WO2013062425A1

WO2013062425A1 - Ionophore antibiotic veterinary composition and method of manufacture

Info

Publication number: WO2013062425A1
Application number: PCT/NZ2012/000196
Authority: WO
Inventors: John Morley MUNRO; Raymond Nigel Simms; Kin-Wai Mok
Original assignee: Glenmark Ip Limited
Priority date: 2011-10-26
Filing date: 2012-10-25
Publication date: 2013-05-02
Also published as: NZ596017A

Abstract

The present invention relates to an ionophore antibiotic composition in the form of a water dispersible granule which is a dry flowable formulation capable of direct dispersion in the drinking water of animals (i.e. via trough treatment). The ionophore antibiotic remains in a substantially stable solution uniformly dispersed in the drinking water for up to 62 days and thus provides a safe and practical form of treatment. The formulation is also capable of being mixed with water for oral administration by drenching. The water dispersible granule composition comprises at least one ionophore antibiotic (preferably monensin), at least one filler-binder, at least one surfactant, at least one dispersing agent, and at least one disintegrant. The ionophore antibiotic is preferably micronized before inclusion in the composition. The invention also relates to a method of manufacturing the composition comprising a dry milling step to reduce the particle size of the ionophore antibiotic to less than 30 microns, a mixing step and a dry granulation step.

Description

FIELD OF THE INVENTION This invention relates to veterinary compositions comprising ionophore antibiotics, and to methods of manufacturing same. It has particular, but not sole application to ionophore antibiotic compositions suitable for inclusion directly or indirectly (via a holding tank and/or dispensing system) in the drinking water of animals, or suitable for oral administration by way of a drench formulation. BACKGROUND OF THE INVENTION

Ionophore antibiotics such as monensin have been used in the farming industry for a number of years. They are commonly administered to ruminant animals to increase feed efficiency and weight gain. Ionophores are known to reduce protein degradation in the rumen thus aiding post ruminal digestion. They are also known to increase production of the VFA propionate by modifying the microbial fermentation in the rumen. They reduce methane production thus lowering energy loss, and they also prevent ruminal acidosis in animals that are rapidly changed from roughage diets to high carbohydrate diets. Therefore, by manipulating the composition of the microflora of the rumen, ionophores are able to improve feed conversion, and enable ruminant animals to get more metabolizable energy from feed. Examples of commonly used ionophore antibiotics include monensin, narasin, lasalocid and salinomycin. Ionophores such as monensin are known to be insoluble or poorly soluble in water. For this reason it has been difficult to find adequate and practical means of administering liquid ionophores to animals. Over the years, various techniques have been used. Due to their insolubility in water, ionophore antibiotics were traditionally administered in dry powder form in animal feeds. In some cases the dry powder was mixed with liquid feeds to try to give the animal a more consistent and controlled dose, however due to the insolubility of the ionophore antibiotic, it would settle out of solution creating gradients of antibiotic concentrations in the liquid compositions on standing, such that the top layers contained ineffectually low concentrations of the antibiotics, while the bottom layers contained the antibiotics in toxic, harmful concentrations, causing poisoning of the animals fed with these compositions. Vigorous mixing was required prior to administration to ensure ingestion before substantial concentration gradients began to appear due to settling. Such dry powder compositions did not remain evenly distributed in liquid feeds for a sufficient period of time to make them practical or safe for use in this manner.

For this reason dry liquid-milk replacer compositions were developed to attempt to more safely administer ionophore antibiotics in the milk portion of the animal's diet. One example of such a composition is described in New Zealand Patent No. 280384 to Eli Lilly & Company (NZ) Limited, which relates to a wettable powder comprising monensin sodium which is designed to be delivered as a calf feed e.g. as a milk replacer and/or milk extender. Since calves receive and ingest milk replacers and extenders within 24 hours of preparation, the wettable powder is only required to remain stable and evenly distributed in the liquid milk composition for 24 hours after homogenous mixing. The ionophore antibiotic will not remain stable for much longer than this and will settle out unless constant agitation is used. Therefore such a composition is not designed to be added to drinking water systems and could not be used for trough treatment as it would not remain evenly distributed in water for a sufficient period of time to make it practical and safe for use in this manner. Furthermore, dry formulations in the form of powders are very dusty and can be difficult to safely handle, measure and mix.

Liquid formulations of ionophore antibiotics are known. These have been formulated with organic solvents such as described in European Patent Specification 0,139,595 to Koffolk (1949) Ltd. They have also been formulated as aqueous suspension concentrates for drenching of animals, as described in New Zealand Patent No. 510023 to Eli Lilly & Company (NZ) Limited. These drench formulations are not ideal as they require an aggressive supporting system in order to hold the active in suspension.

An aqueous suspension of monensin sodium which is designed to be added to drinking water systems is currently commercially available, under the trade name RUMENSIN TROUGH TREATMENT (TT). It is a liquid suspension formulation containing a suspending agent which exists as a smooth colloid in water after intensive homogenization during production. Each litre contains 60 grams of monensin (as monensin sodium). The product must be diluted with water then thoroughly mixed for full dispersion before pouring into the dispenser solution tank. An agitation pump is recommended for continuous "stirring" of the solution tank. While this product is generally successful, it only contains about 6% active. It is difficult to incorporate concentrations of active much higher than this into liquid formulations due to the poor solubility characteristics of ionophore antibiotics. A more aggressive supporting system including suspension agents would be required to increase the concentration of the active by even a small amount. Further disadvantages of liquid formulations include higher transportation and storage costs due to the higher volume of formulation required to deliver the required amount of active. Also liquid formulations can be difficult to handle, as the liquids are commonly thick and viscous and are difficult to accurately measure and mix. Accurate measuring and mixing of ionophore antibiotic formulations is of paramount importance due to the toxicity of ionophore antibiotics to humans, non-target animals and target animals when used at the wrong dosage rate. Residues of the active ingredient remaining in used containers are also a significant problem due to their toxicity.

Therefore there continues to be a need for an improved ionophore antibiotic composition which can be easily and safely administered to animals.

OBJECTS OF THE INVENTION It is therefore an object of the present invention to provide an improved ionophore antibiotic composition which overcomes at least one of the shortcomings of the prior art, or one which will at least provide the public with a useful choice. It is a further object of the present invention to provide a method of manufacturing said composition, or one which will at least provide the public with a useful choice. SUMMARY OF THE INVENTION

The present invention relates to an ionophore antibiotic composition in the form of a water dispersible granule which is a dry flowable formulation capable of direct dispersion in the drinking water of animals (i.e. via trough treatment) to allow self-administration of the ionophore antibiotic to the animal through drinking. The ionophore antibiotic remains in a substantially stable solution uniformly dispersed in the drinking water for a sufficient period of time to provide a safe and practical form of treatment. The formulation is also capable of being mixed with water to be orally administered to an animal (for example, by drenching).

In a first aspect the invention broadly consists in a water dispersible granule ionophore antibiotic composition, said composition comprising at least one ionophore antibiotic, at least one filler-binder, at least one surfactant, at least one dispersing agent, and at least one disintegrant.

Preferably said ionophore antibiotic is selected from the group comprising monensin, salinomycin, narasin, lasalocid, maduramycin, semduramycin, laidlomycin, tetronasin, lonomycin, ionomycin, nigericin, grisorixin, dianemycin, lenoremycin, antibiotic X206, alborixin, septamycin, antibiotic A204, compound 47224, mutalomycin, isolasalocid A, lysocellin, echeromycin, antibiotic X-14766A, antibiotic A23187, antibiotic A32887, compound 51532 and K41.

