LV10578B

LV10578B - A stable water-soluble veterinary composition and a process for the preparation thereof

Info

Publication number: LV10578B
Application number: LVP-93-1183A
Authority: LV
Inventors: Pal Fekete; Denes Bezzegh; Nee Kertesz Ildiko Palfi; Nee Hernyes Magdolna Gora; Attila Nagy; Laszlo Puskas; Maria Krisztian; Eszter Moldvai; Nee Murai Eva Szentgroti
Original assignee: Egis Gyegyszergyar Rt
Priority date: 1992-11-06
Filing date: 1993-11-05
Publication date: 1996-06-20
Also published as: LTIP1448A; HU9203477D0; SI9300580A; SK107593A3; HU212498B; ITMI932342A0; GB2272156B; DE4338047A1; IT1266671B1; HUT69405A; GB2272156A; PL300937A1; GB9322677D0; YU70493A; EE9400061A; LT3395B; HRP931367A2; FR2697751A1; ITMI932342A1; LV10578A

Description

LV 10578 A stable water-soluble veterinary composition and a process for the preparation thereof

The invention refers to a stable, solid veterinary composition being soluble in water, wherein the active substance consists of the sodium salt of N-(6-chloro-3-pyridazinyl)--sulfanilamide (sulfachlorpyridazine-sodium) and 2,4-diamino--5-(3' , 4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) in a mass ratio of 5 to 1, and a process for the preparation of the composition.

It is well known that the action of sulfonamides is potentiated by trimethoprim (British Patent No. 1 176 395). Sulfonamides including sulfachlorpyridazine-sodium and trimethoprim are combined in a mass ratio of 5 to 1, in general. Such combinations have potent antimicrobic activity and are extensively employed in both the human and the veterinary medicine.

In the veterinary medicine, special requirements should be fulfilled when using the above combination of active substances. Namely, in case of bacterial infections effecting large groups of animals, the easiest administration of the active substances consists in the addition thereof to the feed. However, due to the reduced intake of feed, the sufficient medication of the ill animals is not assured by the latter method. In principle, it is possible to administer the active substances in form of solid veterinary compositions such as capsules or tablets or injectable veterinary compositions, but this method of treatment is rather laboursome. Actually, in case of smaller animals such as poultry, such a treatment lasting 3 to 5 days is practically unfeasible. -2-

Regarding the difficulties outlined above, in case of bacterial infections influencing large groups of animals, the most practical and economical mode of treatment is to dissolve the active substances in the drinking water of the animals. 5 Namely, in the acute stage of illness the water intake of the animals is increased, in contrast to the reduced food uptake.

However, the latter administration method can be accomplished if the active substances are dissolved in the drinking water sufficiently and in a short time such as some 10 minūtes. In case of sulfonamides and trimethoprim it is a problem that these active substances are practically insoluble in water. The solubility of sulfonamides can be increased by using the sodium salt, and, in general, trimethoprim is treated with surface active aģents to enhance the solubility. As a most common 15 practice, the active substances are dissolved in organic solvents to obtain a solution that can be admixed to water.

Veterinary compositions comprising trimethoprim and sulfonamides are well known in the literature. A composition in the form of powder is described by the 20 Hungarian Patent No. 191 890 wherein the active substances consist of trimethoprim, sulfachlorpyridazine-sodium and 4-amino-N-(5-methyl-3-isoxazolyl)-benzenesulfonamide (sulfamethoxazole). Glucose, sodium chloride, potassium chloride, sodium hydrogen carbonate, sodium citrate and calcium carbonate 25 are the diluents. According to the description, a peroral dose of 25 g o’f the powder mixture can be employed for the effective treatment of a calf having an infection caused by Escherichia coli. However, the knov/n composition cannot be dissolved in the drinking water completely because of the insolubility of 30 sulfamethoxazole and calcium carbonate. -3- LV 10578 A further synergistic combination is described in U.S.

Patent No. 4,470,978 wherein the active substances consist of sulfachloropyridazine-sodium, trimethoprim and phenoxyethanol.

In addition to the active substances, the combination contains only saccharose. The knovrn composition was admixed to the drinking water of chickens to prove the efficacy thereof.

In accordance with our tests, several hours were needed to dissolve the knovm composition in water.

