WO2001045667A2

WO2001045667A2 - Water-soluble powders for oral solution and use thereof

Info

Publication number: WO2001045667A2
Application number: PCT/SI2000/000028
Authority: WO
Inventors: Vesna ŠKULJ; Alenka MIHELIČ VIPOTNIK
Original assignee: LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d.
Priority date: 1999-12-22
Filing date: 2000-12-19
Publication date: 2001-06-28
Also published as: PL358255A1; AU1912501A; WO2001045667A3; SI20411A

Abstract

Described are novel water-soluble powder or granular pharmaceutical forms for use in veterinary medicine containing therapeutically effective amounts of amoxicillin trihydrate and potassium clavulanate in composition with a filler acceptable in veterinary medicine and with at least one buffering agent suitable for maintaining the pH value of the medium between 6.0 and 8.5 at a quick and complete dissolution of the given pharmaceutical forms in drinking water for animals. After dissolution in water the clear solutions are stable for at least 24 hours. Preferably there are used phosphate buffers, preferably monosodium dihydrogen phosphate dihydrate/sodium hexametaphosphate buffer, which maintain the pH values of the aqueous medium between 6.5 and 7.5, preferably about 7.0.

Description

Water-soluble Powders for Oral Solution and Use Thereof

Technical Field of the Invention

(IPC A61K 31/43 31/42)

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

Powder water-soluble forms according to the invention may also be used in human medicine, especially in paediatrics and geriatrics where, prior to oral use, the dry powder is dissolved in water that is suitable for use in human medicine.

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

Technical Problem

Known and previously described powder and granular dry pharmaceutical dosage forms of a combination of amoxycillin trihydrate and potassium clavulanate do not dissolve completely in drinking water for fattening animals and domestic animals, but a suspension is formed, which may cause problems in water tanks for cattle, namely formation of sediments on the bottom of the tank and resulting technical problems such as clogging of the installations and plumbing for administering drinking water to animals. Therefore, there exists a constant need for novel and completely water-soluble powders or granules of the therapeutic combination of amoxycillin trihydrate and potassium clavulanate for the preparation of a clear aqueous solution.

Prior Art

Amoxicillin, its salts and hydrates as a trihydrate form were disclosed in GB 1,241,844 as antibacterial agents useful in the treatment of gram-negative and gram-positive bacterial infections. However, some bacteria are resistant to amoxicillin by virtue of the β-lactamases they produce.

Clavulanic acid and its salts were disclosed in GB 1,508,977 as β-lactamase inhibitors capable of enhancing the antibacterial action of penicillins and cephalosporins.

Clavulanic acid is a generic name for (2R, 5R, Z)-3-(2-hydroxyethylidene)-7-oxo-4- oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. Its alkali metal salts and esters act as inhibitors of β-lactamases produced by some gram-positive and gram-negative microorganisms.

In addition to their β-lactamase inhibitory activity, clavulanic acid and its alkali metal salts have also a synergistic effect in the combination with β-lactam antibiotics of penicillinic and cephalosporinic type, therefore clavulanic acid and its alkali metal salts are used in pharmaceutical forms to prevent the deactivation of β-lactam antibiotics. Commercial forms contain the more stable potassium salt of clavulanic acid (clavulanic acid per se is quite unstable) in combination with amoxicillin trihydrate.

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

GB 1,508,977 discloses pharmaceutical forms of a synergistic combination of clavulanic acid or its salts and a penicillinic or a cephalosporinic antibiotic such as amoxicillin (in the form of trihydrate) in a weight ratio from 10:1 to 1 :10, e.g. from 4: 1 to 1 :4.

The forms decribed by this invention may be used for the treatment of bacterial infections in domestic animals, e.g. mastitis in cattle.

GB 2,005,538 describes pharmaceutical forms for oral administration in the treatment of bacterial infections.

The invention describes dry unit-dose pharmaceutical forms suitable for oral administration containing 20 mg to 1500 mg of amoxicillin trihydrate, 20 mg to 500 mg of potassium clavulanate and a pharmaceutically acceptable carrier with the proviso that the weight ratio of amoxicillin trihydrate to potassium clavulanate is from 6: 1 to 1 : 1.

Oral dosage units may also be in the form of powder or granules for reconstitution with water prior to use and are packed in sachets or other suitable containers or packages.

Pharmaceutical forms are dry i.e. completely water-free, for example obtained by a thorough drying to completely remove moisture other than the water of crystallization present in amoxicillin trihydrate.