More preferably said ionophore antibiotic is selected from the group comprising monensin, salinomycin, narasin, lasalocid, maduramycin, semduramycin, laidlomycin and tetronasin.

Most preferably said ionophore antibiotic is monensin.

Preferably said monensin is sodium monensin. More preferably said monensin is crystalline sodium monensin.

Preferably said ionophore antibiotic has a particle size of less than about 30 microns. More preferably about 90% of the particles are less than about 15 microns. Even more preferably the mean particle size is less than about 7 microns.

We have determined that a micronised form of the ionophore antibiotic having a smaller mass to surface area ratio provides a significant advantage in the composition over the inclusion of ionophore antibiotics having a larger particle size. Preferably said ionophore antibiotic is present in the composition in an amount in the range of about 5 - 80% w/w. More preferably the ionophore antibiotic is present in the composition in an amount in the range of about 20 - 40% w/w.

In respect of compositions where the ionophore antibiotic is monensin sodium, the preferred concentration of active monensin in the composition is about 30% w/w. Preferably the filler-binder(s) is/are selected from the group comprising lactose monohydrate, lactose, microcrystalline cellulose, glucose, sucrose, sugars, mannitol, modified sugars, povidone, crospovidone, hydroxypropyl cellulose, ethyl cellulose, celluloses, modified celluloses, and combinations thereof. A preferred filler-binder is lactose monohydrate, or a combination of lactose monohydrate and microcrystalline cellulose.

Preferably the filler-binder(s) is/are present in the composition in an amount in the range of about 10 - 90% w/w. More preferably the filler-binder(s) is/are present in an amount in the range of about 40 - 70% w/w.

Preferably the surfactant(s) is/are selected from the group comprising anionic surfactants (for example, alkyl sulphates such as sodium lauryl sulphate, sulphonates such as sodium dodecylbenzene sulphonate, carboxylates, dioctyl sodium sulfosuccinate); cationic surfactants (for example quaternary ammonium salts such as benzalkonium chloride); amphoteric surfactants (for example alkyl betaines and cocamidoalkyl betaines); and non- ionic surfactants with HLB values greater than 8 (for example, polyoxyethylene glycol sorbitan alkyl esters (or polysorbates) and alkoxylates).

Preferably the surfactant is anionic. More preferably the surfactant is sodium lauryl sulphate. Preferably the surfactant(s) is/are present in the composition in an amount in the range of about 0.1 - 20% w/w. More preferably the surfactant is present in an amount in the range of about 2 - 10% w/w.

Preferably the dispersing agent(s) is/are selected from the group comprising anionic dispersing agents (for example lignosulphonates); non-ionic dispersing agents (for example hydroxypropyl cellulose and hydroxypropylmethyl cellulose); and polymeric dispersing agents (for example polyvinylpyrrolidone).

Preferably the dispersing agent is anionic. More preferably the dispersing agent is sodium lignosulphonate.

Preferably the dispersing agent(s) is/are present in the composition in an amount in the range of about 0.1 - 20% w/w. More preferably the dispersing agent is present in an amount in the range of about 2 - 10% w/w.

Preferably the disintegrant(s) is/are selected from the group comprising microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, hydroxypropyl cellulose, other modified starch and modified cellulose, and combinations thereof. More preferably the disintegrant is microcrystalline cellulose, or a combination of microcrystalline cellulose and sodium starch glycolate.

Preferably the disintegrant(s) is/are present in the composition in an amount in the range of about 0.1 - 30% w/w. More preferably the disintegrant is present in an amount of about 10— 20% w/w.

In a second aspect the invention broadly consists in a water dispersible granule ionophore antibiotic composition, said composition comprising at least one ionophore antibiotic, at least one filler-binder, at least one surfactant, at least one dispersing agent and at least one disintegrant, wherein the ionophore antibiotic is included in the composition in an amount in the range of about 20 - 40% w/w.

Most preferably said ionophore antibiotic is monensin. Preferably said monensin is sodium monensin. More preferably said monensin is crystalline sodium monensin.

Preferably said ionophore antibiotic has a particle size range of less than about 30 microns. More preferably about 90% of the particles are less than about 15 microns. Even more preferably the mean particle size is less than about 7 microns. In respect of compositions where the ionophore antibiotic is monensin, the preferred concentration of active monensin in the composition is about 30% w/w.

Preferably the filler-binder(s) is/are selected from the group comprising lactose monohydrate, lactose, microcrystalline cellulose, glucose, sucrose, sugars, mannitol, modified sugars, povidone, crospovidone, hydroxypropyl cellulose, ethyl cellulose, celluloses, modified celluloses, and combinations thereof.

A preferred filler-binder is lactose monohydrate, or a combination of lactose monohydrate and microcrystalline cellulose. Preferably the filler-binder(s) is/are present in the composition in an amount in the range of about 10 - 90% w/w. More preferably the filler-binder(s) is/are present in an amount in the range of about 40 - 70% w/w.

Preferably the surfactant(s) is/are selected from the group comprising anionic surfactants (for example, alkyl sulphates such as sodium lauryl sulphate, sulphonates such as sodium dodecylbenzene sulphonate, carboxylates, dioctyl sodium sulfosuccinate); cationic surfactants (for example quaternary ammonium salts such as benzalkonium chloride); amphoteric surfactants (for example alkyl betaines and cocamidoalkyl betaines); and non- ionic surfactants with HLB values greater than 8 (for example, polyoxyethylene glycol sorbitan alkyl esters (or polysorbates) and alkoxylates). Preferably the surfactant is anionic. More preferably the surfactant is sodium lauryl sulphate.

Preferably the surfactant(s) is/are present in the composition in an amount in the range of about 0.1 - 20% w/w. More preferably the surfactant is present in an amount in the range of about 2 - 10% w/w. Preferably the dispersing agent(s) is/are selected from the group comprising anionic dispersing agents (for example lignosulphonates); non-ionic dispersing agents (for example hydroxypropyl cellulose and hydroxypropylmethyl cellulose); and polymeric dispersing agents (for example polyvinylpyrrolidone).

Preferably the dispersing agent(s) is/are present in the composition in an amount in the range of about 0.1 - 20%» w/w. More preferably the dispersing agent is present in an amount in the range of about 2 - 10% w/w. Preferably the disintegrant(s) is/are selected from the group comprising microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, hydroxypropyl cellulose, other modified starch and modified cellulose. More preferably the disintegrant is microcrystalline cellulose, or a combination of microcrystalline cellulose and sodium starch glycolate.

Preferably the disintegrant(s) is/are present in the composition in an amount in the range of about 0.1 - 30% w/w. More preferably the disintegrant is present in an amount of about 10 - 20% w/w.

When the composition is used as a trough treatment, once it is added to the drinking water of the animal(s) to be treated, the ionophore antibiotic remains in a substantially stable solution in the drinking water for up to 62 days. Preferably the ionophore antibiotic is present in the drinking water in an acceptable concentration range for the animal(s) having access to the drinking water. Preferably the acceptable concentration range in the animal's drinking water is between about 1 to 12 mg/L (or 1 - 12 ppm). More preferably the acceptable concentration range is from about 3 to 6 mg/L (or 3 - 6 ppm).

In a further aspect the invention broadly consists in a water dispersible granule ionophore antibiotic composition, said composition comprising: from 5 to 80% w/w of at least one ionophore antibiotic; from 10 to 90% w/w of at least one filler-binder; from 0.1 to 20% w/w of at least one surfactant; from 0.1 to 20% w/w of at least one dispersing agent; and from 0.1 to 30% w/w of at least one disintegrant.

