Mixed metal compounds applicable as antacids

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using mixed metal compounds for preparing a drug preparation for neutralisation of gastric acid or buffer action thereon, as well as for treatment of a condition or a disease related to high gastric levels of acid. The mixed metal compound is a compound of formula (I): MII1-aMIIIaObAn-c.zH2O (I), wherein MII and MIII mean a two-valence and three-valence metal respectively, An- means an n-valence anion, 0.2≤a≤0.4, 0.2≤b≤1.5, 2+a is equal to 2b+Σcn, Σcn<0.9a, and z is equal to 2 or less. According to the invention, the mixed metal compound is presented in the form of a granulated material, wherein a diametre of 50 wt % of the granules makes 106 to 1180 mcm with the material comprising 50 wt % of the mixed metal compound, 3 to 12 wt % of noncovalent water and no more than 47 wt % of an excipient on granulated material weight basis. The mixed metal compound in the form of the granulated material represents a compound of formula (I) or a compound of formula (III): MII1-xMIIIx(OH)2An-y·mH2O (III) ; wherein MII and MIII mean a two-valence and three-valence metal respectively, An- means an n-valence anion, x=Σyn, 0<x≤0.4, 0<y≤1, and 0≤m≤10.

EFFECT: invention provides the buffer action on gastric acid, causing no effect of rebound acid hypersecretion.

46 cl, 3 tbl, 1 dwg

 

The scope of the invention

The present invention relates to the use of compounds as antacids. In addition, it refers to the use of such compounds for treating conditions or diseases associated with unfavorable levels of acid in the stomach, such as peptic ulcer, dyspepsia, heartburn and acid reflux.

The background to the present invention

Two major product secreted by the stomach, hydrochloric acid and pepsin (protease), both involved in the metabolism of protein. Hydrochloric acid helps dissolve food particles and provides the optimum pH for activity of pepsin. Frequent increased levels of gastric acid and pepsin can damage the gastric mucosa, which, in turn, can cause the breakdown of the mucosal cells and the development of peptic ulcers. The term "peptic ulcer" refers to the ulceration of the mucous membrane, while the mucosa of the stomach (gastric ulcer) or duodenum (duodenal ulcer) is subjected to the action of the acid components of the stomach. When hit hydrochloric acid from the stomach to the naked nerves when the ulcer is the transmission of pain signals in the Central nervous system. Stomach acid can also cause ulcers food is ode.

Antacids reduce the intensity of symptoms of peptic ulcers by neutralizing environment of the stomach, i.e. they neutralize stomach acid, raising the pH and reducing the acidity of the stomach. Antacids also lead to weakening of heartburn (hit hydrochloric acid from the stomach into the esophagus). In article Playle and others described that antacids based hydrotalcite (MgAl) reduce the intensity of symptoms by inhibiting the activity of pepsin and protects the mucous membranes due to their ability to mimic the properties of the gel of the gastric mucosa.

Examples of antacids include Al(Oh)3, Mg(OH)2, calcium carbonate and hydrotalcite MgAl. Despite the efficiency, with the introduction of antacids there are a number of new problems.

Some antacids suspend the splitting of proteins in the stomach by raising the pH to about 7, which may lead to irreversible inactivation of pepsin. The presence of undigested protein in the gastrointestinal tract can cause numerous problems including flatulence, bloating of the abdomen and constipation. The presence of food may also lead to an increase in the pH of the stomach, and gastrin levels, therefore, the combination of food and some antacids can lead to a sudden increase of pH in the stomach more than 7 before gastric emptying and re when iginio pH. There is a need for connection, used to treat stomach ulcers, not only have been effective as an acid buffer agent, but did not lead to sudden changes in the pH values of the stomach. In addition, the antacid should inhibit pepsin, but not enough to kill it permanently.

Another problem arising from the use of antacids is "rebound effect acid" due to "biological switch" or feedback mechanism existing in the stomach. For example, if the pH in the stomach is increased, there is a stimulation of the hormone gastrin, which in turn stimulates further secretion of acid, in which even more increases the concentration of gastric acid. Thus, this effect can lead to a positive feedback loop, and therefore require more antacids. This phenomenon is associated with antacids, which are characterized by the most rapid action in the pH suddenly rises to a higher value (usually more than 5).

It is also known that excessive amounts of acid (usually at pH less than 3) can aggravate the condition of the ulcer, the pain may occur upon stimulation of acid nerve endings when the plague. Thus, the optimum is the interval which antacid should provide a buffering effect on the pH of the stomach varies from 3 to 4.5, if the antacid is administered in the absence of food, and the pH should not exceed 7 in the presence of food.

It is known that the application of some antacids causes the following problems:

- Magnesium hydroxide characterized by the laxative properties, can release significant amounts of magnesium and cause a sudden rise in pH in the stomach (i.e. more than 7).

Periodic introduction of high levels of carbonates, which is usually some antacids on the basis of carbonates such as calcium carbonate) can cause alkalosis.

- Hydrotalcite MgFe or MgAl may contain carbonates, but usually at a lower level (less than 100 grams of CO3/kg), compared with the content in caso3(600 g CO3/kg) or MgCO3(710 g CO3/kg).

- It is known that hydrotalcite MgAl not cause a rebound effect of acid and protects the mucous membrane. However, with the introduction of antacids on the basis of aluminum, is absorbed Al3+that can lead to the accumulation of aluminum in the body to toxic levels.

Some antacids contain large amounts of sodium and should not be administered to patients who follow a diet low in sodium.

Preferred are materials on the basis of hydrotalcites, p is because they have a double effect. It is assumed that gastric acid fast interacts with hydrotalcite by the mechanism of anion-exchange neutralization with the formation of chloride compounds. Then the mineral interacts with the physiological fluid, thus there is a slow destruction of the mineral structure, providing a continuous buffer action. This dual action compounds provides a rapid decrease in the intensity of symptoms of acute digestive disorders and prolonged action, which is required when the recurrence of indigestion.

Increasing the surface area of the crystallites or particles hydrotalcite may lead to increased response speed. The higher the size of the crystallites or particles, the more time is required for dissolving hydrotalcite under the action of acid on hydroxide ions. In addition, it is assumed that particles of small size faster dispersed in food. Thus, the buffer effect depends on the particle size and crystallite.

Another important factor in obtaining tablets containing antacids is that they raspadaemost. Anticity not absorbed into the blood, but rather act in a local way in the gastrointestinal tract, and they are administered in the form of a solid inorganic forms. In these cases raspadaemost tablets must provide education to frequent the d antacid with increased surface area. The increased surface area of usually formed when chewed tablets.

When pelletizing hydrotalcite MgAl significantly reduced its ability to neutralize acids and the rate of acid neutralization by reducing the available surface area of particles in the tablet pressing.

In this regard, in the present commercial forms of hydrotalcite released only in the form of chewable tablets or liquid suspensions. Commercial forms of hydrotalcite MgAl include tablets or liquid Talcid Plus and liquid Ultacit, Talidat and Altacit Plus.

The residence time in the stomach chewable tablets and liquid suspensions significantly less compared to other dosage forms, such as Nerevarine tablets. Duration antacid largely depends on the rate of gastric emptying. With the introduction of on an empty stomach antacid neutralizes the acid only in the period from 30 to 60 min, as antacid quickly leaves the stomach, while with the introduction of food protective action is 2 or 3 o'clock, However, the effectiveness of some antacids may decrease in the presence of food, because the interaction of the drug with food competes with antacid effect.

Powder hydrotalcite usually characterized by low turnover, primarily the EU and they are finely ground powders, however, the use of more coarse materials leads to the inhibition of antacid actions (see table 1). Powders with low fluidity is usually characterized by stickiness, high ratio Hausner, angles of wall friction medium to high values, a significant shift when pressing. Low turnover leads to problems when filling capsules or tablets on an industrial scale, first of all, if you want a high content material-based hydrotalcite in the dosage form.

Chewable tablets containing antacids, may have an unpleasant taste due to liming, bitter or metallic taste, grain size, dryness and astringent properties of these materials. The use of chewable tablets may cause dental problems and causes difficulty in masking the taste of the active ingredient. In addition, patients usually do not chew the tablets to a uniform consistency that can change the effectiveness of antacid. Disadvantages of liquid suspensions are their instability during storage and use, as well as the inconvenience of transport. In addition, these dosage forms provide delivery of the active ingredient with greater speed, which, in turn, may increase the possibility of ricochet efficiency is the acid.

It was supposed to put on an antacid tablet coating that does not dissolve in the oral cavity, but dissolves in the stomach. However, most of the coating dissolves in the intestine, not the stomach that leads to the delivery of antacid in the wrong Department of the organism. In addition, although it is possible to use a coating that dissolves it in the stomach, the rate of dissolution is insufficient to provide sufficient time to neutralize the stomach acid before removing antacid from the stomach. However, if the dissolution rate is too high, the initial pH of stomach acid may increase too quickly, thus causing the so-called rebound effect acid.

Antagonists of the receptor N2or proton pump inhibitors block the production of acid in the stomach for several hours. However, the risk of more severe side effects may be higher in the distribution of these drugs throughout the body through the bloodstream. Thus, antagonist receptor inhibitor H2or proton pump, basically can not replace antacids with less risk of side effects.

A brief description of the essence of the present invention

Thus, the first object of the present invention features the label of mixed metal compounds to obtain medicines designed to neutralize or buffer action on gastric acid, and the mixed compound metals includes

at least one trivalent metal selected from iron (III) and aluminium and

at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,

where

(A) a mixed combination of metals is a compound of formula (I):

MII1-aMIIIaObAn-czH2O(I)

where MIIdenotes at least one divalent metal,

M represents at least one trivalent metal,

Andndenotes at least one n-valent anion,

2+a is equal to 2b+∑cn,

∑cn<0,9a, and

z is 2 or less, and/or

(B) a mixed combination of metals is provided in the form of a granular material, including:

(1) at least 50 wt.% mixed metal compounds based on the mass of granular material

(2) from 3 to 12 wt.% ecovalence with the provided water per mass of granular material, and

(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

The second object of the present invention features the use of mixed metal compounds aimed to produce medicines for the treatment of a condition or disease associated with adverse levels of acid in the stomach, and the mixed compound metals includes

at least one trivalent metal selected from iron (III) and aluminium and

at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,

where

(A) a mixed combination of metals is a compound of formula (I):

MII1-aMIIIaObAn-czH2O(I)

where MIIdenotes at least one divalent metal,

MIIIrepresents at least one trivalent metal,

And indicates at least one n-valent anion,

2+and 2b+∑cn,

∑cn<0,9a, and

z is equal to or less

and/or

(B) a mixed combination of metals is provided in the form of a granular material, including:

(1) at least 50 wt.% mixed metal compounds based on the mass of granular material

(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and

(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

The third object of the present invention proposes a mixed combination of metals, intended to neutralize or buffer action on gastric acid, and the mixed compound metals includes

at least one trivalent metal selected from iron (III) and aluminium and

at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,

where

(A) a mixed combination of metals is a compound of formula (I):

MII1-aMIIIaObAn-czH2O(I)

where MII/sup> denotes at least one divalent metal,

MIIIrepresents at least one trivalent metal,

Andndenotes at least one n-valent anion,

2+and 2b+∑cn,

∑cn<0,9a, and

z is 2 or less,

and/or

(B) a mixed combination of metals is provided in the form of a granular material, including:

(1) at least 50 wt.% mixed metal compounds based on the mass of granular material

(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and

(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

The fourth object of the present invention proposes a mixed combination of metals, intended for treatment of a condition or disease associated with adverse levels of acid in the stomach, and the mixed compound metals includes

at least one trivalent metal selected from iron (III) and aluminium and

at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,

where

(A) a mixed combination of metals is a compound of formula (I):

MII1-aMIII aObAn-czH2O(I)

where MIIdenotes at least one divalent metal,

MIIIrepresents at least one trivalent metal,

Andndenotes at least one n-valent anion,

2+and 2b+∑cn,

∑JV<0,9a, and

z is 2 or less,

and/or

(B) a mixed combination of metals is provided in the form of a granular material, including:

(1) at least 50 wt.% mixed metal compounds based on the mass of granular material

(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and

(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

The terms "granular" and "granular material" used in the context of the present invention are interchangeable.

