CZ347099A3 - Magnesium aluminium hydroxide carbonate - Google Patents

Abstract

The present invention relates to a basic magnesium aluminum carbonate formula Al2Vfet (OH) 12CO3.3H2O (I) and crystallizing in a vault (rombohedral) system that has the following parameters lattices: a = b = 3.046 A; c = 22.79 A; α = β = 90 °; y = 120 ° and volume cell = 183 A3, with spectral X-ray diffraction following d (A): 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 characteristic band at 1361,785 and 449 cm < -1 >, and with thermogram diffraction Calorimetry (DSC). This compound is useful as a compound antacidumagastroprotective agent

Description

Basic magnesium aluminum carbonate

Technical field

The present invention relates to a novel basic magnesium aluminum carbonate of the formula Al 2 Mg 4 (OH) ₁₂ CO 3. 3H ₂ O (I) and crystallizing in a rhombohedral (rhombohedral) system, which has the following lattice parameters: a = b = 3.046 Å; c = 22.79 Å; α = β = 90 °; γ = 120 ° and cell volume = 183 Å ³ , and whose X-ray diffraction spectrum has 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; 1.388528 and 1.31011; whose infrared spectrum has characteristic bands at 1361, 785 and 449 cm ^-1 (Fig. 1) and whose differential scanning calorimetry (DSC) thermogram is shown in Fig. 2.

BACKGROUND OF THE INVENTION

The use of several magnesium aluminum carbonates is already known as an antacid in medicine. Examples of magnesium aluminum carbonates include those made according to U.S. Pat. 3,539,306 and 3,650,704 (hydrotalcite [Talcid ™] of formula Al ₂ Mg ₆ (OH) 1 ₆ CO 3. 4H ₂ O), U.S. Pat. 4,447,417 and 4,560,545 (almagate [Almax ™ and Almax ™

Forte] of formula Al ₂ Mg 6 (OH) 14 (CO ₃ ) ₂ . 4H ₂ O and U.S. Patent No. 4,539,195 (compound of formula Al ₂ Mg ₆ (OH) ₁₂ (CO ₃ ) _3. XH ₂ O.

A compound having better properties than hitherto used substances has now been produced.

SUMMARY OF THE INVENTION

The compound of the invention is prepared by reacting aluminum hydroxide with magnesium hydroxide and sodium bicarbonate

aqueous medium at boiling point of the mixture. The stoichiometric ratio of aluminum hydroxide to magnesium hydroxide should be 1: 2. Sodium bicarbonate is used in molar excess such that the average pH is between 9 and 11. Once the system has cooled, the product is collected by filtration, washed with water and dried under vacuum at a temperature between 50 and 70 ° C to constant weight to obtain a solid which is resuspended in water and heated to reflux. The solid is filtered off, washed with water and dried under vacuum at a temperature between 50 and 70 ° C to give the compound, both aluminum hydroxide trihydrate and magnesium aluminum carbonate (Al ₂ Mg 4 (OH) and ₂ CO 3. 3 H ₂ O) (I) as gem crystals. Its lattice parameters are a = b = 3.046 Å; c = 22.79 Å; α = β = 90 °; γ = 120 °. Cell volume of the crystal is 183 Å ³ and X ray diffraction spectrum having the following d values (Å): 7597; 3,798; 2.6202; 2.5698; 2.5322; 2.2830; 1,93545; 1.72447; 1,62930;

1,52289; 1,49318; 1,46002; 1,41351; 1.388528 and 1.31011 (Table 1).

• · · ·

- 3 Table 1

H TO L 2-pos. ^[1] 2-očt calcd. ^[2] Δ [3] d 0 0 3 11,708 11,705 0.003 700 7,957 0 0 6 23,467 23,467 0,000 300 3,798 1 0 1 34,260 34,258 0,002 40 2,6202 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 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 0 1 14 67,654 67,632 0,022 5 1,38528 2 0 2 72.092 72,089 0.003 4 1,31011

^[1] observed ^[2] calculated ^[3] intensity

Explanation of each column:

Η. K. L .: Grid locations of a compound (elementary cells) that allow for the assignment of three indexes or integers to each diffraction line (K.. K. L.).