Preferably said ionophore antibiotic is monensin. More preferably it is crystalline sodium monensin.

Preferably said ionophore antibiotic comprises from about 20 to 40% w/w of the composition. Preferably said ionophore antibiotic has a particle size range of less than about 30 microns. More preferably about 90% of the particles are less than about 15 microns. Even more preferably the mean particle size is less than about 7 microns.

Preferably said filler-binder comprises from about 40 to 70% w/w of the composition. Preferably said surfactant comprises from about 2 to 10% w/w of the composition. Preferably said dispersing agent comprises from about 2 to 10% w/w of the composition.

Preferably said disintegrant comprises from about 2 to 20% w/w of the composition.

Preferably once the composition is added to the drinking water of animals to be treated, the ionophore antibiotic stays in a substantially stable solution uniformly dispersed in the water for up to 62 days, in a concentration of from about 3 to 6 mg/L (or 3 - 6 ppm).

In a further aspect the invention broadly consists in a water dispersible granule ionophore antibiotic composition, said composition comprising: from 20 to 40% w/w of crystalline sodium monensin; from 40 to 50% w/w of lactose monohydrate; from 2 to 10% w/w of sodium lauryl sulphate; from 2 to 10% w/w of sodium lignosulphonate; from 10 to 20% w/w of microcrystalline cellulose; and from 2 to 10% w/w of sodium starch glycolate.

Preferably said crystalline sodium monensin comprises about 34% w/w of the composition.

Preferably said crystalline sodium monensin has a particle size range of less than about 30 microns. More preferably about 90% of the particles are less than about 15 microns. Even more preferably the mean particle size is less than about 7 microns. Preferably said lactose monohydrate comprises about 47% w/w of the composition.

Preferably said sodium lauryl sulphate comprises about 3% w/w of the composition.

Preferably said sodium lignosulphonate comprises about 3% w/w of the composition.

Preferably said microcrystalline cellulose comprises about 10% w/w of the composition.

Preferably said sodium starch glycolate comprises about 3% w/w of the composition. Preferably once the composition is added to the drinking water of animals to be treated, the ionophore antibiotic stays in a substantially stable solution uniformly dispersed in the water for up to 62 days, in a concentration of from about 3 to 6 mg/L (or 3 - 6 ppm).

In another aspect the invention broadly consists in a dry ionophore antibiotic composition suitable for adding directly or indirectly to water from which one or more animals can drink, said composition comprising: at least one ionophore antibiotic, at least one filler-binder, at least one surfactant, at least one dispersing agent, and at least one disintegrant. Preferably said composition is a water dispersible granule composition.

Preferably once said composition is added to the drinking water, the ionophore antibiotic remains in a substantially stable solution uniformly dispersed in the drinking water for up to 62 days. Preferably the ionophore antibiotic is present in the drinking water in an acceptable concentration range for the animal(s) having access to the drinking water.

Preferably the acceptable concentration range in the drinking water is between about 1 to 12 mg/L (or 1 - 12 ppm). More preferably the acceptable concentration range is from about 3 to 6 mg/L (or 3 - 6 ppm). Preferably said ionophore antibiotic is selected from the group comprising monensin, salinomycin, narasin, lasalocid, maduramycin, semduramycin, laidlomycin, tetronasin, lonomycin, ionomycin, nigericin, grisorixin, dianemycin, lenoremycin, antibiotic X206, alborixin, septamycin, antibiotic A204, compound 47224, mutalomycin, isolasalocid A, lysocellin, echeromycin, antibiotic X-14766A, antibiotic A23187, antibiotic A32887, compound 51532 and K41.

Most preferably said ionophore antibiotic is monensin.

Preferably said ionophore antibiotic is present in the composition in an amount in the range of about 5 - 80% w/w. More preferably the ionophore antibiotic is present in the composition in an amount in the range of about 20 - 40% w/w.

In respect of compositions where the ionophore antibiotic is monensin sodium, the preferred concentration of active monensin in the composition is 30% w/w. Preferably the filler-binder(s) is/are selected from the group comprising lactose monohydrate, lactose, microcrystalline cellulose, glucose, sucrose, sugars, mannitol, modified sugars, povidone, crospovidone, hydroxypropyl cellulose, ethyl cellulose, celluloses, modified celluloses, and combinations thereof. A preferred filler-binder is lactose monohydrate, or a combination of lactose monohydrate and microcrystalline cellulose.

Preferably the filler-binder(s) is/are present in the composition in an amount in the range of about 10 - 90% w/w. More preferably the filler-binder(s) is/are present in an amount in the range of about 40 - 70% w/w. Preferably the surfactant(s) is/are selected from the group comprising anionic surfactants (for example, alkyl sulphates such as sodium lauryl sulphate, sulphonates such as sodium dodecylbenzene sulphonate, carboxylates, dioctyl sodium sulfosuccinate); cationic surfactants (for example quaternary ammonium salts such as benzalkonium chloride); amphoteric surfactants (for example alkyl betaines and cocamidoalkyl betaines); and non- ionic surfactants with HLB values greater than 8 (for example, polyoxyethylene glycol sorbitan alkyl esters (or polysorbates) and alkoxylates).

Preferably the surfactant is anionic. More preferably the surfactant is sodium lauryl sulphate.

Preferably the surfactant(s) is/are present in the composition in an amount in the range of about 0.1 - 20% w/w. More preferably the surfactant is present in an amount in the range of about 2 - 10% w/w.

Preferably the dispersing agent is anionic. More preferably the dispersing agent is sodium lignosulphonate. Preferably the dispersing agent(s) is/are present in the composition in an amount in the range of about 0.1 - 20% w/w. More preferably the dispersing agent is present in an amount in the range of about 2 - 10% w/w.

Unless otherwise specified herein all amounts of the ingredients of the composition are expressed as percentages by weight with respect to the overall weight of the dry composition. In a further aspect the invention broadly consists in a method of providing an ionophore antibiotic to a target animal which comprises directly or indirectly adding an effective amount of the composition of the present invention to the drinking water of said animal to enable self administration orally of the composition.

Preferably once said composition is added to the drinking water, the ionophore antibiotic remains in a substantially stable solution uniformly dispersed in the drinking water for up to 62 days.

Preferably the ionophore antibiotic is present in the drinking water in an acceptable concentration range for the animal(s) having access to the drinking water.

Preferably the acceptable concentration range in the drinking water is between about 1 to 12 mg/L (or 1 - 12 ppm). More preferably the acceptable concentration range is from about 3 to 6 mg/L (or 3 - 6 ppm).

In a further aspect the invention broadly consists in a method of increasing feed conversion and growth rate of ruminants which comprises directly or indirectly adding an effective amount of the composition of the present invention to the drinking water of said ruminants to enable self administration orally of the composition.

In a further aspect the invention broadly consists in a method of treating or preventing bloat and/or ketosis in ruminants which comprises directly or indirectly adding an effective amount of the composition of the present invention to the drinking water system of said ruminants to enable self administration orally of the composition. Preferably once said composition is added to the drinking water, the ionophore antibiotic remains in a substantially stable solution uniformly dispersed in the drinking water for up to 62 days.

Preferably the ionophore antibiotic is present in the drinking water in an acceptable concentration range for the animal(s) having access to the drinking water. Preferably the acceptable concentration range in the drinking water is between about 1 to 12 mg/L (or 1 - 12 ppm). More preferably the acceptable concentration range is from about 3 to 6 mg/L (or 3 - 6 ppm).

