WO2013147618A1

WO2013147618A1 - Ionophore antibiotic suspension

Info

Publication number: WO2013147618A1
Application number: PCT/NZ2013/000049
Authority: WO
Inventors: Karen Yeritsyan; Jeremy SILVA
Original assignee: Donaghys Industries Limited
Priority date: 2012-03-26
Filing date: 2013-03-22
Publication date: 2013-10-03

Abstract

An alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase including at least one polyol and benzyl alcohol and at least one or more of at least one anionic and/or non-ionic surfactant; at least one stabilising agent or water in an amount of less than or equal to 15% v/v of the total formulation. Methods of manufacture of the formulation are also described along with methods of use for selected treatments.

Description

IONOPHORE ANTIBIOTIC SUSPENSION

RELATED APPLICATIONS

This application derives priority from New Zealand Patent Application No. 599028 and New Zealand Patent Application No. 601896, the contents of both incorporated herein by reference.

TECHNICAL FIELD

Described herein are ionophore antibiotic formulations for administration as a veterinary product to animals. Methods of manufacture and use of the formulation are also described.

BACKGROUND ART

Sodium monensin is ionophore antibiotic. When used at appropriate dosages, sodium monensin is known to provide range of advantages in veterinary applications such as the treatment and prevention of ketosis, bloat and also coccidiosis. Sodium monensin may also assist in the enhancement of milk production, enhancement of mineral uptake, efficiency of feed conversion, weight gain improvements and enhancement of reproduction. As a result of these advantages, delivery formulations for sodium monensin are of considerable interest in the veterinary industry along with delivery of ionophore antibiotics generally.

Ionophore antibiotics are however difficult to formulate in easy to deliver suspension owing to their inherent insolubility and hence instability when in liquid state. As a result few suspension products exist and while solid powders may be purchased, they require mixing at use and even then quick settle or separate from the liquid hence are not well suited to drench or oral administration.

Further discussion is made in reference to sodium monensin however it should be appreciated that owing to similar chemical and physical properties, the discussion may equally relate to other types of ionophore antibiotic.

One aqueous suspension for monensin is described in NZ272574. An alternative oil based approach is described in NZ513536.

Patent NZ272574 describes a liquid concentrate that, after dilution, is used as a drench and also can be pre-mixed with liquid vitamins or mineral supplement concentrates. The patent also teaches of the possibility of adding this concentrate to animal drinking water. The patent describes that the formulation achieves a good stability on standing for a prolonged period of time. The inventor's understand that the corresponding commercial product relating to this patent is Rumensin™ Liquid. The very low solubility in water of sodium monensin is addressed in the patent by use of thickening/ stabilsing agents, in particular xanthan gum, to achieve the stated stability.

The above patent refers to an earlier publication, EP013959582, where ionophore antibiotics were mixed with propylene glycol and exposed to ultrasound for two hours in order to achieve the desired stability. Despite all these efforts, only 50% of added sodium monensin was found to be stable and present in the treated solution.

NZ513536 noted above describes an oil based suspension that stably supports ionophore antibiotic or mixture thereof with the majority of antibiotics being contained within the oil system for administering to an animal directly after dilution. NZ513536 shows that ionophore antibiotics can successfully fully be suspended in oil. The specification also shows that, in conjunction with surface active agents and thickening/stabilising agents, the oil based formulation is

microbiologically, chemically and physically stable and also is capable of supporting a wide range of minerals and metabolic additives.

As should be appreciated from the above, providing formulations that are able to address the poor solubility of ionophore antibiotics and provide a liquid suspension are of value, particularly if the product is shelf stable during storage.

For the purpose of this specification the term 'comprise' and grammatical variations thereof shall have an inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements.

Further aspects and advantages of the formulation, method of manufacture and use will become apparent from the ensuing description that is given by way of example only.

SUMMARY

Described herein are shelf stable ionophore antibiotic formulations for administration as a veterinary product to animals. Methods of manufacture and use of the formulation are also described herein.

In a first aspect there is provided an alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase including at least one polyol and benzyl alcohol and at least one or more of the following agents:

(a) at least one anionic and/or non-ionic surfactant;

(b) at least one stabilising agent;

(c) water in an amount of less than or equal to 15% v/v of the total formulation.

