Quick soluble granules and method for production thereof

FIELD: pharmacology.

SUBSTANCE: according to the present invention pharmacological composition is in form of quick soluble granules, containing particles of at least two different carrier materials with surface being at least partially coated with at least one layer, comprising 50-120 wt.pts, preferably, 60-100 wt.pts of at least one active ingredient based on 100 wt.pts of carrier material. Active ingredient is preferably insoluble or low soluble substance such as amino acids or antioxidants. The first carrier material comprises about 50-80 wt.% of total carrier material and has bulk density of 58-100 g/ml, preferably of 63-90 g/100 ml. The second carrier material has bulk density of 30-55 g/100 ml, preferably of 33-50 g/100 ml. Granulated composition has high solubility, high content of active ingredient and little amount of excipients. Further composition is quickly suspended in little amount of water, doesn't form agglomerates for a long time, ant has acceptable taste.

EFFECT: pharmacological composition in form of quick soluble granules with improved quality.

22 cl, 4 tbl, 5 ex

 

The invention relates to pharmaceutical compositions in the form of quick-dissolving granule in accordance with the restrictive part of paragraph 1 of the claims. Such a composition is described, for example, in application EP-B1-232277. In this publication discusses the fact that, according to the invention, can be subjected to the processing of amino acids (e.g. tryptophan in example 1)as an active ingredient, or can be subjected to processing many active substances (such as vitamins and mineral salts in example 2, applied to the material of the medium containing the acid, which is a problem for patients with kidney disease). It also argues that the material of granular media from soluble carbohydrate using a solution of the binder can be applied many layers to secure relatively large quantities of active substances.

The last statement, if you do not take special measures in practice has limitations, especially in the case of amino acids. In particular, it has been found that quantities of the active substance is larger than the number found in the mentioned in the application EP-B1-232277 examples, and for active substances, which are very loose, the active substance on carbohydrate media cannot be sufficiently secured only by a layer of binder, and too many active substances OS is W-free, so in the end it is impossible to achieve satisfactory results, neither in the required properties of a suspension, or in the fluidity of the product.

If the quantities of active substances from 60 to 100 weight parts, relative to 100 weight parts of the carrier, when the binder is applied again, is undesirable agglomeration of the active substance so that when the water required suspension no longer achieved, and the particles settle to the bottom or remain on the surface of the water.

Therefore, the aim of the invention is to improve the composition described in EP-B1-232277, and receive it in such a way as to provide instant granules and method of production thereof, through which could easily accommodate even very large numbers and even different, especially insoluble or poorly soluble, active substances, in particular, many amino acids, analgesics, antioxidants, such as, for example, paracetamol, beta-carotene, etc. After entering the water, the pharmaceutical composition should be suspended within a fairly short time under stirring, must have pleasant taste and must also remain in suspension for a sufficiently long time.

This requirement is particularly applicable to the amino acids, because they should be administered in a dosage in Bo is isih quantities and in the case of use as a food additive, and especially as a drug for patients with kidney disease who require a low protein diet and require a great replacement of amino acids. Replenish essential amino acids, it is possible to satisfactorily compensate for the deficit, as a result, it is possible to prevent adverse symptoms and, in certain circumstances, to postpone the need for dialysis.

On the market there are a number of products containing amino acids with essential amino acids in the form of tablets or capsules, however, for example, patients with kidney disease should take them 5 pieces 3 times a day, which is problematic for the patient or consumer, especially in this group all - mainly elderly patients generally should also take certain other drugs, usually in the form of tablets. Therefore, for a given medical intervention amino acids required dosage form, which can be introduced in liquid form to facilitate the intake of the patient.

Therefore, another aim of the invention was to develop instant compositions containing a high dose of the active substance and a small amount of excipients, compositions that can be quickly suspended in a small amount of water, for example from 50 to 100 ml, and taste which can easily be perceived by the patient. Therefore, it is consumption for the patient will be significantly lightened.

The difficulty in designing such a product, which is suspendiruemye in water, associated with the weight and volume relationships of the material of the carrier and the active substance. One granulation of active substances goals cannot be reached, because it leads, on the one hand, to the agglomerates of active substances that are not broken down into the individual particles during distribution in water, therefore, are not suspendiruemye, and settle on the bottom of the glass, and on the other hand, the active substance is partially not granulated and therefore floats on the surface, and no real suspension cannot be obtained (see negative example 1).

A similar, slightly better, the effect was observed when the excipients were granulated together with the active substances, as in this case, on the one hand, the addition of a solution caused agglomeration of the material is readily soluble carrier, and, on the other hand, the obtained granulation of the particles of active substance are inadequate to achieve the fluidity of the product (see also negative example 2).