In a further aspect the invention broadly consists in a method of providing an ionophore antibiotic to a target animal which comprises mixing an effective amount of the composition of the present invention with water and administering an effective amount of the resulting liquid composition to the animal orally (for example, by drenching).

In a further aspect the invention broadly consists in a method of increasing feed conversion and growth rate of ruminants which comprises mixing an effective amount of the composition of the present invention with water and administering an effective amount of the resulting liquid composition to the animal orally (for example, by drenching).

In a further aspect the invention broadly consists in a method of treating or preventing bloat and/or ketosis in ruminants which comprises mixing an effective amount of the composition of the present invention with water and administering an effective amount of the resulting liquid composition to the animal orally (for example, by drenching).

In a further aspect the invention broadly consists in a method of manufacturing a water dispersible granule ionophore antibiotic composition, said method comprising: milling at least one ionophore antibiotic to a smaller particle size; mixing said milled ionophore antibiotic with at least one filler-binder, at least one surfactant, at least one dispersing agent, and at least one disintegrant, and granulating the resulting product to form said water dispersible granule composition.

Preferably said ionophore antibiotic is milled to a mean particle size of less than about 30 microns. More preferably about 90% of the particles are milled to a mean particle size of less than about 15 microns. Even more preferably said milling is to a mean particle size of less than about 7 microns.

We have determined that a micronised form of the ionophore antibiotic having a smaller mass to surface area ratio provides a significant advantage in the composition over the inclusion of ionophore antibiotics having a larger particle size. Preferably said milling step is carried out by a dry milling process, for example, an air milling or jet milling process.

Preferably said granulating step comprises a dry granulation process.

Preferably the mean particle size of the resulting granule is from about 0.15 mm to 3 mm.

In a further aspect the invention broadly consists in a method of manufacturing a water dispersible granule ionophore antibiotic composition, said method comprising: milling at least one ionophore antibiotic with at least one surfactant and at least one dispersing agent to a smaller particle size; mixing the resulting milled product with at least one filler-binder, and at least one disintegrant, and granulating the resulting mixed product to form said water dispersible granule composition. Preferably said ionophore antibiotic is milled to a mean particle size of less than about 30 microns. More preferably about 90% of the particles are milled to a mean particle size of less than about 15 microns. Even more preferably said milling is to a mean particle size of less than about 7 microns. Preferably said milling step is carried out by a dry milling process, for example, an air milling or jet milling process.

Preferably the milling of the components is simultaneous although it can be in part or totally serially.

Preferably said granulating step comprises a dry granulation process. Preferably the mean particle size of the resulting granule is from about 0.15 mm to 3 mm.

In a further aspect the invention broadly consists in a water dispersible granule ionophore antibiotic composition prepared according to the method described herein.

In yet another aspect the invention broadly consists in a water dispersible granule ionophore antibiotic composition comprising: at least one ionophore antibiotic having a mean particle size of less than 30 microns; at least one filler-binder; at least one surfactant; at least one dispersing agent; and at least one disintegrant.

More preferably said ionophore antibiotic has a mean particle size of less than about 7 microns.

In yet another aspect the invention broadly consists in a water dispersible granule ionophore antibiotic composition comprising: at least one ionophore antibiotic; at least one filler- binder; at least one surfactant; at least one dispersing agent; and at least one disintegrant; wherein the ionophore antibiotic(s) and the surfactant(s) and the dispersing agent(s) have been milled together to a mean particle size of less than 30 microns and the remaining components have been added post-milling and prior to granulating. More preferably said milling is to a mean particle size of less than about 7 microns.

Preferably said milling step is carried out by a dry milling process, for example by an air milling or j et milling process . Preferably the milling of the components is simultaneous although it can be in part or totally serially.

DETAILED DESCRIPTION

The following description will describe the invention in relation to preferred embodiments of the invention. The invention is in no way limited to these preferred embodiments as they are purely to exemplify the invention only and it is to be understood that possible variations and modifications that would be readily apparent are intended to be included without departing from the spirit and scope of the invention.

The present invention relates to a dry flowable water dispersible granule ionophore antibiotic composition which is readily dispersible directly or indirectly in the drinking water of an animal or animals to be treated, so that self-administration of an effective amount of the ionophore antibiotic is achieved. The composition is suitable for use in all types of trough treatment systems such as proportional feed systems (for example, DOSATRON), dump systems and individual trough treatment systems (for example, the PETA dispenser). The composition is also capable of being mixed with water and administered to an animal orally by way of known drench systems.

Water dispersible granule compositions which are readily dispersable in water can be difficult to formulate as there are a number of key requirements to consider, such as granule size distribution, strength and friability of granules, water dispersability performance, and stability of the active ingredient both in its granule form and upon its dispersion in water. Selection of the appropriate excipients and the amount of each to be included in the composition is fundamental to the production of a water dispersible granule with acceptable characteristics. After extensive investigation and trialling, we have managed to manufacture a successful water dispersible granule composition, which comprises the following essential components: at least one ionophore antibiotic; at least one filler-binder; at least one surfactant; at least one dispersing agent; and at least one disintegrant.

Ionophore antibiotics

In the preferred forms of the invention the ionophore antibiotic is selected from the group comprising monensin, salinomycin, narasin, lasalocid, maduramycin, semduramycin, laidlomycin, tetronasin, and combinations thereof. Other ionophore antibiotics however fall within the scope of the present invention and these include, without limitation, lonomycin, ionomycin, nigericin, grisorixin, dianemycin, lenoremycin, antibiotic X206, alborixin, septamycin, antibiotic A204, compound 47224, mutalomycin, isolasalocid A, lysocellin, echeromycin, antibiotic X-14766A, antibiotic A23187, antibiotic A32887, compound 51532, K 1 and combinations thereof.

Reference herein to "ionophore antibiotic" refers to the antibiotic in any suitable form (e.g. acid or salt) and includes all salts thereof and esters thereof. Preferably a crystalline form of the ionophore antibiotic is used in the compositions of the invention.

A particularly preferred ionophore antibiotic is monensin and this can be used in the compositions of the invention in any of its appropriate forms. However, a preferred form is the sodium salt of the acid, i.e. sodium monensin, which is usually commercially available in two forms, namely a crystalline form or a mycelial form. The mycelial form has only about a 20% activity while the crystalline form has a potency of not less than 800 μg/mg being as a standard pharmacopoeial material (e.g. USP), which is preferred. Crystalline sodium monensin useable in this invention is commercially available from many sources, for example, Eli Lilly, Biovet JSC, and preferably should have a potency of not less than 900 Mg/mg.

The ionophore antibiotic is preferably present in the composition in an amount in the range of about 5 — 80% w/w. More preferably the ionophore antibiotic is present in the composition in an amount of between about 20 - 40% w/w. In compositions comprising monensin, the preferred concentration of monensin is about 30% w/w. With particular reference to crystalline sodium monensin, this equates to about 34% w/w of commercially available sodium monensin because of impurities in the raw material (i.e. less than 100% of the material is active). In one particular embodiment of the invention, the ionophore antibiotic is crystalline sodium monensin present in an amount of about 34% w/w, which is intended to provide a composition with an active concentration of about 30% w/w such that only 1 gram of the composition is required to provide the recommended daily dose of monensin to an animal such as a cow. The current recommended dose of monensin for adult cattle is 300 mg per animal per day. Therefore each kilogram of the granule composition of the invention should contain about 300 grams of monensin. The ionophore antibiotic may optionally be coated or admixed with a surfactant, to improve its dispersion in water. For a water dispersible granule composition containing a high concentration of active, a coated active is preferred. Preferred surfactants for coating include liquid surfactants such as polysorbates, polyethylene sorbitol esters (for example TWEEN 80), polyethoxylated castor oil, and lecithin. An amount of about 1% w/w of surfactant is typically used. Coating can be done by spraying and/or mixing the surfactant with the ionophore antibiotic, or the surfactant can be milled together with the ionophore antibiotic to coat the active.

