Effervescent granules and method thereof

 

(57) Abstract:

The invention relates to the field of medicine. Effervescent granules in the preparation of the pharmaceutical composition contains calcium carbonate and citric acid, with 5 to 20 weight.h. required for the reaction with calcium carbonate amount of the total acid substitute at least one of the following compounds: malic acid, gluconic acid and lactic acid, as well as their predominantly acidic salt. Citric acid and calcium carbonate granularity with partial interaction and, accordingly, at least one part partially substitute citric acid compounds in solid, powdered form is granulated together with citric acid and calcium carbonate and/or granulation liquid or buffer solution. The proposed granulate allows to obtain more stable fizzy drinks. The granulate is simpler to manufacture. 3 S. and 3 C.p. f-crystals, 1 Il.

The invention relates to the effervescent granules for the preparation of pharmaceutical compositions containing calcium carbonate and citric acid, as well as how to obtain it. The production of such products is described, for example, in French patent FR-A-tin 1000 mg of calcium) and 4-4,5 g of citric acid, however, show that effervescent products with high concentration of calcium ions dissolved in 150 or 200 ml of water, after longer standing intended for consumption as a beverage solution, have the tendency to precipitation of insoluble recalcitrate. The time until the deposition of recalcitrate and the amount of sludge depend on the concentration of calcium ions and citric acid intended for use as a beverage solution. Since, however, the consumer preferably dissolving tablet 150: max 200 ml of water, and very often the solution is not immediately drink, this phenomenon is always a negative point, especially as effervescent tablets that contain only 500 mg of calcium ions in 150 ml of water, show the same deposition, although more slow time, i.e. approximately up to 1 hour.

In the publication WO 94/00107 have been proposed to slow down this undesirable effect due to the replacement of a significant proportion (25-73%) citric acid, malic acid, and, if necessary, various salts. Obviously, due to partial binding of calcium carbonate and the formation of mixed salts they interfere with obrazovaniia masses.

Such large amounts of malic acid, however, considerably increases the cost of the product and limit the use of essentially powder mixtures, which are only due to the special measures may be compressed into tablets. Granulation properties of mass due to these large quantities of additives significantly worse: the mass becomes very viscous. In addition, these tablets dissolve slowly, and when dissolved, depending on the circumstances, a precipitate, as during the dissolution process transformation, for example, malate calcium, is very slow; consequently, further formed by precipitation of unreacted calcium carbonate.

Additive proposed in French patent FR-A-2552308 (example 4) Delta-lactone of gluconic acid gives only a much weaker effect according to the invention, since the lactone releases gluconic acid only in the presence of much larger quantities of water, so that the benefits expected in the preparation of effervescent granules (see below), do not appear.

These problems for the first time in an unexpected way to solve due to the fact that 5-20, mostly 10-15 wt.% citric acid is substituted by at least one share acid. Other acids are less preferred because tartaric acid forms insoluble calcium tartrate; adipic acid and ascorbic acid have no or only a weak degree have the desired effect, and adipic acid in addition itself only with difficulty soluble. On the other hand, also important is the specified lower limit: declare acid also have no or only weak extent have the desired effect if they are used in amounts less than 5 wt.%.

Numerous attempts to resolve the problem it was the replacement of 100 mg of citric acid malic acid in effervescent tablet 1000 mg of calcium causes the slow deposition time in 125 ml of water: very much prone to the deposition of the sample shows the improvement in time by 30% from the original 7 minutes to 9.5, and with the addition of 200 mg - 50%, up to 11 minutes. To obtain a more objective parameters, turbidity determined photometrically in the form of absorption at 480 nm at the same value.

Already replaced only 5-15 wt.% citric acid malic acid lengthens the time of deposition by almost half, and at least about 50% (see drawing), without changing the pH of the solution. Next, have let or dry mix, although - and not least for technological reasons, it is preferable granulation.

Other acids that have discovered the benefits are gluconic acid and lactic acid, the latter of which simultaneously can be used as a granulation solution. To replace citric acid suitable salts of these acids, such as lactate, maleate or Delta-lactone of gluconic acid.

In the precipitation to obtain the effervescent granulate favorable was the addition of the second acid. Upon receipt of effervescent granules of calcium carbonate and possibly carbonates and bicarbonates of alkali metals with citric acid required large quantities of fluids, to achieve the interaction of calcium carbonate with citric acid; in addition, or by granulation or drying is additionally influenced by elevated temperature; as a consequence, in part, already upon receipt of the granulate come to the formation of small amounts of recalcitrate that immediately after dissolution of the granules or tablets in a glass manifests itself in the form of insoluble precipitate.

Therefore, when the formation of granulation recalcitrate during granulation and drying to produce this kind of effervescent tablet can be significantly easier without special precautions.

Thus obtaining granules in the presence of any acid is improved due to the fact that when the wetting solutions come to a mutual dissolution of citric acid and any acid, i.e., for example, malic acid, resulting in lowering the melting point of both acids, which has a very good help when pressing. This makes possible a simpler manufacture of the product, so be largely independent of grain structures and you can work with powdered citric acid or a mixture of crystalline citric acid and powdered malic acid without formation already in the process of granulation recalcitrate due to intensive contact of the calcium carbonate with citric acid. Due to the aforementioned decrease in the melting point and the mutual penetration of solutions you can get extremely elastic and well-pressed pellets.

The granulation can be carried out using polar solvents and mixtures of polar solvents, and needless to say, preferably also the use of buffer solutions to prevent too intense reactions.

The dal in polar solvents, it saved effects best behavior when granulating, discouraging the formation of recalcitrate during cooking and slower deposition in the glass.

