SI20411A - Watersoluble powders for peroral solution and their use - Google Patents

Abstract

New water-soluble powdery or grainy pharmaceutical forms for the use in the veterinary medicine are described, containing a therapeutically effective quantity of amoxicillin trihydrate and potassium clavulanate combined with a filler acceptable in the veterinary medicine and at least one buffer compound. The latter is suitable to maintain the pH value of a medium between 6,0 and 8,5 under the fast and complete dissolution of the above mentioned pharmaceutical forms in drinking water for animals. After dissolution in water, clear solutions are stable for at least 24 hours. Phosphate buffers, such as monosodium dihydrogen phosphate dihydrate/ sodium hexametaphosphate, are used preferentially, maintaining the pH value of water medium between 6,5 and 7,5, preferably near 7,0. In accordance with the scope of the invention, the occurrence of any solutions known for causing problems in water tanks for cattle is avoided, such as the sedimentation at the bottom of a tank, bringing about technical problems of cloggings in the piping system for the supply of drinking water for animals.

Description

The present invention relates to novel dry water-soluble powders as a pharmaceutical form for use in veterinary medicine for the treatment of bacterial infections containing penicillin antibiotic amoxicillin trihydrate and potassium clavulanate as a β-lactamase inhibitor and rapidly and completely dissolved in drinking water for drinking animals or domestic animals animals such as cattle, calves, horses, pigs, pigs, sheep, lambs, dogs, cats, poultry (chickens, ducks, geese, turkeys). The aqueous solutions of the pharmaceutical forms of the invention are stable for at least 24 hours.

The powder and water-soluble forms of the invention may also be used in human medicine, especially in pediatrics and geriatrics, where dry powder is dissolved in water suitable for human use before oral administration.

In addition to the dry powder dosage units, the present invention also relates to granules as a pharmaceutical form for the preparation of aqueous solutions for human and veterinary use.

A technical problem

The known powder and granular dry pharmaceutical dosage forms of the combination of amoxicillin trihydrate and potassium clavulanate are not fully dissolved in drinking water for drinking animals or for domestic animals, but a suspension is formed which may cause problems in aquatic livestock tanks, namely sedimentation at the bottom of the tank and, consequently, technical problems, such as clogging of the fixtures or piping to provide drinking water to the animals.

Therefore, there is an ongoing need for a novel and water-soluble powder or granules of a therapeutic combination of amoxicillin trihydrate and potassium clavulanate to prepare a clear aqueous solution.

The state of the art

Amoxicillin, its salts and hydrates, as a trihydrate form, is described in British patent file no. GB 1241844 as an antibacterial agent suitable for the treatment of gram-negative and gram-positive bacterial infections. However, some bacteria are resistant to amoxicillin due to the β-lactamases that these bacteria produce.

Clavulanic acid and its salts are described in British patent file no. GB 1508977 as β-lactamase inhibitors that increase the antibacterial activity of penicillins and cephalosporins.

Clavulanic acid is a generic name for (2R, 5R, Z) -3- (2-hydroxyethylidene) -7-oxo4-oxa-1-azabicyclo / 3.2.0) heptane-2-carboxylic acid. Its alkali salts and esters act as inhibitors of β-lactamases produced by certain gram-positive and gram-negative microorganisms.

In addition to βlactamase inhibitory activity, clavulanic acid and its alkali salts have a synergistic effect in combination with β-lactam antibiotics of the penicillin and cephalosporin species, so clavulanic acid and its alkali salts are used in pharmaceutical forms to prevent deactivation of βlactam antibiotics. Commercial forms contain the more stable potassium salt of clavulanic acid (clavulanic acid itself is quite unstable) in combination with amoxicillin trihydrate.

Clavulanic acid is prepared by the fermentation of a microorganism producing clavulanic acid, such as various microorganisms belonging to the genus Streptomyces, such as S.clavuligerus NRRL 3585 and S.clavuligerus ATCC 27064, S.jumoninensis NRRL 5741, S.katsurahamanus IFO 13716, and S.O. . P 6621 FERM 2804.

British patent file no. GB 1508977 describes pharmaceutical forms of a synergistic combination of clavulanic acid or its salts and a penicillin or cephalosporin antibiotic, such as amoxicillin (as trihydrate) in a weight ratio of 10: 1 to 1:10, for example from 4: 1 to 1: 4.

The forms described by the present invention can be used to treat bacterial infections in domestic animals, such as mastitis in bovine animals.