In order to achieve the desired water dispersible granule composition of the invention, it has been found that it is advantageous for the ionophore antibiotic to have a very small particle size. It is preferred that the particle size range of the ionophore antibiotic is from about 1 - 30 microns, with 90% of the particles being less than about 15 microns, and the mean particle size being less than about 7 microns. Given that current commercially available forms of ionophore antibiotic such as monensin sodium may have a particle size range of about 40 to 90 microns, preferably the raw material is milled or micronized to a smaller particle size during manufacture of the composition. Possible milling processes will be described in more detail later in the specification.

The compositions of the invention may contain more than one ionophore antibiotic and/or one or more further pharmaceutically active ingredients that do not interfere with or otherwise hamper the effectiveness of the ionophore antibiotic(s). Examples of such further actives may include essential minerals such as copper, selenium, cobalt, iodine, zinc, boron and manganese.

A number of excipients are required in the compositions of the invention in order to provide a successful water dispersible granule composition, with the appropriate characteristics of flowability, friability, dispersability and re-suspensibility. These will be discussed in turn.

Filler-Binder Agents

Polyvinylpyrrolidone (PVP) is a common binding agent for pharmaceutical granules used in tablet compression. However we found that granules containing monensin using PVP were not strong enough. Betonite clay, another common binding agent, was also tried and although it produced strong granules, the granules were not water dispersible. After further investigation, we found that the following non-limiting list of filler-binders are useable in the compositions of the invention: lactose monohydrate, lactose, microcrystalline cellulose, glucose, sucrose, sugars, mannitol, modified sugars, povidone, crospovidone, hydroxypropyl cellulose, ethyl cellulose, celluloses, modified celluloses, pre-gelatinized starch, and combinations thereof. It is preferred that the majority of the filler-binder is water soluble. The most preferred filler-binder is lactose monohydrate. An example is PHARMATOSE 200 which is commercially available from Fonterra Limited. Another preferred filler-binder is microcrystalline cellulose (which may also act as a disintegrant) which is available from JRS Pharma under the trade name VIVAPUR TYPE 101. A preferred combination of filler- binders is a combination of lactose monohydrate and microcrystalline cellulose. Preferably the filler-binder(s) is/are present in the composition in an amount in the range of about 10 - 90% w/w. More preferably the filler-binder(s) is/are present in an amount in the range of about 40 - 70% w/w.

In one preferred composition of the invention, the filler-binder is lactose monohydrate present in an amount of about 47% w/w. This composition also comprises microcrystalline cellulose in an amount of about 10% w/w which acts as both a filler-binder and a disintegrant. The amount of filler-binder added to the composition will generally be adjusted according to the amount of ionophore antibiotic included in the composition.

Surfactants

A surfactant is required for wetting the ionophore antibiotic. Given that ionophore antibiotics are particularly hydrophobic, an ideal composition must be able to maintain the wetted state of the ionophore antibiotic. A non-limiting list of surfactants or wetting agents useable in the compositions of the invention include: anionic surfactants (for example, alkyl sulphates such as sodium lauryl sulphate, sulphonates such as sodium dodecylbenzene sulphonate, carboxylates, dioctyl sodium sulfosuccinate); cationic surfactants (for example quaternary ammonium salts such as benzalkonium chloride); amphoteric surfactants (for example alkyl betaines and cocamidoalkyl betaines); and non-ionic surfactants with HLB values greater than 8 (for example, polyoxyethylene glycol sorbitan alkyl esters (or polysorbates) and alkoxylates). Preferably the surfactant is anionic. Preferably the surfactant(s) is/are in a powder form. The most preferred surfactant is sodium lauryl sulphate, which is commercially available from Kao under the trade name EMAL 10, or from Cognis under the trade name TEXAPON K 12P PH.

Preferably the surfactant(s) is/are present in the composition in an amount in the range of about 0.1 - 20% w/w. More preferably the surfactant(s) comprise from about 2 to 10% w/w of the composition. In one particular embodiment, the surfactant is sodium lauryl sulphate present in an amount of about 3% w/w.

Dispersing Agents

A non-limiting list of dispersing agents useable in the compositions of the invention include: anionic dispersing agents (for example lignosulphonates); non-ionic dispersing agents (for example hydroxypropyl cellulose and hydroxypropylmethyl cellulose); and polymeric dispersing agents (for example polyvinylpyrrolidone). Preferably the dispersing agent is anionic. Preferably the dispersing agent(s) is/are in a powder form.

The most preferred dispersing agent is sodium lignosulphonate, which is commercially available from Borregaard under the trade name BORRESPERSE NA.

Preferably the dispersing agent(s) is/are present in the composition in an amount in the range of about 0.1 - 20% w/w. More preferably the dispersing agent(s) comprise from about 2 to 10% w/w of the composition. In one particular embodiment, the dispersing agent is sodium lignosulphonate present in an amount of about 3% w/w. Disintegrants

A non-limiting list of disintegrants useable in the compositions of the invention include microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, hydroxypropyl cellulose, other modified starch and modified cellulose, and combinations thereof. The most preferred disintegrants are microcrystalline cellulose (which may also act as a filler-binder), and sodium starch glycolate. Microcrystalline cellulose is commercially available from JRS Pharma under the trade name VIVAPUR TYPE 101. Sodium starch glycolate (Type A) is commercially available from JRS Pharma under the trade name VIVASTAR P. An especially preferred combination of disintegrants is a combination of microcrystalline cellulose and sodium starch glycolate. Preferably the disintegrant(s) is/are present in the composition in a total amount in the range of about 0.1 - 30% w/w. More preferably the disintegrant(s) comprise(s) from about 10 to 20% w/w of the composition. In one preferred composition of the invention, the composition comprises a combination of disintegrants, being microcrystalline cellulose present in an amount of about 10% w/w (which also acts as a filler-binder), and sodium starch glycolate present in an amount of about 3% w/w.

The compositions of the invention may include further excipients and/or additives such as dyes, colorants, fillers, diluents, anti-caking agents, anti-foaming agents, sweeteners, flavourings, preservatives, antioxidants, stabilizers and other auxiliary additives as may be desired by end-users. However, it is generally preferred not to add too many additional additives or excipients to the compositions in order to keep the loading of the compositions to a minimum. If other additives or excipients are included, the amount of each should be very low, for example less than about 1% w/w of the composition, or preferably even lower, such as up to 0.1% w/w. Some non-limiting examples of the compositions of the invention will now be described.

