AU2276799A - Basic aluminum magnesium carbonate, method for the preparation thereof and its use as a pharmaceutical composition for treating stomach acidity - Google Patents

Description

WO 99/35088 PCT/EP98/08498 BASIC ALUMINUM MAGNESIUM CARBONATE, METHOD FOR THE PREPARATION THEREOF AND ITS USE AS A PHARMACEUTICAL COMPOSITION FOR TREATING STOMACH ACIDITY 5 The present invention relates to a new basic aluminum magnesium carbonate of the formula Al 2 Mg 4

(OH)

12

CO

3 .3H 2 0 (I) and rhombohedral crystallization, whose reticular parameters are a=b=3,046 A; c=22,79 A; a==90 0 ; y=120 0 and cell volume = 183 ', whose X-ray diffraction spectrum shows the following d(A) 10 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, 785 and 449 cm - 1 (Figure 1) and whose differential scanning calorimetry (DSC) is illustrated 15 in Figure 2. The compound of this invention is prepared by reacting aluminum hydroxide with magnesium hydroxide and sodium acid carbonate in an aqueous medium at the boiling temperature of 20 the mixture. The stoichiometric ratio of aluminum hydroxide to magnesium hydroxide should be 1:2. The sodium acid carbonate is used in a molar excess, in such a way that the medium pH ranges between 9 and 11. Once the system is cooled, the product is separated by filtration, washed with water and 25 dried in vacuo at a temperature between 50 and 70 0 C until evidence of weight to give a solid, which is suspended in water again and heated at reflux. The solid is filtered, washed with water and dried in vacuo at a temperature between WO99/35088 PCT/EP98/08498 2 50 and 70 0 C to give the compound, aluminum magnesium carbonate hydroxide trihydrate (Al 2 Mg 4 (OH) 12

CO

3 .3H 2 0) (I) as rhombohedral crystals. Its reticular parameters are a=b=3,046 A; c=22,79 A; a=0=90 0 ; y=120 0 . The crystalline cell 5 volume is 183 A 3 and the X-ray diffraction spectrum shows the following d(A) 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). 10 Table 1 [HK L11 2-8 obs.' 2-E cal. I d 0 0 3 11,708 11.705 0.003 700 7.597 0 0 6 23.467 23.467 0.000 300 3.798 1 0 1 34.260 34.258 0.002 40 2.6202 15 0 1 2 34.947 34.951 -0.004 190 2.5698 0 0 9 35.533 35.485 0.048 40 2.5322 0 1 5 39.492 39.503 -0.011 150 2.2830 0 1 8 46.958 46.971 -0.013 130 1.93545 1 0 10 53.067 53.127 -0.060 40 1.72447 20 0 1 11 56.467 56.494 -0.027 30 1.62930 1 1 0 60.858 60.835 0.023 90 1.52289 1 1 3 62.183 62.177 0.006 85 1.49318 1 0 13 63.758 63.751 0.007 7 1.46002 1 1 6 66.108 66.107 0.001 5 1.41351 25 0 1 14 67.654 67.632 0.022 5 1.38528 2 0 2 72.092 72.089 0.003 4 1.31011 i Observed i21 Calculated 31 Intensity 30 WO99/35088 PCT/EP98/08498 3 Explanation of the columns: H. K, L: Sites of the reticular parameters of the compound (elemental cell) that allow to assign a triplet of indices or integers (H. K. L) to each line of diffraction. 5 2-0: Angular variable that shows the angular position where the line of diffraction (H. K. L) appears on the diagram. If the elemental cell of the compound and the triplet (H. K. L) are known, the theoretical position, which should coincide with the observed one, can be calculated (obs.: observed; 10 cal.: calculated). Intensity: It provides the height of the diffraction line, which is characteristic of the atomic positions in the crystalline cell, in contrast to the angular position, which is characteristic of the size of the crystalline cell. 15 d: atomic spacing. It is also characteristic of the elemental cell of the compound and, unlike 2-e, it is independent of the wavelength of the radiation used. Rhombohedral system. Reticular parameters: a=b=3.046 A; c=22.79 A; =P==90*; 20 y=120 0 . Volume of the crystalline cell = 183 A 3 . Similarly, the infrared spectrum shows bands at 3500-3400 (wide) (Figure 1'), 1361, 785 and 449 cm - (Figure 1), the three last bands being only characteristic. The differential 25 scanning calorimetry (DSC) is illustrated in Figure 2. Several aluminum magnesium carbonates are already known to be used as antacids in therapeutics. As examples of aluminum WO99/35088 PCT/EP98/08498 4 magnesium carbonates, those prepared in accordance with US Patents Nos. 3,539,306 and 3,650,704 (hydrotalcyte [TalcidTM] of the formula Al 2 Mg 6