• ·

- 4 2-Θ: Angular variable that indicates the angular position of the point where the diffraction line (K. K. K.) appears on the diagram. If the elemental cell of the compound and the triplet (K. K. L.) are known, the theoretical position can be calculated, which should correspond to the position observed (pos: observed; calculated: calculated).

Intensity: Intensity indicates the height of the diffraction line that is characteristic of the positions of atoms in the crystalline cell, as opposed to the angular position that is characteristic of the size of the crystalline cell.

d; Distances of atoms. This value is also characteristic of the w cell of the compound, but unlike the 2-hodnoty value, it is not dependent on the wavelength of the radiation used.

Klencová soustava.

Grid parameters: a = b = 3.046 Å; c = 22.79 Å; α = β = 90 °; γ = 120 °. Crystalline cell volume = 183 Å ³ .

Similarly, the infrared spectrum has bands at 3500-3400 cm ^-1 (wide) (Fig. 1), 1361, 785 and 449 cm ^-1 (Fig. 1), where the last three bands are merely characteristic. The differential scanning calorimetry (DSC) diffractogram is shown in Figure 2.

The compound of the present invention (I) is from the compounds

2o described in the patents cited in the prior art is different, and although its chemical formula is similar, it is not obvious from these compounds. Indeed, compound (I) has a unique crystalline structure, as evidenced by its X-ray diffraction spectrum (Table 1). Similarly, the DSC thermogram shows the presence of a unique compound with the appropriate structure (Fig. 2). The compound of the present invention has antacid properties and has very good gastroprotective effects over other known compounds.

The safety and efficacy of the compound of the present invention obtained according to Example 1 was demonstrated by the Irwin test, as shown in the Irwin test. · ··· ···· ·· ··

- 5 (safety) and by measuring antacid and gastroprotective effects (efficacy).

Irwin test:

The method described in R. A. Turner (Screening

Methods in Pharmacology, 1965, pp. 27-34, Academic Press, New York and London). In this comparative test, the compound of Example 1 and the almagate were administered orally to Swiss mice of both sexes at doses of 0.3, 1 and 3 g / kg in a volume of 30 ml / kg. None of these three doses tested induced changes in endpoints (alertness and mood, motor activity, CNS irritation, muscle tone, optic symptoms, secretory-excretion symptoms, general symptoms, acute mortality and delayed mortality) in any of the groups and absence of changes. in emptying and mortality. Therefore he proved

Irwin test for the safety of the compound of Example 1 and almagate.

Antacid efficacy:

Antacid efficacy measurements were performed on female Wistar rats weighing 140-160 g. Animals were housed in metabolic cages and fasted 24 hours prior to the experiment to 1 hour prior to the start of the experiment, allowing free access to water. The animals were anesthetized with a mixture of ketolar (91 mg / kg) and thiazine (3.6 mg / kg) and then laparotomized; pylor was carefully ligated and the abdominal cavity closed with a sterile suture (H. Shay et al., "Gastroenterology", 1954, 5, 43-61). Three hours after pylor ligation, drugs were orally administered to conscious animals. One group of 10 animals received the compound of Example 1 in a 0.25% Bacto-agar suspension at 125 mg / kg and the other group of 10 animals at 62.5 mg / kg; a control group of 10 animals received 10 ml / kg of 0.25% Bacto-agar.

Similarly, the experiment was repeated with the almagate using the same

- 6 doses and an equal number of animals; a new control dose of 10 animals received the same dose of Bacto-agar as in the experiment with the compound of Example 1. Sixty minutes after administration, the animals were sacrificed, the stomach content was collected and the volume measured. The present material was centrifuged at 3000 rpm for 10 min, the supernatant was collected and the pH was measured and the concentration of hydrochloric acid in the material was determined by titration (Titrilab, Radiometer). The results obtained are shown in Table 2.

io Table 2

Product Dosage [1] Volume [2] pH Sekr.kys. [3] Sekr.kys. [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 ... Almagát 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

From these results it can be concluded that although the dose

125 mg / kg of the compound of the present invention causes acid neutralization similar to that of almagate at the same dose, dose

62.5 mg / kg, the neutralizing effect of the compound of the invention is superior to that of almagate at the same dose.