Unexpectedly, it was found that mixed metal compounds used according to the present invention, give antacids one or more of the following properties:

- nievely form,

- high content of the active ingredient,

- the absence of you who are aware of or reduction in the release of aluminum,

- reducing the release of ions of magnesium, calcium, iron, zinc or carbonates,

maintaining the pH of the stomach in the not too acidic or too alkaline range (buffer effect in the range of pH from 3 to 4.5),

lack or reduction of the ricochet effect of the acid,

- the possibility of introducing food or in its absence,

- no effect on the digestion of food,

- protection of the mucous membranes,

- low sodium (i.e. less than 1 mmole/tablet or /in 10 ml dose),

- slow release from the stomach,

- fast action, high buffer capacity and high duration,

- receipt of tablets small size.

The water content of the granules intended for use according to the present invention, defined in the form of content ecovalence bound water in the composition of the granules. Therefore, the specified ecovalence bound water does not include covalently bound water. Covalently bound water is also called structured water.

The number ecovalence bound water is determined using IR scales. Determination of moisture spend on the IR scale Satorius MA30 when 75º with automatic module to determine the final value. The method of determination of moisture on the scales Satorius correspond drying to the constant weight at 105º in the oven. Mass equivalent ecovalence bound water can be calculated in mass percent based on the weight of the granules.

One object of the present invention offers granular material in the form of standard dosage forms for oral administration, including water-resistant capsules containing granular material described in this context.

Another object of the present invention offers granular material in the form of standard dosage forms for oral administration, comprising a pressed tablet of granular material described in this context. In a preferred embodiment, the tablet is applied waterproof coating.

Preferred methods of obtaining granular material and other preferred objects of standard dosage forms described in the application WO 2007088343.

Water-resistant capsule, intended for use in the present invention, is a hard gelatin capsule. In the case of water-resistant capsules, the term "water resistant" means that during storage for 4 weeks at 40 º C and a relative humidity of 75% water absorption standard dosage form (e.g. capsule containing granules according to the first object of the present invention) due to changes in the level of humidity in the preferred embodiment, the pillar is t less than 10 wt.%, in a more preferred embodiment, less than 5 wt.% in calculating the weight of a standard dosage forms. The advantage of these capsules is to ensure stabilize the moisture level of the pellets during storage.

On tablets, intended for use in the present invention, in the preferred embodiment, is applied waterproof coating to prevent moisture penetration into tablets or moisture loss from the tablet during storage. However, the waterproof coating should provide the disintegration of a tablet through a suitable period of time after the introduction to the mixed compound metals have been effective in the intestine of the patient. The term "water resistant" means that during storage for 4 weeks at 40 º C and a relative humidity of 75% of the water absorption of the tablet with the coating due to the changes in the level of humidity in the preferred embodiment, is less than 10 wt.%, in a more preferred embodiment, less than 5 wt.% based on the weight of the coated tablets. In a preferred embodiment, the term "water resistant" means that during storage for 12 months at 30 º C and a relative humidity of 65% of the water absorption of the tablet with the coating due to the changes in the level of humidity in the preferred embodiment, is less than 10 wt.%, in a more preferred embodiment, less than 5 wt.% counting on a lot of tablets with pokr is a tie. In another more preferred aspect, the term "water resistant" means that during storage for 12 months at 30 º C and a relative humidity of 65% of the water absorption of the tablet with the coating due to the changes in the level of humidity in the preferred embodiment, is less than 10 wt.%, in a more preferred embodiment, less than 5 wt.% based on the weight of the coated tablets. In the most preferred embodiment, the term "water resistant" means that during storage for 12 months at 40 º C and a relative humidity of 75% of the water absorption of the tablet with the coating due to the changes in the level of humidity in the preferred embodiment, is less than 10 wt.%, in a more preferred embodiment, less than 5 wt.% based on the weight of the coated tablets.

Detailed description of embodiments of the present invention

As described above, the present invention proposes the use of mixed metal compounds to obtain a medicinal product intended to neutralize or buffer action on gastric acid, and the mixed compound metals includes

at least one trivalent metal selected from iron (III) and aluminium and

at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,

where

(A) a mixed combination of metals is one the camping compound of formula (I):

MII1-aMIIIaObAn-czH2O(I)

where MIIdenotes at least one divalent metal,

MIIIrepresents at least one trivalent metal,

Andndenotes at least one n-valent anion,

2+and 2b+∑cn,

∑cn<0,9a, and

z is 2 or less,

and/or

(B) a mixed combination of metals is provided in the form of a granular material, including:

(1) at least 50 wt.% mixed metal compounds based on the mass of granular material

(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and

(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

The value for each anion is determined by the need for charge neutralization by the formula 2+a=2b+∑cn.

It should be understood that in one preferred object of the mixed compound metal is a compound of formula (I):

MII1-aMIIIaObAn-czH2O(I)

where MIIdenotes at least one divalent metal,

MIIIrepresents at least one trivalent metal,

Andndenotes at least one n-valent anion,

2+and 2b+∑cn,

∑cn<0,9a, and

z is 2 or less.

The compound of formula (I) are usually obtained by heating a source material comprising a layered double hydroxides, hydrotalcite or pyroaurite at temperatures between 200ºC to 600ºC, preferably at a temperature of from 250º to 500º.

Source material preferably includes a compound of formula (II):

MII1-xMIIIx(OH)2An-ymH2O (II)

where MIIdenotes at least one divalent metal,

MIIIrepresents at least one trivalent metal,

And indicates at least one n-valent anion,

x=∑yn

0<x≤0,4,

0<y≤1 and

0<m≤10.

In the formula (I) the value of z is usually equal to 2 or less, more preferably 1.8 or less, more preferably 1.5 or less. The value of z is equal to 1 or less.

In the formula (I) amount a is equal to from 0.2 to 0.4. In the formula (I) is a<0,3. The value of a is equal to from 0.1 to 0.4, preferably from 0.2 to 0.45.

Preferably the amount is from 0.1 to 0.34, more preferably from 0.2 to 0.34.

In the formula (I), the value of b is usually equal to 1.5 or less, preferably 1.2 or less. The value of b is preferably equal to about 0.2, more preferably greater than 0.4, even more preferably more than 0.6, most preferably higher than 0.9.

If a≤0.3, then it is preferable that ∑cn was less than 0,7a. Thus, in the formula (I) in a single object 0,03a<∑cn<0,7a. In another object in the formula (I), 0,03a<∑cn<0,5a.

The value for each anion is determined by the need for charge neutralization by the formula 2+a=2b+∑cn.

It should be understood that in one preferred object of the mixed compound of metals is provided in the form of a granular material, including:

(1) at the ore 50 wt.% mixed metal compounds based on the mass of granular material

(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and

(3) not more than 47 wt.% excipient in the calculation of the mass of granular material. The value for each anion is determined by the need for charge neutralization by the formula 2+a=2b+∑cn.

A mixed combination of metals is provided in the form of a granular material, preferably of the formula (III):

MII1-xMIIIx(OH)2An-ymH2O(III)

where MIIdenotes at least one divalent metal,

MIIIrepresents at least one trivalent metal,

Andndenotes at least one n-valent anion,

x=∑yn

0<x≤0,4,

0<y≤1 and

0<m≤10.

In one preferred object 0<x≤0,4. In one preferred object of 0.1<x≤0,4, while the 0.2<x≤0,4, or 0.3<x≤0,4. It should be understood that x=[MIII]/([MII]+[MIII]), where [MII] denotes the number of moles MIIon the mol of compound of the formula is I, while [MIII] denotes the number of moles per mol of the compounds of formula I.

In one preferred object 0<y≤1. Preferably 0<y≤0,8. Preferably 0<y≤0,6. Preferably 0<y≤0,4. Preferably of 0.05<y≤0,3. Preferably of 0.05<y≤0,2. Preferably of 0.1<y≤0,2. Preferably of 0.15<y≤0,2.

In one preferred object 0≤m≤10. Preferably 0≤m≤8. Preferably 0≤m≤6. Preferably 0≤m≤4. Preferably 0≤m≤2. Preferably 0,1≤m≤2. Preferably 0,5≤m≤2. Preferably 1≤m≤2. Preferably 1≤m≤1.5A. Preferably 1≤m≤1,4. Preferably 1,2≤m≤1,4. Preferably m is approximately equal to 1.4.

Preferably 0<x≤0,4, 0<y≤1 and 0≤m≤10.

It should be understood that each of the preferred value of x, y and m can be used in combination. Thus, any combination of each variable, described in the table below, included in the scope of the present invention, and is suggested in the present invention.

Xm
of 0.1<x≤0,40<y≤0,80≤m≤10
of 0.2<x≤0,40<y≤0,60≤m≤8
of 0.3<x≤0,4 0<y≤0,40≤m≤6
0,3≤x≤0,4of 0.05<y≤0,30≤m≤4
0<x≤0,4of 0.05<y≤0,20≤m≤2
of 0.1<y≤0,20,1≤m≤2
of 0.15<y≤0,20,5≤m≤2
1≤m≤2
1≤m≤1,5
1≤m≤1,4
1,1≤m≤1,4

In the above formula (III), And indicates if more than one anion, the valence (n) each of them may vary. "∑ny" denotes the sum of the number of moles of each anion, multiplied by their corresponding value.

The crystallite size

The powder size of the crystallites of the compounds of the formula (II) or (III) were determined from the broadening of the lines on the powder x-ray analysis and was calculated using the so-called equation of Scherer (instrumental broadening factors neoficial). The broadening of the lines depends on the average size of the crystallites.