(OH)

16

CO

3 .4H 2 0), US Patents Nos. 4,447,417 and 4,560,545 (almagate [AlmaxTM and Almax

T

M Forte] of the 5 formula Al 2 Mg6(OH) 14

(CO

3

)

2 .4H20, and US Patent No. 4,539,195 (compound of the formula Al 2 Mg 6 (OH) 12

(CO

3

)

3 .xH 2 0) can be used. The compound of the present invention (I) is different from the compounds disclosed in the aforesaid patents and does not 10 turn to be obvious despite the similarity between their chemical formulas. As a matter of fact, the compound (I) has a unique crystalline structure as evidenced by its X-ray diffraction spectrum (Table 1). Likewise the DSC thermogram shows the presence of a properly structured unique compound 15 (Figure 2). The compound of this invention has antacid properties and also exhibits an advantageous superior gastroprotective activity over known compounds. The safety and efficacy of the compound of this invention 20 obtained according to Example 1 has been demonstrated by Irwin test (safety) and by measurement of its antacid and gastroprotective activities (efficacy). Irwin test: The technique described by R.A. Turner (Screening 25 Methods in Pharmacology, 1965, p. 27-34. Academic Press, New York and London) was employed. In this comparative test, the compound of Example 1 and almagate were orally administered to Swiss mice of either sex at doses of 0.3, 1 and 3 g/kg in WO99/35088 PCT/EP98/08498 5 a volume of 30 mL/kg. None of the three doses tested induced changes in the parameters assessed (awareness and mood, reflexes, motor activity, CNS excitation, muscle tone, optical signs, secretory-excretory signs, general signs, 5 acute mortality and delayed mortality) in either group, and the absence of changes in the defecation and mortality should be emphasized. Therefore, Irwin test revealed the safety of the compound of Example 1 and almagate. 10 Antacid activity: Measurement of the antacid activity was performed in female Wistar rats, weighing 140 - 160 g. The animals were housed in metabolism cages and fasted from 24 h before the experiment to 1 h before the start of experiment but with free access to water. The animals were anesthetized 15 with a mixture of Ketolar (91 mg/kg) and Tiazine (3.6 mg/kg) and then laparotomized; the pylorus was carefully ligated and the abdominal cavity was closed using a sterile suture (H. Shay et al. "Gastroenterology", 1954, 5, 43-61). Three hours after the pyloric ligature, test drugs were given orally to 20 the conscious animals. One group of 10 animals received the compound of Example 1 in 0.25% Bacto-agar suspension at a dose of 125 mg/kg and another group of 10 animals at a dose of 62.5 mg/kg; a control group of 10 animals dosed with 10 mL/kg of 0.25% Bacto-agar was used. Similarly, the experiment 25 was repeated with almagate at the same doses and using the same number of animals; a new control group of 10 animals was given the same dose of Bacto-agar as in the experiment with the compound of Example 1. Sixty minutes after the WO99/35088 PCT/EP98/08498 6 administration, the animals were sacrificed, the gastric contents was collected and volume was determined. The specimens were centrifuged at 3000 rpm for 10 minutes, the supernatant was separated, and ph and concentration of 5 hydrochloric acid in the specimens were determined by titration (Titrilab, Radiometer). The results obtained are presented in Table 2. Table 2 Dose Gas.vol. Ac.sec. Ac.sec. 10 Product pH [1] [2] [3] [4] Bacto-agar (*) 3.8±0.4 1.7±0.04 88.7±4.2 -- Example 1 125 4.6±0.2 3.2±0.2 42.4±1.8 52% 62.5 3.9±0.3 2.7+0.3 44.0±5.8 50% Bacto-agar (*) 3.6+0.4 1.7±0.2 65.9±3.8 -- 15 Almagate 125 4.5±0.2 3.8±0.2 28.0±3.8 57% 62.5 4.0+0.2 2.8±0.2 47.3±6.3 28% [1] mg/kg.[2] Gastric volume(mL) . [3] Acid secretion (mEq/L) [4] Acid secretion (Inhibition rate)(*)10 mL/Kg 20 It can be concluded from the above results that although a dose of 125 mg/kg of the compound of this invention causes acid neutralization similar to that of almagate at the same dose, at a dose of 62.5 mg/kg its acid neutralizing activity 25 is superior to that of almagate at the same dose. Gastroprotective activity: To measure the gastroprotective activity the experimental method of ethanol-induced gastric necrosis described by A. Robert et al. (Gastroenterology, 30 1979, 77(3), 433-443) was employed. The experiment was WO99/35088 PCT/EP98/08498 7 carried out in female Sprague-Dawley rats weighing 180-200 g which were fasted since 24 h before the start of experiment. The compound of this invention was compared to almagate in the same manner as in the preceding test. The compound of 5 Example 1 was administered in a 0.25% Bacto-agar suspension. Both test products were administered orally at doses of 100 and 50 mg/kg. Simultaneously, a control group received 0.25% Bacto-agar. After 30 minutes, the animals were given absolute ethanol at a dose of 1 mL/rat. Sixty minutes after ethanol 10 administration, the animals were sacrificed and the length of lesions in the gastric mucosa measured. The results obtained are tabulated in Table 3. Table 3 Dose n Mean length of 15 Product Inhibition mg/rat [I] lesion [2] Bacto-agar --- 21 59.62±6.77 -- Example 1 100 8 28.90±6.44 52% 50 7 40.18±3.77 33% Almagate 100 7 49.13±10.25 18% ] 20 50 7 43.30±11.84 27% j [11 Number of animals; [2] mm These results show that the compound of the present 25 invention, as a gastroprotector, is slightly superior to almagate at the dose of 50 mg/rat, but remarkably superior to almagate at the dose of 100 mg/rat.