Example 1

Component Function of Component Concentration (% w/w)

Monensin sodium, milled Ionophore antibiotic 34.0 (intended to provide about 30% w/w active monensin content)

Lactose monohydrate Filler-Binder 47.0

Microcrystalline cellulose Filler-Binder / Disintegrant 10.0

Sodium lauryl sulphate Surfactant/Wetting Agent 3.0

(EMAL 10 (powder))

Sodium lignosulphonate Dispersing agent 3.0

(BORRESPERSE NA

(powder))

Sodium starch glycolate Disintegrant 3.0 Example 2

Component Function of Component Concentration (% w/w)

Monensin sodium, milled lonophore antibiotic 34.0 (intended to provide about 30% w/w active monensin content)

Lactose monohydrate Filler-Binder 52.0

Microcrystalline cellulose Filler-Binder / Disintegrant 10.0

Sodium lauryl sulphate Surfactant/Wetting Agent 2.0

(EMAL 10 (powder))

Sodium lignosulphonate Dispersing agent 1.0

(BORRESPERSE A

(powder))

Sodium starch glycolate Disintegrant 1.0

Example 3

Component Function of Component Concentration (% w/w)

Monensin sodium, milled, lonophore antibiotic coated 80.0 (intended to provide coated with 1% Polysorbate with surfactant about 70% w/w active 20 monensin content)

Microcrystalline cellulose Filler-Binder / Disintegrant 8.0

Hydroxypropyl cellulose Filler-Binder 4.0

(Klucel LF)

Dioctyl sodium Surfactant/Wetting Agent 1.0

sulfosuccinate

Sodium lignosulphonate Dispersing agent 3.0

(BORRESPERSE NA

(powder))

Croscarmellose sodium (Ac- Disintegrant 4.0

Di-Sol, FMC) Example 4

Example 5

Component Function of Component Concentration (% w/w)

Monensin sodium, milled lonophore antibiotic 45.0 (intended to provide about 40% w/w active monensin content)

Microcrystalline cellulose - Filler-Binder / Disintegrant 46.0

mannitol blend (Avicel HFE)

Sodium lauryl sulphate Surfactant/Wetting Agent 3.0

(EMAL 10 (powder))

Sodium lignosulphonate Dispersing agent 3.0

(BORRESPERSE NA

(powder))

Croscarmellose sodium (Ac- Disintegrant 3.0

Di-Sol) Example 6

Component Function of Component Concentration (% w w)

Monensin sodium, milled, Ionophore antibiotic 23.0 (intended to provide about 20% w/w active monensin content)

Sucrose (SugarTAB) Filler-Binder 61.0

Macrocrystalline cellulose Filler-Binder / Disintegrant 10.0

Sodium lauryl sulphate Surfactant/Wetting Agent 2.0

(EMAL 10 (powder))

Polyvinylpyrrolidone Dispersing agent 2.0

(Povidone K- 15)

Sodium starch glycolate Disintegrant 2.0

Example 7

Component Function of Component Concentration (% w/w)

Monensin sodium, milled, Ionophore antibiotic 17.0 (intended to provide about 15% w/w active monensin content)

Sucrose (SugarTAB) Filler-Binder 68.5

Microcrystalline cellulose Filler-Binder / Disintegrant 10.0

Sodium lauryl sulphate Surfactant/Wetting Agent 1.50

(EMAL 10 (powder))

Hydroxypropyl cellulose Dispersing agent 2.0

(Klucel LF)

Sodium starch glycolate Disintegrant 1.0 Example 8

The above example compositions are suitable for addition to the drinking water system of animals' to be treated, or they can be mixed with water to provide a drench formulation.

Method of Manufacture

After extensive investigation and trialling, we have found that a successful water dispersible granule composition including the components as described above can be prepared as follows. Referring to the accompanying drawings, Figure 1 shows a method of manufacture in accordance with one embodiment of the invention, while Figure 2 shows an alternative method of manufacture.

Figure 1 shows that there are essentially three steps required in the process: a milling step, a mixing step and a granulation step. Figure 2 shows that optionally a pre-milling mixing step can be carried out. The composition of example 1 above was prepared by the procedure as shown in Figure 2. The composition of example 2 above was prepared by the procedure as shown in Figure 1.

The milling step involves milling of the ionophore antibiotic(s) to the desired particle size. We have found that the particle size of the ionophore antibiotic is important in order to produce a water dispersible granule composition with appropriate flowability, friability, dispersability and re-suspensibility characteristics. The preferred particle size range is between about 1 - 30 microns, with 90% of the particles being less than about 15 microns, and the mean particle size being less than about 7 microns. The milling step can be carried out using any type of conventional milling process and equipment, however a dry milling process is preferred, because dry milling allows superior control and consistency of the particle size which is of critical importance in the final product. It also allows an increased choice of filler binders, disintegrants and dispersing agents that may be affected by moisture in an alternative milling process. Of the dry milling processes, jet milling or air milling is preferred. If necessary, excipients such as anti-caking agents can be added during milling, however we have found that this should not be necessary if jet milling is used. Optionally the ionophore antibiotic(s) can be pre-mixed with the surfactant(s) and the dispersing agent(s) before milling. We believe that this pre-milling mixing step is advantageous as it improves the ability of the ionophore antibiotic to remain stable upon dispersion in water. If these three components are to be pre-mixed prior to milling, they should be added to a mixing vessel alternatively and sequentially (in no particular order) in small portions and blended until a homogenous mixture is produced. Preferably the mixture is blended for about 60 minutes, but this depends on the batch size (for example, a batch size of about 200 kg requires about 60 minutes of blending).

The ionophore antibiotic may optionally be coated or admixed with a surfactant (preferably a liquid surfactant) prior to inclusion in the composition, to improve its dispersion in water. Coating can be done by spraying and/or mixing the surfactant with the ionophore antibiotic prior to milling, or the surfactant can be milled together with the ionophore antibiotic to coat the active.

Once the ionophore antibiotic(s) or the ionophore antibiotic(s)/surfactant(s)/dispersing agent(s) pre-mix has been milled to the desired particle size, the milled product can be taken away as an intermediate product (e.g. post mill product) for subsequent use elsewhere for blending. Preferably however the milled product is then mixed with the remaining excipients (i.e. the filler-binder(s) and the disintegrant(s)) if there has been pre-mixing of the ionophore antibiotic(s) (refer Figure 2), but if no pre-milling mixing step has been carried out, then the milled ionophore antibiotic should be mixed with all of the excipients after milling (refer Figure 1)). This is preferably done by adding small portions of each of the components to a mixing vessel alternatively and sequentially and blending until a homogenous mixture is produced. Blending time will vary depending on batch size, but preferably the blending time is between 30 and 60 minutes (a batch size of about 200 kg requires about 60 minutes of blending). Preferably in the post-milling mixing step, the order of addition of the components is as shown in Figure 2, that is, the filler-binder(s) are added first (1), followed by the disintegrant(s) (2) and then the pre-mixed milled product (3) comprising the ionophore antibiotic(s), the surfactant(s) and the dispersing agent(s).

Once the components of the composition have been mixed, the mixed product is then granulated. Any type of granulation process could be used to produce the compositions of the invention, for example, extrusion, wet granulation, fluid bed granulation, tray dry granulation etc. The preferred method of granulation is dry granulation as it has been found to produce the most successful composition in terms of the desired characteristics of the resulting water dispersible granule (i.e. granule size distribution, strength and friability of granules, water dispersability performance, and stability of the active ingredient both in its granule form and upon its dispersion in water).

Several types of dry granulation are possible, but the preferred method involves the processing of fine powders into densified sheets by the use of mechanical pressure exerted on two compacting rolls. The basic concept of compaction is to force fine powders between two counter rotating rolls. As the volume decreases through the region of maximum pressure, the material is formed into a solid compact or sheet. The densified sheets are then granulated to a desired mesh size. Any type of dry granulation process and equipment can be used in the process of the invention. Examples of suitable dry granulation equipment include the CHILSONATOR by the Fitzpatrick Company, and the SERIES DRY TYPE GRANULATOR by Zhejiang Jiangnan Pharmaceutical Machinery Co., Ltd.

Once the fine powder has been put through the dry granulator to form the granules, there is an optional sieving step to remove finer particles and to ensure that the resulting granules are of a consistent size. The finer particles can then be returned to the granulator to be processed again.