British patent file no. 2005538 describes oral dosage forms for the treatment of bacterial infections.

The invention describes dry dosage units of oral dosage forms containing from 20 mg to 1500 mg of amoxicillin trihydrate, 20 mg to 500 mg of potassium clavulanate and a pharmaceutically acceptable carrier, with a weight ratio of amoxicillin trihydrate and potassium clavulanate of 6: 1 to 1: 1.

Oral dosage units may also be in powder or granule form for reconstitution with water prior to use and may be contained in bags or other suitable containers or packaging.

The pharmaceutical forms are dry, i.e. completely anhydrous, for example obtained by thorough drying which completely removes moisture except the crystallization water contained in amoxicillin trihydrate.

The invention further relates to pharmaceutical forms which are packaged in a sealed container which prevents moisture from entering and thereby increases stability in feeding. These pharmaceutical forms contain one or more dosage units of the desired pharmaceutical form.

Particularly preferred is the use of a suitable desiccant inside the container or packaging. Non-toxic drying agents such as silica gel or crystalline sodium, potassium or calcium alumosilicate (known as molecular sieves) are used as suitable desiccants. Such desiccant may be contained in bags or other suitable sealed containers or packaging.

Due to the known hygroscopicity and rapid hydrolysis of potassium clavulanate in water, the pharmaceutical compositions of the invention are prepared in a dry atmosphere, for example, one containing less than 30% relative humidity and even better if it contains less than 20% relative humidity. Due to these properties, potassium clavulanate must be stored in an extremely dry environment, such as one containing 30% or less relative humidity.

Dosage forms are prepared in conventional and known manner, such as by mixing dry powder ingredients and filling into bags or other suitable sealed containers or packaging.

Description of a solution to a technical case problem

The invention is based on the task of solving a problem known in the art by preparing new water-soluble powder or granular pharmaceutical forms of a combination of amoxicillin (in the form of amoxicillin trihydrate) and clavulanic acid (in the form of potassium clavulanate) for use in veterinary, less than one (1) minute, and completely dissolve in drinking water for drinking animals or for domestic animals, avoiding the risk of clogging on installations or installations for delivering drinking water to animals. The clear solutions of the invention are stable for at least 24 hours after dissolution in water. In addition, the solutions are preferred over the suspensions for oral administration because the active substances in the solutions are absorbed more rapidly.

In accordance with the invention, amoxicillin in the form of amoxicillin trihydrate is used, and optionally the sodium salt of amoxicillin, for example the crystalline form of sodium amoxicillin, can be used.

Clavulanic acid is used in the form of potassium clavulanate.

Dry powdered or granular veterinary pharmaceutical forms which are rapidly and completely dissolved in water according to the invention are prepared by any suitable method of dry mixing of ingredients commonly used in the art. The dry blended powder may then be granulated dry in a manner known in the art.

The ingredients for the preparation of the pharmaceutical formulations of the invention for veterinary use are low in moisture and it is preferable to dry them before removing the formulations of the invention in order to remove moisture other than crystallization water in amoxicillin trihydrate.

Due to the known hygroscopicity of potassium clavulanate, pharmaceutical forms for veterinary use are prepared in a dry atmosphere, for example, one that contains less than 30% relative humidity and preferably if it contains less than 20% relative humidity.

The invention further relates to a method of treating and preventing bacterial infectious diseases in a feeding animal or a domestic animal by administering to the animal drinking water in which a powdered or granular veterinary pharmaceutical formulation containing an antibacterially effective amount of amoxicillin trihydrate and potassium clavulanate is dissolved.

Amoxicillin is known to be poorly soluble in water. As noted in The Merck lndex, 12 ^th Edition, 1996, under Monograph number 617, is the solubility of amoxicillin trihydrate, 4 mg / ml. In contrast, the good water solubility of amoxicillin salts, such as its sodium salts, is known. The disadvantage of this form is the instability of amoxicillin in an alkaline medium.

The instability of clavulanic acid and its alkali salts in the alkaline environment is also known.

Example 4 of British patent file no. GB 2005538 lists the dosage unit in the bag and the composition of the dry powder for reconstitution with water before use. Due to the instability of amoxicillin and clavulanic acid or its potassium salt in an alkaline environment after reconstitution with water, the pharmaceutical formulation contains a buffering agent to adjust the appropriate pH value of the medium. Because the powder composition contains a significant proportion of desiccant and glide, after reconstitution with water, the suspension is suitable for human use.

