SK107593A3 - Process for the preparation of water-soluble veterinary composition - Google Patents

Abstract

A stable, solid, water-soluble veterinary composition, wherein the active substance consists of the sodium salt of sulfachlorpyridazine and trimethoprim in a mass ratio of 5 to 1, and contains a mixture of (a) 1.6 to 3.3 per cent by mass of trimethoprim citrate applied to the surface of the particles of a water-soluble solid carrier, (b) 8.4 to 16.7 percent by mass of sulfachlorpyridazine-sodium and, optionally, (c) pharmaceutically acceptable additives consisting of poly(vinyl pyrrolidone) and/or silica.

Description

Technical field

The invention relates to a stable solid veterinary preparation which is soluble in water, wherein the active ingredient consists of sodium salt of N- (6-chloro-3-pyridazinyl) sulfanilamide (sodium sulfachloropyridazine) and 2,4-diamino-5- (3 '). 4 ', 5'-trimethoxybenzyl) -pyrimidine (trimethoprim) in a weight ratio of 5 to 1, and a process for preparing the composition.

BACKGROUND OF THE INVENTION

It is known that the effect of sulfonamides is enhanced by trimethoprim (GB Patent No. 1,176,395). Sulfonamides, including sodium sulfachloropyridazine and trimethoprim, are usually mixed in a weight ratio of 5 to 1. Such mixtures have potent antimicrobial activity and are widely used in both human and veterinary medicine.

In veterinary medicine, special conditions must be met when the combination of active ingredients mentioned is used. In the case of bacterial infections affecting large groups of animals, the easiest administration of the active substances is to add them to the feed. However, due to the reduced feed intake, this method does not provide sufficient treatment for sick animals.

As a rule, it is possible to administer the active ingredients in the form of solid veterinary preparations such as capsules or tablets, or injectable veterinary preparations, but this method of treatment is rather laborious. Indeed, in the case of smaller animals such as poultry, such a treatment of 3 to 5 days is practically impracticable.

In view of the difficulties mentioned above, in the case of bacterial infections affecting large groups of animals, the most practical and economical method of treatment is to dissolve the active ingredient in water intended for drinking for animals. Namely, in the acute state of disease in animals, water intake increases as opposed to reduced food intake.

However, the latter dosage method can be carried out if the active ingredients are sufficiently dissolved in the drinking water for a short period of several minutes. In the case of sulfonamides and trimethoprim, the problem is that these active ingredients are practically insoluble in water. The solubility of the sulfonamides can be increased by using the sodium salt, and generally, trimethoprim is treated with surfactants to increase solubility. The most common method is to dissolve the active ingredients in organic solvents to give a solution that can be admixed with water.

Veterinary preparations containing trimethoprim and sulfonamides are well known in the literature.

The powder formulation is described in HU Patent No. 191,890 wherein the active ingredients comprise trimethoprim, sodium sulfachloropyridazine and 4-amino-N- (5-methyl-3-isoxazolyl) -benzenesulfonamide (su1 fametoxaz o). Glucose, sodium chloride, potassium chloride, sodium bicarbonate, sodium citrate and calcium carbonate are diluents. As described, an oral dose of 25 g powder mixture can be used to effectively treat a calf having an infection caused by Escherichia coli. However, the known formulation cannot be completely dissolved in drinking water due to the insolubility of sulfamethoxazole and calcium carbonate.

Another synergistic combination is disclosed in U.S. Pat. And A70 978 wherein the active ingredients comprise sodium sulfachloropyridazine, trimethoprim and phenoxyethanol. In addition, the formulation contains only sucrose in addition to the active ingredients. The known preparation was mixed into drinking water for chickens to prove its effectiveness. In accordance with our tests, holo takes a few hours to dissolve a known formulation in water.

An aqueous solution suitable for intravenous injection is known from DE patent no. The solution contains 3-methoxy-4- (4-aminobenzenesulfonamido) -1,2,5-thiadiazole (sulfametrol) and trimethoprim as active ingredients, as well as sugars and resp. sugar alcohols as solubilizing agent. However, the concentration of trimethoprim in the aqueous composition is less than 0.6 mg / ml, and therefore about 10-fold dilution is required to produce satisfactory drinking water. So a huge amount of solution would have to be imported to farms.

EP application no. No. 22,342 discloses solutions suitable for parenteral administration. Known solutions contain trimethoprim and sulfamethoxazole or 4-amino-N- (5,6-dimethoxy-4-pyridinyl) -benzenesulfonamide (sulfadoxine) as active ingredients dissolved in 60 to 80 wt.% 2-pyrrolidone, further 1 to 5 wt. % benzyl alcohol and water.