WO 99/35088 PCT/EP98/08498 8 Duration of the gastroprotective activity: For this experiment, female Sprague-Dawley rats weighing 180-200 g were used and kept under the same conditions as in the preceding experiment. The compound of this invention was 5 compared to almagate. A suspension of the compound of Example 1 in 0.25% Bacto-agar was prepared. Test products were given orally at a single dose of 250 mg/rat 90 and 180 minutes prior to the administration of absolute ethanol at a dose of 1 mL/rat. Sixty minutes after ethanol administration, the 10 animals were sacrificed and the length of lesions in the gastric mucosa was measured. The results obtained are presented in Table 4 (90 minutes) and Table 5 (180 minutes) Table 4 15 Product n [1] Length of lesion [2] Inhibition Bacto-agar 14 81.62±7.66 -- Example 1 7 25.84±8.40 68% Almagate 7 39.27±21.39 52% 20 [1] number of animals; [2] mm Table 5 Product ]n [1] Length of lesion [2] Inhibition Bacto-agar 14 76.13±6.21 -- 25 Example 1 7 14.41±4.70 81% Almagate 7 68.89±8.18 10% [1] number of animals; [2] mm WO99/35088 PCT/EP98/08498 9 The results show that the compound of this invention has advantageously and surprisingly a longer duration of gastroprotective action than almagate, and the difference was increased in favour of the compound of Example 1 along the 5 time course. From the pharmacological tests that the applicants have performed, it can be concluded that the compound of this invention is characterized by inhibiting the stomach acid 10 secretion, minimizing the aggressive factors on the gastric mucosa and, in addition, exhibiting a surprising gastroprotective action. The gastroprotection afforded by the compound of this invention has a higher potency and longer duration than almagate, which advantageously results in a 15 much more effective improvement of the defense mechanisms of gastric mucosa. Finally, the therapeutic application of the compound of this invention is as an antacid and gastroprotector, and can be administered to treat hyperchlorhydria, gastritis, gastroduodenitis, dyspepsia, 20 esophagitis, diverticulitis, hyatal hernia, gastric and duodenal ulcers, gastric post-operated patients, vagotomized patients and, in general, to alleviate all those disturbances or episodes causing increased acidity in the stomach. The compound of this invention mixed with suitable carriers can 25 be administered orally at daily doses ranging from 250 mg to 10 g, preferably between 1 and 6 g, in the form of suspensions, granules, tablets, capsules, powders, coated tablets and the like.