In most cases, the size of the crystallites of the compounds of the formula (II) or (III) is preferably less than 200 Å, more preferably less than 175 Å, even more preferably less than 150 Å, most preferably less than 100 Å.

In most cases, the crystallites smaller gain of which is not growing crystals. Which is not growing crystals get with the exception of hydrothermal maturation process of crystals (i.e. the process in which the reaction suspension is heated or kept for a long period of time).

Preferably the compound of formula (I) is obtained from freshly prepared compounds of formula (II).

Granules

Granules for use in the present invention comprise at least 50 wt.%, preferably at least 60 wt.%, more preferably at least 70 wt.% and most preferably at least 75 wt.% mixed metal compounds.

Granules of the present invention include from 3 to 12 wt.% ecovalence bound water, preferably from 5 to 10 wt.%.

The rest of the pellets may include a pharmaceutically acceptable carrier for mixed metal compounds, preferably excipient or a mixture of excipients, ensuring the formation of stable granules. Granules can in order to win no more than 47 wt.% excipient. Preferably the granules comprise from 5 to 47 wt.% excipient, more preferably from 10 to 47 wt.% excipient, most preferably from 15 to 47 wt.% excipient.

The mixed compound of the metals in the form of a granular material in the ideal case contains less than 15 wt.% crystallohydrates water. The preferred number crystallohydrates water is less than 10 wt.%.

The size of the granules

Typically, the diameter of at least 90 wt.% granules is less than 1180 microns according to sifting.

Typically, the diameter of at least 50 wt.% granules is less than 710 μm according to sifting.

More preferably, the diameter of at least 50 wt.% granules ranges from 106 to 1180 microns, preferably from 106 to 500 microns.

Even more preferably the diameter of at least 70 wt.% granules ranges from 106 to 1180 microns, preferably from 106 to 500 microns.

Preferably, the mass-average particle diameter of the granules ranges from 200 to 400 microns.

Larger granules can provide slow buffering action at pH (table 1). The presence of a too large fraction of granules with a diameter of less than 106 μm may cause problems due to low flowability of the granules. Preferably the diameter of at least 50 wt.% granules is less than 106 μm according to the screening, more preferably at least 80 wt.%.

The composition of the granules

P is egodnya excipients, you can add a granule, include standard solid diluents, such as lactose, starch or talc, as well as materials derived from animal or vegetable proteins such as gelatins, dextrins and soy, wheat proteins and plantain seed, gums, such as Arabian, guar, agar, and xanthan gum, polysaccharides, alginates, carboxymethylcellulose, carrageenan, dextrans, pectins; synthetic polymers, such as polyvinylpyrrolidon, polypeptide/protein or complexes of polysaccharides such as gelatin complex/Arabian gum, sugars such as mannitol, dextrose, lactose, galactose and trehalose, cyclic sugars such as cyclodextrin, inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates, and amino acids, containing from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

The term "excipient"used in this context, also includes auxiliary components, such as agents for structuring tablets or adhesives, dezintegriruetsja agents or agents that promote swelling.

Suitable agents for structuring tablets include the Arabian gum, alginic acid, carboxymethylcellulose, Hydra is citycalculate, hydroxypropylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hypromellose, maltodextrin, methylcellulose, polyethylene oxide, povidone, sodium alginate and gidrirovanie vegetable oil.

Suitable dezintegriruetsja agents include crosslinked dezintegriruetsja agents. For example, suitable desintegrasii agents include crosslinked sodium carboxymethyl cellulose, crosslinked hydroxypropylcellulose, macromolecular hydroxypropylcellulose, carboxymethylated, potassium salt of a copolymer of methacrylate and polystyrene, polymethyl methacrylate, crosslinked polyvinylpyrrolidone (PVP) and high molecular weight polyvinyl alcohols.

Crosslinked polyvinylpyrrolidone (also known as crosspovidone, for example, the product Kollidon CL-M™ BASF) is the most preferred excipients intended for use in the tablets of the present invention. Typically, pellets, tablets of the present invention comprise from 1 to 15 wt.% crosslinked polyvinylpyrrolidone, preferably from 1 to 10%, more preferably from 2 to 8%. In a preferred embodiment, mass-average particle size of crosslinked polyvinylpyrrolidone d50until granulation is less than 50 μm (so-called crosslinked PVP type). This material is also known as micronized crosspovidone. Setup the network, that the use of stitched polyvinylpyrrolidone in such quantities allows to obtain tablets with a high raspadaemost, but with a smaller buffer capacity compared to some of the other excipients. The use of crosslinked polyvinylpyrrolidone with a preferred particle size reduces the grain size and the hardness of the particles formed during the disintegration of the tablets.

Other preferred excipients, suitable for use in the granules of the tablet is pre-gelatinizing starch. In a preferred embodiment, the granules comprise from 5 to 20 wt.% pre gelatinizing starch, more preferably from 10 to 20% and even more preferably from 12 to 18 wt.%. The use of pre-gelatinizing starch in these quantities leads to increased duration of action and cohesion of the tablets, without compromising raspadaemosti tablets in the application. Usually pre-gelatinizing starch is fully gelatinizing, the moisture content therein is from 1 to 15 wt.%, and the mass-average particle diameter is from 100 to 250 μm. Suitable material is the product Lycotab™ company Roquette, which is fully gelatinizing rice starch.

Most preferred is the combined excipient, including p is evritania gelatinizing starch and crosspovidone, because of this combination of excipients allows to obtain reliable way pressed tablets of various shapes with high homogeneity of the granules and high raspadaemost granules of the present invention.

The granules may also include preservatives, wetting agents, antioxidants, surfactants, effervescent agents, dyes, fragrances, pH modifiers, sweeteners or agents, masking unpleasant vkusit dyes include red, black and yellow iron oxides, dyes, FD & C, such as FD & C blue No. 2 and FD & C red No. 40 firms Ellis &Everard. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors, and combinations thereof. Suitable pH modifiers include sodium bicarbonate (i.e. bicarbonate), citric ciloto, wine ciloto, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, Acesulfame K and thaumatin. Suitable agents for masking unpleasant taste include sodium bicarbonate, ion exchange resin, cyclodextrin containing compounds and adsorbents. Suitable wetting agents include sodium lauryl sulfate and sodium docusinate. Suitable effervescent agents include a mixture of sodium bicarbonate and citric acid.

Granulation

The granulation is conducted by a process comprising the following stages:

1) mixing the mixed metal link with one or more excipients, you get a homogeneous mixture,

2) contacts suitable liquid homogeneous mixture and mixing in a granulator, you get wet granules

3) optional transmission wet granules through a sieve to remove granules that are larger than the pore size of the sieve,

4) drying the wet granules by dry granules,

5) grinding and/or sieving of dry granules. The granulation is conducted by the wet granulation comprising the following stages:

1) mixing the mixed metal link with one or more excipients, you get a homogeneous mixture,

2) adding a suitable liquid in a homogeneous mixture and mixing in a granulator, thus receive granules

3) optional transmission wet granules through a sieve to remove granules that are larger than the pore size of the sieve,

4) drying the granules

5) grinding and sieving the granules.

Suitable liquids for granulation include water, ethanol, and mixtures thereof. The preferred liquid for granulation is water.

The granules are dried to the desired moisture content, as described above, and then used to produce tablets or filling capsules, which is remaneat as dosage forms.

Lubricant

Prior to pelletizing granules in the composition preferably they are mixed with lubricating material or regulator flowability, thus lubricating material or control flowability is distributed on the surface of the granules and between them in the process of pressing the granules into tablets.

Usually the optimum quantity of lubricating material depends on the size of its particles and the available surface area of the granules. Suitable lubricants include silicon dioxide, talc, stearic acid, calcium stearate or magnesium, sodium fumarate and mixtures thereof. Lubricants added to the granules in finely powdered form, usually the amount of 100% of particles less than 150 μm, preferably 98% of the particles less than 38 microns, and most preferably no particles with a diameter exceeding 40 μm (usually according to the screening). The surface area of the particles of lubricating material is usually from 1 to 10 m2/g, preferably from 6 to 10 m2/, lubricants are usually added to the granules in an amount of from 0.1 to 1.0%, preferably from 0.1 to 0.4%, more preferably from 0.2 to 0.3%, based on the weight of the granules. The reduction can lead to sticking and jamming of the plug for tablets, and the increasing number of can cause the decline raspadaemosti tablets. As smasis the existing material can be used salts of fatty acids, such as calcium stearate and/or magnesium. The preferred lubricant is chosen from the group comprising magnesium stearate, sodium fumarate and mixtures thereof. Found that some lubricants, such as fatty acids, lead to a point pitting and damage to the continuity of the coating layer tablets. It is believed that this phenomenon may occur due to partial melting lubricating material during drying of the coating layer. Thus, the melting temperature lubricating material preferably should be more than 55ºC.

Tablets

Tablets of the present invention is produced by extrusion of granules at high pressure and get a tablet, characterized by the tensile strength required for handling during packaging and distribution. The use of pellets, derived from granulated powder mixture, improves the fluidity of the storage hoppers in the press for tableting, which, in turn, increases the efficiency of tableting. Mixed metal compounds used in the tablets of the present invention, typically are characterized by low flow at the desired particle size, as described above. Since preferably the high content of mixed metal compounds of the present invention, i.e. approximately 50% or more in the calculation is the mass of the tablet, the mixed compound metals should be recycled into pellets to obtain tablets. Micronized powders usually are compacted and stuck in the hopper, the feeding plate and the punch, which complicates the process of obtaining tablets with the same mass or the same density. Even if there is a possibility of pressing finely ground powders to the desired density, the mixture may be air, which is shrinked in a pill, which can lead to splitting of tablets at the exit of the press. Application of granules eliminates these problems. Another advantage of granulation is to increase the bulk density of the final tablets obtained from pellets, compared to the tablets of the fine powder, to reduce the size of the final tablets and improve the patient's consent to treatment.

The tablets of the present invention is preferably round, but preferably get a tablet in the shape of a ball or torpedoes (the so-called oblong biconvex tablets), i.e. tablets are characterized by an elongated shape to facilitate ingestion of large doses. The form of tablets containing lower doses (250 mg) of the active component, is round and pills containing high doses (500 mg) of the active component, are usually obtained in the form of a torus is food. For example, get a tablet in the form of a cylinder with rounded ends or ellipse in one direction and the ball in another direction, or ellipse in both directions. The tablet can also apply one or more flat sections.

If you get a tablet with "kumudam", its width is preferably 2 mm or more. It is established that if a pill to get heatcom smaller width, this can disrupt the continuity of the coating or delamination resistant coating tablets.

The hardness of tablets of the second object of the present invention is from 5 to 30 kgf according to the testing device for measuring the strength tablets Holland C50.

Water-resistant coating

On tablets, obtained from the granules, preferably applied waterproof coating.