An aqueous solution suitable for intravenous injection is knovm from German Patent No. 30 17 032. The solution comprises 3-methoxy-4-(41-aminobenzenesulfonamido)-1,2,5-thiadiazole (sulfametrole) and trimethoprim as the active substances, furthermore sugars and sugar alcohols, respectively, as the solubilizing aģent. Hov/ever, the trimethoprim concentration of the aqueous composition is as low as 0.6 mg/ml, consequently, only about 10 times dilution is needed to producē a suitable drinking water. Thus, an enormous amount of solution ought to be transported to the farms.

European Patent Application No. 22,342 describes Solutions suitable for parenteral administration. The knovm Solutions comprise trimethoprim and sulfamethoxazole or 4-amino-N-(5,6--dimethoxy-4-pyridinyl)-benzenesulfonamide (sulfadoxine) as the active substances dissolved in 60 to 80 per cent by mass of 2-pyrrolidone, furthermore 1 to 5 per cent by mass of benzyl-alcohol and water.

Further injectable Solutions are knovm from German Patent No. 24 45 400 wherein trimethoprim, 4-amino-N-(4,6-dimethyl--2-pyrimidinyl)-benzenesulfonamide (sulfadimidine) and 4-amino--N-(2-thiazolyl)-benzenesulfonamide (sulfathiazole) are dissolved in dimethyl acetamide containing 20 percent of water. -4-

Injectable Solutions are known from German Patent No. 27 04 708, too, wherein the diethylaraine salt of a sulfonamide and 2,4-diamino-5-veratryl-pyrimidine-lactate (diaveridine lactate) are dissolved in a mixture of 10 to 50 parts of water, 15 to 30 parts of propylene glycol and 20 to 40 parts of N-methyl-pyrrolidone.

According to German Patent No. 25 38 67Š an injectable solution is prepared by lyophilizing a solution of trimethoprim in ethanol comprising an acidic buffer, and dissolving the lyophilized product, directly before use, in a solution of sulfa-methoxazole in propylene glycol, ethanol and water.

European Patent Application No. 7,591 refers to liquid compositions that can be added to the drinking water of animals. The active components of the known composition consist of trimethoprim and sulfachlorpyridazine or N-pyrazinyl-sulfanilamide (sulfapyrazine) or the salts of the sulfonamides. The active components are dissolved in N-methylpyrrolidone or in a mixture of N-methylpyrrolidone and glycol monomethyl ether in the presence of tensides, and the dissolution is enhanced by the addition of hydroxyethyl-theophylline, nicotinic amide or sodium benzoate. Ethanolamine proved to be most favourable for forming a salt of the sulfonamides. Although it is claimed by the description that the carriers used are phys'iologically neutral, it is obvious for an expert that the solvents used i.e. N-methyl-pyrrolidone and glycol monomethyl ether are not less harmful than propylene glycol, glycerol formai, dimethyl acetamide etc. given in the State of art.

To sum up, the known veterinary compositions suitable for being incorporated into the drinking water of animals either comprise the active substances in a low concentration (DE-P -5- LV 10578

No. 30 17 032), or contain organic solvents, too (E-P No. 22,342, DE-P No. 24 45 400, DE-P No. 27 04 708, E-P No. 7,591), or the active substances are separately dissolved, then combined (DE-P No. 25 38 678), or the dissolution of the active substances in water takes a rather long time (US-P No. 4,470,978).

The aim of the invention is to provide a stable and solid veterinary composition that can be added to the drinking water of animals, dissolves in water in a short time, comprises both active substances in the required concentration and does not contain any organic solvent being harmful for the animals.

It has been found that the above aim is achieved by the veterinary composition of the invention comprising a mixture of (a) 1.6 to 3.3 per cent by mass of trimethoprim citrate applied to the surface of the pārticies of a water-soluble solid carrier, (b) 8.4 to 16.7 per cent by mass of sulfamethoxazole-sodium and, optionally, (c) pharmaceutically acceptable additives consisting of poly(vinyl pyrrolidone) and/or silica.

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 a sugar alcohol such as mannitol.

The invention is based on the perception that trimethoprim i citrate dissolves relatively well in water, and, if trimethoprim citrate is applied to a suitable water-soluble carrier, a granulated product is obtained which is compatible with sulfa-chlorpyridazine-sodium i.e. the active substances of the mixture do not decompose during storage. On the other hand, the mixture of the carrier coated by trimethoprim and of the sulfachlor-pyridazine-sodium dissolves readily in water and supplies both active substances in the concentration needed. -6-