Gastroprotective efficacy:

The experimental method of ethanol-induced gastric necrosis described in A. Robert et al (Gastroenterology, 1979, 77 (3), 433 5 443) was used to measure gastroprotective efficacy. The experiment was performed on female Sprague-Dawley rats weighing 180-200 g, which were fasted 24 hours prior to the start of the experiment. The compound of the invention was compared to the almagate in the same manner as in the previous assay. The compound of Example 1 was administered in a 0.25% suspension of Bacto-agar. Both test products were administered orally at doses of 100 and 50 mg / rat. At the same time, the control group received a 0.25% suspension of Bacto-agar. After 30 min, the animals received a dose of absolute ethanol of 1 ml / rat. 60 min after ethanol administration, the animals were sacrificed and the duration of gastric mucosal damage was measured. The results obtained are shown in Table 3.

Table 3

Product Dosage mg / rat n [1] Medium length damage [2] Inhibition Bacto-agar - 21 59.62 ± 6.77 - Example 1 100 ALIGN! 8 28.90 ± 6.44 52% 50 7 40.18 ± 3.77 33% Almagát 100 ALIGN! 7 49.13 ± 10.25 18% 50 7 43.30 ± 11.84 27%

[1] number of animals; [2] mm

The results shown show that the compound of the present invention has slightly better gastroprotective effects than almagate at 50 mg / rat, but significantly better than almagate at 100 mg / rat.

Length of gastroprotective effect:

For the purposes of this experiment, female SpragueDawley rats weighing 180-200 g were used and treated as in the previous experiment. The compound of the present invention was compared to an almagate. A suspension of the compound of Example 1 in 0.25% Bacto-agar was prepared. The test products were administered orally in a single dose of 250 mg / rat 90 and 180 min prior to administration of absolute ethanol at a dose of 1 ml / rat. 60 min after ethanol administration, the animals were sacrificed and the duration of gastric mucosal damage was measured. The results obtained are shown in Table 4 (90 minutes) and Table 5 (180 minutes).

Table 4

Product n [1] Damage length [2] Inhibition Bacto-agar 14 81.62 ± 7.66 Example 1 7 25.84 ± 8.40 68% Almagát 7 39.27 ± 21.39 52%

[1] number of animals; [2] mm

- 9 Table 5

Product n [1] Damage length [2] Inhibition Bacto-agar 14 76.13 ± 6.21 ___ Example 1 7 14.41 ± 4.70 8% Almagát 7 68.89 ± 8.18 10%

[1] number of animals; [2] mm

The results show that the compound of the present invention has advantageous and surprisingly longer duration of gastroprotective effects than almagate, with the difference increasing over time in favor of the compound of Example 1.

From the pharmacological tests performed by the Applicants, it has also been found that the compound of the present invention is characterized by inhibition of gastric acid secretion, minimization of aggressive factors on the gastric mucosa and, moreover, a surprising gastroprotective action. The gastric mucosal protection provided by the compound of the present invention is higher and has a longer duration than that of almagate, which is advantageously reflected in a much more effective improvement of the gastric mucosal defense mechanisms. The compound of the present invention may be used in medicine as antacids and gastric mucosal agents, and the compound may be administered for the treatment of excessive amounts of hydrochloric acid, gastritis, gastroduodenitis, dyspepsia, esophagitis, diverticulitis, hyatniotic hernia, stomach and duodenal ulcers in patients after surgery. stomach, in vagotomized patients, and generally to alleviate any adverse effects and symptoms caused by increased gastric acidity. The compound of the present invention in admixture with suitable carriers may be administered orally in daily dosages from

- 10 · · t t t t * 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

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.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Magnesium aluminum carbonate trihydrate

