagitis, diverticulitis, Hytal hernia, gastric and duodenal ulcer, patients after gastric surgery, To treat patients who have undergone vagal transection and All disorders or episodes causing acidity For administration. Compounds of this invention mixed with a suitable carrier , Suspension, granules, tablets, capsules, powders, coated tablets, etc. It can be administered orally at a daily dose in the range of 0 g, preferably 1-6 g. come.Example 1: Magnesium hydroxide aluminum carbonate trihydrateAl ₂ Mg ₄ (OH) ₁₂ CO ₃ . 3H ₂ O (I)   9.4 of aluminum hydroxide in 400 ml of water in a 1 liter round bottom flask 4g (Al_TwoO_Three5.4 g; 53 mmol), Mg (OH)_Two12.3 of 7 g (212 mmol) and NaHCO_Three34.4 g (409 mmol) of suspension The suspension was heated under reflux for 3 hours. After cooling, the insoluble compounds were filtered and washed with water (2 × 30 0 ml) and vacuum dried at 60 ° C. for 20 hours. PH of water is 10 Should. The obtained solid was resuspended in 400 ml of water and added under reflux for 24 hours. Heated, washed with water and vacuum dried at 60 ° C. The yield was 90%. IR (KBr): 3500-3400 (non-specific band) (FIG. 1 '), 1361, 785 and 449 cm^-1(FIG. 1). DSC (differential scanning calorimetry): FIG.X-ray diffraction crystal structure analysis analysis:   A Siemens D5000 diffractometer was used. In the course of the experiment And adapted to the following parameters: Measurement interval at 2-θ: 5-105 ° Angle increase: 0.02 Interval time: 2.5 seconds Irradiation λ = 1.40556 ° Potency: 1.8 kW Receiver slot: 0.2 ° Divergency slot: 1 °   The values found for d (Å) are already shown in Table 1.Example 2: Preparation of a suspension of magnesium aluminum hydroxide carbonate trihydrate:Formulation per 100ml of suspension Magnesium aluminum hydroxide carbonate trihydrate 10.00g 0.16 g of methyl p-hydroxybenzoate 0.04 g of propyl p-hydroxybenzoate Methylcellulose 400cps 1.03g Sorbitol 70% 24.00g Saccharin sodium 0.10g Dimethicone 0.20g Mint (mint piperita) flavoring 0.05g Amount to make 100 ml of distilled water   This suspension may be placed in a 100 ml container or may contain 1.5 g of the active ingredient. In a 15 ml unit dose sachet containingExample 3: Preparation of dispersible granules of magnesium aluminum hydroxide carbonate trihydrate:Formulation per 5g of granules Magnesium aluminum carbonate trihydrate 1.50 g Dimethylpolysiloxane 0.20g Sorbitol powder 1.00g Saccharin sodium 0.01g Polyvinyl pyrrolidone K-25 0.03 g 0.0005 g of butylhydroxytoluene 0.0050g lemon flavor Skim milk powder 5.000g amount   The granulate is placed in a unit dose small container for its dispersion in water.Example 4: Preparation of chewing tablets of magnesium aluminum hydroxide carbonate trihydrate:Formulation per 500 mg tablet: Magnesium hydroxide aluminum carbonate trihydrate 500mg Microcrystalline cellulose 120mg Polyvinyl pyrrolidone 50mg 20mg talc Magnesium stearate 10mg Mint flavoring 5mg Mannitol 1200mg   These tablets are placed in aluminum tubes or blisters May be put in and dissolved or chewed in mouth.

────────────────────────────────────────────────── ─── Continuation of front page    (72) Inventors Castelo and Joseph Em.             Spain, Barcelona, Prince Puda             Stries, 35 (72) Inventor Alteis, Jose A.             Spain, Barcelona, Corsega, 429

Claims (1)

Claims: 1. Formula Al ₂ Mg ₄ (OH) ₁₂ CO ₃ . 3H ₂ O (I) and rhombohedral basic magnesium aluminum carbonate, whose network parameters are a = b = 3.046 °; c = 22.79 °; α = β = 90 ° C .; γ = 120 ° C. and a cell volume = 1 83 Å ^3, the X-ray diffraction spectrum shows the following d (Å) values: 7.59 7; 3.798; 2.6202; 2.5698; 2.5322; 2.2830 1.93545; 1.72447; 1.6930; 1.52289; 1.49 318; 1.60002; 1.41351; 1.38528; and 1.31011, whose infrared spectra are 1361, 785 and 449 cm. The basic magnesium aluminum carbonate described above, which exhibits a characteristic band at ^-1 (FIG. 1 ') and DSC (differential scanning calorimetry) is illustrated in FIG. 2. In an aqueous medium and at the boiling temperature of the mixture, the aluminum hydroxide is reacted with magnesium hydroxide and with an excess of sodium bicarbonate in respective molar ratios from 1: 2 and thereafter the standard isolation and A process for preparing a compound of claim 1 comprising operating by using purification techniques. 3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 4. Use of a compound according to claim 1 for making a pharmaceutical composition for treating increased acidity in the stomach. 5. A method for treating increased acidity in the stomach comprising administering to a mammal an effective amount of the compound of claim 1.