The present invention relates to a powder or granular pharmaceutical form for use in veterinary medicine which is rapidly and completely dissolved in drinking water for drinking animals or for domestic animals. The pharmaceutical forms of the invention which solve the problem known in the art comprise, in addition to a therapeutically effective amount of amoxicillin trihydrate and potassium clavulanate and a veterinarily acceptable filler, at least one putative agent suitable for maintaining the pH of the medium suitable for dissolving said pharmaceutical forms in water.

Buffer is a compound, or more specifically a mixture of compounds, that maintains the pH of a medium in a given pH range during and after dissolution, which, according to the invention, allows the ingredients to be dissolved very quickly so that the aqueous solutions of the pharmaceutical forms of the invention are stable for at least 24 hours.

The buffering agent according to the invention is preferably selected from the group consisting of phosphate buffers maintaining the pH of the medium between 6.5 and 8.0, preferably between 6.5 and 7.5, particularly preferably about pH 7.0 , as monosodium dihydrogen phosphate dihydrate / sodium hexametaphosphate buffer, citrophosphate buffers, borate buffers and all possible combinations to obtain a buffer in the desired pH range. Preferably, phosphate buffers are selected. Monosodium dihydrogen phosphate dihydrate / sodium hexametaphosphate buffer is particularly preferred.

As fillers, conventional fillers known in the pharmaceutical art as mannitol, sorbitol, powdered sugar, dextrin, dextrose, lactose, glucose and others are used. Mannitol is chosen as a particularly preferred filler, preferably in the form of a mannitol powder, also mannitol granules, which in the process of preparing the powder according to the invention are crushed and mixed with other active ingredients.

Surprisingly, we have found that by omitting desiccants such as silica and a slider in the composition of the dry powder or granular pharmaceutical form, which are otherwise constituents of the dry powder described in Example 4 of British Patent GB 2005538, after rapid and complete dissolution of the pharmaceutical form in terms of The invention provides a clear solution in water to avoid problems in veterinary medicine known in the art when using suspensions.

Instead of the presence of desiccant and slider in powder or granular pharmaceutical composition, the preferred desiccant inside the bags or containers or other packaging is used according to the invention. Silica gel (silica) or crystalline sodium, potassium or calcium alumosilicate (known as molecular sieves) may be used as the drying agent.

After preparation of the dosage units of the pharmaceutical formulations of the invention, the formulations are filled into bags or suitable closed containers containing the desiccant themselves and then closed to prevent access to moisture.

The veterinary pharmaceutical formulations of the invention may additionally contain odor and taste enhancing agents such as saccharin sodium, aspartame, menthol, vanilla aroma, and other excipients.

The present invention also optionally relates to novel dry powder or granular pharmaceutical forms of a combination of amoxicillin (in the form of amoxicillin trihydrate) and clavulanic acid (in the form of potassium clavulanate) for use in veterinary medicine, containing an alkaline agent in the composition of a new formulation, sodium hydrogen carbonate (NaHCO ₃ ), sodium carbonate, the alkali metal salt of amino acid carbonate as sodium glycine carbonate, amino acids such as arginine, lysine and their alkali salts. The choice of sodium hydrogen carbonate is preferred. Also, these forms contain conventional fillers known in the pharmaceutical art, preferably mannitol, odor and flavor enhancers, and other excipients such as lubricants such as polyethylene glycol and the like.

Information and properties on fillers and other excipients are available from manufacturers, relevant brochures, or other sources, as in A.Wade and P.J.Veller, Handbook of Pharmaceutical Excipients, Second Edition, 1994, American Pharmaceutical Association, Washington.

For example, mannitol is manufactured by Roquette Freres, France, polyethylene glycol 4000 firm Hoechst, Germany.

Also, these forms of the invention are rapidly and completely dissolved in water, but due to their slightly alkaline environment, they are slightly less stable than the above preferred formulation containing the buffering agent.

The dose of the new dry powder or granular dosage form for veterinary use is determined by type of animal, age, weight and average daily amount of drinking water.

The water-soluble powder of the invention is contained in suitable sealed containers, for example 100 grams or 500 grams powder.