The application of the solution of phospholipids (Epikuron®as surface-active substances in granular active substances as well as granulated together excipients, improved suspension active substances, but the suspension was still larger h is Stacy, and part of the active compounds was still floated to the surface (see negative examples 1A and 2A).

If to the solution was added the appropriate amount of binder in the received unwanted agglomeration of large particles of active substances and/or active substances from the material of the carrier, which, despite grinding to the desired particle size, showed a reduced suspension properties and sinking to the bottom with stirring in the water.

All these problems are overcome according to the invention by fixing only part of the active substances on the ground, preferably compacted and/or crystalline material carrier having a bulk density of from 58 to 100, preferably from 60 to 95 g/100 ml, while the excess of active substances, not fixed on the surface of the material of the first media granularit by making the second volume, for example, spray dried, the material of the carrier, which is selected from materials of the carriers having a bulk density of 30 to 55, preferably from 33 to 50 g/100 ml, and thus usually lighter and/or rapidly soluble than the material of the first carrier. The preferred materials of the carriers listed in table 1.

Bulk density conventional products available in the market, does not directly depend on particle size distribution, which which can vary within wide limits.

A preferential embodiment, the further development and improvements of the invention are described in dependent claims.

Table 1
Granulometric composition of the conventional products
Material mediaBulk density (g/100 ml)> 0.5 mm

(the weight. %)
0.2-0.5 mm (the weight. %)< 0.2 mm (the weight. %)
The materials for the first medium
Sorbitol5805842
Mannitol630928
Lactose6903664
Sucrose (fine)8107129
Sucrose (coarse)8828684
Hydrogenated maltose909910
Trinatriytsitrat ·2H2O9522 708
Monocalcium phosphate ·N2About820892
Materials for the second media
Maltodextrin (spray dried or granulated)33163945
Sorbitol (spray dried)4519774
Mannitol (spray dried)4502080
Glucose syrup (dried)500397
Instant sugar5093655

This invention is based on the fact that when on a diet or for medical reasons or for economic reasons require a small amount of excipients, it is necessary to find a methodology that will allow you to combine bulk insoluble or poorly soluble active substances in a weight ratio of from 60 to 100 weight parts to 100 weight parts of all material media.

This is possible with the introduction of media in two or B. the more stages. In the first stage, initially take part in all media materials, consisting of at least 80, preferably at least 100 wt.% from the material of the first carrier; the surface is then moistened by adding water, ethanol, a mixture of ethanol/water and/or solution of the binder. After that add the active substance and at least partially fix them on the surface of the particle carrier. In the second stage, by introducing a different material media and by partial dissolution of the surface, due to the existence in the material residual moisture or, if necessary, add more water, ethanol, a mixture of ethanol/water or solution of the binder, at least partially consolidate and/or granularit with the material of the second media remaining, still loose particles of the active substance. This stage can, if required, be repeated.

In practice found that the best results are obtained with amounts of liquid from 1 to 10, preferably from about 3 to about 7 weight parts relative to 100 weight parts of the material of the carrier and the active substance). The lower limit is applicable when using pure water and essentially insoluble or very poorly soluble active substances; the average value should be used in the case of ethanol or mixtures of ethanol/water, and sparingly soluble active the substances; the upper limit is applicable when using the binder solution, especially if the carrier particles and the active substance is less amenable to sintering.

It has also proven expedient if the original is used for wetting the material of the first carrier only from 10 to 25, in particular from 15 to 20 wt.% the total number of reserved liquid. In fact, it should essentially be dampened, but only with minimal dissolution of the surface, since otherwise the material of the carrier tends itself to form agglomerates, resulting in a homogeneous distribution, namely the uniform application of the active substance on the individual crystals of the media becomes more difficult.

The remaining amount of liquid is then used to soak the remaining active substance and the material of the second medium. In many cases proved to be appropriate for the same reason, namely because of prevent agglomeration of the material media, to distribute the remaining amount of the liquid material of the first media already covered by particles of the active substance, and free particles of the active substance before adding the material of the second carrier. Depending on the type of ingredients and techniques then receive the product of the material of the second carrier, similarly covered with activemodeler and/or particles, granulated with the active substance and the material of the carrier.

You can then proceed to the next step of obtaining a composition in which from 70 to 80 weight parts of granular, insoluble or poorly soluble active substances, taken on 100 weight parts of the carrier, must be received freely flowing, suspendiruemye granules.

In the first stage, from 60 to 80% of the particles of the first media hydrate, for example, a solution of the binder. The binder solution may be a solution in ethanol or in a mixture of ethanol/water, at least one of the following substances: sugar, sugar alcohol, maltodextrin, polyvinylpyrrolidone or other hydrocolloids. In some cases it is preferable to slightly moisten the particles of the material of the first medium with ethanol or a mixture of ethanol/water in the ratio of 70:30 before applying the binder solution to avoid undesirable agglomeration of these particles.