Water-resistant coating can be applied to tablets using any standard method of coating and equipment known in the pharmaceutical industry. For example, coatings can be applied to tablets using equipment with pseudovirions layer (for example, the desiccant with pseudovirions layer type "Wurster"), trays for coating (rotating, with side slits, convection etc), spray nozzles or sprinklers or other types of sprayers, or by dipping or using a more modern who's technologies, including installation for coating on tablets Supercell firm Niro PharmaSystems. Modification of equipment available include the size, shape, placement of the nozzle and the inlet and outlet openings for air flow, air flow and test equipment. For drying the tablets with the coating, you can use heated air to ensure a continuous spray while drying the tablets. You can also use intermittent or periodic spraying, but in this case usually requires a long duration of cycles of application. You can vary the number and location of nozzles, if necessary, depending on the stage of coating and the nozzle(nozzle) is preferably set perpendicular or almost perpendicular to the layer, although you can install them in the other direction. The pallet can be rotated at a speed which is chosen from a variety of operating speeds. You can use any suitable system for providing coating compositions of the coating on the pill. In principle, any tablets that are described in this context, are suitable for coating. The term "tablet" includes the tablet, pellet or pill. It is generally preferable to use tablets in any form, characterized by high physical and chemical Stabi what inetu for effective coating system, including some movement tablets, for example, in the fluidized bed, such as a dehumidifier with pseudovirions layer or pallet for coating with side slits, combinations thereof and the like, the Coating can be applied to the tablet directly, for example, with the exception of the stage of deposition of the lower layer coating for surface preparation. You can use the lower and upper layers of the coating. If necessary for the application of both of the first or second or more coatings you can use the same or similar equipment for coating. The composition of the coatings are produced taking into account the physical properties of its components, i.e. soluble materials are dissolved and the insoluble material was dispersed. The method of mixing depends also on the properties of the ingredients. For the soluble materials are used mixers for fluid at low shear, and for insoluble materials used mixers for liquids with high shear. Typically, the coating composition includes two parts: colloid polymer suspension and the suspension or solution of a pigment (for example, dye-based red oxide or yellow quinoline). These parts are prepared separately and mixed before use.

You can use a wide range of materials for coating, for example, cellulose derivatives, polyvinyl shall irreligion, polyvinyl alcohol, polyvinyl acetate, polyethylene glycols, copolymers of styrene and acrylate, copolymers of acrylic acid and methacrylic acid, copolymers of methacrylic acid and ethyl acrylate, copolymers of methyl methacrylate and methacrylate, copolymers of methacrylate and tert-aminoalkylsilane, copolymers of acrylate, methacrylate and Quaternary aminoalkylation, and combinations of two or more of these materials. In a preferred embodiment, use salts of copolymers of methacrylates, for example, a copolymer of butylated methacrylate (commercial product Eudragit EPO).

The amount of coating is usually from 0.05 to 10% based on the weight of coated tablets, preferably from 0.5 to 7%. In a preferred embodiment, the coating material used in combination with dye - red iron oxide (Fe2About3, 1% or more, preferably 2% or more based on the weight of the dried coating layer), which is dispersed in the coating material, and provide uniform staining of the coating layer of the tablet, which gives it a nice uniform appearance.

In addition to ensuring protection of core tablets from loss or moisture during storage, water-resistant coating layer also allows you to prevent rapid disintegration of the tablet in the mouth, i.e. to ensure the disintegration only after hitting t is blecki in the stomach. Given this fact, it is preferable to low solubility of the coating material in an alkaline environment, such as the oral cavity, and a higher solubility in a neutral or acidic environment. Preferred coating materials are salts of copolymers of methacrylates, especially a copolymer of butyl methacrylate (commercial series products Eudragit EPO). Preferably the coating layer includes at least 30 wt.% polymer, more preferably at least 40 wt.%.

Loss or capture of water tablets coated is usually measured as described above for measuring the amount of ecovalence bound water granules. For some tablets from the series of freshly prepared tablets coated determine the number ecovalence bound water immediately after receiving them, and for some specified amount is determined after storage, as described above.

Capsules

Suitable capsules for use by the second object of the present invention are hard gelatin capsules, although it is also possible to use other suitable capsules coated.

The use of standard dosage forms

To ensure the desired results mixed compound metals preferably once daily at a dose of from 0.1 to 500, preferably from 1 to 200 mg/kg of body weight of the patient. Those who are not less sometimes it is necessary to change the dose, depending on the body weight of the patient, the type of animal and its individual reaction to the drug or type of composition or time or interval of the injection medicines. In special cases it is enough to enter the dose is less than the above lower limit, in other cases it is possible to exceed the above maximum dose. In the case of large doses it is recommended to divide the dose into several smaller single doses. Eventually, the dose depends on the doctor's appointment, but is also suitable for self-treatment. It is recommended to get a dose before a meal, for example, for 1 h before meals. In another embodiment, a dose can be administered during a meal or after a meal.

Standard tablet of the present invention for the introduction of an adult ranges from 1 mg to 5 g, preferably from 10 mg to 2 g, more preferably from 100 mg to 1 g, for example, from 150 mg to 750 mg, 200 mg to 750 mg, or from 250 mg to 750 mg of mixed metal compounds.

Preferably the standard dosage forms of the present invention include at least 100 mg of mixed metal compounds. Preferably the standard dosage forms of the present invention include at least 120 mg of mixed metal compounds. Predpochtitel is but the standard dosage forms of the present invention include at least 150 mg of mixed metal compounds. Preferably the standard dosage forms of the present invention include at least 200 mg of mixed metal compounds. Preferably the standard dosage forms of the present invention include at least 250 mg of mixed metal compounds. Preferably the standard dosage forms of the present invention include at least 300 mg of mixed metal compounds. Most preferably the standard dosage forms of the present invention include 500 mg of mixed metal compounds. To improve the patient's consent to treatment with oral weight preferred dosage form is less than 750 mg, more preferably less than 700 mg. Primarily suitable dosage form contains 200 mg (±20 mg) mixed metal compounds. Primarily suitable dosage form contains 250 mg of (±20 mg) mixed metal compounds. Primarily suitable dosage form contains 300 mg of (±20 mg) mixed metal compounds. If the dosage form is a tablet, the preferred dosage form contains any suitable coating.

For the convenience of the patient tablets can be packaged in the container in foil blister packs or the like, for example, indicating days of the week recom is nuesa enter the appropriate dose.

Metals and anions

As described above, at least one trivalent metal selected from iron (III) and aluminium and at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium.

In one preferred object of the divalent metal is at least one magnesium ion, iron, zinc and calcium.

In yet another preferred object of the divalent metal is at least one ion of iron, zinc and calcium.

In one preferred object of the divalent metal is at least one magnesium ion, iron and calcium.

In yet another preferred object of the divalent metal is at least one magnesium ion, zinc and calcium.

In one preferred object of the divalent metal is at least one magnesium ion, iron and zinc.

In another preferred object of the divalent metal is at least one magnesium ion and calcium.

In yet another preferred object of the divalent metal is at least one magnesium ion and iron.

In one preferred object of the divalent metal is at least one magnesium ion and zinc.

In another preferred object of the divalent metal is at least one ion of iron and zinc.

In another, preferred is a recreational facility divalent metal is at least one ion of iron and calcium.

In one preferred object of the divalent metal is at least one ion zinc and calcium.

In one preferred object of the trivalent metal is at least iron (III). In one preferred object of the trivalent metal is iron (III).

In one preferred object of the divalent metal is at least magnesium. In one preferred object of the divalent metal is magnesium.

In the formula (I) value and is preferably from 0.2 to 0.4. If the value is more than 0.4, the antacid activity decreases due to the reduction of the number of layers MgOH2. If the value is greater than 0.4 or less than 0.2, the connection of the mixed metal may collapse with formation of a mixture of individual compounds of the metals. If the value is less than 0.2, the amount of MgOH2is too high and increases the probability of a laxative effect. If the value is greater than 0.4 or less than 0.2, then the connection may not provide the optimum range of pH from 3 to 4.5.

Commercial magnesia tablets contain approximately 280 g of magnesium/kg weight of the tablet, while the mixed compound metals 2 contains approximately 136 g of magnesium/kg weight of the tablets.

In the formula (III) value x preference is sustained fashion ranges from 0.2 to 0.4 for the same reasons, specified for an index, and in the formula (I).

In one preferred object of the mixed compound metal contains at least one anion hydroxyl and carbonate.

Divalent metal and/or M in the formula (I), (II) and (III) is preferably selected from Mg (II), Zn (II), Fe (II), cu (II), CA (II), La (II) and Ni(II). Among them, most preferred is Mg.

Trivalent metal and/or M in the formula (I), (II) and (III) is preferably selected from Mn(III), Fe(III), La(III), Al(III), Ni (III) and Ce(III). Among them, most preferred are Fe(III) and Al(III) and especially preferred is Fe(III). In this context, the symbol (II) indicates the metal in the divalent state, and (III) refers to the metal in the trivalent state.

Andnpreferably selected from one or more of carbonate, hydroxycarbonate, oxoanions (e.g., nitrate, sulfate), anion complex with the metal (e.g., ferrocyanide), polyoxometalates, organic anions of halides, hydroxides, and mixtures thereof. Among them, most preferred is sodium carbonate.

Preferably the compound contains less than 200 g/kg of aluminum metal, more preferably less than 100 g/kg, even more preferably less than 50 g/kg based on the weight of the connection.

More preferably the compound contains only low levels of aluminum, for example, less than 10 g/kg, preferably m is 5 g/kg

Even more preferably the compound does not contain aluminum (Al). The term "does not contain aluminum" means that the content of elemental aluminum in the material is less than 1 g/kg, more preferably less than 500 mg/kg, even more preferably less than 200 mg/kg, most preferably less than 120 mg/kg based on the weight of the connection.

Typically, the compound contains iron(III) and at least one of the metals, including magnesium, iron, zinc, calcium, lanthanum or cerium, at least one of the metals, including magnesium, lanthanum or cerium, most preferably magnesium.

Preferably, the content of elemental calcium in combination is less than 100 g/kg of calcium, more preferably less than 50 g/kg, even more preferably less than 25 g/kg based on the weight of the connection.

More preferably the compound contains only low levels of calcium, for example, less than 10 g/kg, preferably less than 5 g/kg

Even more preferably the compound does not contain calcium. The term "does not contain calcium" means that the content of elemental calcium in the material is less than 1 g/kg, more preferably less than 500 mg/kg, even more preferably less than 200 mg/kg, most preferably less than 120 mg/kg per weight of material.