A dosage unit, such as 100 gram powder according to the invention contains from 10 g to 60 g of amoxicillin (in the form of amoxicillin trihydrate) and from 2 g to 20 g of clavulanic acid (in the form of potassium clavulanate), with a weight ratio of amoxicillin and clavulanic acids in the range from 12: 1 to 1: 1, preferably from 7: 1 to 1: 1, especially preferably from 4: 1 to 1: 1.

The dosage forms of the invention comprise from about 10, 20, 30, 40, 50 to 60% of amoxicillin (in the form of amoxicillin trihydrate) and from about 2, 2.5, 5, 7.5, 10,

12.5 to 15% clavulanic acid (in the form of potassium clavulanate). An example dosage unit is 100 gram powder. Formulations containing higher doses of both active ingredients are preferably used.

For example, a once daily dose of the pharmaceutical formulation of the invention for use in poultry is from 10 mg to 20 mg of amoxicillin (as amoxicillin trihydrate) and 2.5 mg to 5 mg of clavulanic acid (as potassium clavulanate) per 1 kg body weight and is given for 3 to 5 days. For use in pigs, the daily dose is 2 mg to 10 mg amoxicillin (as amoxicillin trihydrate) and 0.5 mg to 2.5 mg clavulanic acid (potassium clavulanate) per 1 kg body weight given 2 times daily for 2 to 5 days.

For example, a 100 gram powder dosage unit with the composition described in Example 1 or Example 2 is dissolved in from about 20 I to about 27 I drinking water, while a 100 gram powder powder unit with the composition described in Example 3 is dissolved in from about 4 I to about 6 I drinking water.

Powdered or granular pharmaceutical forms for veterinary use according to the invention are preferably used in a composition containing higher doses of active ingredients, for example 50% by weight amoxicillin (as amoxicillin trihydrate), and

12.5% by weight of clavulanic acid (in the form of potassium clavulanate), buffering agent and suitable filler. The stability of aqueous solutions of these forms for veterinary use shall be at least 24 hours.

A new dry powder or granular pharmaceutical formulation of the invention which contains, instead of a buffer agent, an alkaline agent such as sodium hydrogen carbonate, is stable for about 6 hours after dissolution in drinking water for animals.

The stability of the powder or granular pharmaceutical forms of the invention is at least 2 years.

The present invention also relates to aqueous solutions of pharmaceutical formulations for veterinary use containing powder or granular form and water.

The present invention also relates to a process for preparing aqueous solutions of powder or granular forms according to the invention, comprising:

a) preparing powder or granular forms according to the invention

b) dissolving said powder or granular forms in a suitable amount of drinking water to prepare a solution that is stable for at least 24 hours.

Preferred aqueous solutions of powder or granular dosage forms for veterinary use according to the invention which, in addition to amoxicillin trihydrate and potassium clavulanate, contain a buffering agent and a suitable veterinary acceptable filler are stable for at least 24 hours.

Because new powdered or granular veterinary pharmaceutical dosage forms are rapidly and completely dissolved in an adequate amount of drinking water, this avoids working with suspensions that can cause problems such as sedimentation at the bottom of water tanks and, consequently, major technical problems such as clogging of devices or installations for delivering drinking water to animals.

The present invention also optionally relates to novel dry powder or granular pharmaceutical forms of a combination of amoxicillin (in the form of amoxicillin trihydrate) and clavulanic acid (in the form of potassium clavulanate) for use in pediatrics and geriatrics, where dry powder or granules (oral powder) in an appropriate amount of water for human use.

Therapeutic doses as described in, for example, Drugs Journal 39 (2): 264-307, 1990 may be used. The clear solution according to the invention is particularly preferred for use in pediatrics over suspension, which describes the prior art, such as the aforementioned journal or publication of international patent application WO 96/34605, since the composition of the novel formulation of the invention avoids the use of colloidal silica and certain other excipients.

The invention is explained in more detail, but is not limited by the following examples:

EXAMPLE 1

62.5% water-soluble powder (50% amoxicillin and 12.5% clavulanic acid)

The 100 gram powder in the container contains the following ingredients:

Ingridients Mr Rücker wt.% amoxicillin trihydrate (calculated on 85% amoxicillin content, 50 g equivalent of amoxicillin) 58,824 th most common 58,8 potassium clavulanate (calculated on 82% content of clavulanic acid, 12.5 g of clavulanic acid equivalent) 15,243 th most common 15.2 NaH ₂ PO ₄ .2H ₂ O 5,000 5.0 sodium hexametaphosphate 20,000 20,0 mannitol (powder) 0.933 0.9

In the mixer (Soneco type), mix the indicated portions of sodium dihydrogen phosphate dihydrate, sodium hexametaphosphate, mannitol and potassium clavulanate for 10 minutes, then grind the resulting mixture through a mill (Frevvitt MGH-6 type) with a mesh size of 1.0 mm, and then add the resulting mixture to said proportion of amoxicillin trihydrate. The resulting mixture was stirred for another 25 minutes in a mixer of the same type (Soneco) and the resulting water-soluble powders were filled into containers.