The compositions of the invention are designed to be readily dispersable in water so that they can be added directly or indirectly (via a dispensing system such as a DOSATRON) to animals' drinking water systems such as troughs, or so that they can be mixed with water and administered to animals via drench. If the composition is added to the drinking water system of animals, upon addition to the water, the composition disperses readily to provide a substantially stable solution of the ionophore antibiotic uniformly through the water, so that an animal receives an acceptable dose of the ionophore antibiotic when drinking. Therefore the invention also encompasses methods of providing ionophore antibiotics to animals and methods of increasing feed conversion and growth rate of animals (namely ruminants) and methods of treating or preventing bloat and/or ketosis, which involve dispersing the composition of the present invention in the drinking water system of said animals to enable self administration orally of the composition. As will be appreciated by those of ordinary skill, the animals will drink the treated water ad libitum, but it is contemplated that they will receive substantially the recommended daily dose of the active components of the composition based on the average amount of water that an animal generally drinks per day.

It is therefore important that the ionophore antibiotic remains in a substantially stable solution in the drinking water, in an acceptable concentration. An acceptable concentration in the animals' drinking water is in the range of about 1 to 12 mg/L (or 1 - 12 ppm), but preferably from about 3 to 6 mg/L (or 3 - 6 ppm). This is based on the recommended dosage rate of monensin, that is, 300 mg per adult animal per day. So for an animal drinking about 100 litres of water per day, an acceptable concentration is 3 mg/L, while for an animal drinking about 50 litres of water per day, an acceptable concentration is 6 mg/L, and for an animal drinking about 25 litres of water per day, an acceptable concentration is 12 mg/L.

It is also important that the ionophore antibiotic remains uniformly dispersed through the body of drinking water for a sufficient period of time in order to provide a safe and practical form of treatment.

A study on the positional stability of the ionophore antibiotic in livestock drinking water was carried out. In this study a water dispersible granule composition of the invention comprising 30% w/w active monensin was tested for its chemical stability at typical drinking trough concentration and the uniformity of that solution over time. The duration of the study encompasses a typical rotational time where a dosed drinking trough could remain unused for up to 28 days. This study monitored the trough water out to over 60 days (with test points at 0, 7, 15, 22 and 62 days). The procedure used for the trough stability study was as follows: a 3.0g quantity of the granule composition of the invention was premixed with 3L of tap water. This mixture was transferred to a 150L commercial trough (black pigmented HDPE) containing 147L of tap water so that the final content in the trough results in 6mg/L (ppm) of monensin. The dispersion was then thoroughly mixed with a milk vat stirrer. The trough contents were allowed to settle for 30 minutes. The timing was started for stability monitoring. At each sampling point, 20.0mL of the drinking water was removed (in 5 duplicate) from the top, middle and bottom levels of the trough. Each of the samples was transferred to a 20mL glass scintillation vial for analysis. The same sampling procedure was repeated after 7, 15, 22 and 62 days. The collected samples were analysed by a testing laboratory for monensin content using liquid chromatography (HPLC).

The test results are summarized in Table 1 below. The results show that the concentration of 10 monensin during the test period remained at approximately 6 ppm with an average at 5.8 ppm and standard deviation of 0.2 ppm (n=23) regardless of trough level and time. Duplicate results were in good agreement.

Table 1. Monensin concentration (mg/L) from 30% monensin water dispersible granule composition in trough water

15 * rejected as outliner by Dixon 's Q-Test

The test results show that the monensin was found to be evenly distributed in the trough at the three positional levels tested (top, middle and bottom). The monensin remained chemically stable throughout the trial duration. However, the analytical data suggests that some decrease in the concentration of monensin may be occurring at the 62 day test point. The observed relative decrease was approximately 5% from the initial concentration.

These results demonstrate that the water dispersible granule compositions of the invention remain in a substantially stable solution in the water and provide a uniform distribution of ionophore antibiotic (at the desired concentration) through a body of drinking water for a period of up to 62 days. If the composition is delivered to the drinking water system by way of a dispensing system such as a DOSATRON, the composition is added directly to the dispenser solution tank of the DOSATRON, and must remain in a stable and uniform suspension or dispersion in the dispenser solution tank (which is preferably continually mixed or agitated) until it is fed into one or more troughs (that is for up to about 24 hours). While in the dispenser solution tank the composition will be in a concentration of between about 300 - 600 mg/L (or ppm). The composition is then diluted with water as it is fed into one or more trough(s), and the ionophore antibiotic readily dissolves and becomes substantially in solution in the trough(s). It then remains in a substantially stable solution uniformly dispersed in the drinking water for up to 62 days, in an acceptable concentration as discussed above.

If the composition is to be mixed with water and administered by way of drench, the water dispersible granules can be added directly to the mixing tank of a power drench system. The usual drench volume for adult cattle is 100 ml per animal. Therefore, in order to obtain the desired dose for once daily drenching, 10 grams of granules would be added to each litre of water.

Dissolution Test Results

Assay samples and dissolution test samples of the compositions of Example 1 and Example 2 above were prepared and tested. Granule assay and dissolution test results are given in Table 1 below. Also in Table 1, for comparison purposes, are the results obtained from testing of an earlier version of the composition in which the ionophore antibiotic (monensin) was not milled to a smaller particle size before incorporation into the composition.

Table 1

Sample ID Sample Description Target Analysed %

Value Results Dissolved

Granule composition comprising unmilled monensin

7A1 Assay 30.0% w/w 30.0% w/w

7A2 Assay duplicate 30.0% w/w 30.2% w/w ^— 7T1 Total in water 6.0 ppm 6.1 ppm -

7T2 Total in water duplicate 6.0 ppm 5.9 ppm

7S1 Soluble in water 6.0 ppm 3.8 ppm 62 (=3.8/6.1)

7S2 Soluble in water duplicate 6.0 ppm 3.2 ppm 54 (=3.2/5.9)

Granule composition of Example 2 (comprising milled monensin)

8G1 Assay 30.0% w/w 31.7% w/w -

8G2 Assay duplicate 30.0% w/w 31.4% w/w

8AT Total in water 6.0 ppm 6.8 ppm

8BT Total in water duplicate 6.0 ppm 7.2 ppm

8AS Soluble in water 6.0 ppm 6.1 ppm 90 (=6.1/6.8)

8BS Soluble in water duplicate 6.0 ppm 6.3 ppm 88 (=6.3/7.2)

Granule composition of Example 1 (comprising milled monensin)

9A1 Assay 30.0% w/w 30.8% w/w -

9A2 Assay duplicate 30.0% w/w 31.4% w/w

9T1 Total in water 6.0 ppm 6.2 ppm

9T2 Total in water duplicate 6.0 ppm 5.6 ppm

9S1 Soluble in water 6.0 ppm 6.6 ppm 106

(=6.6/6.2)

9S2 Soluble in water duplicate 6.0 ppm 4.9 ppm 87 (=4.9/5.6)

As can be seen from the above, the monensin assay of all three compositions was found to be around 30% w/w with good duplicate results. The percentages of dissolved monensin show that the composition of Example 1 reached an average of over 90% dissolved monensin in water. Both the compositions of Example 1 and Example 2 show improved solubility in water over the composition comprising the unmilled monensin. This shows that milling of the monensin (or ionophore antibiotic) to a smaller particle size is important in order to achieve the desired solubility. Stability Studies

Regulatory and accelerated stability trials were carried out to determine the acceptable shelf life of a granule composition of the invention comprising 30% active monensin. The stability trials were conducted as real time studies (with storage conditions of 25°C / 60% relative humidity and 30°C / 65% relative humidity) and accelerated studies (with storage conditions of 40°C / 75% relative humidity). The results of the stability studies showed the following: (1) that there was no change in the appearance or characteristics of the granule composition during the stability studies; (2) that the monensin assay of all stability test samples remained between 29.0 - 32.2% w/w, with no obvious trends in the active content at any condition; (3) that there was no significant change in the moisture content of all stability test samples, with all moisture contents remaining below 3% w/w and no clear trends in the moisture content being evident; (4) that dustiness of all test samples remained at not more than 0.1% w/w indicating that there was no physical breakdown of the product during the stability studies. These results support the conclusion that the compositions of the present invention will remain chemically and physically stable for a minimum period of 12 months when stored at or below 30 C / 65% relative humidity.