It was trieci to apply other acid addition salts of trimethoprim to the water-soluble solid carrier to obtain a granulated product containing trimethoprim in the required concentration and dissolving in water in a short time. Acid addition salts of trimethoprim formed with tartaric, fumaric, maleinic, acetic or hydrochloric acid failed to have a solubility needed to producē a granulated product having the requisite trimethoprim content. From the point of view of solubility, acid addition salts of trimethoprim formed with lactic, sulfuric or citric acid proved to be equally satisfactory, however, compositions containig trimethoprim lactate or sulfate did not have the necessary stability during storage. It is surprising that carboxylic acids having very similar Chemical structure i.e. tartaric acid (2,3-dihydroxybutanedicarboxylic acid), lactic acid (2-hydroxypropionic acid) and citric acid (2-hydroxy--1,2,3-propanetricarbocylic acid) form acid addition salts having quite different characteristics. Thus, the expert could not foresee that a suitable veterinary composition can be produced using trimethoprim in the form of the čitrate salt.

The veterinary composition of the invention is prepared by reacting 1.6 to 3.3 per cent by mass of trimethoprim with citric acid in the presence of water, applying the solution of trimethoprim citrate obtained to the surface of the pārticies of a water-soluble carrier, drying the pārticies and mixing them with sulfachlorpyridazine-sodium.

If desired, the water-soluble carrier is pretreated with poly(vinyl-pyrrolidone).

The dried pārticies of the water-soluble carrier coated with trimethoprim citrate can be mixed with silica, too, to avoid sticking together of the pārticies of the end-product. -7- LV 10578

It is preferred to use the water-soluble carrier with very low water content or rather in an anhydrous form.

According to a preferred method the veterinary composition of the invention is prepared as follows: 1 part by mass of trimethoprira is dissolved in 10 to 50 parts by mass of water in the presence of 0.5 to 2.5 parts by mass of citric acid at 40 to 80 °C. Since an aqueous solution is prepared, citric acid can be used both in anhydrous or mono-hydrate form. The solution obtained is applied to the surface of the pārticies of 25 to 100 parts by mass of water-soluble solid carrier preferably a mono- or disaccharide or a sugar alcohol or a mixture thereof. If desired, the carrier is pretreated with 0.5 to 5 parts by mass of poly(vinyl-pyrrolidone) calculated to the amount of trimethoprim. Preferably, the solid carrier is kneaded with the aqueous solution of trimethoprim citrate, the wet mass obtained is granulated by pressing it through a sieve. The wet pārticies are dried to reduce the water content below 1 per cent by mass, then sieved and/or ground to obtain a powder having smaller pārticies than 0.5 mm. The powder obtained is mixed with sulfachlorpyridazine-sodium consisting of smaller pārticies than 0.5 mm and, if desired, v/ith silica. The powder mixture obtained can be ground again.

For the treatment of animals the veterinary composition of the invention is added to the drinking water the quantity of which is at least 100 times, generally 1000 times the mass of the composition. The composition is dissolved in a very short time, generally in one or two minūtes, and a clear or somewhat opalescent solution is obtained depending on the silica content of the composition. The drinking water containing the potent anti- bacterial aģents is suitable for the treatment of large -8- number of animals having bacterial infections; this type of treatment being very simple, economical and efficacious. Due to the high rāte of dilution merely a relatively low quantity of the veterinary composition has to be transported to the site 5 of treatment.

The stability of the veterinary composition of the invention is significantly influenced by the water content. In our experiments it was stated that the stability of the sulfa-chlorpyridazine-sodium is retained if the water content of the 10 composition is not higher than 1 per cent by mass. For this reason, the granulated carrier pārticies coated with trimethoprim citrate is preferably dried until the water content is lower than 1 per cent by mass. Since the adjustment of the water content of the granulated carrier pārticies coated with tri-15 methoprim citrate is a must, it is not essential to employ the citric acid and/or the water-soluble carrier in an anhydrous form.

The veterinary composition of the invention having a water content of not higher than 1 per cent by mass is very stable: 20 it can be stored at 40 °C for 90 days without any degradation or discolouration.

The veterinary composition of the invention was compared with the known composition of US-P No. 4,470,978 as to solubility. Example 1 of US-P No. 4,470,978 was reproduced with 25 the difference that phenoxyethanol was not added. Thus, the contents of the powder mixture used for comparison was as follows: 39.4 g 7.8 g sulfachlorpyridazine-sodium trimethoprim 30 saccharose 13.14 g -9- LV 10578 A sample of the powder mixture obtained was dissolved in water as described in Example 6 of the above Patent Specification (see Example 6, treatment 3) to obtain a solution of concentration 0.5 g/1. Thus, 0.5 g of the above powder mixture 5 were added to 1 litre tap water at 20 to 22 °C in a beaker of 1 litre capacity, then the liquid was stirred at every 5 to 10 minūtes with a glass rod and the time needed for complete dissolution was determined.