Other injectable solutions are known from DE patent 24 45 400 according to which trimethoprim, 4-amino-N- (4,6-dimethyl-2-pyrimidinyl) -benzenesulfonamide (sulfadimidine) and 4-amino-N- (2-thiazolyl) -benzenesulfonamide (su1 fatiaz 1) are dissolved in dimethylacetamide containing 20 percent water.

Injectable solutions are also known from DE patent 27 04 708, wherein the diethylamine salt of sulfonamide and 2,4-diamino-5-veratrylpyrimidine lactate (diaveridine lactate) are dissolved in a mixture of 10 to 50 parts water, 15 to 30 parts propylene glycol and 20 to 40 parts of N-methyl-pyrrolidone.

According to DE patent no. 25 38 678, a solution for injection is prepared by lyophilizing a solution of trimethoprim in ethanol containing an acidic buffer, and dissolving the lyophilized product, immediately prior to use, in a solution of fametoxaz 1 in propylene glycol, ethanol and water.

EP-A-7 591 refers to liquid preparations which can be added to the drinking water of animals. The active ingredients of the known formulation comprise trimethoprim and sulfachloropyridazine or N-pyrazinyl-sulfanyl amide (sulfapyrazine) or sulfonamide salts. The active ingredients are dissolved in N-methylpyrrolidone or a mixture of N-methylpyrrolidone and glycol monomethyl ether in the presence of surfactants, and dissolution is enhanced by the addition of hydroxyethyl-theophylline, nicotinamide or sodium benzoate. Ethanolamine has proven to be most suitable for the formation of sulfonamide salts.

Although it is claimed in the specification that the carriers used are physiologically neutral, it will be apparent to those skilled in the art that the solvents used, i. N-methylpyrrolidone and glycol monomethyl ether are no less harmful than the propylene glycol, glycerol formate, dimethylacetamide, etc. disclosed in the prior art.

In summary, the known veterinary preparations suitable for addition to the drinking water of animals either contain the active ingredients in low concentration (DE Patent No. 30 17 032) or also contain organic solvents (EP No. 22 342, DE Pat. 45 400, DE pat. 27 04 708, EP no. 7 591), or the active ingredients are separately dissolved and then mixed (DE pat. No. 25 38 678), or dissolving the active ingredients in water takes quite a long time ( U.S. Pat. No. 4,470,978).

SUMMARY OF THE INVENTION

It is an object of the invention to provide a stable and solid veterinary preparation which can be added to the drinking water of animals, dissolves in water for a short period of time, contains both active ingredients at the desired concentration and contains no organic solvent harmful to animals.

It has been found that said object is achieved by a veterinary preparation according to the invention comprising a mixture of (a) 1.6 to 1.6

3.3 masses. (b) 8.4 to 16.7% by weight of sodium fametoxazole, and preferably, (c) pharmaceutically acceptable additives comprising polyvinylpyrrolidone and / or silicon dioxide.

The water-soluble solid carrier is a monosaccharide such as D-glucose, a disaccharide such as lactose /(4- beta-D-galactosyl(1.5)-D-glucose(1.5)/ or an alcohol sugar such as mannitol.

The invention is based on the finding that trimethoprim citrate dissolves relatively well in water, and when trimethoprim is applied to a water-soluble carrier, a granular product is obtained which is compatible with sodium sulfachloropyridazine, i. the active ingredients of the mixture do not decompose during storage. On the other hand, a mixture of the trimetoprim supported carrier and sodium sulfachloropyridazine readily dissolves in water and provides both active ingredients at the desired concentration.

It has been attempted to use other acid addition salts of trimethoprim with a water-soluble solid carrier to obtain a granular product containing trimethoprim at the desired concentration and dissolving in water in a short time. The acid addition salts of trimethoprim formed with tartaric, fumaric, maleic, acetic or hydrochloric acid did not achieve the solubility necessary to form a granular product having the necessary trimethoprim content. In terms of solubility, the acid addition salts of trimethoprim formed with lactic, sulfuric or citric acid proved equally satisfactory, but the formulations containing trimethoprim lactate or sulfate did not have the necessary storage stability. It is surprising that carboxylic acids having a very similar chemical structure, i. tartaric acid (2,3-dihydroxybutanedicarboxylic acid), lactic acid (2-hydroxypropionic acid) and citric acid (2-hydroxy-1,2,3-propanetricarboxylic acid) form acid addition salts having completely different properties. Thus, one of ordinary skill in the art would not have foreseen that a suitable veterinary preparation can be prepared in the form of citric acid.