EXAMPLE 2

62.5% water-soluble powder (50% amoxicillin and 12.5% clavulanic acid)

The 100 gram powder in the container contains the following ingredients:

Ingridients Mr Rücker wt.% amoxicillin trihydrate (calculated on 85% amoxicillin content, 50 g equivalent of amoxicillin) 58,824 th most common 58,8 potassium clavulanate (calculated on 82% content of clavulanic acid, 12.5 g of clavulanic acid equivalent) 15,244 th most common 15.2 sodium hydrogen carbonate 12,369 th most common 12,4 polyethylene glycol (PEG 4000) powder 5,000 5.0 mannitol (powder) 8,563 th most common 8.6

Mix the contents of sodium hydrogen carbonate, polyethylene glycol, mannitol and potassium clavulanate in the mixer (Soneco type) for 10 minutes, then grind the resulting mixture through a mill (Frevvitt MGH-6 type) with a mesh size of 1.0 mm and add the resulting mixture to the indicated proportion amoxicillin trihydrate. The resulting mixture was stirred for another 25 minutes in a mixer of the same type (Seneco) and the resulting water-soluble powder was filled into containers.

EXAMPLE 3

12.5% water-soluble powder (10% amoxicillin and 2.5% clavulanic acid)

The 100 gram powder in the container contains the following ingredients:

Ingridients Mr Rücker ut% amoxicillin trihydrate (calculated on 85% amoxicillin content, 10 g equivalent of amoxicillin) 11,765 th most common 11,8 potassium clavulanate (calculated on 82% content of clavulanic acid, 2.5 g of clavulanic acid equivalent) 3,049 3.0 sodium hydrogen carbonate 2,474 th most common 2.5 polyethylene glycol (PEG 4000) powder 5,000 5.0 mannitol (powder) 77,712 77,7

To prepare the water-soluble powder, proceed as in Example 2.

EXAMPLE 4

Tests of water solubility, stability in aqueous solution and stability of dry powders of three different powder formulations for veterinary use

The purpose of the comparative tests of three different powder formulations for veterinary use was to determine the preferred composition of the powder, which, with good water solubility, dry powder stability and after rapid and complete dissolution in animal drinking water, would be the most stable in aqueous solution. For this purpose, we have tested the powder no. (1) with the composition as indicated in Example 1, powder no. (2) with the composition as indicated in example (2) and powder no. (3) with composition as indicated in Example 3.

1) Water solubility of powders

Table 1: Water solubility of powders

Water solubility in mg / ml Powder no. (1) 3.8 Powder no. (2) 5.0 Powder no. (3) 25,0

2) Stability of dry powders

The amoxicillin and clavulanic acid content of the powders after one month of storage at room temperature was analyzed.

Table 2: Stability of dry powders

Amoxicillin content (%) Clavulanic acid content (%) Powder no. (1) 98.7 97.7 Powder no. (2) 98.0 101,7 Powder no. (3) 96.8 101,5

The content of amoxicillin and clavulanic acid in powder no. (2) with the composition indicated in Example 2 and sealed in a container containing silica gel as a desiccant under conditions of accelerated stability at 30 ° C and 60% relative humidity. The results of the accelerated stability test analyzes are illustrated in Table 3.

Table 3: Dry powder stability no. (2) under conditions of accelerated stability

feeding time (months) amoxicillin content (%) content of clavulanic acid (%) 0 (initial) 100.1 96.3 3 101.3 96.5 6 100.9 93.7

Based on the analyzes of the Accelerated Stability Test, the stability of dry powders has been estimated for more than 2 years.

3) Stability in aqueous solution

The stability of aqueous solutions of powders was compared by preparing such aqueous solutions that the concentration of amoxicillin was 2 g of amoxicillin / liter of solution and the concentration of clavulanic acid of 0.5 g of clavulanic acid / liter of solution.