In a second aspect there is provided an alcohol based suspension formulation including:

(a) 0.1-50% w/v sodium monensin in an organic liquid phase including at least one polyol and 4-35% w/v benzyl alcohol;

and (b) 3-40% w/v of at least one anionic and/or non-ionic surfactant;

(c) 0.1 to 4.0% w/v of at least one stabilising agent;

(d) 5 to 15% w/v water.

In a third aspect there is provided an ionophore antibiotic formulation including at least one ionophore antibiotic in an alcohol based suspension wherein the suspension includes: at least one stabilising agent, at least one non-ionic and/or anionic surfactant, at least one polyol, benzyl alcohol and water;

wherein the ionophore antibiotic and surfactant system have been milled together in the presence of benzyl alcohol;

and wherein the stabilising agent has been added post-milling and before addition of water.

In the above aspects, the formulation may be diluted with water.

In a fourth aspect there is provided a drench including the formulation or diluted formulation as described above.

In a fifth aspect there is provided a method of manufacturing an alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase, said method including the steps of:

(a) wetting and mixing the ionophore antibiotic with benzyl alcohol and surfactant; and

(b) adding water and/or at least one stabilising agent to the mixture of step (a);

(c) adding at least one polyol to volume to the mixture of step (b).

In a sixth aspect there is provided a method of manufacturing an alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase, said method including the steps of:

(a) mill at least one ionophore antibiotic in the presence of at least one surfactant and benzyl alcohol until a homogenous paste is formed and the antibiotic particle size is less than 50 microns;

(b) mix the paste with at least one polyol;

(c) add at least one stabilising agent to the mixture of paste and polyol(s) and mixing to form a homogenous suspension;

(d) add water and mix.

In a seventh aspect there is provided a method of treatment and/or prevention of bloat, ketosis, coccidiosis and combinations thereof in an animal by oral administration of a formulation or drench as described above.

In an eighth aspect there is provided a method of enhancing milk production from a lactating animal by oral administration of a formulation or drench as described above.

In a ninth aspect there is provided a method of: (a) enhancing mineral uptake of an animal,

(b) increasing the feed efficiency of an animal,

(c) increasing weight gain by an animal,

(d) enhancing reproduction by an animal,

(e) and combinations of the above;

by the step of orally administering a formulation or drench as described above; or by the step of co-administration of the formulation or drench as described above with a mineral supplement formulation.

In a tenth aspect there is provided the use of a formulation or drench as described above in the production of an orally administered medicament for the treatment and/or prevention of conditions selected from: bloat, ketosis, coccidiosis, and combinations thereof.

In an eleventh aspect there is provided the use of a formulation or drench as described above in the production of an orally administered medicament for enhancing milk production from a lactating animal.

In an twelfth aspect there is provided the use of a formulation or drench as described above in the production of an orally administered medicament for:

(a) enhancing mineral uptake of an animal,

(b) increasing the feed efficiency of an animal,

(c) increasing weight gain by an animal,

(d) enhancing reproduction by an animal,

(e) and completing combinations of the above.

Advantages of the formulations, methods of manufacture, methods of treatment and uses thereof should be apparent including enhanced stability during storage and faster/easier manufacture by minimising manufacturing steps and duration of mixing. In the inventor's research, the formulation does not show significant aging over a prolonged period of time. A further advantage is that a wide range of stabilising agents may be used in the current formulation unlike art formulations such as that described in NZ272574 where the only claimed stabilsing agent is xanthan gum. Indeed in the inventor's experience, a number of other stabilising agents show superior aging qualities when used in the present formulation. A yet further advantage is that the alcohol based formulation described maintains an unexpectedly lower viscosity than art water based formulations along for easier handling, pouring, drench administration and easier/lower energy mixing. DETAILED DESCRIPTION

As noted above, shelf stable ionophore antibiotic formulations are described for administration as a veterinary product to animals. Methods of manufacture and use of the formulations are also described herein.

For the purposes of this specification, the term 'about' or 'approximately' and grammatical variations thereof mean a quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 % to a reference quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length.

The term 'substantially' or grammatical variations thereof refers to at least about 50%, for example 75%, 85%, 95% or 98%.