The veterinary preparation of the invention is prepared by reacting 1.6 to 3.3 wt. % trimethoprim with citric acid in the presence of water to form a solution of trimethoprim citrate obtained on the surface of the particles of a water-soluble carrier, followed by drying the particles and mixing with sodium sulfachloropyridazine.

If desired, the water-soluble carrier is pretreated with polyvinylpyrrolidone.

The dried water-soluble carrier particles coated with trimethoprim citrate may also be mixed with the silica to prevent sticking of the resulting product particles.

Preferably, a water-soluble carrier with a very low water content or preferably in anhydrous form is used.

According to a preferred method, the veterinary preparation according to the invention is prepared as follows:

materials. parts of trimethoprim are dissolved in 10 to 50 wt. parts of water in the presence of 0.5 to 2.5 parts by weight of citric acid at 40 to 80 ° C. As an aqueous solution is prepared, citric acid in anhydrous or monohydrate form may be used. The solution obtained is applied to the surface of the particles of 25 to 100 parts by weight of a water-soluble carrier, preferably a monosaccharide or disaccharide or an alcohol sugar or a mixture thereof. If desired, the carrier is pretreated with 0.5 to 5 wt. parts by weight of polyvinylpyrrolidone, calculated on the amount of trimethoprim. Preferably, the solid carrier is kneaded with an aqueous solution of trimethoprim citrate, the resulting wet mass is granulated by passing it through a sieve. The wet particles are dried to reduce the water content below 1 wt. %, then sieving and / or grinding to obtain a powder having a particle size of less than 0.5 mm. The powder obtained is admixed with sodium sulfopyridazine having a particle size of less than 0.5 mm and, if necessary, with silica. The powder mixture obtained can be milled again.

In the treatment of animals, the veterinary preparation of the invention is added to the drinking water, the amount of which is at least 100 times, usually 1000 times the weight of the preparation. The preparation dissolves in a very short time, usually within one to two minutes, and a clear or slightly opalescent solution is obtained depending on the silica content of the preparation. Drinking water containing strong antibacterial agents is suitable for the treatment of a large number of animals infected with a bacterial infection. This method of treatment is very simple, economical and effective. Because of the high solubility of the formulation, only a relatively small amount of the veterinary formulation should be transported to the treatment site.

The stability of the veterinary preparation according to the invention is significantly influenced by the water content. In our experiments, it has been found that the stability of sodium sulfachloropyridazine is maintained if the water content of the formulation is not more than 1 wt. %. For this reason, the granular carrier particles coated with trimethoprim citrate are preferably dried until a water content of less than 1% by weight is achieved. While adjusting the water content of the granular carrier particles coated with trimethoprim citrate is a necessity, the use of citric acid and / or the water-soluble carrier in anhydrous form is not essential.

The veterinary preparation of the invention having a water content of not more than 1% by weight is very stable: it can be stored at 40 ° C for 90 days without decomposition or discoloration.

The veterinary formulation of the invention was compared to the known formulation of U.S. Pat. No. 4,470,978 in terms of solubility. Example 1 of US Pat. No. 4,470,978 except that phenoxyethanol was not added. Thus, the composition of the powder mixture used for comparison was as follows:

sodium sulfachloropyridazine 39.4 g trimethoprim 7.8 g sucrose 13.14 g

The obtained sample of the powder mixture was dissolved in water as described in Example 6 of the aforementioned patent specification (see Example 6, Procedure 3) and a solution of 0.5 g / l was obtained. Thus, 0.5 g of said powder mixture was added to 1 liter of tap water at 20-22 ° C in a 1 liter beaker, after which the liquid was mixed with a glass rod every 5 to 10 minutes and the time required for complete dissolution was measured. .

At the same time, the veterinary preparation according to the invention was tested. Thus, 3.0 g of the formulation prepared according to Example 3 of this invention was added to 1 liter of tap water at 20-22 ° C in a 1 liter beaker, then the water was mixed with a glass rod and the time required for complete dissolution was measured.

The results obtained are shown in Table 1.

Table 1

agent Dissolution time Example 6 of US Pat. 4,470,978 90 min Example 3 according to the invention 1.5 min

From Table 1 it can be seen that the veterinary formulation of the invention dissolves in water 60 times faster than the known formulation used for comparison.

The invention is further illustrated by the following examples.

EXAMPLES

Example 1

1.5 g of citric acid, 2.0 g of trimethoprim and 8.0 ml of demineralized water are placed in a 100 ml beaker and mixed at 75 ° C until dissolved. 81 g of anhydrous glucose is kneaded with an aqueous solution of trimethoprim citrate and the wet mass is passed through a 1.0 mm sieve. The obtained wet granules are dried in a dish at 60 ° C until a water content of 1% is reached. The dry granules are passed through a 0.5 mm mesh screen, then blended with 10 g of sodium sulfachloropyridazine, and the resulting mixture is passed through the same screen again.