Further, the invention relates to pharmaceutical forms packed in a closed container that prevents the ingress of moisture and thereby enhances storage stability. These pharmaceutical forms contain one or more dosage units of the desired pharmaceutical form.

Particularly preferred is the use of a suitable desiccant within the container or the package. As suitable desiccants there are used non-toxic desiccants such as silica gel or crystalline sodium, potassium or calcium aluminosilicate (known as "molecular sieves"). Such a desiccant may be included in sachets or other suitable closed containers or packages.

Due to known hygroscopicity and the quick hydrolysis of potassium clavulanate in water, the pharmaceutical forms according to the above invention are prepared in a dry atmosphere, e.g. in one containing less than a 30% relative humidity or, even more suitably, less than a 20% relative humidity. Owing to the mentioned properties, potassium clavulanate has to be stored in an extremely dry environment, e.g. in one containing a 30% relative humidity or even less.

The dosage forms are prepared in conventional and known manners, e.g. by blending the dry powder ingredients and filling them into sachets and other suitable closed containers or packages.

Description of the Solution to the Technical Problem with Examples

The object of the invention is to solve the problem known from prior art by preparing novel 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 medicine, which forms will dissolve quickly, in less than one (1) minute, and completely in the drinking water for fattening animals and domestic animals, thereby avoiding the danger of clogging the devices and installations for administering drinking water to animals. After dissolution in water, the clear solutions according to the invention are stable for at least 24 hours. In addition, solutions are preferred to suspensions for oral use because active substances in solutions are absorbed faster.

In accordance with the aim of the invention amoxicillin is used in the form of amoxicillin trihydrate but, optionally, also the sodium salt of amoxicillin e.g. the crystalline form of sodium amoxicillin can be used.

Clavulanic acid is used in the form of potassium clavulanate.

Dry powder or granular pharmaceutical forms for use in veterinary medicine, which quickly and completely dissolve in water in accordance with the aim of the invention, are prepared in any suitable manner of dry blending of ingredients as generally used in the art. Subsequently, the dry blended powder can be dry-granulated in a manner known from the prior art.

The ingredients for the preparation of pharmaceutical forms according to the invention for use in veterinary medicine have a low content of moisture and it is preferable that, prior to the preparation of the forms according to the invention, they are pre-dried to remove moisture other than the water of crystallization present in amoxicillin trihydrate.

Due to the known hygroscopicity of potassium clavulanate, the pharmaceutical forms for use in veterinary medicine are prepared in a dry atmosphere e.g. in one containing less than a 30% relative humidity, most suitably containing less than a 20% relative humidity.

Further, the invention relates to a method of treatment and prophylaxis of bacterial infectious diseases in fattening animals and domestic animals by administering to animals drinking water in which the powder or granular pharmaceutical form for use in veterinary medicine containing an antibacterially effective amount of amoxicillin trihydrate and potassium clavulanate has been dissolved. It has been known that amoxicillin is poorly soluble in water. As cited in The Merck Index, 12^th Edition, 1996, under monographic No. 617, the solubility of amoxicillin trihydrate is 4 mg/ml. On the other hand, the good water-solubility of salts of amoxicillin such as its sodium salt has been known. A disadvantage of this form is the instability of amoxicillin in an alkaline medium.

The instability of clavulanic acid and its alkali metal salts in an alkaline medium is known as well.

Example 4 of GB 2,005,538 discloses a dosage unit in a sachet and the composition of a dry powder for reconstitution with water before administration. Due to the instability of amoxicillin and of clavulanic acid or its potassium salt in an alkaline medium after the reconstitution with water, the pharmaceutical form contains a buffering agent for the regulation of a suitable pH value of the medium. Since the composition of the powder contains a considerable portion of a desiccant and a glidant, after the reconstitution with water a suspension is formed, which is suitable for use in human medicine.

The present invention relates to a powder or granular pharmaceutical form for use in veterinary medicine, which quickly and completely dissolves in drinking water for fattening animals and domestic animals. Pharmaceutical forms according to the invention, whereby the problem known from the prior art has been solved, contain in their composition, in addition to therapeutically effective amounts of amoxicillin trihydrate and potassium clavulanate and to a filler acceptable in veterinary medicine, also at least one buffering agent suitable for maintaining the pH value of the medium suitable for dissolution of the cited pharmaceutical forms in water.

The buffer is a compound or more precisely a mixture of compounds which maintains the pH value of the medium in a specific range of pH values during and after dissolution, thus, in accordance with the aim of the invention, enabling a very fast dissolution of the ingredients in such a manner that the aqueous solutions of pharmaceutical forms according to the invention are stable for at least 24 hours.