(a) at least one anionic and/or non-ionic surfactant;

(b) at least one stabilising agent;

The ionophore antibiotic may be monensin. The ionophore antibiotic may be sodium monensin. The ionophore antibiotic may be present in a concentration of between about 0.1 % w/v and 50% w/v of total final formulation. Alternatively, the concentration may be between about 0.5, or 1 .0, or 1 .5, or 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, or 10, or 15, or 20, or 25, or 30, or 35, or 40, or 45, or 50% w/v of total final formulation. The concentration may be between about 0.5% w/v and 10% w/v of total final formulation. Alternatively, the concentration may be between about 1 % w/v and 6% w/v of total final formulation. Alternatively, the concentration may be between about 20% w/v and 50% w/v of total final formulation. It should be appreciated that the concentration of active may be varied to suit the desired end product concentration and, by varying the amount of other agents used, the active concentration may be varied accordingly.

The ionophore antibiotic used may be in crystalline form however, the mycelial form may also be used.

In the embodiment where crystalline sodium monensin is used, different particle sizes may be used. By way of example, larger particle sizes may more appropriate for where the formulation is not diluted before application. Formulations that are diluted may suit smaller particle sizes.

The ionophore antibiotic may be milled prior to use. In one embodiment, the milling step is completed after or at the same time as mixing the ionophore antibiotic with benzyl alcohol. In a further embodiment, at least one surfactant may be added to the monensin before or during milling. Milling may be completed using various apparatus including a ball mill, a dyno-mill or a colloid mill.

The particle size of the ionophore antibiotic may be less than 50, or 45, or 40, or 35, or 30, or 25, or 20, or 15, or 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2, or 1 micron particle size. In one embodiment, the formulation may be formulated for administration via a drench and may have a particle size less than 50 micron. In an alternative embodiment, the formulation may be formulated for dilution and may have a particle size less than 5 micron.

The polyol may be a sugar alcohol. The polyol may be selected from: sorbitol, maltitol, xylitol and combinations thereof. The polyol is understood by the inventors to act as a solvent and carrier in the formulation.

Benzyl alcohol may be present in a concentration of about 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11 , or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21 , or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30, or 31 , or 32, or 33, or 34, or 35% w/v of the final formulation. The benzyl alcohol may be present in a concentration of about 4 to 35% w/v of total formulation. The benzyl alcohol may be present in a concentration of about 4 to 20% w/v of total formulation. Benzyl alcohol may be present in a concentration of about 6 to 15% w/v of total formulation. The benzyl alcohol is understood by the inventors to act as a co-solvent and carrier in the formulation.

Benzyl alcohol has been found by the inventors to be particularly beneficial in the above described formulation. Besides being useful as a solvent and carrier for suspended matter, benzyl alcohol also has acts as a preservative and as an anti-foaming agent. Both of these properties are helpful in the present formulation as they act to extend the shelf stability of the formulation and minimise foaming during mixing, both being problems with art formulations.

The organic liquid phase including polyol and benzyl alcohol may be at least approximately 70%, or 75%, or 80%, or 85%, or 90%, or 95% of the total solvents in the formulation.

The surfactant(s), stabilising agent(s) and water may all be present in the liquid concentrate formulation.

Non-ionic surfactants where used may be selected from: alcohol ethoxylates, alcohol ethoxylates propoxylates, alkyl polyglucosides, EO/PO block co-polymers, polysorbates, lanolin ethoxylates, and combinations thereof. In one embodiment, the non-ionic surfactant may be C₉- On alcohol ethoxylated propoxylate.

Anionic surfactants where used may be selected from: alkyl benzene sulphonic acids and /or their salts, sodium lignosulphonate and combinations thereof.

Total surfactant that may be present in the formulation may be at a rate of about 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11 , or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21 , or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30, or 31 , or 32, or 33, or 34, or 35, or 36, or 37, or 38, or 39, or 40% w/v. The total surfactant that may be present in the formulation may be at a rate of about 3% to 40% w/v. The total surfactant that may be present in the formulation may be at a rate of about 3% to 35% w/v.

The stabilising agent may be selected from: a gum or gums, polyvinylpyrrolidone, microcrystaliine cellulose, carboxymethyl cellulose and combinations thereof. The gum may be selected from: xanthan gum, guar gum, locust bean gum and combinations thereof. As may be appreciated, the desired viscosity of the final formulation may determine the choice of stabiliser and the concentration used as the stabilising agents may also vary the viscosity of the formulation.

Viscosity increases may be the result of cross-linking reactions. The amount of stabilising agent may be from about 0.1 , or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1 , or 1.5, or 2, or 2.5, or 3, or 3.5 or 4% w/v of total final formulation. The amount of stabilising agent may be from about 0.1 % w/v to about 4% w/v of total final formulation. The amount of stabilising agent may be from about 0.1 % w/v to about 2% w/v of total final formulation.