Usually, repeated administration of antacids containing high levels of carbonate,such as caso 3or MgCO3provides high levels of carbonate (respectively 600 g/kg and 710 g/kg), which may cause alkalosis. At the same time, the introduction of mixed metal compounds provides a level of carbonate of less than 100 g/kg of the compound of the present invention, the carbonate is preferably present in amounts of less than 600 g/kg, more preferably less than 200 g/kg, even more preferably less than 100 g/kg

The material compound (II)obtained by heat treatment of the compound (I), typically contains smaller amounts of carbonate.

Preferably the compound does not contain calcium and does not contain aluminum.

The final standard dosage form comprising granules and any other material that is part of the final dosage form, in a preferred embodiment, in General, does not contain aluminum and/or preferably does not contain calcium (these terms are defined above).

Preferably the mixed compound metals include at least some material, which is a layered double hydroxide (LDH). More preferably, the mixed compound of metals of the formula (I) is a layered double hydroxide. The term "layered double hydroxide used in this context, refers to synthetic or natural layered hydroxides containing cations of a metal of the TLD is of different types in the core layers, and containing anions in the interlayer sites. This large family of compounds also known as anionic clays, compared to conventional cationic clays containing cations in the interlayer sites. SDG also referred to as compounds hydrotalcite type the name of the polytype of the corresponding mineral on the basis of [Mg-Al].

First of all fit the mixed compound metal includes at least one carbonate ion and one hydroxyl ion.

The most preferred compound contains as MIIand MIIImagnesium and iron (III), respectively.

The mixed compound or metal compounds obtained by coprecipitation from a solution, for example, as described in the application WO 99/15189, followed by centrifugation or filtration, drying, grinding and/or sieving. Then the mixed compound metals again moisturize during the process of wet granulation and the obtained granules are dried in pseudovirions layer. Drying in pseudovirions layer is used to provide the desired water content in the final tablet.

You can use 2 methods of coprecipitation, namely the first way is by coprecipitation from a solution with a low degree of saturation, the pH of the solution support at a constant value when adding a second alkaline solution, while the second method requires that the tsya in the coprecipitation from a solution with a high degree of saturation, the pH of the solution continuously change when adding the mixed solution of the metal in the alkali solution, already present in the reaction vessel. Preferred is the precipitation at a constant pH, which eliminates the formation of individual compounds of metals, such as M(OH)gand/or M(OH)3instead of mixed metal compounds.

You can also use other ways to get mixed metal compounds: for example, a process comprising a stage of formation of the crystals and the stage of maturation of the crystals, as described in Zhao and others (Zhao Y., etc., Chem Mater, t, s (2002)), or hydrolysis in the presence of urea-induced hydrolysis method using salt-oxide, Sol-gel, oxidation MII in situ method "Chimie Douce" or in another embodiment, the mixed compound metals are by heating a homogeneous mixture of finely ground salts of certain metals at the reaction temperature solid-solid substance, you get a mixed compound of metals.

In addition, you can use the different stages of heat treatment, for example, hydrothermal processing, processing in a microwave reactor, ultrasonic treatment, after deposition of mixed metal compounds to accelerate maturation of the crystals with the aim of obtaining vysokomaslichnoy phase, but is preferably to avoid a stage of maturation of the crystals to form crystallites of small size. In addition, you can use options cues mixed metal compounds from the reaction medium or stage of leaching. For processing of the final product, you can also use different methods of drying or grinding.

The mixed compound of metals of the formula (II) calcined at more than 200ºC to reduce the index z in the formula and to reduce the amount of carbonate. In this case, it may be necessary to add water after annealing and before the inclusion of mixed metal compounds in the composition of the granules to ensure the required level ecovalence bound water in the granules.

Specialists in the art it is evident that the amount of water (z2In the formula (I)is from 3 to 12 wt.% ecovalence bound water (calculated on the weight of the granular material). It should also be understood that the z-index you can define a standard chemical methods. After the separation of the material number ecovalence bound water can be determined by methods as described in this context.

The term "mixed compound of metals" means that the atomic structure of the compound comprises cations of at least two different metals, uniformly distributed in the structure connection. The term "mixed compound of metals" does not include a mixture of cu the growth of the two salts, in which each type of crystal includes only one metal cation. Mixed metal compounds are usually formed by coprecipitation from a solution of various compounds of certain metals in contrast to a simple solid physical mixture of salts of two different metals. The term "mixed metal compounds"used in this context, includes the connection of one type of metal, but with different valence, for example, Fe(II) and Fe(III), and compounds containing the same connection more than 2 different types of metals.

The mixed compound of the metal may also include amorphous (non-crystalline) material. The term "amorphous" means that the material is or contains a crystalline phase, crystallite size which is below the limit of detection by x-ray diffraction, or crystalline phases, which are characterized by some degree of orderliness, but not characterized by the diffraction pattern for crystalline structures, and/or amorphous material, characterized by the structure of the middle order, and not the structure of long-range order.

The compound of formula (II) are usually obtained in the following way: (1) the emulsion is not subjected to ripening stages crystals (e.g., without heating or deposition of the emulsion before washing and highlighting) or (2) the emulsion is not all Laut stage hydrothermal treatment, to avoid increasing the size of the crystals of the compound and to provide a high surface area that contributes to the release of hydroxide ions (Oh-). For the compounds of formula (II)obtained with the exception of stage of ripening, it is preferable to obtain particles of small size after synthesis for high activity (but the particle size should not be too small, to avoid problems with fluidity).

To increase the yield of compounds of formula (I) or (II) is generally preferable to obtain particles of larger size, while, in turn, decreases the accessible surface area and reduced buffer capacity. However, the authors found that the exception to the stage of maturation of the crystals in the reaction emulsion, the compounds of formula II (thus ensuring the formation of crystallites smaller) and instead increase the size of the particles of the compounds of formula (I) or (II) only at the stage of wet granulation (when mixing the compounds of formula (I) or (II) with the preferred excipients and granulation with the formation of particles in the desired range of particle size) allow to obtain a material with antacid properties and at the same time to eliminate the problem of fluidity, which usually occur when the pelletizing of these powders.

Other objects of this is bretania

In one preferred object of the present invention the mixed compound metal contains iron (III) and magnesium in the form of a granular material, including:

(1) at least 50 wt.% mixed metal compounds based on the mass of granular material

(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and

(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

In yet another preferred object of the present invention offers a mixed compound of metals of the formula (I)

MII1-aMIIIaObAn-czH2O(I)

where MIIdenotes the magnesium

MIIIindicates iron(III)

Andndenotes at least one n-valent anion,

2+a is equal to 2b+ ∑cn,

∑cn<0,9a, and

z is 2 or less.

Disease

As described in this context, a mixed combination of metals can be used to neutralize or description of the buffer effect on the acidity in the stomach. Specialists in the art it is evident that the specified action can be used for prophylaxis or treatment of peptic ulcers, heartburn, indigestion syndrome Zollinger-Ellison or combinations thereof. The present invention first of all you can use for prophylaxis or treatment of peptic ulcers.

The present invention is described in more detail below only as an example with reference to the relevant figures.

Figure 1 shows the pH profile of gastric juice in the presence of food and antacids.

Examples

Connection 1

The specified connection was received by the interaction of magnesium sulfate and iron sulfate III in the presence of sodium hydroxide and sodium carbonate. The reaction can be represented by the following equation:

4MgSO4+Fe2(SO4)3+12NaOH+XSNa2CO3→Mg4Fe2(OH)12×CO3×nH2O+7Na2SO4+(XS-1)Na2CO3.

Used excess (XS) of sodium carbonate. Coprecipitation was carried out at a pH of about 10 and the ambient temperature (15-25ºC), as described in the application WO 99/15189, example 3, method 1, the stage of maturation were excluded (the term "exception ripening stages"used in this context, refers to the exclusion of additional stages of heat treatment of the reaction suspension for before the rotation increases the size of the crystals, and thus achieved a high surface area of the crystals). The precipitate was separated by filtration, washed, dried, crushed and sieved, to receive the material, the size of all particles which were less than 106 μm. In these conditions, coprecipitation received the required ratio of Mg/Fe 2:1 and the connection of the gross formula of Mg4Fe2(OH)12×CO3×4,6H2O. the Specified connection can also be present in the form of oxide 4MgO×Fe2O3×CO2×10,6H2O, for which we should expect the following parameters according to the RFU (x-ray fluorescence spectroscopy): 28,3 wt.% MgO=28.7 wt.%, Fe2About3, i.e. the molar ratio of Mg/Fe=1,9:1. According to the analysis obtained the following formula: [Mg3,8Fe2(OH)11,8][0,72(CO3)0,16(SO4)×4,3H2O] due to the presence of small amounts of sulfate in the material. The carbon content of the compound was determined by the standard method LECO (carbon analyzer) and expressed in the form of CO2or CO3. The sulfate content was determined by the method of the RFU. The water content in the formula of the oxide was determined as follows: N2On=100% - (MgO+Fe2About3+SO3+CO2). According to the method of x-ray diffraction determined that the mixed compound of metals is characterized by the presence nizkoglikemichesky patterns hydrotalcite type harakteryzuyutsya diffraction lines (50% of the width when 20=0,67º), which corresponds to a crystallite size of 150 A. the Number nicollete bound water, some drying to constant weight at 105º in a drying cupboard at 7.3% (wt./wt.). The sodium content (expressed in terms of Na2O) amounted to less than 0.05 wt.%.

Connection 2

Got a dry mixture containing 79,75% sifted powder compounds 1, 15% pre-gelatinizing starch, 5% micronized crosspovidone and 0.25% magnesium stearate (magnesium stearate are stored separately to be added to the dry granules). The dry mixture was mixed in a mixer granulator. Then the powder mixture was granulated with a sufficient quantity of water thus obtained granulate, which is then transferred into the dryer with pseudovirions layer to dry to a moisture content of 5-7 wt.%. Then the pellets were crushed in a high-speed impeller mill prior to the formation of particles which passed through a sieve with mesh size of 425 μm. The sifted granules were then mixed with a previously sifted magnesium stearate (also sifted through a sieve with mesh size of 425 μm), thus obtained mixture to obtain tablets (magnesium stearate was mixed with the granules immediately after sieving). This mixture to obtain tablets extruded on the stationary press Manesty F3 (using convex oblong punch and set the matrix) in tablets with standard hardness from 10 to 20 kgf (defined on the device for estimating the hardness of tablets Holland C50). This tablet contains 500 mg of the active ingredient of the gross formula of Mg4Fe2(OH)12×CO3×4,6N2About (according to the definition of the contents of MgO by the method of the RFU. According to x-ray analysis, it was found that granules containing a mixed combination of metals that are characterized by nizkoglikemichesky structure hydrotalcite type. The number ecovalence bound water in the tablet that is defined using IR scales Satorius ME when 75º with automatic determination of final quantities, was 5 wt%.

Connection 3

Powder (compound 1, sifted through a sieve with mesh size of less than 106 μm) was heated at 500º for 30 min, as described in the application WO-A-2006/085079. The number ecovalence bound water, some drying to constant weight at 105º in a drying Cabinet, was 1.1 wt.%. According to the RFU received material containing 45 wt.% MgO, 47 wt.%, Fe2About3when a molar ratio of Mg/Fe of 1.9:1.