Simultaneously, the veterinary composition of the invention 10 was tested, too. Thus, 3.0 g of the composition prepared as given in Example 3 of the invention were added to 1 litre of tap water at 20 to 22 °c in a beaker of 1 litre capacity, then the water was stirred with a glass rod and the time needed for complete dissolution was determined. 15 The results obtained are shown in Table 1.

Table 1 20 Preparation Dissolution time

Example 6 of US-P No. 4,470,978 90 minūtes

Example 3 of the invention 1.5 minūtes 25 _

From Table 1 it can be seen that the veterinary composition of the invention dissolves in water 60 times more quickly than the known composition used for comparison. 30 The invention is further elucidated by means of the -10- following Examples.

Example 1 1.5 g of citric acid, 2.0 g of trimethoprim and 8.0 ml of demineralized water are transferred into a beaker having 5 100 ml capacity and the contents of the beaker are stirred at 75 °C until dissolution. 81 g of anhydrous glucose are kneaded with the aqueous solution of trimethoprim citrate and the wet mass is passed through a sieve of 1.0 mm mesh size. The wet granules obtained are dried on a tray at 60 °C until a water 10 content of 1 per cent by mass. The dry granules are passed through a sieve having 0.5 mm mesh size, then mixed with 10 g of sulfachlorpyridazine-sodium and the mixture obtained is passed again through the same sieve.

If 1 g of the composition is added to 1 litre of water, 15 it dissolves in 1 minūte yielding a clear solution.

The product was stored at 40 °C for 90 days: no change could be detected as to appearance, solubility and active substance contents.

Example 2 20 240 g of anhydrous glucose and 270 g of mannitol are transferred into a mixer (type M5 produced by Lodige) and homogenized for 5 minūtes. To the homogeneous powder mixture a solution of 12.0 g of trimethoprim and 9.0 g of citric acid in 50 ml of distilled water are added at 70 to 75 °C in several 25 portions under stirring. The mixture is kneaded for further 10 minūtes, then the granules are dried in a fluidization drying apparatus (produced by Uniglatt) introducing the air at 70 °C. Drying is continued for about 30 minūtes until the water content of the granules is lower than 1.0 per cent by mass. The dry 30 granules are sieved in an oscillating granulating apparatus -11- LV 10578 (produced by Erweka) using an acid-resistant sieve of 0.5 mm mesh size. 57.5 g of sulfachlorpyridazine-sodium and 3.0 g of colloidal silica are admixed to the 510 g of granules obtained above and containing 11.5 g of trimethoprim. The powder mixture is ground in a mill type LU 100 using a sieve of 2 mm mesh size.

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

Example 3 830 g of mannitol and 30 g of poly(vinyl pyrrolidone) (type K-30) are transferred into a laboratory mixer (type M5 produced by Lodige) and homogenized for 3 minūtes. To the homogeneous mixture a solution of 20 g of trimethoprim and 15 g of citric acid monohydrate in 150 ml of water are added at 65 to 70 °C under constant stirring. Stirring is continued for further 5 minūtes and the mass is passed in a granulating machine (produced by Erweka) through a sieve having 1.0 mm mesh size. The wet granules are dried on the trays of a drying apparatus heated with steam. Drying is performed at 60 °C until the water content of the granules becomes lower than 1.0 per cent by mass. Then, the dry granules are passed through a sieve of 0.6 mm mesh size. To the granules obtained 100 g of sulfachlorpyridazine and 5 g of colloidal silica are admixed and the mixture is homogenized in a mixer (produced by Lodige) for 5 minūtes, then ground in a mill (produced by Alpin) using a sieve having 3 mm mesh size.