The final formulation viscosity may be less than or equal to 8000, or 7000, or 6000 or 5000cps, or 4000cps, or 3000cps, or 2000cps. The viscosity may be less than or equal to 2000cps. The inventor has found that the formulation described herein is lower than art formulations therefore making the formulation easier to handle such as when pouring the formulation, when administering the formulation via a drench or when diluting formulation. A comparison trial completed by the inventor between the alcohol based formulation described herein and an art water-based formulation identified that the alcohol based formulation described herein had an unexpectedly and dramatically lower viscosity (3.6 to 4.2 times lower) particularly at lower shear rates. A lower viscosity and low shear rates means easier mixing for less energy input meaning better and easier mixing or handling. Having to exert large amounts of energy in order to mix the formulation or pour it is not ideal as, besides added labour or energy costs, mixing may not be as complete as desired. A lower viscosity particularly at low energy inputs is preferable.

Water if present may form about 5, or 6, or 7, or 8, or 9, or 10, or 11 , or 12, or 13, or 14, or 15%w/v of the total final formulation. Water may form about 5%w/v to 15%w/v of the total final formulation. Water may form about 5%w/v to 10%w/v of the total final formulation. Water may form about 7%w/v to 12%w/v of the total final formulation. Water may form about 10%w/v to 15%w/v of the total final formulation. The water is understood to act as a co-solvent and carrier in the formulation.

Additional pharmaceutically and physiologically acceptable agents may also be added.

In one embodiment, certain alcohol ethoxylates and alcohol ethoxylates propoxylates may be used to enhance the bloat treatment effects of the formulation.

Other formulation aids, such as colouring agents, additional antimicrobials, buffering agents, pH adjusters and antifoaming agents may also be added depending on the end application or desired characteristics. These aids are preferably non-toxic and suitable for oral administration.

One example of a colouring agent may be Dye Carmoisene Red.

One example of an antimicrobial may be benzalkonium chloride. One example of a buffering / pH adjusting agent may be triethanolamine.

In one embodiment, the final pH of the formulation may be about 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, or 10.0. The range may be from 4.0 to 10.0. The range may be from 5.0 to 8.0. The range may be from 5.5 to 7.5. The range may be from 6.0 to 7.0.

The above formulation may be a concentrate that may be diluted with a suitable solvent such as water for oral administration. The formulation may be stored and sold in diluted form. In an alternative embodiment, the formulation may be stored and used in a concentrated form, being administered orally as a drench. The inventors have found that the concentrate formulation remains shelf stable i.e. it remains in suspension, minimal change in weight occurs over storage time periods and the product maintains a consistent viscosity during storage. Storage stability may be under conditions of 45°C for 3 weeks representing highly challenging conditions. Art water based formulations for example exhibit poorer shelf stability such as lost of noticeable amount of solvent when stored under the same conditions.

0.1-50% w/v sodium monensin in an organic liquid phase including at least one polyol and 4-35% w/v benzyl alcohol;

and

(a) 3-40% w/v of at least one anionic and/or non-ionic surfactant;

(b) 0.1 to 4% w/v of at least one stabilising agent;

(c) 5 to 15% w/v water.

In the above aspect, the polyol as added to form the balance of the formulation i.e. added to q.s. or 100%.

In the above aspects, the formulation may be diluted with water. By way of example the rate of dilution may be 1 , or 2, or 3, or, 4, or 5, or 6, or 7, or 8, or 9, or 10, or 15, or 20, or 25ml formulation added to 50ml of water.

In a fourth aspect there is provided a drench including the formulation or diluted formulation as described above. In a fifth aspect there is provided a method of manufacturing an alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase, said method including the steps of:

(a) wetting and mixing the ionophore antibiotic with benzyl alcohol and surfactant; and (b) adding water and/or at least one stabilising agent to the mixture of step (a);

(c) adding at least one polyol to volume to the mixture of step (b).

The inventors have established that using the correct order of addition of agents, particularly surfactant(s), benzyl alcohol, stabilising agent(s) and water unexpectedly and significantly influences the stability of the ionophore antibiotic in the formulation. Use of the steps outlined above overcame art issues of instability whilst also allowing relatively fast preparation unlike art methods that need considerably longer processing time.

In the above aspect, step (a) is completed before the presence of water.

In the above method, step (a) may be completed before milling of the ionophore antibiotic or at the same time as milling occurs.