Al _from Mg4OH) 12CO3 3H2O (I)

In a 1 L ball flask, a suspension of 9.44 g of aluminum hydroxide (equivalent to 5.4 g of Al 2 O 3; 53 mmol), 12.37 g of Mg (OH) ₂ (212 mmol) and 34.4 g of NaHCO ₃ was heated to reflux. (409 mmol) in 400 mL of water for 3 hours. After cooling, the insoluble compound was filtered off, washed with water (2 x 300 ml) and dried under vacuum at 60 ° C for 20 hours. The pH of the solution should be 10. The solid obtained was resuspended in 400 ml of water, refluxed for 24 hours. , washed with water and dried under vacuum at 60 ° C. Yield 90%.

IR (KBr): 3500-3400 (non-specific band (Fig. Γ), 1361, 785 and 449 cm ^-1 (Fig. 1). DSC (Differential Scanning Calorimetry): Fig. 2.

X-ray diffraction crystallographic analysis

A Siemens D5000 diffractometer was used. During experiment 20, the following instrument settings were used:

Measuring interval in 2-Θ: Angle increment Spacing time Radiation, λ

Performance

Output slot Divergence slot Observed values for <

- 105 °

0.02

2,5 s

1.54056 Á

1.8 kW 0.2 °

1 ° were already listed in Table 1.

·· ·· · ♦ · · · · · ·

Example 2

Production of a magnesium aluminum carbonate hydroxide trihydrate suspension

Formulations for 100 ml suspension:

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 dimethicon 0.20 g mint flavor 0.5 g distilled water to 100 ml

This suspension may be filled into 100 ml containers or into single-dose sachets of 15 ml containing 1.5 g of active ingredient.

Example 3

Production of dispersible granules of magnesium aluminum carbonate trihydrate

Formulation per 5 g granulate Magnesium aluminum carbonate trihydrate 1.50 g dimethylpolysiloxane 0.20 g sorbitol powder 1.00 g saccharin sodium 0.01 g polyvinylpyrrolidone K-25 0.03 g

- 12 * butyl butyl butylhydroxytoluene 0.0005 g lemon flavor 0.0050 g skimmed milk powder up to 5.0000 g

This granulate is filled into single-dose sachets for dispersing in water.

Example 4

Manufacture of magnesium aluminum carbonate trihydrate chewable tablets

Tablet formulation 500 mg magnesium aluminum carbonate trihydrate 500 mg microcrystalline cellulose polyvinylpyrrolidone talc magnesium stearate mint flavor mannitol

120 mg 50 mg 20 mg 10 mg 5 mg 1200 mg

The tablets may be filled into aluminum tubes or blister packs and dissolved in the mouth or chewed.

Claims (5)

A basic magnesium aluminum carbonate of the formula Al ₂ Mg 4 (OH) ₁₂ CO 3. 5 3H ₂ O (I) crystallizing in a gem system, characterized in that its lattice parameters have the following values a = b = 3.046 Å; c = 22.79 Å; α = β = 90 °; γ = 120 ° and the cell volume is 183 A ³ , its X-ray diffraction spectrum has the following d values of d (A): 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; 1.388528 and 1.31011; whose infrared spectrum has characteristic bands at 1361, 785 and 449 cm ^-1 as shown in Fig. 1 ', and whose differential scanning calorimetry diffractogram is 15 shown in FIG. 2. A process for the preparation of a compound according to claim 1, characterized in that the aluminum hydroxide is reacted with magnesium hydroxide in a molar 20 ratio of 1: 2a with an excess of sodium bicarbonate in aqueous medium and at the boiling point of the mixture, and the product is then isolated and purified in a standard manner. 3. A pharmaceutical composition comprising: 25 comprising a compound of claim 1 and a pharmaceutically acceptable carrier. ⁴ Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition for the treatment of increased gastric acidity. - 14 »♦ · · · · · · · A method of treating increased gastric acidity comprising administering an effective amount of a compound of claim 1 to a mammal.