ADVANTAGES

The development of a dry flowable water dispersible granule ionophore antibiotic composition that can be added directly or indirectly to drinking water systems of animals to be treated, or that can be readily mixed with water to provide a drench, will provide several potentially realisable advantages to the industry. These include:

• Ability of the compositions to deliver a stable solution of an ionophore antibiotic uniformly dispersed in drinking water systems in an acceptable imbibing concentration of between 1 to 12 (preferably 3 - 6) ppm, for up to 62 days;

• Facilitation of administration of the active ingredient to multiple animals by passive means requiring little time, man-power or cost, and no pre-mixing step; • Ability to include a high concentration of active ingredient in the compositions (i.e. at least 30% compared to the 6% of current commercially available formulations) thereby significantly reducing the amount of composition required to achieve the recommended dosage rates;

• Reduced manufacturing and packaging costs due to the lower volumes of composition required;

• Reduced storage and transportation costs due to the lower volumes of composition required;

• Free-flowing composition which is safer and easier to handle, measure and mix, thereby providing a safer formulation for target animals due to more accurate and reliable measurement and mixing;

• Reduced dust with a granule formulation thereby providing reduced inhalation hazard during handling and a safer formulation for the user;

• Formulation leaves no unsafe residues in used containers so it is safer for users and non-target animals.

VARIATIONS

It will be appreciated that the compositions presented in Examples 1 to 8 above are examples only and that other compositions are contemplated without departing from the spirit and scope of the invention. For example, although the compositions comprise monensin sodium as the active ingredient, it is envisaged that other ionophore antibiotics may be used as the active ingredient in the compositions. Furthermore, it will be appreciated that the composition may include more than one ionophore antibiotic, or other additional active ingredients, such as essential minerals or the like that can usefully be administered simultaneously with the ionophore antibiotic(s). The compositions may also include other additives and/or excipients which are capable of being incorporated in the composition without adversely affecting the flowability, friability, dispersability and re-suspensibility of the granule composition. For example, additional additives and/or excipients may be included within the compositions of the present invention to tailor them to suit a specific administration method or a specific condition to be treated. Throughout the description of this specification, the word "comprise" and variations of that word such as "comprising" and "comprises", are not intended to exclude other additives, components, integers or steps.

It will of course be realised that while the foregoing has been given by way of illustrative example of this invention, all such and other modifications and variations thereto as would be apparent to persons skilled in the art are deemed to fall within the broad scope and ambit of this invention as is hereinbefore described.

Claims

A water dispersible granule ionophore antibiotic composition, said composition comprising: from 5 to 80% w/w of at least one ionophore antibiotic; from 10 to 90% w/w of at least one filler-binder; from 0.1 to 20% w/w of at least one surfactant; from 0.1 to 20% w/w of at least one dispersing agent; and from 0.1 to 30% w/w of at least one disintegrant.

The water dispersible granule composition as claimed in claim 1, wherein the ionophore antibiotic is monensin, and is present in an amount in the range of about 20 - 40% w/w.

The water dispersible granule composition as claimed in claim 1 or 2, wherein the mean particle size of the ionophore antibiotic is less than 30 microns.

The water dispersible granule composition as claimed in any one of the preceding claims, wherein the filler-binder(s) is/are selected from the group comprising lactose monohydrate, lactose, microcrystalline cellulose, glucose, sucrose, sugars, mannitol, modified sugars, povidone, crospovidone, hydroxypropyl cellulose, ethyl cellulose, celluloses, modified celluloses, pre-gelatinized starch, and combinations thereof.

The water dispersible granule composition as claimed in any one of the preceding claims, wherein the surfactant(s) is/are selected from the group comprising alkyl sulphates, sodium lauryl sulphate, sulphonates, sodium dodecylbenzene sulphonate, carboxylates, dioctyl sodium sulfosuccinate, quaternary ammonium salts, benzalkonium chloride, alkyl betaines, cocamidoalkyl betaines, polyoxyethylene glycol sorbitan alkyl esters, polysorbates, alkoxylates, and combinations thereof.

The water dispersible granule composition as claimed in any one of the preceding claims, wherein the dispersing agent(s) is/are selected from the group comprising lignosulphonates, sodium lignosulphonate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and combinations thereof. The water dispersible granule composition as claimed in any one of the preceding claims, wherein the disintegrant(s) is/are selected from the group comprising microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, hydroxypropyl cellulose, other modified starch and modified cellulose, and combinations thereof.

8. A water dispersible granule ionophore antibiotic composition, said composition comprising: from 20 to 40% w/w of monensin; from 40 to 50% w/w of lactose monohydrate; from 2 to 10% w/w of sodium lauryl sulphate; from 2 to 10% w/w of sodium lignosulphonate; from 10 to 20% w/w of microcrystalline cellulose; and from 2 to 10% w/w of sodium starch glycolate.

9. The water dispersible granule ionophore antibiotic composition as claimed in any one of the preceding claims, wherein the composition is capable of dispersion in water to provide a substantially stable solution of the ionophore antibiotic uniformly dispersed through the water for up to 62 days.

10. A liquid composition comprising an effective amount of the water dispersible granule ionophore antibiotic composition as claimed in any one of the preceding claims, dispersed in water.

11. A method of providing an ionophore antibiotic to an animal, said method comprising mixing an effective amount of the water dispersible granule composition as claimed in any one of claims 1 to 9 with water, and orally administering the composition to said animal.

12. A method of providing an ionophore antibiotic to an animal, said method comprising directly or indirectly adding an effective amount of the water dispersible granule composition as claimed in any one of claims 1 to 9, to the drinking water of said animal.

13. The method as claimed in claim 12, wherein the effective amount is an amount sufficient to achieve a concentration of ionophore antibiotic in the drinking water in the range of from about 1 to 12 mg/L.

14. A method of manufacturing a water dispersible granule ionophore antibiotic composition, said method comprising: milling at least one ionophore antibiotic to a mean particle size of less than 30 microns; mixing said milled ionophore antibiotic with at least one filler-binder, at least one surfactant, at least one dispersing agent, and at least one disintegrant; and granulating the resulting product to form said water dispersible granule composition.

15. A method of manufacturing a water dispersible granule ionophore antibiotic composition, said method comprising: milling at least one ionophore antibiotic with at least one surfactant and at least one dispersing agent, to a mean particle size of less than 30 microns; mixing the resulting milled product with at least one filler-binder, and at least one disintegrant; and granulating the resulting mixed product to form said water dispersible granule composition.

16. The method as claimed in claim 14 or 15, wherein the ionophore antibiotic is milled to a mean particle size of less than about 7 microns.

17. The method as claimed in any one of claims 14 to 16, wherein the milling step comprises a dry milling process.

18. The method as claimed in any one of claims 14 to 17, wherein the granulating step comprises a dry granulation process.