(b) mix the paste with at least one polyol;

(d) add water and mix.

In the above aspect, the ionophore is crystalline sodium monensin.

The surfactant(s) and benzyl alcohol may be added prior to or at the same time as milling is completed. In one embodiment the surfactant(s) and benzyl alcohol are added immediately prior to milling or within 5-10 minutes of milling.

One of the surfactants present during milling step (a) may be C₉-Cn alcohol ethoxylated propoxylate. A commercial example of this surfactant is Terwet 245™ manufactured by

Huntsman™.

A further surfactant that may be present during milling step (a) may be at least one EO/PO block co-polymer surfactant. Commercial examples of such surfactants include the Pluronic PE™ range of products manufactured by BASF™.

Anionic surfactants that may also be used during milling step (a) include alkyl benzene suiphonic acids or their salts. Commercial examples of these surfactants may be sold as LABSA™ or calcium dodecylbenzene sulphonate, or sodium lignosulphate.

In one embodiment, the surfactants used may be Terwet 245™ and Pluronic PE6200™ mixed at a ratio of about 2:1 to 1 :5. The examples provided are given by way of example and it should be understood that a wide variety of other surfactants may also be used.

Milling in step (a) may continue until the particle size is less than 45, or 40, or 35, or 30, or 25, or 20, or 15, or 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2, or 1 micron particle size.

Mixing in step (b) and subsequent steps may occur in a mixing vessel with an agitator.

Step (b) may be completed by first adding the polyol to the mixing vessel and then adding the paste of step (a). In one embodiment, approximately 50%, or 55%, or 60%, or 65%, or 70%, or 75%), or 80%, or 85%, or 90%, or 95% parts of the total polyol content are added to the mixing vessel in step (b) with the remainder of the polyol added after the addition of water to the mixture.

Mixing in step (c) may occur for approximately 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11 , or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20 minutes.

Mixing in step (d) may occur for approximately 1 , or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11 , or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20 minutes. Mixing in step (d) may end when the desired viscosity is reached. As may be appreciated, the formulation tends to increase in viscosity during mixing dependent on the various agents used, in particular dependent on what stabilising agents are used. Gums for example tend to thicken once mixed with liquids as cross-linking occurs.

In a ninth aspect there is provided a method of:

(a) enhancing mineral uptake of an animal,

(b) increasing the feed efficiency of an animal,

(c) increasing weight gain by an animal,

(d) enhancing reproduction by an animal,

(e) and combinations of the above;

(a) enhancing mineral uptake of an animal,

(b) increasing the feed efficiency of an animal,

(c) increasing weight gain by an animal,

(d) enhancing reproduction by an animal,

(e) and completing combinations of the above.

In the above aspects, the animal may be a non-human animal. The non-human animal may be selected from the genus: bovine, cervine, ovine, equine or caprine. The animal may be a cow, a dairy cow, calf, steer, deer, sheep, lamb, horse or goat. Other animals may also be treated and this list is provided by way of example only.

As may be appreciated, the above manufacturing method is faster than art methods as the stabilising step time period is minimised. By way of example, in art methods the procedure of adding stabilising agent into the system usually involves dispersing it in a water miscible liquid and adding this mixture into the system to avoid the agent not being dispersed particles of stabilising agent formulation. For example, a common technique is to make a paste of stabilising agent in glycerin or propylene glycol and then carefully adding the formed paste to a water system. It is also usual to allow this paste to stand for up to 24 hours to ensure complete hydration of the polymer. By contrast, in the above method, stabilising agent is added either at the stage of milling (if milling is completed) or in to the reaction vessel during the manufacturing process before water is added. This avoids tricky handling, speeds the manufacturing process, and avoids the additional step of stabilising agent paste preparation.

Advantages of the formulation should be apparent including enhanced stability during storage. In the inventor's research, the formulation does not show significant aging over a prolonged period of time. Another advantage is that a wide range of stabilising agents may be used in the current formulation unlike art formulations such as that described in NZ272574 where the only claimed stabilising agent is xanthan gum. Indeed, in the inventor's experience, a number of other stabilising agents show superior aging resistance when used in the present formulation. A further advantage is that the formulation exhibits an unexpectedly lower viscosity particularly at lower shear rates than existing art water based formulations allowing for easier handling, lower energy requirements for formulating and diluting and greater homogeneity in mixtures containing the alcohol based formulation described herein. The embodiments described above may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which the embodiments relates, such known equivalents are deemed to be incorporated herein as of individually set forth,

Where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.