After that add at least a portion, preferably a major part, active substances and at least partially fix them on the surface of the particle carrier. Optional add balance - or something more - liquid, and the remaining particles of the active substance moisturize, by means of this additional binder solution and fixed on existing particles of the material of the first novtel is, - already covered part of the active substance, and/or others. When the surface of the material of the first carrier and/or active substances too dissolved (diluted), it may be advantageous to partially dry the mixture before or during the process of adding the remaining part of this liquid, the particles of the material of the second carrier, and/or any remaining part of the active substances.

In the second stage adds the material of the second carrier. For example, spray dried, granulated while spraying or agglomerated materials, for example, sugar alcohols such as sorbitol, xylitol or mannitol; soluble sugar (that is spray dried sucrose), and other products of the hydrolysis of starch, such as maltodextrin, soluble solid corn syrup or ochrany starch (for example, dried glucose syrup) are suitable for this purpose due to their bulk density, fluffy, granular structure, good ability of surface dissolution. If the material of the second media use maltodextrin, recommended particle size: 20-25% > 0.4 mm, 35-65% < 0.4 mm > 0.1 mm, and the fraction of < 0.1 mm to a maximum of 20-35%. Naturally, the above materials of the second carrier can also be obtained in other ways, in addition to spray drying and granulation, spraying, when the conditions is, the materials of the carrier received within the corresponding bulk density.

Thanks already present in the material moisture or, if required, optional additional input, the surface of the particles of the second carrier also partially dissolved, and after that is still available active substances are fixed; on the other hand, the particles of the second media serve as nuclei for granulation is still not fixed active substances with the advantage that after you make the water core quickly dissolves, the particles of active substance are released and, therefore, a good suspension. The materials of the device can also be made in several stages. If the material of the second carrier was made at an earlier stage, when there are no amino acids, acting more as a buffer, agglomeration of the particles of the medium would have happened before the active substance can be mounted on the surface of the particles of the medium.

As a material of the first media you can use the compact, for example, sorbitol or mannitol. In the case of such sugar alcohols should be avoided too much dust fraction, in order to prevent agglomeration of media wetted by the partial dissolution of the finer fractions; preferably, only a maximum of 5% of the carrier particles had a size less than 0.1 mm, They can PR is to attend and in crystalline form, and as dried by spray or granular raw materials. In addition, as the material of the carrier can also be used sucrose, with the following granulometrically composition:

< 0.5 mm > 0.3 mm: 0-60 wt.%

< 0.3 mm > 0.1 mm: 10 to 85 wt.% (main disqualified fraction)

< 0.1 mm: 0-15 wt.%.

For amino acids, you can use the following particle size distribution: in group L-isoleucine, L-leucine and L-valine to a maximum of 15 wt.% must be > 0.3 mm, 70-95 wt.% must be between 0.1 and 0.3 mm, and 1-20 wt.% must be < 0,1 mm In the group: L-phenylalanine, L-histidine, L-methionine, L-threonine, L-tryptophan and L-tyrosine - a maximum of 5 wt.% must be > 0.3 mm, 30 to 90 wt.% must be between 0.1 and 0.3 mm, and 5-60 wt.% must be < 0,1 mm For L-lizinata, 5-30 wt.% must be > 0.3 mm, 30-70 wt.% must be between 0.1 and 0.3 mm, and a maximum of 25 wt.% must be < 0,1 mm

For β-carotene or DL-α-tocopherol acetate to a maximum of 15 wt.% must be > 0.3 mm, 70 to 95 wt.% particle size distribution should be between 0.1 and 0.3 mm, and a maximum of 30 wt.% must be < 0,1 mm

In order to achieve improved suspension, improved taste and/or suspension, add tools such as CA(H2PO4)2·N2O or trinatriytsitrat ·2H2O. Both salt and other soluble alkali metal salts of edible organic acids can also act as Materialovedenie. For example, trinatriytsitrat ·2H2O together with other materials of the device can be used as the first carrier. In addition, you can also use wetting agents. For this purpose suitable anionic surfactants such as sodium lauryl sulfate or dioctylsulfosuccinate, and sugar esters, and phospholipids, Polysorbate or hydrogenated castor oil.

To improve the taste to the composition, you can add artificial sweeteners and flavorings, or acid or acidic salt in permitted amount or the amount allowed for this group of patients, as well as vitamins.

It is thus possible, according to the invention, to combine vitamins, such as ascorbic acid, b vitamins, folic acid, Biotin, calcium Pantothenate, and fat-soluble vitamins such as tocopherol, retinol and cholecalciferol (vitamins A, D and E), and also, if required, trace elements such as selenium, chromium, manganese, molybdenum, zinc, iron, and minerals such as magnesium and calcium, with an active substance, such as amino acids.