The product was stored at 40 °C for 90 days: no change could be detected as to appearance, solubility and active substance contents. -12- LV 10578 CLAIMS: 1. A stable, solid veterinary composition being soluble in water, wherein the active substance consists of sulfachlor-pyridazine-sodium and trimethoprim in a mass ratio of 5 to 1, comprising a mixture of (a) 1.6 to 3.3 per cent by mass of trimethoprim citrate applied to the surface of the pārticies of a water-soluble solid carrier, (b) 8.4 to 16.7 per cent by mass of sulfachlorpyridazine-sodium and, optionally, (c) pharmaceutically acceptable additives consisting of poly(vinyl pyrrolidone) and/or silica. 2. A veterinary composition as claimed in Claim 1, in which the water-soluble carrier is a mono- or disaccharide or a sugar alcohol or a mixture thereof. 3. A veterinary composition as claimed in Claim 1 or 2, in which the mass ratio of the water-soluble carrier to the trimethoprim citrate is equivalent to (25-50):1. 4. A veterinary composition as claimed in Claim 2, in which the monosaccharide is D-glucose. 5. A veterinary composition as claimed in Claim 2, in which the disaccharide is lactose. 6. A veterinary composition as claimed in Claim 2, in which the sugar alcohol is mannitol. 7. A process for the preparation of a stable, solid veterinary composition being soluble in water, v/herein the active substance consists of sulfachlorpyridazine-sodium and trimethoprim in a mass ratio of 5 to 1, in which 1.6 to 3.3 per cent by mass of trimethoprim is reacted with citric acid in the presence of water, the solution of the trimethoprim citrate obtained is applied to the surface of the pārticies of a water-soluble carrier, the pārticies are dried, -13- then mixed with sulfachlorpyridazine-sodium. 8. A process as claimed in Claim 7, in which 1 part by mass of trimethoprim is reacted with 0.5 to 2.5 parts by mass of citric acid in 10 to 50 parts by mass of water at 40 to 80 °C. 9. A process as claimed in Claim 7 or 8, in which the water-soluble carrier is pretreated with poly(vinyl pyrrolidone). 10. A process as claimed in Claim 7 or 9, in which the water-soluble carrier is a mono- or disaccharide or a sugar alcohol or a mixture thereof. 11. A process as claimed in any of Claims 7 to 10, in which the water-soluble carrier coated with trimethoprim citrate is mixed with sulfachlorpyridazine and silica. LV 10578

Abstract A stable water-soluble veterinary composition and a process for the preparation thereof

The invention refers to a stable, solid veterinary composition being soluble in water, wherein the active substance consists of the sodium salt of sulfachlorpyridazine and trimethoprim in a raass ratio of 5 to 1, and a process for the preparation thereof.

The veterinary composition of the invention contains a mixture of (a) 1.6 to 3.3 per cent by mass of trimethoprim citrate applied to the surface of the pārticies of a water-soluble solid carrier, (b) 8.4 to 16.7 per cent by mass of sulfachlorpyridazine-sodium and, optionally, (c) pharmaceutically acceptable additives consisting of poly(vinyl pyrrolidone) and/or silica.

Claims

Formula 1. A stable, solid, water-soluble veterinary composition, wherein the active ingredients are in the weight ratio of 5: 1 sulfachlorpyridazine sodium to trimethoprim, wherein the mixture comprises, as a percentage of the total weight: a) trimethoprim citrate, connected to a water soluble solid carrier particle surface of 1.6 - 3.3; b) Sulfachlorpyridazine sodium 8.4 - 16.7; c) optional pharmaceutically acceptable excipients consisting of polyvinylpyrrolidone and / or silicon dioxide.

2. A veterinary composition according to claim 1, wherein the water-soluble carrier is a mono- or disaccharide, or a sugar alcohol, or a mixture thereof.

3. A veterinary composition according to claim 1 or 2, wherein the weight ratio of water-soluble carrier and trimethoprim citrate is from 25 to 50: 1.

The veterinary composition of claim 2, wherein the monosaccharide is glucose.

The veterinary composition according to claim 2, wherein the disaccharide is lactose.

6. The veterinary composition of claim 2, wherein the sugar alcohol is mannitol.

7. A method for preparing a stable, solid, water-soluble composition for use in veterinary medicine wherein the active ingredients are in the weight ratio of 5 to 1 sulfachloropyridazine sodium and trimethoprim, characterized in that 1.6 to 3.3% of the total composition is trimethoprim treated. with citric acid in the presence of water, the resulting trimethoprim citrate is combined with the surface of the water-soluble carrier particles, the particles are dried and mixed with the sulfachloropyridazine sodium salt.

8. A process according to claim 7, wherein 1 part by weight of trimethoprim is treated with 0.5 to 2.5 parts by weight of 10 to 50 parts by weight of citric acid in water.

Method according to claim 7 or 8, characterized in that the water-soluble carrier is first treated with polyvinylpyrrolidone.

Method according to claim 7 or 9, characterized in that the water-soluble carrier is a mono- or disaccharide, or a sugar alcohol, or a mixture thereof.

A method according to any one of claims 7-10. characterized in that the water-soluble carrier is coated with trimethoprim citrate and mixed with sulfachloropyridazine and silicon dioxide.