When 1 g of the formulation is added to 1 l of water, it dissolves in 1 minute to give a clear solution.

The product was stored at 40 ° C for 90 days: no change in appearance, solubility and active ingredient content was observed.

Example 2

240 g of anhydrous glucose and 270 g of mannitol are placed in a mixer (type M5 manufactured by Lodige) and homogenized for 5 minutes. A solution of 12.0 g of trimethoprim and 9.0 g of citric acid in 50 ml of distilled water at 70-75 ° C is added in several portions with stirring to the homogeneous powder mixture. The mixture is kneaded for an additional 10 minutes, the wet mass is passed through a sieve, then the obtained granules are dried in a fluid dryer (manufactured by Uniglatt) to which air is supplied at 70 ° C. Drying is continued for about 30 minutes until the water content of the granules is less than 1.0 wt. percent. The dry granules are sieved in a vibrating granulate sorter (manufactured by Erweka) using an acid-resistant sieve with a mesh size of 2 mm. 57.5 g of sodium sulfachloropyridazine and 3.0 g of colloidal silica are admixed with 510 g of granules obtained as above and containing 11.5 g of trimethoprim. The powder mixture is ground in a LU 100 mill and sieved on a sieve with a mesh size of mm.

The product obtained has the same stability and solubility as the product of Example 1.

Example 3

830 g of mannitol and 30 g of polyvinylpyrrolidone (type K-30) are placed in a laboratory mixer (type M5, manufactured by Lodige) and homogenized for 3 minutes. To the homogeneous mixture was added a solution of 20 g of trimethoprim and 15 g of citric acid monohydrate in 150 ml of water at 65-70 ° C with stirring. Stirring is continued for an additional 5 minutes and the mass is forced through a 1.0 mm mesh screen in a granulation device (manufactured by Erweka). The wet granules are dried on a tray in a steam-heated oven. Drying is carried out at 60 ° C until a water content in the granules of less than 1.0 wt. percent. The dry granules are then screened through a 0.6 mm sieve. The obtained granules are admixed with 100 g of dry pyridine dazine and 5.0 g of colloidal silica and the mixture is homogenized in a mixer (manufactured by Lodige) for 5 minutes, then milled in a mill (manufactured by Alpin) using a mesh millimeter.

The product is stored at 40 ° C for 90 days: no change in appearance, solubility and active ingredient content has been observed.

Claims (8)

PATENT CLAIMS A stable, water-soluble solid veterinary preparation, in which the active ingredient consists of sodium sulfachloropyridazine and trimethoprim in a weight ratio of 5 to 1, characterized in that it comprises from a) 1.6 to 3.3% by weight. percent trimethoprim citrate deposited on the surface of the water-soluble carrier particles, b) 8.4 to 16.7 wt. percent of sodium sulfachloropyridazine; and preferably c) pharmaceutically acceptable additives comprising polyvinylpyrrolidone and / or silica. The veterinary preparation according to claim 1, characterized in that the water-soluble carrier is a mono- or disaccharide or an alcohol sugar or a mixture thereof. Veterinary preparation according to claim 1 or 2, characterized in that the weight ratio of the water-soluble carrier to trimethoprim citrate is (25 to 50) to 1. The veterinary preparation of claim 2, wherein the monosaccharide is D-glucose. The veterinary preparation of claim 2, wherein the disaccharide is lactose. The veterinary preparation of claim 2, wherein the alcohol sugar is mannitol. characterized by, characterized by: A process for the preparation of a stable, solid water-soluble veterinary preparation, wherein the active ingredient comprises sodium sulfachloropyridazine and trimethoprim in a weight ratio of 5 to 1, characterized in that it is 1, 6 to 3.3% by weight. % of trimethoprim is reacted with citric acid in the presence of water, the obtained solution of trimethoprim citrate is applied to the surface of the particles of a water-soluble carrier, dried, and then mixed with sodium sulfopyrrolidazine. Method according to claim 7, characterized in that one mass. A portion of trimethoprim is reacted with 0.5 to 2.5 wt. parts by weight of citric acid in 10 to 50 wt. parts of water at 40 to 80 ° C. Process according to claim 7 or 8, characterized in that the water-soluble carrier is pretreated with polyvinylpyrrolidone. Process according to claim 7 or 9, characterized in that the water-soluble carrier is a mono- or disaccharide or an alcohol sugar or a mixture thereof. Process according to one of Claims 7 to 10, characterized in that the water-soluble carrier with the applied trimetroprim citrate is admixed with sulfachloropyridazine and silica.