Connection 4

Compound 4 was obtained according to the method described for compound 1, but at a molar ratio of Mg/Fe 3:1.

Connection 5

Powder compounds 4 (sifted through a sieve with mesh size of less than 106 μm) was heated at 500º for 30 min, as described in the application PCT/GB 2006/000452.

Connection 6

The specified connection was received by the interaction of sulfate mA the of and of aluminum sulfate in the presence of sodium hydroxide and sodium carbonate. The reaction can be represented by the following equation:

6MgSO4+Al2(SO4)3×14N2O+16NaOH+XSN2CO3→[Mg6Al2(OH)16CO3×4H2O]+9Na2SO4+(XS-1)PA2CO3+10H2O.

Used an excess of sodium carbonate (XS). Coprecipitation was carried out in the range of pH of 9.5-10 at ambient temperature (15-25ºC). Solution a contained metal salts, and the solution contained In the hydroxide and sodium carbonate.

The molar ratio Paon/PA2CO3the solution was 4.3:1. Both solutions were added simultaneously for 45 min using peristalticheskogo pump (speed of 6.9 rpm for a solution and 5.6 rpm for a solution). The speed of addition of the solution changed to maintain pH in the range of 9.5-10. The resulting suspension was subjected to ripening stages (i.e., the suspension was immediately filtered, and additional stages, such as heat, not used to prevent further growth of the crystals). The precipitate was separated by filtration, washed, dried, crushed and sieved, to receive the material, the size of all particles which were less than 106 μm, gross formula [Mg6Al2(OH)16CO3×4H2O]. The product according to the RFU contained 15 wt.% MgO and 26 wt.% Al2O3when a molar ratio of Mg/Al 2,9:. According to PCA compound characterized by the structure hydrotalcite type.

Connection 7

Powder of compound 6 was granulated and extruded into pellets according to the method described for compound 2. In the tablet according to the definition of the contents of MgO (RFU) contained 500 mg of the active ingredient [Mg6Al2(OH)16CO3×4H2O].

Compound 8

Compound 8 was obtained in the same way as described for compound 2, but the coating was applied as follows. The coating was performed using a hand sprayer, 300-400 core tablets were placed in a rotating pan, purged with a stream of hot air from termoizolata (for drying of tablets). Suspension coating was applied at a rate sufficient to promote adhesion of the coating to the core of the tablet, but low enough to avoid destruction of the tablets during the coating process.

Suspension of coverage included: 84% of purified water, 0.8% of sodium dodecyl sulfate, 8,08% butylated methacrylate copolymer (Eudragit EPO), 1,21% stearic acid, 2,09% talc, and 2.83% of stearate magnesium, 0,64% titanium dioxide, 0,32% red iron oxide. After application, the coating was dried in a stream of hot air at 40ºC. Film coating Eudragit EPO was applied in the amount of about 4.5 wt.% to ensure uniformity of the coating. Time, u is demote tablets coated, measured at the device for determining raspadaemosti Copley DTG 2000 IS was less than 30 min in hot water and in acidic environment. This tablet contained 500 mg of the active ingredient of the gross formula of Mg4Fe2(HE)12×CO3×4,6N2Oh, calculated as MgO content (RFU). The number ecovalence bound water in the tablet that is defined using IR scales Satorius MA30 when 75º with automatic determination of final quantities, was 6 wt.%.

Connection 9

Compound 7, but with a coating was prepared as follows. The coating was performed using a hand sprayer, 300-400 core tablets were placed in a rotating pan, purged with a stream of hot air from a heat gun (for drying of tablets). Suspension coating was applied at a rate sufficient to promote adhesion of the coating to the core of the tablet, but low enough to prevent destruction of the tablets during the coating process.

Suspension of coverage included: 84% of purified water, 0.8% of sodium dodecyl sulfate, 8,08% butylated methacrylate copolymer (Eudragit EPO), 1,21% stearic acid, 2,09% talc, and 2.83% of stearate magnesium, 0,64% titanium dioxide, 0,32% yellow iron oxide. After application, the coating was dried in a stream of hot air at 40ºC. Film coating Eudragit EPO was applied in the amount of approximately 4.5 mA is.% to ensure uniformity of the coating. Time raspadaemosti tablets coated defined on the device for determining raspadaemosti Copley DTG 2000 IS was less than 30 min in hot water and in acidic environment. This tablet contained 500 mg of the active ingredient gross formulas MD6Al2(OH)12×CO3×4,6N2Oh, calculated as MgO content (RFU).

Connection 10

The core tablets were obtained as described for compound 2, but the grinding of the pellets was carried out in a device with high speed, thus obtained granules passing through a sieve with a mesh size of 1000 μm. Then on the core tablet was coated as described for compound 8. This tablet contained 500 mg of the active ingredient of the gross formula of Mg4Fe2(OH)12×CO3×4,6N2Oh, calculated as MgO content (RFU).

Connection 11

Compound 6 was screened to obtain a particle size of less than 106 μm and heated at 500º within 30 minutes

Connection 12

Compound 6 was screened to obtain a particle size of less than 106 μm and heated at 750º within 30 minutes

Product Macrosorb™

Hydrotalcite formula Al2Mg6(OH)16CO3×4H2O company Ineos Silicas.

Product Altacite plus

Altacit formula similar to hydrotalcite Macrosorb produced in the form of a water suspension.

Rennie™, Alucap™, Talcid™, Ultacit™, Talidat™ and Ceam of Magnesia (Boots)

All of these materials are commercial products.

Method 1

The effectiveness of neutralizing acid (EHC) was evaluated as follows.

The investigated compound was added to a beaker containing 70 ml (pure for analysis) water, when 37º using orbital rocking Grant OLS200. During the experiment the temperature was maintained at 37±3 º C. In the studied composition under stirring on a magnetic stirrer were added 30 ml of 1.0 N. hydrochloric acid. The resulting solution was stirred precisely for 15 minutes Then immediately (through no more than 5 min), the solution was titrated 0,5h. sodium hydroxide until a stable pH of 3.5 (within 10 to 15). For titration used the device And 718 Stat Titrino. Each compound was analyzed in the triple repetition. Tablets for grinding prior to analysis were crushed in a mortar with a pestle to stimulate the process of grinding. This method corresponds to the standard USP (USP), Chapter 301. The value in mEq./g was determined by the following equation = (30×H·HCl) - (volume Paon×H·NaOH)/g of the compounds.

Method 2

To determine the maximum value of pH, which is achieved by adding acid, 100 ml of water was added to the beaker and was heated at 37º on an orbital shaker Grant OLS200 at a speed of 170 rpm Water previously was titrated to pH 4 by adding 0,1N. HCl Investigational compound was added into the solution, in which with the use of device Metrom Stat Titrino 718 was added 0.1 n Hcl with a speed of 3 ml/s Then every 30 s during the 1800 measured pH and temperature. Register all maximum pH within the specified time. The pH was measured on a standard pH-meter, Jenway model 3520, provided with an electrode VWR 6621759. Prior to each measurement, the pH meter was calibrated using buffer solutions at room temperature (25ºC).

This method allows to evaluate the ability of the ricochet effect of the acid. This effect is observed when using antacids too fast action, which instantly increases the pH to a value of more than 5, i.e. pH below 5 is more preferable (however, the pH value should not be reduced to too low values, i.e. pH less than 2, since in this case antacid inactive).

Method 3

Buffer action in the presence of food was determined on the model of the gastrointestinal tract in vitro.

Control (in the absence of antacid), one capsule Alucap (contains 475 mg of the active ingredient), 1 tablet of compound 8, 500 mg of the compound 1 (2 gelatin capsules), 500 mg of powdered compound 3 (2 gelatin capsules) each in a separate experiment (three or four repetitions, n=3 or 4) was mixed with standard food (food that is designed in compliance with the standards of the Committee of the U.S. food and drug products (FDA), usually used for the investigation of bioavailability and maximum effects on the physiological condition of the gastrointestinal tract). Compounds 1 and 3 were added in the form of gelatin capsules, each of which contains 250 mg of the powder antacid. The experiments were conducted using a device Tiny-TIM (Nederlandse Organisatie voor Toegepast-Natuurwetenschappelijk Onderzoek TNO, Zeist, the Netherlands). A detailed description of the model published in the literature, for example, in patent US 5525305. The experiments were conducted in secondary physiological conditions of the gastrointestinal tract of man. These conditions include the dynamics of gastric emptying and the times of passage through the intestine, the pH in the stomach and intestines, as well as the composition and activity of the secretions. The pH value in the Department of the stomach was measured for 300 min (figure 1).

Based on the data presented in the figure, we can draw the following conclusions:

Preferred compounds have a buffering effect on the pH value within approximately 2 hours (compared to a control containing only food). In this model, the emptying of the stomach occurs at approximately 80% within 2 h, approximately 95% within 3 hours and 100% after 6 hours Thus, the obtained results indicate that the preferred antacid characterized prodolzhitelnostyu, i.e. antacid activity remains up until the stomach is emptied at approximately 80%.

Preferred compounds have a buffer action in the presence of food. Unlike commercial antacid based AlOH3that does not have a buffer action in the presence of food.

- Instantaneous change in pH in the stomach is not (or is less than pH 7) in the presence of food and, thus, eliminates the ricochet effect of the acid or irreversible inactivation of pepsin.

Method 4

Volume pills was determined by adding 5 tablets per cylinder containing 50 ml of water. The displaced volume was determined from the change in volume of water after addition of 5 tablets per cylinder. Then the expected volume of each tablet according to the formula: displaced volume/5. The volume change was measured immediately after addition of the tablets in the cylinder, i.e. before the disintegration of tablets in water.

Literature

1. Hirahara Hidetoshi, Sawai Yoshiyuki, Aisawa Sumio, Satoshi Takahashi, Umetsu Yoshio, Narita Eiichi, "Synthesis and antacid property of Mg-Fe layered double hydroxide", Department of Chemical Engineering, Faculty of Engineering, Iwate University, Morioka, Japan, Called Nendo, V.42, №2, cc.70-76 (2002).

2. Application IN-A1-192168.

3. Miederer S.-E., Wirtz M., Fladung B. "Acid neutralization and bile acid binding capacity of hydrotalcite compared with other antacids: an in vitro study", Department of Internal Medicine, Gastroenterology and Metabolism, University of Bonn, University of Bielefeld, Leverkusen, Germany, Chinese Journal of Digestive Diseases, V. 4, No. 3, cc.140-146 (2003).

4. Lin Mei-Shu, Sun Pin, Yu Hsiu-Ying, "Evaluaton of buffering capacity and acid neutralizing-pH-time profile of antacids". School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, Journal of the Formosan Medical Association, t, No. 10, cc.704-710 (1998).