A buffering agent in accordance with the aim of the invention is preferably selected from a group comprising phosphate buffers maintaining pH values of the medium between 6.5 and 8.0, preferably between 6.5 and 7.5 and especially preferably about 7.0, such as monosodium dihydrogen phosphate dihydrate / sodium hexameta- phosphate buffer, citrophosphate buffers, borate buffers and all possible combinations for obtaining a buffer in the desired range of pH values. Preferably, phosphate buffers are selected. Monosodium dihydrogen phosphate dihydrate / sodium hexameta- phosphate buffer is selected as the particularly preferred one.

As fillers there are used conventional fillers known in pharmaceutics such as mannitol, sorbitol, sugar powder, dextrin, dextrose, lactose, glucose and others. Mannitol is selected as the particularly preferred filler, preferably in the form of mannitol powder, but also in the form of mannitol granules, which in the preparation process of the powder according to the invention are crushed and blended with other ingredients.

We have now suprisingly found that by omitting a dessicant such as silicon dioxide, and a glidant in the composition of the dry powder or granular pharmaceutical form, which are usual ingredients of the dry powder as described in Example 4 of GB 2,005,538, after a quick and complete dissolution of the pharmaceutical form according to the invention in water, a clear solution is obtained, whereby the problems in veterinary medicine known from the prior art in connection with the use of suspensions are avoided.

Instead of the presence of a desiccant and a glidant in the composition of the powder or granular pharmaceutical form, there is, according to the invention, preferably used a desiccant within sachets and containers or other packages. As the desiccant silica gel (silicon dioxide) or crystalline sodium, potassium or calcium aluminosilicate (known as "molecular sieves") can be used. After the dosage units of pharmaceutical forms according to the present invention have been prepared, they are filled into sachets or suitable closed containers, which themselves contain a desiccant and are subsequently closed to prevent the ingress of moisture.

Pharmaceutical forms for use in veterinary medicine according to the invention may additionally contain substances for improving the flavour and taste such as saccharin sodium, aspartame, menthol, vanilla flavor and other adjuvants.

Optionally, the present invention also 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, wherein in the composition of the novel form the buffering agent is replaced by an alkaline agent such as sodium hydrogen carbonate (NaHC0₃), sodium carbonate, an alkali salt of amino acid carbonate such as sodium glycine carbonate, an amino acid such as arginine, lysine and their alkali salts. Preferred is the selection of sodium hydrogen carbonate. Also these forms contain usual fillers known in pharmaceutics, preferably mannitol, substances for improving the flavour and taste and other adjuvants e.g. lubricants such as polyethylene glycol and the like.

Information on the fillers and other adjuvants and the properties thereof are available with manufacturers, in suitable brochures or other sources such as A. Wade and P.J. Weller, Handbook of Pharmaceutical Excipients, Second Edition, 1994, American Pharmaceutical Association Washington.

Thus, mannitol is produced by the company Roquette Freres, France, and polyethylene glycol 4000 is produced by the company Hoechst, Germany. Also these forms according to the invention quickly and completely dissolve in water, but due to the slightly alkaline environment they are somewhat less stable than the above-mentioned preferable form containing a buffering agent.

The dose of the novel dry powder or granular pharmaceutical form for use in veterinary medicine is defined with respect to the animal species, age, weight and the average daily amount of drinking water.

The water-soluble powder according to the invention is placed in suitable closed containers, for example as 100 g or 500 g powder packages.

A dosage unit e.g. a 100 g powder package 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 the proviso that the weight ratio of amoxicillin to clavulanic acid is 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 according to the invention contain 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% of clavulanic acid (in the form of potassium clavulanate). An example of a dosage form is a 100 g powder package. Preferably, there are used forms containing higher doses of both active ingredients.

Thus, a single daily dose of the pharmaceutical form according to the invention for use in poultry amounts to 10 mg to 20 mg of amoxicillin (in the form of amoxicillin trihydrate) and 2.5 g to 5 g of clavulanic acid (in the form of potassium clavulanate) per 1 kg of body weight and is administered from 3 to 5 days. For use in pigs the daily dose amounts to 2 mg to 10 mg of amoxicillin (in the form of amoxicillin trihydrate) and from 0.5 mg to 2.5 mg of clavulanic acid (in the form of potassium clavulanate) per 1 kg of body weight and is administered twice a day for 2 to 5 days. For example, a 100 g dosage unit of the powder with the composition as described in Example 1 or Example 2 is dissolved in about 20 1 to about 27 1 of drinking water, whereas a 100 g dosage unit of the powder with the composition as described in Example 3 is dissolved in about 4 1 to about 6 1 of drinking water.