Accordingly, it is also possible to apply at least one antioxidant and/or a vitamin as an active substance together with trace elements such as selenium, chromium, manganese, molybdenum, zinc, iron and/or minerals is, such as magnesium and calcium.

The specific composition is soluble amino acid composition for patients with kidney disease. For medical reasons, special attention must be paid to the composition. For example, the dose that is given three times a day, should contain as little sugar as possible, and mannitol or sorbitol in an amount of not more than 1.5 g, and, moreover, as small amount as possible, organic acids such as citric acid or tartaric acid, or their acid salts. Excipients containing phosphates, are also undesirable.

Essential amino acids, that is, L-valine, L-isoleucine, L-tyrosine, L-threonine, L-methionine, L-leucine and L-lysine must be present in the dose in an appropriate amount, it is advisable to add some other amino acids, such as L-histidine, L-tryptophan, L-phenylalanine and argininepatch. If the daily demand is divided in three doses, was appropriate to use, for example, 450 mg of L-leucine, 675 mg of L-valine, 300 mg of L-isoleucine, 325 mg of L-histidine, 375 mg of L-tyrosine 125 mg of L-tryptophan, 325 mg of L-threonine, 450 mg of L-methionine, 350 mg of L-phenylalanine and 480 mg L-lizinata per dose.

Instant granules according to the invention, containing the above doses can be easily suspended in 50-100 melody and - together with sweeteners and flavors - they are pleasant to drink. As patients with kidney disease have limitations in the use of liquid, it was necessary to solve the problem of instant product that has very good suspension properties in a very small amount of solution, it is necessary that the amount of water at a dose as possible, not exceed 100 ml of the Product can also be suspended in 50 ml of water, but the stability of the suspension is better in a larger amount of water, so it is recommended to dissolve in 75 ml of water.

To clarify the dependence of the stability of the suspension to the amount of water conducted experiments to determine the amount of amino acids that is deposited per unit of time. One bag of each product according to example 1, below, were made respectively in 50 ml, 75 ml and 100 ml of water, was stirred for 20 sec and measured deposition after 1-15 minutes Used vessel in the form of a measuring cylinder of 100 ml with a diameter of 25 mm the Results are presented in table 2.

It was found that the suspension is very stable, and when the quantity of water 50 ml and 75 ml was observed only small differences. When dissolved in 100 ml of water, the product was behaving a little better. If the product was stirred in a beaker with 50 ml and 100 ml of water, after one minute was formed sky is Lishou sediment and no longer increased, to a certain extent, after 20-25 minutes, the suspension was a little bit flaky.

These advantages - from a technical point of view and in taste - could be achieved only due to the composition and method of reception according to the invention, based on the fact that the receipt should be carried out in two stages, on the one hand, due to the preferred large amounts of active substance (s) and, on the other hand, also as a result of any use of the materials of the carrier, is actually very easy and instant, such as, for example, spray dried or granulated while spraying sorbitol, xylitol, mannitol, maltodextrin, soluble sugar and glucose syrup. Under certain circumstances, it may even be advisable in any case to use the solution of the second binder, based on ethanol or a mixture of ethanol/water, if it is necessary to put other quantities of the active substance.

The composition and method should be chosen in such a way that it was possible to prevent agglomeration of the carrier substances in order to provide more surface for the application of active substances and, on the other hand, moisturize and partially dissolve the surface so well that you can put a large portion of amino acids on n the surface of the media. This can be achieved by selecting ingredients and composition according to the invention.

Furthermore, the acid components in the composition, which contains sucrose, is not mixed with carrier substances and watered in order to prevent the inversion of sugar and, therefore, undesirable sticking together of the materials of the carrier due to the increased adhesion of invert sugar. Therefore, the acidic components and soluble lipincott added not earlier than shortly before the final drying, when there is only a small humidity and adhesive ability of the granules, so that it was possible to get a more stable product.

Example 1.

In the vessel for mixing, preferably the vacuum vessel, making 930 g of finely granulated mannitol, 823 g of crystalline sugar and 18 g of sodium chloride, optionally with artificial sweeteners, and heated to 60°under stirring. After degassing carry out vacuum filling and distribution of 22 ml of 96% ethanol. Then suck and distribute solution consisting of 5.5 ml 96% ethanol, and 5.5 ml of water, 6 g of sugar and 0.4 g of citric acid; then add the 1965 mixture of the desired amino acids.