5. Patent JP-A-10236960.

6. Grubel p, Bhaskar .R., Cave D.R., P. Garik, Stanley H.E., Lamont J.., "Interaction of an aluminum-magnesium-containing antacid and gastric mucus: possible contribution to the cytoprotective function of antacids", Division of Gastroenterology, St. Elizabeth's Medical Center of Boston, Harvard Medical School, Boston University, Boston, MA, USA. Alimentary Pharmacology and Therapeutics, t, No. 1, s-145(1997).

7. Patent EP-A-0638313.

8. Vatier j, Ramdani, A., Vitre M.L., Mignon M., "Antacid activity of calcium carbonate and hydrotalcite tablets: Comparison between in vitro evaluation using the "artificial stomach-duodenum" model and in vivo pH-metry in healthy volunteers", Cent. Hospitaller Univ. X. Bichat, Paris, Fr. Arzneimittel-Forschung, t, No. 4, cc.514-18(1994).

9. Patent ES-A-2018952.

10. Patent CA-A-1198674.

11. Patent DE-A-3346943.

12. Playle A.C., Gunning S.R., Llewellyn, "The in vitro antacid and anti-pepsin activity of hydrotalcite", Pharm. Acta Helv., v.49, no.9/10 (1974).

13. Acid neutralization capacity of Canadian antacid formulations". Can Med. Assoc J., t, March 1, cc.523-527 (1985).

14. Patent US 3650704.

All publications, patents and applications for patents mentioned in this context included in the present invention as references. Specialists in the art it is evident that various modifications and embodiments of the present invention, which are within the scope and essence of the invention. Although the present invention is described on the example of certain preferred variants of its implementation, it should be understood, Thu the, as defined in the accompanying claims, the invention is not limited to such variants of its implementation. Indeed, various modifications of the described methods of implementation of the present invention that are obvious to experts in the field of chemistry, biology or related areas, do not go beyond the scope of the attached claims.

1. The use of mixed metal compounds to obtain a medicinal product intended for neutralization of gastric acid or the buffer of the action, and the mixed compound metal includes at least one trivalent metal selected from iron (III) and aluminium and at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,
where
(A) a mixed combination of metals is a compound of formula (I):
MII1-aMIIIaObAn-czH2O, (I)
where MIIdenotes at least one divalent metal,
MIIIrepresents at least one trivalent metal,
Andndenotes at least one n-valent anion,
n denotes the valence of the anion And,
0,2≤a≤0,4,
0,2<b≤1.5A,
2+a is equal to 2b+Σcn,
Σcn<0,9a, and
z is 2 or less, or
(B) a mixed combination of metals is provided in the form of a granular material, where the diameter of at least 50 wt.% granules in the composition of the granular material is from 106 to 1180 microns, including:
(1) at least 50 wt.% mixed metal compounds based on the mass of granular material
(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and
(3) not more than 47 wt.% excipient in the calculation of the mass of granular material;
and where the mixed compound metal is a compound of formula (I) or formula (III):
MII1-xMIIIx(OH)2An-ymH2 O,(III)
where MIIdenotes at least one divalent metal,
MIIIrepresents at least one trivalent metal,
Andndenotes at least one n-valent anion,
n denotes the valence of the anion And,
x=Σyn,
0<x≤0,4,
0<y≤1, and
0≤m≤10.

2. The use according to claim 1, where
(A) a mixed combination of metals is a compound of formula (I):
MII1-aMIIIaObAn-czH2O,(I)
where MIIdenotes at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,
MIIIrepresents at least one trivalent metal selected from iron (III) and aluminum
Andndenotes at least one n-valent anion,
n denotes the valence of the anion And,
0,2≤a≤0,4,
0,2<b≤1.5A,
2+a is equal to 2b+Σcn,
Σcn<0,9a, and
z R the VNO 2 or less.

3. The use according to claim 1 or 2, where in the formula (I) z is equal to 1.8 or less.

4. The use according to claim 1 or 2, where in the formula (I) z is equal to 1.5 or less.

5. The use according to claim 1 or 2, where in the formula (I) index and ranges from 0.2 to 0.4.

6. The use according to claim 1 or 2, where in the formula (I) index a is from 0.2 to 0.34.

7. The use according to claim 1 or 2, where in the formula (I) index and<0,3.

8. The use according to claim 1 or 2, where in the formula (I) index b is equal to 1.5 or less.

9. The use according to claim 1 or 2, where in the formula (I) index b is 1.2 or less.

10. The use according to claim 1 or 2, where in the formula (I), 0,03a<Σcn<0,7a.

11. The use according to claim 1 or 2, where in the formula (I), 0,03a<Σcn<0,5a.

12. The use according to claim 1 or 2, where the compound of formula (I) are obtained by heating a source material containing a double hydroxide of the layered structure at a temperature of from 200°to 600°C.

13. The application indicated in paragraph 12, where the compound of formula (I) are obtained by heating a source material containing a double hydroxide of the layered structure at a temperature of from 250°C to 500°C.

14. The application indicated in paragraph 12, where the source material includes the compound of formula (III):
MII1-xMIIIx(OH)2An- ymH2O,(III)
where MIIdenotes at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,
MIIIrepresents at least one trivalent metal selected from iron (III) and aluminum
Andndenotes at least one n-valent anion,
x=[MIII]/([MII]+[MIII]), where [MII] denotes the number of moles MIIand [MIII] denotes the number of moles MIII,
and x=Σyn,
0<x≤0,4,
0<y≤1, and
0<m≤10.

15. The use according to claim 1 where (B) a mixed combination of metals is provided in the form of a granular material, including
(1) at least 50 wt.% mixed metal compounds corresponding to the formula (I) or formula (III) in the calculation of the mass of granular material
(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and
(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

16. The application indicated in paragraph 15, where the mixed compound metal has the formula (III):
MII1-xMI IIx(OH)2An-ymH2O,(III)
where MIIdenotes at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and series,
MIIIrepresents at least one trivalent metal selected from iron (III) and aluminum
Andndenotes at least one n-valent anion,
x=[MIII]/([MII]+[MIII]), where [MII] denotes the number of moles MIIand [MIII] denotes the number of moles MIII,
and x=Σny,
0<x≤0,4,
0<y≤1, and
0≤m≤10.

17. The application of article 16, where in the formula (III) 0<x≤0,4.

18. The application of article 16, where in the formula (III) of 0.2<x≤0,4.

19. The application of article 16, where in the formula (III) x<0,3.

20. The application of article 16, where in the formula (III) 0<y≤1.

21. The application of article 16, where in the formula (III) 0≤m≤10.

22. The application of article 16, where the mixed compound of metals is provided in the form of granulated material containing less than 15 wt.% water absorbed on the surface of the crystallites.

23. The application of article 22, where the mixed compound metals contains Myung is e 10 wt.% water absorbed on the surface of the crystallites.

24. The application of article 22, where the mixed compound metal contains less than 1 wt.% water absorbed on the surface of the crystallites.

25. The use according to claim 1, where the granular material includes as excipient from 5 to 20 wt.% pre gelatinizing starch based on the weight of the granular material.

26. The use according to claim 1, where the granular material includes as excipient from 1 to 15 wt.% crosslinked polyvinylpyrrolidone in the calculation of the mass of granular material.

27. Use p where excipient includes at least pre-gelatinizing starch and crosspovidone.

28. The use according to claim 1, where the granular material is inside the water-resistant capsules.

29. The use according to claim 1, where between granules is grease.

30. The application of clause 29, where the lubricating material is or comprises magnesium stearate.

31. The use according to claim 1, where the granular material is applied waterproof coating.

32. Use p, where water-resistant coating comprises at least 30 wt.% copolymer butylated methacrylate.

33. The use according to claim 1 or 2, where the mixed compound metals presented in the form of standard dosage forms, containing a mixed compound of the metal to which icesto at least 200 mg.

34. The use according to claim 1 or 2, where the trivalent metal is at least iron (III).

35. The use according to claim 1 or 2, where the trivalent metal is iron (III).

36. The use according to claim 1 or 2, where the divalent metal is at least magnesium.

37. The use according to claim 1 or 2, where the divalent metal is magnesium.

38. The use according to claim 1 or 2, where
the mixed compound metals includes iron (III) and magnesium, and is provided in the form of a granular material, where the diameter of at least 50 wt.% granules in the composition of the granular material is from 106 to 1180 microns, including:
(1) at least 50 wt.% mixed metal compounds based on the mass of granular material
(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and
(3) not more than 47 wt.% excipient in the calculation of the mass of granular material
and where the mixed compound metal is a compound of formula (I) or formula (III).

39. The use according to claim 1 or 2, where the mixed compound metal is a compound of formula (I):
MII1-aMIIIaObAn-cmo> ⋅zH2O,(I)
where MIIdenotes magnesium,
MIIIindicates iron (III),
Andndenotes at least one n-valent anion,
n denotes the valence of the anion And,
0,2≤a≤0,4,
0,2<b≤1.5A,
2+a is equal to 2b+Σcn,
Σcn<0,9a, and
z is 2 or less.

40. The use according to claim 1 or 2, where the mixed compound metal contains at least one hydroxyl anion and the carbonate anion.

41. The use according to claim 1, where
(A) a mixed combination of metals is a compound of formula (I):
MII1-aMIIIaObAn-czH2O,(I)
where MIIdenotes at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium,
MIIIrepresents at least one trivalent metal selected from iron (III) and aluminum
Andndenotes at least one palenty anion,
n denotes the valence of the anion And,
0,2≤a≤0,4,
0,2<b≤1.5A,
2+a is equal to 2b+Σcn,
Σcn<0,9a, and
z is 2 or less,
and
(B) a mixed combination of metals is provided in the form of a granular material, where the diameter of at least 50 wt.% granules in the composition of the granular material is from 106 to 1180 microns, including:
(1) at least 50 wt.% mixed metal compounds based on the mass of granular material
(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and
(3) not more than 47 wt.% excipient in the calculation of the mass of granular material.

42. The use of mixed metal compounds to obtain a medicinal product intended to treat a condition or disease associated with high levels of acid in the stomach, and the mixed compound metal includes at least one trivalent metal selected from iron (III) and aluminium and at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium, where
(A) a mixed combination of metals is a compound of formula (I):
MII1-aMIIIaObAn -czH2O,(I)
where MIIdenotes at least one divalent metal,
MIIIrepresents at least one trivalent metal, Andndenotes at least one n-valent anion,
n denotes the valence of the anion And,
0,2≤a≤0,4,
0,2<b≤1.5A,
2+a is equal to 2b+Σcn,
Σcn<0,9a, and
z is 2 or less,
or
(B) a mixed combination of metals is provided in the form of a granular material, where the diameter of at least 50 wt.% granules in the composition of the granular material is from 106 to 1180 microns, including:
(1) at least 50 wt.% mixed metal compounds based on the mass of granular material
(2) from 3 to 12 wt.% ecovalence bound water per mass of granular material, and
(3) not more than 47 wt.% excipient in the calculation of the mass of granular material
and where the mixed compound metal is a compound of formula (I) or formula (III):
MII1-xMIIIx(OH) 2An-ymH2O,(III)
where MIIdenotes at least one divalent metal,
MIIIrepresents at least one trivalent metal,
Andndenotes at least one n-valent anion,
n denotes the valence of the anion And,
x=Σyn,
0<x≤0,4,
0<y≤1, and
0≤m≤10.