Powder or granular pharmaceutical forms for use in veterinary medicine according to the invention are preferably used in compositions containing higher doses of the active ingredients, for example 50% wt. of amoxicillin (in the form of amoxicillin trihydrate) and 12.5% wt. of clavulanic acid (in the form of potassium clavulanate). a buffering agent and a suitable filler. The stability of aqueous solutions of these forms for use in veterinary medicine is at least 24 hours.

The novel dry powder or granular pharmaceutical form according to the invention that instead of the buffering agent contains an alkaline agent such as sodium hydrogen carbonate is, after dissolution in drinking water for animals, stable for about 6 hours.

The stability of powder and granular pharmaceutical forms according to the invention is at least 2 years.

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

The present invention also relates to a process for the preparation of aqueous solutions of powder or granular forms according to the invention comprising: a) the preparation of powder or granular forms according to the invention, b) the dissolution of the given powder or granular forms in a suitable amount of drinking water for the preparation of a solution which is stable for at least 24 hours.

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

Since the novel powder or granular pharmaceutical forms for use in veterinary medicine quickly and completely dissolve in a suitable amount of drinking water, it is thereby avoided to have to work with suspensions, which may cause problems such as formation of sediments on the bottom of water tanks and resulting bigger technical problems such as clogging of the installations and plumbing for administering drinking water to animals.

Optionally, the present invention also 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 paediatrics and geriatrics, where prior to oral use dry powder or granules (granulate) are dissolved in a suitable amount of water for use in human medicine.

There may be used therapeutic doses as described e.g. in the periodical Drugs 39(2):264-307, 1990. Especially in paediatrics, the clear solution according to the invention is preferred over a suspension described in prior art such as the above- mentioned periodical or WO 96/34605 because the composition of the novel form according to the present invention avoids the use of colloidal silicon dioxide and some other adjuvants.

The invention is further explained but in no way limited by the following examples. EXAMPLE 1

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

100 g powder in a container contained the following ingredients:

The cited portions of sodium dihydrogen phosphate dihydrate, sodium hexametaphosphate, mannitol and potassium clavulanate were blended in a blender (type Soneco) for 10 minutes, the obtained mixture was milled through a mill (type Frewitt MGH-6) with a mesh size of 1 mm and the resulting mixture was added to the cited portion of amoxicillin trihydrate. The obtained mixture was blended in a blender of the same type (Soneco) for further 25 minutes and the obtained water-soluble powders were filled into containers.

EXAMPLE 2

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

100 g powder in a container contained the following ingredients:

The cited portions of sodium hydrogen carbonate, polyethylene glycol, mannitol and potassium clavulanate were blended in a blender (type Soneco) for 10 minutes, the obtained mixture was milled through a mill (type Frewitt MGH-6) with a mesh size of 1.0 mm and the resulting mixture was added to the cited portion of amoxicillin trihydrate. The obtained mixture was blended in a blender of the same type (Soneco) for further 25 minutes and the obtained water-soluble powder was filled into containers.

EXAMPLE 3

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

100 g powder in a container contained the following ingredients:

For the preparation of a water-soluble powder it was proceeded in the same manner as in Example 2.

EXAMPLE 4

Tests for water-solubility, stability in an aqueous solution and stability of dry powders of three different compositions of powders for use in veterinary medicine

The aim of comparative tests of three different compositions of powders for use in veterinary medicine was to find out the preferable composition of the powder which would be - at a good water-solubility, stability of the dry powder and after a quick and complete dissolution in drinking water for animals - the most stable in an aqueous solution. For these comparison purposes there were tested powder No. (1) with the composition as given in Example 1, powder No. (2) with the composition as given in Example 2 and powder No. (3) with the composition as given in Example 3. 1) Water-solubility of powders

Table 1 : Water-solubility of powders

2) Stability of dry powders

The contents of amoxicillin and clavulanic acid in powders after a storage for one month at room temperature were analyzed.

Table 2: Stability of dry powders

By means of high pressure liquid chromatography (HPLC) there were analyzed the contents of amoxicillin and clavulanic acid in the powder No. (2) with the composition as given in Example 2 and closed in a container containing silica gel as a desiccant under conditions of accelerated stability at 30°C and 60% relative humidity. Analysis results of the accelerated stability test are demonstrated in Table 3.