Then 180 ml (= 208,4 g) of the same solution which contains 133 ml of water, 71 grams of sugar and 4.4 g of citric acid, suck, site is preferably in vacuum, distribute the solution and then mixed with 900 g of maltodextrin. Surface maltodextrin dissolved (diluted) under the influence of moisture, now present in the material and binds the loose particles of the active substance. Then suck and distribute the material 160 ml of solution, which consists of 135 ml of ethanol and 21 g Epikuron®(phospholipids). Finally, also introduce 246 g of a mixture of citric acid/tartaric acid and, optionally, 288 g of another, for example, coarse, soluble amino acids, such as, for example, L-lipincott, 30 g of rice starch and 48 g of lemon flavor. After final drying, sieve the granules of up to 1.2 mm

The result of this procedure receive instant granules containing amino acids in the amount of 3.75 g per dose to 8.94 g, easily suspendiruemye in 75 ml of water and having good taste.

Samples of one dose (the contents of one bag, for example, "Sasha") was stirred in 75 ml of water at 17°C for 30 sec, and then determine the size of the granules suspended particles. Granulometric composition of suspended particles can be described as follows: 80-100 wt.% < 0.3 mm; 40-60 wt.% < 0.09 mm; and 5-20 wt.% < 0,01 mm

Example 2. Composition not containing sugar

In the vessel for mixing, preferably in vakuumirovaniya vessel, contribute 1750 finely granulated is Anita and 18 g of sodium chloride, optional with artificial sweeteners, and heated to 60°under stirring. After degassing carry out vacuum filling (suction) and the distribution of 40 ml of a solution containing 18 g of sorbitol and 1.1 g of citric acid in 27 ml of water; then add the 1965 mixture of the desired amino acids.

Then suck, preferably in vacuum, 220 ml of the same solution (containing 145 ml of water, 98 g of sorbitol and 5.4 g of citric acid; the solution is distributed and then mixed with 800 g of spray dried sorbitol. In the result of the presence in the material of the moisture from the surface of sorbitol dissolved (diluted) and binds the loose particles of the active substance. Then suck and distribute the material 160 ml of solution, which consists of 130 ml of ethanol and 21 g Epikuron®(phospholipid). Finally, also introduce 245 g of a mixture of citric acid/tartaric acid and optional 288 g other, for example, coarse soluble amino acids, such as, for example, lipincott, and 48 g of lemon flavor. After final drying, sieve the granules of up to 1.2 mm

The result of this procedure get sugar free instant granules containing amino acids in the amount of 3.75 g per dose cent to 8.85 g, easily suspendiruemye in 75 ml of water and having good taste.

Amino acid products that meet the following examples 1 and 2, you can not only be entered as a suspension in water, but also to stir in mild drinks or orange juice or add to milk products. Depending on the introduction of the product can also be added without flavoring and sweetener to various drinks, even to such as milk and milk drinks.

Example 3. Antioxidants

500 parts by weight of finely granulated sucrose, 866 parts by weight of spray dried mannitol and 12 parts by weight of saccharin heated to 60°under stirring. These materials media moisturize 30 ml of water. Then enter the active substance consisting of 1000 parts by weight of dry powder 50%of vitamin E and 120 weight parts of 10% beta-carotene (bulk density of 70 g/100 ml). Following this, allocate a solution of 50 parts by weight of sorbitol in 100 weight parts of ethanol and then injected 500 parts by weight of soluble sugar. The product is dried and mixed with granules consisting of 100 weight parts of citric acid, 150 parts by weight of vitamin C, 25 weight parts of sodium carbonate and the required quantity of flavoring.

The finished product contains 65 parts by weight of active substance and 100 parts by weight of the carrier and provide a pleasant taste to the composition, which is easily suspendiruemye in the water.

Simple mixing of the active substance or substances with excipient the mi did not give a satisfactory result, because, on the one hand, the desired uniformity of the active substance at the dose could not be achieved and, on the other hand, the product does not have sufficient fluidity to fill their sacks as a single dose. In addition, amino acids it is not easy to form a suspension in water, and aglomerated and remain on the surface of the liquid.

Therefore, granulation is necessary in order to resolve the aforementioned problems and to obtain the drug, which can easily be measured for the needs of the patient and which allows a uniform dosage of the active substances.

For example, if the components of example 1 were mixed, the mixture had a bulk density of 55 g per 100 ml and was stagnant, while the granulated product obtained according to the invention has a bulk density 6-70 g per 100 ml; it can be well and uniformly to measure by conventional packaging lines.

Example 4.

In the vessel for mixing, preferably in a vacuum vessel, introducing 475 g of dihydrate of triacrylate, 1170 g of granular sugar, 90 g of the monohydrate of primary calcium phosphate and 50 g of sodium chloride, optionally with artificial sweeteners, and heated to 60°under stirring. Then vaccum and suck 182 ml (= 210 g) of a solution consisting of 125 ml of water, 80 g of sugar and 5 g of citric acid, this solution is distributed and then add the 800 g of L-leucine, 400 g of L-valine and 400 g of L-isoleucine.