WORKING EXAMPLES

The above described formulations, methods of manufacture, methods of treatment and uses thereof are now described by reference to specific examples.

EXAMPLE 1

As noted above, an ionophore antibiotic useful is sodium monensin. Three formulations and the amounts of each agent are illustrated below in Tables 1 to 3.

Table 1 - Example Formulation

Agnique PG8107 12% w/v

Carrier, Co-solvent Benzyl alcohol 4% w/v

Carrier, Co-solvent Water 10% w/v

Stabilising Agent Guar gum 0.6% w/v

Carrier, Solvent Sorbitol To volume q.s.

Table 3- Example Formulation

Function Agent Concentration

Active Agent Sodium monensin 6% w/v

Surfactant(s) Pluronic PE6200 12% w/v

LABSA 15% w/v

Carrier, Co-solvent Benzyl alcohol 7% w/v

Carrier, Co-solvent Water 12% w/v

Stabilising Agent Carboxymethyl cellulose 1 % w/v

Carrier, Solvent Glycerin To volume q.s.

EXAMPLE 2

Other formulation aids, such as colouring agents, additional antimicrobials, buffering agents, pH adjusters and antifoaming agent may also be added depending on the end application or desired characteristics. An example formulation using other agents is described in Table 4 below.

Table 4- Example Formulation With Extra Formulation Aids

Preservative / Anti-microbial Benzalkonium chloride 0.05 pH Adjusting Agent Triethanolamine 0.2-1

Colouring Agent Dye Carmoisene Red 0.01

Carrier, Solvent Sorbitol To volume q.s.

Final pH 4 to 10

EXAMPLE 3

As noted above, the method of manufacture of the formulation contains important steps and the order of mixing may also be important to conferring the observed stability. In this example, a method of manufacture is described.

Ingredients:

Crystalline sodium monensin 90% - 6.66% (equivalent to 6% of Sodium monensin)

Benzyl alcohol: 4.0%

Water: 10%

Surfactants: Pluronic PE6200: 18%(EO/PO block co-polymers), Terwet 245: 12% (Cg-Cn alcohol ethoxylated propoxylate)

Anti-microbial: Tecsol BAC50: 0.1 % (50% benzalkonium chloride),

Stabilising agent: guar gum: 0.6%,

Polyol: sorbitol - up to 100% volume or q.s.

Process of making WOOL:

66.67 kg sodium monensin is milled with 180kg Pluronic PE6200 in the presence of 40 kg benzyl alcohol. The product after milling is a paste with a mean particle size of sodium monensin of approximately 1 micron.

Without stopping the milling process, 120kg of Terwet 245 is added to the vessel and milling continued for another 10-15 min.

Separate to the above paste formation and milling step, a mixing vat is filled up with 300kg of a calculated amount of sorbitol and 6kg of guar gum is added. The mixture is then stirred until a homogeneous mixture forms.

The milled paste noted above is then slowly added to the vat containing sorbitol and guar gum. Additional sorbitol may also be added at this stage.

If any additional formulation aids are used in the final product, they may also be added after the paste is completely dispersed through whole liquid system.

Once the paste has been added, the mixture is then agitated for another 10-15 minutes and 100L of water is added.

The mixture is brought to 1000L volume using the remaining amount of sorbitol.

If required, the pH may be adjusted at this stage by adding small amounts of pH adjuster such as triethanolamine.

When product is completely homogenous, the mixer may be turned off. The viscosity of the mixture tends to increase on standing.

EXAMPLE 4

The final formulation properties were studied and the findings noted below.

It was surprisingly found that product manufactured by the method described in Example 3 has a viscosity much lower than it is expected for water based suspensions, without affecting final composition stability as concentrate or as already diluted product. This result is highly advantageous, especially when the dilution rate has to be precise. High viscosity makes it very hard to measure the exact amount of product especially if dose rate is only several millilitres.

The resulting product illustrated good stability at a wide temperature range for at least 28 days with no significant aging observed.

EXAMPLE 5

The product is typically administered by oral drench. In order to administer the formulation, the farmer or user typically dilutes the concentrate immediately prior to administration. The dilution process and subsequent stability were analysed.

Samples of formulated product were diluted to appropriate for administrating rate with water at rate of 5ml per 50ml of final solution.

The diluted suspensions were stored at 15°C, 25°C and 30°C to determine the suspension stability.