Based on an analysis of the accelerated stability test, the stability of dry powders was estimated to be more than 2 years.

3) Stability in aqueous solution

The stability of aqueous solutions of powders was compared by preparing aqueous solutions with the concentration of amoxicillin being 2 g of amoxicillin/litre of solution and the concentration of clavulanic acid being 0.5 g of clavulanic acid/litre of solution.

Each time 100 g of powder were dissolved in the quantity of water as given in Table 4 and by analyzing the reduction in contents of amoxicillin and clavulanic acid after 6 hours (t₆), 12 hours (t₁₂) and 24 hours (t₂₄) the stability of aqueous solutions of the powders was established.

Table 4: Stability in an aqueous solution

* The reduction of contents of both ingredients was quite substantial.

It is evident from table 4 that the stability of aqueous solutions of the powders according to the invention is the highest for the powder No. (1) with the ingredients given in Example 1.

Good water-solubility of the combination of amoxicillin (in the form of amoxicillin trihydrate) and clavulanic acid (in a form of potassium clavulanate) in the range of pH values of the medium between 6.5 to 7.5 substantially improves the stability of aqueous solutions of the powders according to the invention. Powders with higher contents of both active ingredients and with ingredients as given in Example 1 have a stability of at least 24 hours. Preferably, compositions of powders according to the invention having the lowest possible portion of adjuvants such as fillers are used.

Claims

1. Water-soluble powder or granular pharmaceutical forms for use in veterinary medicine, characterized in that they contain therapeutically effective amounts of amoxicillin trihydrate and potassium clavulanate in composition with a filler acceptable in veterinary medicine and at least one buffering agent for maintaining the pH value of the medium between 6.5 and 8.0 at dissolving the given pharmaceutical forms in drinking water for animals.

2. Water-soluble powder or granular pharmaceutical forms for use in veterinary medicine according to claim 1, characterized in that the buffering agent is selected from a group comprising phosphate buffers, citrate buffers, borate buffers and their combinations.

3. Water-soluble powder or granular pharmaceutical 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 the phosphate buffering agent.

4. Water-soluble powder or granular pharmaceutical forms for use in veterinary medicine according to claims 1 to 3, characterized in that the pH of the medium is maintained between 6.5 to 7.5.

5. Water-soluble powder or granular pharmaceutical forms for use in veterinary medicine according to claims 1 to 4, characterized in that the weight ratio of amoxicillin trihydrate to potassium clavulanate is from 12: 1 to 1 : 1.

6. Water-soluble powder or granular pharmaceutical forms for use in veterinary medicine according to claims 1 to 5, characterized in that the weight ratio of amoxicillin trihydrate to potassium clavulanate is from 4: 1 to 1 :1.

7. Water-soluble powder or granular pharmaceutical forms for use in veterinary medicine according to claims 1 to 6, characterized in that they contain from 10% to 60% of amoxicillin (in the form of trihydrate) and 2% to 15% of clavulanic acid (in the form of potassium clavulanate).

8. Water-soluble powder or granular pharmaceutical forms for use in veterinary medicine according to claims 1 to 7, characterized in that the filler acceptable in veterinary medicine is mannitol.

9. Aqueous solutions of pharmaceutical forms for use in veterinary medicine, characterized in that they contain a powder or granular form according to any of the claims 1 to 8 and water.

10. A process for the preparation of aqueous solutions of powder or granular pharmaceutical forms for use in veterinary medicine, characterized in that the powder or granular pharmaceutical forms for use in veterinary medicine according to any of the claims 1 to 8 are prepared and subsequently dissolved in an amount of water suitable for the preparation of the desired aqueous solution which is stable for at least 24 hours.

11. Use of a water-soluble powder or granular pharmaceutical form in veterinary medicine containing therapeutically effective amounts of amoxicillin trihydrate and potassium clavulanate, a buffering agent and a filler acceptable in veterinary medicine for the preparation of a medicament for oral use in prophylaxis and treatment of bacterical infectious diseases in fattening animals and domestic animals by administering to animals drinking water wherein a therapeutically effective amount of the given active ingredients has been dissolved.

12. A pharmaceutical form for oral use in veterinary medicine, characterized in that it contains a powder or granular form according to any of claims 1 to 8 and drinking water.

3. A pharmaceutical form for oral use in the treatment of bacterial infections of pediatric patients, characterized in that it contains a powder or granular form according to any of the claims 1 to 8 and water.