Then admixed 850 g spray dried maltodextrin. Maltodextrin, partially soluble (diluted) under the influence of moisture, now present in the material, and connects the treated particles of the active substance. Then suck and distribute the material 225 ml of a solution consisting of 185 ml of ethanol and 25 g Epikuron (phospholipids). Finally, enter 950 g of citric acid and, optionally 900 g other, for example, soluble amino acids, such as, for example, argininepatch, 50 g of rice starch, 4,2 d 33%vitamin B6 and 50 g of lemon flavor. After final drying, sieve the granules of up to 1.2 mm

Through this procedure, receive instant granules containing amino acids in amounts of 2.5 g per dose 6,34 g, easily suspendiruemye in 75 ml of water and having good taste.

Example 5. The time of dissolution of materials of different media

Test conditions: 10 g material each medium was added to 100 ml of water at 17°With 400 ml beaker and stirred with a magnetic stirrer at 500 rpm./minutes Dissolution was determined visually. The time corresponding to the dissolution are shown in table 3.

Table 3
MediaBulk density in g/100 ml The time of dissolution in seconds.
The material of the first media
Sorbitol5890
Mannitol (finely granulated)6295
Hydrogenated maltose90200
Lactose69120
Trinatriytsitrat ·2H2O9585
The material of the second media
Maltodextrin (spray dried or granulated)3355
Sorbitol (spray dried)4550
Mannitol (spray dried)4555
Dried glucose syrup5045
Soluble sugar (spray dried sucrose)4515

Negative example 1. Granulation of some amino acids

Preparing a mixture of 1965 amino acid, and the mixture was heated to 60°under stirring. After which was added 200 ml of a solution containing 133 ml of water, 89 g of sucrose and 9.6 g of citric acid, and distributed solution with stirring. ZAT is m granules were dried.

With the introduction of the pellets into the water, it was found that with a given quantity of a solution of any granulation can be achieved with difficulty, and amino acids, in large part, remain on the surface of the water and glass; in fact it was impossible to obtain any suspension of amino acids.

Negative example 1A.

Then the experiment of a negative example 1 was repeated with double the amount of solution, i.e. with 400 ml.

The result: a set of heterogeneous granulation amino acids, with the result that, if introduced into the water part remained on the surface and on the rim of the glass, some settled on the bottom and a piece floated in water in the form of large flakes, some of which rose to the surface, and the other part was settled to the bottom. However, in practice approximately homogeneous suspension was not formed.

Based on this result, the granules was affected by solution Epikuron as in example 1 (150 ml ethanol and 21 g Epikuron [phospholipid]). When making the water was faced with a situation similar to the situation in the experiment without Epikuron, however, formed a suspension containing particles, some of which were larger, but the pop-up agglomerates of amino acids no more. Beneficial effect of excipients suspension on the behavior of the suspension was obvious.

Negative example 2. Media and amino acids, the granulated is the place

In the vessel for mixing, preferably vakuumirovaniya vessel was introduced 930 g of finely granulated mannitol, 793 g of crystalline sugar, 18 g of sodium chloride and 900 g of maltodextrin, optional with artificial sweeteners, 1965 mixture of the required amino acids and, in addition, 245 g of a mixture of citric acid/tartaric acid and optional 288 g other, for example, coarse-soluble amino acids such as, for example, lipincott, and was heated to 60°under stirring.

Then sucked 400 ml of a solution containing 288 ml of water, of 153.6 g of sucrose and 9.6 g of citric acid, preferably in vacuum and distributed solution. After the final drying were selected granules to 1.2 mm

Result: as a negative example 1A, but some of the amino acids was suspended.

Negative example 2A.

Repeated negative example 2 with the use of a solution containing 150 ml of ethanol and 21 g Epikuron.

When introduced into water and after stirring for 20 seconds on the surface of the formed foam layer of amino acids, some settled on the bottom, and some amino acids were suspended in suspension were distinguishable larger particles.

Measured the speed of sedimentation, but since some amino acids remained on the surface, the amount of sludge is of course not very informative because of the different structure of the s particles.

Conducted experiments to determine how many amino acids deposited per unit of time. One bag of each product according to the invention was made in respectively 50 ml, 75 ml and 100 ml of water, was stirred for 20 seconds and after 1-15 minutes was measured sediment. Used 100 ml measuring cylinder with a diameter of 25 mm

The results are shown in table 4.

1. Pharmaceutical composition in the form of quick-dissolving granule in which the surface of particles of at least two different materials soluble carriers partially coated or covered with at least one layer which contains at least one, preferably insoluble or poorly soluble active substance, characterized in that the material of the first carrier is from about 50 to about 80 wt.% General material carrier and it is chosen from materials media with bulk densities from 58 to 100 g/100 ml, preferably 60-95 g/100 ml, while the material of the second carrier is selected from materials of the carriers having a bulk density of 30 to 55 g/100 ml, preferably from 33 to 50 g/100 ml, per 100 parts of the material of the carrier is from 50 to 120 parts, preferably from about 60 to about 100 parts of the total quantity of active substances.