43. The application of § 42, where the condition or disease is a peptic ulcer, heartburn and acid reflux.

44. The application of § 42, where the condition or disease is a peptic ulcer.

45. The use according to claim 1, where the granules have a diameter of 1000 μm or less.

46. Use item 43, where the granules have a diameter of 1000 μm or less.



 

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SUBSTANCE: invention can be applied in chemical industry, metallurgy and purification of industrial and domestic sewages. Extraction of iron with vegetable oils is realised from water solution with ratio water (W) to organic (O) phase W:O≥3 for Fe (III) and W:O= 3-6 for Fe(II); at pH 2-3 for Fe (III) and 9-11 for Fe (II) and Fe (III). Time of extraction for Fe (III) is 1-3 min and not more than 60 min for Fe (II).

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FIELD: medicine.

SUBSTANCE: the invention relates to method of purifying bischofite solution, which is used as a medication and balneal solution, from technical iron inclusions. The method includes adsorption on magnesium oxide with the use of oxidation agents, such as magnesium peroxide with amount of 0,5-1 g/l or hydrogen peroxide 30% solution with amount of 0,1-1 g/l, furthermore, mixing stage is carried out by aeration with a pressurized air stream maintained for 1-8 h.

EFFECT: more efficient removal of iron compounds, reduced process duration, simplified instrumentation.

2 tbl, 1 ex.

Material // 2437650

FIELD: chemistry.

SUBSTANCE: granular material contains (a) at least 50 wt %, in terms of the weight of granular material, of a solid water-insoluble inorganic mixed compound of layered double hydroxides of metals capable of binding phosphate, and which contains iron (III) and at least one of the following metals: magnesium, calcium, lanthanum or cerium; (b) 3-10 wt % chemically bound water in terms of the weight of granular material; (c) not more than 47 wt % filler in terms of the weight of granular material. The granular material is obtained via wet granulation. The disclosed granular material is meant for use in therapy for a condition or disease associated with unfavourable content of phosphate in the body.

EFFECT: invention enables to maintain physical integrity of granules and batches during storage, good phosphate binding after ingestion of the granules without their excessive breakdown in the mouth.

22 cl, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to production of oxide powder with composition Pb(Mg1/3Ta2/3O3) having a perovskite structure and can be used in producing materials for piezoelectric engineering. The method involves mixing a tantalum compound with aqueous solutions of lead and magnesium salts in stoichiometric ratio which yields a composition of lead magnotantalate with a perovskite structure - Pb(Mg1/3Ta2/3O3), and then thermal treatment of the obtained suspension. The tantalum compound used is tantalum hydroxide and the solutions of magnesium and lead salts are solutions of magnesium and lead acetates which are added successively, the product being thermally treated at 800-850°C.

EFFECT: low synthesis temperature, high output and purity of the end product.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: method of producing organically modified layered double hydroxide involves preparation of a suspension containing a divalent metal ion source selected from oxides and hydroxides of a divalent metal, and a trivalent metal ion source selected from oxides and hydroxides of a trivalent metal; thermal or solvothermal treatment of the said suspension to obtain layered double hydroxide. An organic anion is added before or during or after formation of the layered double hydroxide. The organic anion has 8 or more carbon atoms, wherein a deoxycholic acid anion is not the only organic anion. The divalent and/or trivalent metal ion source is crushed and the suspending medium used is water. As a result, an organically modified layered double hydroxide is obtained, having distance between separate layers greater than 1.5 nm and containing an organic anion as a charge-compensating anion.

EFFECT: low amount of streams of harmful wastes formed during production of organically modified layered double hydroxides.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: monomer used is a vinyl monomer selected from a group consisting of vinyl-substituted aromatic, heterocyclic and alicyclic compounds, unsaturated aliphatic carboxylic acids and their derivatives, unsaturated aliphatic nitriles, vinly esters of aromatic and saturated aliphatic carboxylic acids, divinyl compound or mixtures thereof. The method involves a) separate supply of at least one stream of monomer of at least one stream of carbon dioxide, a stream of initiator and, optionally, a stream of a modifying additive, wherein said streams of monomer and/or carbon dioxide are fed at supercritical pressure; b) heating said monomer and carbon dioxide streams at least to supercritical temperature of the monomer and/or carbon dioxide to form a supercritical fluid; c) merging said monomer, carbon dioxide and initiator streams and, optionally, modifying additive in a jet mixer (6) of a pipe reactor with linear velocity which ensures pressure lower than supercritical pressure of the monomer and/or carbon dioxide, during which at least partial transition of the supercritical fluid into gas phase takes place, wherein the period of time during which said merging takes place is essentially less than 1 second, preferably less than 0.1 second; d) sharp reduction of linear velocity of the obtained reaction mixture in a direct flow pipe reactor (7) to a value which ensures pressure higher than supercritical pressure of the monomer and/or carbon dioxide, during which at least partial transition of the gas phase to supercritical fluid takes place and said reaction mixture reacts in essentially adiabatic conditions to form polymer particles, in the initial period of which instantaneous increase in temperature of the said reaction mixture by at least approximately 20°C takes place. The period of time during which said interaction takes place is essentially approximately between 60 and 120 seconds; e) throttling the obtained stream of polymer solution through a reducing device (8) into an evaporative separator (9) with lower pressure, in which owing to sharp reduction of density of the said polymer solution, the supercritical fluid turns into a solid phase with subsequent formation of polymer particles, wherein the reducing device (8) simultaneously maintains the required supercritical pressure of the monomer and/or carbon dioxide in the reaction zone of the pipe reactor (7), after which a gas stream primarily containing carbon dioxide comes out from the top of the evaporative separator (9) and a powdered stream primarily containing fine granules of polymer is obtained at the lower part. The invention also discloses a device for producing copolymers.

EFFECT: obtaining copolymers with good performance properties and high level of long-chain branching.

20 cl, 5 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention can be used in chemical industry. Polychlorozincates of group IIA metals are obtained by reacting chlorides of group IIA metals with zinc chloride in diethyl ether medium and have general chemical formula nMCl2·ZnCl2·mEt2O, where M = Mg n = 1, m = 2; when when M = Ca, Sr n = 1, m = 4; when M = Ba n = 2, m = 6.

EFFECT: said chemical compounds are suitable for use as reagents in purifying oil products and natural gas from mercaptans and hydrogen sulphide, catalysts used in chloromethylation and alkylation of aromatic hydrocarbons and starting materials during production of metal hydrides.

6 tbl

FIELD: chemistry.

SUBSTANCE: invention can be used in chemical industry. Polychloroaluminates of alkali-earth metals are obtained by reacting chlorides of alkali-earth metals with aluminium chloride in diethyl ether medium and have general chemical formula MCl2·4AlCl3·nEt2O, where when M = Ca n = 4.5; when M = Sr n = 1, 1.5; when M = Ba n = 2.5.

EFFECT: said chemical compounds are suitable for use as reagents in purifying oil products and natural gas from mercaptans and hydrogen sulphide, catalysts used in chloromethylation and alkylation of aromatic hydrocarbons and starting materials during production of metal hydrides.

6 tbl

FIELD: chemistry.

SUBSTANCE: method of producing layered hydroxides of formula Mg(1-X)Mex3+(OH)2(CO3)x/2·nH2O, where the trivalent metal is scandium Sc3+ or iron and aluminium at the same time in the form FeyAlx-y, where y is less than x and x is not more than 0.4. A solution containing Mg2+ and Sc3+ chlorides or nitrates, or a solution containing Mg2+ and Al3+ chlorides or nitrates and Fe3+ sulphates or chlorides or nitrates is added to a precipitation agent solution, containing sodium hydroxide and sodium carbonate. The ratio of ions Me3+: Mg2+: [OH-] : [CO32-] in the solution is 1:3:8:1. The precipitate formed is kept in a mother solution at 96-98°C for two days. After cooling to room temperature, the mother solution with the precipitate is decanted. The residue is subjected to anion exchange with Na2CO3 three times. After settling, the solution is decanted and the residue is washed with distilled water until negative results of presence of sodium ions are obtained, and then dried at 80-105°C. Total concentration of metal salts in the precipitation agent solution is not more than 3 M, and total concentration of the precipitation agent solution is not more than 3 M.

EFFECT: obtaining good crystallised, homogeneous samples of hydrotalcite-like compounds, wider field of their use.

4 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns synthetic lamellar hydroxides of the general formula Mg(1·x)Mex(OH)2(CO3)x/2 •n H2O, where a trivalent metal Me combines scandium and aluminium in the form of ScyAlx-y, so that "y" is less than "x", and "x" is not more than 0.4. The method involves sedimentation of hydrotalcite-like compound from a solution of bivalent magnesium and trivalent scandium and aluminium salts by adding a sedimentation solution containing sodium hydroxide and cardonate, so than the general metal salt concentration in the solution prepared for sedimentation and containing chlorides or nitrates of Mg2+, Al3+ and Sc3+ metals, comprises not more than 3M, and general concentration of the sedimentation solution is not more than 3M. Substance batches for source and sedimentation solutions are calculated on the base of ion ratio in the solution: [Al3+ and Sc3+]:Mg2+:[OH"]:[CO32"] = 1:3:8:1. The sediment is thermostated in the mother solution at 96-98°C for two days, then it is cooled to the room temperature, the mother solution with lamellar hydroxide sediment is decanted and undergoes triple anion exchange with Na2CO3; after sedimentation the solution is decanted, and the sediment is flushed by distilled water till sodium ion is not detected. Afterwards the sediment is dried at 80 -105 C.

EFFECT: obtaining of a new hydrotalcite-like compound.

2 cl, 1 dwg, 1 ex

The invention relates to inorganic chemistry, in particular to methods of producing salt concentrates of natural mineral waters, and in the first place can be used for the production of inorganic drilling reagents that perform the function of controllers in the density of drilling fluids and inhibitors of hydration and dissolution of rock-forming minerals

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to substituted imidazo[1,2-a]pyridines of formula I

,

where R is -CH2COOH or -COOH. The invention also relates to a method of producing a compound of formula I and use of the compound of formula I.

EFFECT: obtaining novel substituted imidazo[1,2-a]pyridines, which inhibit exogenically or endogenically stimulated secretion of gastric acid and which can be used in preventing or treating diseases associated with gastric acid, and inflammatory gastrointestinal diseases.

6 cl, 3 ex

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