WO99/35088 PCT/EP98/08498 10 Example 1: Aluminum magnesium carbonate hydroxide trihyrate Al 2 Mg 4 (OH) 12

CO

3 .3H 2 0) (I) In a 1-litre round-bottomed flask a suspension of 9.44 g of 5 aluminum hydroxide (corresponding to 5.4 g of A1 2 0 3 ; 53 mmoles), 12.37 g of Mg(OH) 2 (212 mmoles) and 34.4 g of NaHCO 3 (409 mmoles) in 400 mL of water was heated under reflux for 3 hours. After cooling, the insoluble compound was filtered off, washed with water (2 x 300 mL) and dried at vaccum at 10 60 0 C for 20 hours. The pH of water should be 10. The solid obtained was suspended again in 400 mL of water, heated under reflux for 24 hours, washed with water and dried at vaccum for 60'C. Yield was 90%. IR(KBr): 3500-3400 (unspecific band) (Figure 1'), 1361, 785 and 449 cm

-

' (Figure 1). DSC 15 (Differential Scanning Calorimetry): Figure 2. X-ray diffraction crystallographic analysis: A Siemens D5000 diffractometer was used. The following parameters were fitted in the course of the experiment: 20 Measure interval in 2-6: 5-1050 Angular increase: 0.02 Spacing time: 2.5 seconds Radiation A = 1.54056 A Potency: 1.8 kW 25 Receiver slot: 0.2 0 Divergence slot: 10 Values for the d(A) found are already tabulated in Table 1.

WO99/35088 PCTIEP98/08498 11 Example 2: Preparation of a suspension of aluminum magnesium carbonate hydroxide trihydrate Formulation per 100 mL of suspension: 5 aluminum magnesium carbonate hydroxide trihydrate .......................... 10.00 g methyl p-hydroxybenzoate ...................... 0.16 g propyl p-hydroxybenzoate ...................... 0.04 g methylcellulose 400 cps ....................... 1.03 g 10 sorbitol 70% ................................... 24.00 g sodium saccharin .............................. 0.10 g dimethicone ................................... 0.20 g mint piperita flavour ......................... 0.05 g distilled water q.s . .......................... 100.00 mL 15 This suspension may be inserted in 100-mL containers or in unidose 15-mL sachets containing 1.5 g of active ingredient. Example 3: Preparation of a dispersible granulate of aluminum 20 magnesium carbonate hydroxide trihydrate Formulation per 5 g of granulate aluminum magnesium carbonate hydroxide trihydrate ........................... 1.50 g 25 dimethylpolysiloxane ........................... 0.20 g sorbitol powder ................................ 1.00 g sodium saccharin ............................... 0.01 g polyvinylpyrrolidone K-25 ...................... 0.03 g WO99/35088 PCT/EP98/08498 12 butylhydroxytoluene ............................ 0.0005 g lemon flavour .................................. 0.0050 g skim powdered milk q.s . ..... .................. 5.0000 g 5 This granulate is placed in unidose sachets for its dispersion in water. Example 4: Preparation of chewing tablets of aluminum magnesium carbonate hydroxide trihydrate 10 Formulation per tablet of 500 mg aluminum magnesium carbonate hydroxide trihydrate .......................... 500 mg microcrystalline celulose ..................... 120 mg 15 polyvinylpyrrolidone .......................... 50 mg talc .. ....................................... 20 mg magnesium stearate ............................ 10 mg mint flavour ................................... 5 mg mannitol q.s. . ................................. 1200 mg 20 These tablets may be inserted in aluminium tubes or blister and are dissolved in the mouth or chewed. 25

Claims (3)

1. 2.5322; 2.2830; 1.93545; 1.72447; 1.62930; 1.52289; 15 1.49318; 1.46002; 1.41351; 1.38528 and 1.31011; whose infrared spectrum shows characteristic bands at 1361, 785 and 449 cm 1 (Figure 1') and whose DSC (Differential Scanning Calorimetry) is illustrated in Figure 2. 20 2. A process for preparing the compound of claim 1 which comprises reacting aluminum hydroxide with magnesium hydroxyde in a molar ratio from 1 : 2 respectively, and 25 an excess of sodium bicarbonate in an aqueous medium and at the boiling temperature of the mixture, and operating thereafter by using standard isolation and 30 purification techniques. 35 WO 99/35088 PCTIEP98/08498 14
2. 3. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 5 4. The use of the compound according to claim 1 for preparing a pharmaceutical composition for treating increased acidity in the stomach.
3. 5. A method of treating increased acidity in the stomach 0 which comprises administering to a mammal an effective amount of the compound according to claim 1.