2. The composition according to claim 1, characterized in that the material of the first but is Italia selected from the group consisting of sugar alcohols, sucrose, hydrogenated maltose, lactose and soluble alkaline salts of edible organic acids, and the material of the second carrier selected from the group consisting of sugar alcohols, hydrolysis products of starch and soluble sugar.

3. The composition according to claim 2, characterized in that the material of the first carrier of the sugar alcohols are selected from the group consisting of sorbitol and mannitol, and for the material of the second carrier of the sugar alcohols are selected from the group consisting of sorbitol, mannitol and xylitol, while the products of the hydrolysis of starch is chosen from the group consisting of maltodextrin, soluble solid corn syrup and osaharennogo starch, such as dried glucose syrup.

4. The composition according to claim 1, characterized in that the grain composition of any active substance selected from the group consisting of L-isoleucine, L-leucine and L-valine, or the total number of such active substances, a maximum of 15 wt.% particles must be > 0.3 mm, 70-95 wt.% must be between 0.1 and 0.3 mm, and 1-20 wt.% must be < 0,1 mm

5. The composition according to claim 1, characterized in that the grain composition of any active substance or the total number of active substances selected from the group consisting of L-phenylalanine, L-histidine, L-methionine, L-threonine, L-tryptophan and L-tyrosine, maximum 5 wt.% particles must be > 0.3 mm, 30 to 90 wt.% must be between 0.1 and 0.3 mm and 5-60 wt.% must be < 0,1 mm

6. The composition according to claim 1, characterized in that the grain composition of L-lizinata: 5-30 wt.% particles must be > 0.3 mm, 30-70 wt.% must be between 0.1 and 0.3 mm and a maximum of 25 wt.% must be < 0,1 mm

7. The composition according to claim 1, characterized in that the volume density and number of pieces of media, on the one hand, and the granule size and the number of active substances, on the other hand, are chosen so that the dose from 8 to 9 g of the composition, suspended in 75 ml of water, retains at least 80 wt.% composition in the suspension for 10 minutes

8. The composition according to claim 1, characterized in that at least one amino acid, that is, L-valine, L-isoleucine, L-tyrosine, L-threonine, L-methionine, L-lysine or its salt, L-leucine, L-histidine, L-tryptophan, L-phenylalanine, argininepatch, or their mixture is present as the active substance.

9. The composition of claim 8, wherein the mixture is present in the "Sasha" in such quantities that in one to three doses per day contains 1800-2700, preferably about 2025, mg L-valine; 750-1200, preferably about 900 mg of L-isoleucine; 1000-1500, preferably about 1125 mg of L-tyrosine; 800-1300, preferably about 975 mg of L-threonine; 1200-1800, preferably about 1350, mg L-methionine; 800-1500, preferably about 1300, mg L-lizinata, and optionally, by at least one of the following amino acids: 1200-1800, preferably about 1350 mg of L-leucine; 600-1200, preferably about 900 mg of L-histidine; 300-500, preferably about 375 mg of L-tryptophan and 900-1400, preferably about 1050 mg L-phenylalanine.

10. The composition according to claim 9, characterized in that the granule size of the suspended particles is: 80-90 wt.% particles smaller than 0.3 mm, 40-60 wt.% less than 0.09 mm, and 5-20 wt.% less than 0.01 mm after the contents of the "sachet" is stirred in 75 ml of water at 17°C for 30 s

11. Composition according to any one of claims 1 to 10, characterized in that it further comprises at least one of the following substances: food grade organic acid, at least one salt of organic acid, surfactant, emulsifier, sweetener, flavor compounds, masking the taste, such as CA(H2PO4)2·N2O or trinatriytsitrat, and auxiliary substance(substance) for the suspension, such as esters of sugars, phospholipids, Polysorbate, hydrogenated castor oil and anionic surfactants, such as nutriceuticals or dioctylsulfosuccinate.

12. The composition according to claim 1, characterized in that at least one compound selected from the group consisting of antioxidants, such as β-carotene, ascorbic acid or D-α -tocopherol acetate, vitamins such as the b vitamins, folic acid, Biotin, calcium Pantothenate, and fat-soluble vitamins such as retinol and cholecalciferol (vitamins A, D and E); and trace elements such as selenium, chromium, manganese, molybdenum, zinc, iron; and minerals such as magnesium and/or calcium, is present as the active substance.

13. The composition according to item 12, wherein there is at least one antioxidant.

14. The composition according to item 13, wherein the at least one antioxidant is present together with at least one trace element and/or at least one mineral.