Each gram of powder was dissolved in the amount of water indicated in Table 4 each time, and the stability of the aqueous solutions of the powders was determined by analyzing the decrease in amoxicillin and clavulanic acid content after 6 hours (t ₆ ), 12 hours (t ₁₂ ) and 24 hours (t ₂₄ ).

Table 4: Stability in aqueous solution

pH of water solution. Amoxicillin content reduction by (%) Reduction of clavulanic acid content by (%) te tl2 t24 t6 t- | 2 t2 ₄ Powder no. (1) / 251 water 6.65 0.4 2.7 2.8 0.8 2.5 4.7 Powder no. (2) / 251 water 7.01 6.2 18.3 19,0 2.8 6.5 7.5 Powder no. (3) / 51 water 7.05 8.8 29.9 * 1.9 8.6 *

* The reduction in the content of both ingredients was significant

Table 4 shows that the stability of the aqueous powders of the invention according to the invention is the highest in powder no. (1) with the ingredients listed in Example 1.

The good water solubility of the combination of amoxicillin (in the form of amoxicillin trihydrate) and clavulanic acid (in the form of potassium clavulanate) in the pH range of 6.5 to 7.5 significantly improves the stability of the aqueous solutions of the powders of the invention. Powders with a higher content of both active ingredients and the ingredients listed in Example 1 have a stability of at least 24 hours. Preferably, the powder compositions of the invention which have the lowest proportion of excipients as fillers are used.

Claims (13)

PATENT APPLICATIONS 1. Water-soluble powdered or granular pharmaceutical dosage forms for veterinary use, characterized in that they contain a therapeutically effective amount of amoxicillin trihydrate and potassium clavulanate in composition with a veterinarily acceptable filler and at least one buffer for maintaining the pH of the medium between 6.5 to 8 , 0 in the dissolution of said pharmaceutical forms in drinking water for animals. Water-soluble powder or granular veterinary pharmaceutical dosage forms according to claim 1, characterized in that the buffering agent is selected from the group consisting of phosphate buffers, citrate buffers, borate buffers and combinations thereof. Water-soluble powder or granular pharmaceutical dosage forms for use in veterinary medicine according to claim 1 or 2, characterized in that monosodium dihydrogen phosphate dihydrate / sodium hexametaphosphate buffer is selected as phosphate buffer. Water-soluble powdered or granular pharmaceutical formulations for veterinary use according to claims 1 to 3, characterized in that the pH of the medium is maintained between 6.5 and 7.5. Water-soluble powder or granular veterinary pharmaceutical dosage forms according to claims 1 to 4, characterized in that the ratio of amoxicillin trihydrate to potassium clavulanate is from 12: 1 to 1: 1. Water-soluble powdered or granular dosage forms for veterinary use according to claims 1 to 5, characterized in that the ratio of amoxicillin trihydrate to potassium clavulanate is from 4: 1 to 1: 1. 7. Water-soluble powder or granular veterinary pharmaceutical dosage forms according to claims 1 to 6, characterized in that they contain from 10% to 60% amoxicillin (as trihydrate) and 2% to 15% clavulanic acid (as potassium clavulanate) ). Water-soluble powdered or granular pharmaceutical dosage forms for veterinary use according to claims 1 to 7, characterized in that the veterinarily acceptable filler is mannitol. Aqueous solutions of pharmaceutical forms for veterinary use, characterized in that they contain the powder or granular form according to any one of claims 1 to 8, and water. 10. A process for the preparation of aqueous solutions of powder or granular dosage forms for veterinary use, characterized in that powder or granular dosage forms for veterinary use are prepared according to any one of claims 1 to 8, which are subsequently dissolved in an amount of water. suitable for the preparation of the desired aqueous solution, stable for at least 24 hours. Use of a water-soluble powder or granular veterinary pharmaceutical formulation containing a therapeutically effective amount of amoxicillin trihydrate and potassium clavulanate, a buffering agent and a veterinarily acceptable excipient for the preparation of an oral medicament for the prevention and treatment of bacterial infectious diseases in live animals and domestic animals administering to the animals drinking water in which a therapeutically effective amount of said active ingredients is dissolved. 12. A veterinary pharmaceutical dosage form comprising a powder or granular form according to any one of claims 1 to 8, and drinking water. A pharmaceutical form for oral use in the treatment of bacterial infections of pediatric patients, comprising a powder or granular form according to any one of claims 1 to 8, and water.