To these granules, or by embedding these granules can be added also used in the treatment of osteoporosis and fluoride-containing compounds, for example sodium fluoride, monitoroff sodium, fjortoft zinc, etc. can Also be embedded fluorapatite, and Apatity, because of their low solubility in the ground state are suspended in the resulting solution and are suspended.

EXAMPLE 1 (drawing; download 20/5):

Replacement 14% of the total acid powdered malic acid and granulation using a mixture of water with ethanol, and citric acid is used exclusively in powdered form;

2500 weight.parts of calcium carbonate mixed with 3700 weight.parts of powdered citric acid and 600 weight. parts powdered malic acid and at 45oC granularit during the reaction with 200 weight.parts 70% ethanol for 10 minutes.

Then dried using a vacuum at a temperature of 60oC and pressed into tablets.

The last time the way almost twice as long, than the time for the comparative tablets without malic acid.

EXAMPLE 2 (download 20/1 in the drawing):

Replacement 19% of the total acid malic acid; adding citric acid in crystalline and powdered form; granulating with water;

2500 weight. parts of calcium carbonate mixed with 2700 weight.parts of crystalline citric acid, 800 weight.parts of powdered citric acid and 800 weight.parts of malic acid, heated to 45oC, granularit with 120 weight. parts of water and then dried. The granulate may well pressoffice.

The deposition time is 30 minutes compared with 15 minutes product without malic acid; thus can be achieved 100% elongation time.

EXAMPLE 3 (download 20/4 in the drawing):

Replacement 9% acid malic acid: similar to example 2, it is also possible to replace only 400 weight.part of the whole acid malic acid; the mixture is then granularit two-stage buffer solution (for example, a solution prior to the reaction, respectively, U.S. patent N 4867942), which is prepared as follows: 130 weight.parts of citric acid and 27 weight.parts of calcium carbonate dissolved in 180 weight.parts of water. Product 20/4 on mobiles deposition with 18 minutes to almost 30 minutes.

EXAMPLE 4 (download 20/3 in the drawing):

You can act as in example 3, all 400 weight.parts of malic acid is dissolved in acting as a buffer solution granulation fluid from 300 weight.parts ethanol-water (1:1). Target product in relation to time until the beginning of the formation of recalcitrate behaves as the product of example 3.

EXAMPLE 5

Proceed as in example 4 with the difference that the buffer solution instead of malic acid is prepared from 250 weight.parts gluconic or lactic acid (calculated on dry substance) by dilution with 100 ml of water. Target product in relation to time until the beginning of the formation of recalcitrate behaves as example 4.

EXAMPLE 6

Mix 2500 weight. parts of crystalline citric acid and 800 weight. parts of malic acid and moisten 30 weight.parts of water, then add 2500 weight.parts of calcium carbonate and 800 weight.parts of powdered citric acid to the partially dissolved the surface of the particles and crystals of the acid sticks calcium carbonate and partially covers them and partially reacts with the acid. Then make a 90 weight.parts of water, which provides further reaction may be conducted in two stages: a mixture of calcium carbonate with powdered citric acid is divided into two parts, first write the first portion into the already soaked crystalline acid, the particles and crystals of the acid, at least partially, covered by calcium carbonate and partially react with it. Then add the second part of the mixture of calcium carbonate and powdered citric acid, and then the obtained mixture is dried.

EXAMPLE 7

Mix 1570 weight.parts of crystalline citric acid, 40 weight.parts of sodium cyclamate, 6 weight.parts of saccharin and 100 weight.parts of monophosphate sodium. This mixture is moistened with buffer solution consisting of 19 weight.parts of powdered citric acid, 4 weight.parts of calcium carbonate and 35 weight. parts of water. Dipped citric acid make 170 weight.parts of powdered citric acid and 820 weight.parts of calcium carbonate with capping acid calcium carbonate and their partial reaction. Then make another 420 weight.parts of powdered citric acid and 350 weight.parts of calcium carbonate. The resulting mixture is mixed with a buffer solution consisting of 55 weight.parts of water, when this happen partial reaction and granulation. In addition, monitoroff sodium may also be added when you make the last parts of powdered citric acid and calcium carbonate, before drying, or in the end) is tion and citric acid, and other solid edible organic acid and/or its salts, characterized in that 5 to 20 wt.% provided for reaction with potassium carbonate in the amount of organic acids or salts in their total number is substituted by at least one of the compounds of the group consisting of malic acid, gluconic acid, lactic acid and their acid salts.

2. Effervescent granules under item 1, characterized in that the substituted 10 - 15 wt.% the total number of said acids or salts.

3. Effervescent granulate according to p. 1, wherein the organic acid is covered at least part of the calcium carbonate, and are partially reacted with him and granulated condition.

4. Effervescent granules under item 1 or 2, characterized in that it contains a pharmaceutically effective and acceptable amount of at least one fluorine-containing compounds.

5. The method of obtaining effervescent granules, providing a granulating calcium carbonate, citric acid, and other solid edible organic acid and/or its salts, their partial reaction, characterized in that at least part of the compounds selected from the group consisting of malic acid, glucono the Noi in powder form is mixed with citric acid and calcium carbonate and the granulation is carried out at moisture from getting granulate under item 1.

6. The method of obtaining effervescent granules, providing a granulating calcium carbonate, citric acid, and other solid edible organic acid and/or its salts when their partial reaction, characterized in that at least part of the compounds selected from the group consisting of malic acid, gluconic acid, lactic acid and their acid salts, and partially replacing citric acid, dissolved in the liquid for granulation, preferably in a buffer solution, obtaining after granulation the granules under item 1.

 

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