15. A method of obtaining a pharmaceutical composition according to claim 1, characterized in that the particles of the material of the first media moisturize at least part of the intended total quantity of at least one liquid, or a mixture thereof selected from the group consisting of water, ethanol, a mixture of ethanol/water and a solution of a binding, then one by one add the following components: (i) at least part of the granular or powdery active substances; (ii) any remaining portion of the specified fluid; (iii) the particles of the material of the second carrier, and optionally (iv) any the remaining portion of the active substances, followed by drying and final grinding and/or sieving is on the desired particle size of the obtained granules where at least one of the stages (i)-(iv) and the drying is preferably carried out in a vacuum mixer.

16. The method according to item 15, in which the specified fluid use in the total number from 1 to 10 wt.%, preferably from about 3 to about 7 wt.% the total weight of the materials of the carrier and active substances.

17. The method according to item 15 or 16, in which before or during stages (ii)-(iv) of the method, the mixture is subjected to a stage of partial drying.

18. The method according to any of PP-17, in which from 60 to 80 wt.% General material carrier comprising at least 80 wt.%, preferably, at least 100 wt.% the material of the first media moisturize from 10 to 25 wt.%, preferably from 15 to 20 wt.% specified fluid, then one by one add the following components:

(i) one or more active substances in an amount of from 50 to 120 parts, preferably from about 60 to about 100 weight. 'clock on 100 parts total of the material of the carrier, (ii) the remaining number of specified liquid, (iii) the remainder of the material of the carrier, and (iv) the remainder of the active substances.

19. A method of obtaining a pharmaceutical composition according to claim 1, characterized in that the particles of the material of the first media moisturize at least part of the intended total quantity of a liquid selected from the group consisting of water, ethanol, a mixture of ethanol/water or an aqueous solution of the binder, and then note what're asked the following components:

(i) at least part of the granular or powdery active substances,

(ii) any remaining portion of the specified liquid,

(iii) the particles of the material of the second media

(iv) optionally, a surfactant, and then the resulting mixture is subjected to a stage of partial drying and then add at least one of the following substances: food grade organic acid, at least one salt of organic acid, such as trinatriytsitrat, surfactant, emulsifier, sweetener, flavor, taste and/or auxiliary substances for the suspension, such as CA(H2PO4)2·N2O, and another active substance(s), with a subsequent final drying, and grinding and/or sieving to the desired particle size of the obtained granules.

20. The method according to claim 19, in which the surface-active substances and/or auxiliary substances for the suspension selected from the group consisting of esters of sugars, phospholipids, polysorbates, hydrogenated castor oils and anionic surfactants such as sodium lauryl sulfate or dioctylsulfosuccinate.

21. The method according to claim 19, in which other active ingredients include L-lipincott and/or argininepatch.

22. The method according to item 15 or 19, in which, at the ore, one of the stages of the method is repeated at least once.



 

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EFFECT: higher efficiency.

11 cl, 2 dwg, 11 ex

FIELD: medicine, pharmacology.

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EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

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44 cl, 1 tbl, 1 dwg, 7 ex

FIELD: medicine, pharmaceutical technology, pharmacy.

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EFFECT: improved and valuable properties of composition.

16 cl, 2 ex

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23 cl, 3 dwg, 8 tbl, 19 ex

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16 cl

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EFFECT: pharmaceutical composition with accelerated degradation.

24 cl, 9 ex, 3 dwg

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The invention relates to the field of pharmaceutical industry and relates to dosage forms with anti-TB activity

FIELD: medicine.

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EFFECT: higher efficiency of application.

20 cl, 13 ex, 21 tbl

FIELD: medicine.

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EFFECT: higher efficiency.

11 cl, 2 dwg, 11 ex

FIELD: pharmaceutical chemistry.

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34 cl, 10 ex

FIELD: medicine, ophthalmology, pharmacology, pharmacy.

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EFFECT: valuable medicinal properties of agent.

4 ex

FIELD: medicine, pharmacy, pharmaceutical technology.

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EFFECT: improved method for preparing, valuable medicinal properties of suspension.

4 cl, 4 tbl, 1 dwg, 4 ex

FIELD: cosmetology, medicine.

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EFFECT: higher efficiency of therapy.

1 tbl

FIELD: pharmaceutics.

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EFFECT: higher efficiency of application.

23 cl, 15 ex, 19 tbl

FIELD: medicine.

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EFFECT: higher efficiency.

14 cl, 4 dwg, 7 ex, 5 tbl

FIELD: medicine, antibiotics.

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EFFECT: improved pharmaceutical properties of combinations.

23 cl, 3 dwg, 8 tbl, 19 ex

FIELD: medicine, pharmacy.

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EFFECT: improved and valuable properties of composition.

15 cl, 4 dwg, 4 tbl, 3 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

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EFFECT: improved and valuable properties of pharmaceutical preparation.

8 cl

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