All examined samples did not show any significant aging for 18 hours.

It was surprisingly found that invention stays pretty stable for some time even without any stabilising agent enclosure when prepared correctly for at least 7 days, after that some aging was noticeable, however sediments were easily re-dispersed after slight mixing and still fell into acceptable parameters for suspension concentrates. No hard or non-dispersible precipitate was observed.

EXAMPLE 6

As demonstrated above, the formulation can if desired be diluted. In anticipated trials, the method of treatment is expected to involve the steps of optionally diluting the formulation followed by oral administration via a drench. No adverse reactions are anticipated owing to the non-toxic and common nature of the agents used. Efficacy is anticipated to be the same or better than existing ionophore antibiotic formulations owing to the biocompatible nature of the agents used.

EXAMPLE 7

As noted above, a wide variety of polyols, stabilising agents and monensin concentrations may be used.

An alternative embodiment using varying ingredients is described below in Table 5. Table 5 - Example Formulation using different polyol, stabilisers and surfactants

EXAMPLE 8

An alternative embodiment using varying ingredients is described below in Table 6.

Example Formulation using different polyol, stabilisers and surfactants and monensin concentration

EXAMPLE 9

An alternative embodiment using varying ingredients is described below in Table 7.

Stabilising Agent Carboxymethyl cellulose 0.6%

Carrier, Solvent Maltitol syrup 25%

Preservative / AntiBenzalkonium chloride 0.05%

microbial

Carrier, Solvent Sorbitol To volume q.s.

The above formulation (and those of Example 7 and 8) exhibit at least comparable stability characteristics as art commercialised water based suspensions of sodium monensin. In addition, the above formulations are much easier to dilute compared to water based market standard suspension, as they requires only light agitation to achieve complete dilution. Other art formulations require intense agitation for a longer duration to achieve full dilution.

EXAMPLE 10

It was surprisingly found that formulation described herein has a far lower viscosity compared to commercially available water based sodium monensin formulations. Lower viscosity makes mixing, handling and dosing easier.

To verify the above, measurements were performed by independent laboratory using a rotational ViscoStar Plus™ viscometer. The method involved the step of immersing a sensing element in the analysed fluid and driving the meter at a constant rotational speed. The measured viscosity is related to the torque generated by the fluid resistance to the induced movement and is hence determined by measuring the tightening of the spiral spring attached to the spindle (internal). This method is based on measuring the resistance of a fluid, when an internal force is applied which induces it to move under set conditions.

Results are presented in Table 8 below.

Table 8 - Viscosity comparison between an alcohol based monensin formulation described herein and a commercially available water based monensin formulation

50 824 CP 1658 cP

60 763 cP 1420 cP

100 618 cP 932 cP

200 467 cP 540 cP

As noted above, the viscosity of the alcohol based monensin formulation was dramatically lower than water formulations - at low mixing speeds/agitation, the alcohol based formulation was 3.6 to 4.2 times less viscous than the equivalent water based formulation. More vigorous agitation (equating to greater energy input) reduced the difference although the alcohol based formulation still had a consistently lower viscosity. As should be appreciated, lower agitation rates and lower viscosity is preferable to help speed the mixing process and to minimise the amount of energy required during mixing. EXAMPLE 1 1

A further experiment was completed to further investigate and confirm the stability of the alcohol- based formulation.

A sample of the formulation described in Example 1 was stored at 45°C for 3 weeks to represent accelerated aging. For comparison purposes, a commercially available water based formulation was also stored alongside the alcohol-based formulation under the same storage conditions.

At the conclusion of the trial, both samples were examined for any significant changes in appearance, such as precipitation formation, coagulation of dispersed particles or separation of phases.

No observable changes were noticed in the alcohol-based formulation with the product remaining as a homogenous and viscous liquid. A weight comparison was made and the sample had a weight lost of 0.57% over the trial time period. The viscosity of alcohol based formulation sample did not significantly changed and product was free flowing on pouring.

By contrast, the water based formulation comparison sample had total weight loss of 2.92%. Storage of the water-based formulation also adversely affected the formulation viscosity, with the sample becoming very thick and hard to pour to the point where the viscosity resembled a thick gel.

The alcohol-based formulation was also tested for storage stability once diluted replicating the use that might occur on a farm. Dilution at a rate of 1 :100 with distilled water was completed and the formed suspension was then left to stand for 6 hours. On review after 6 hours, no noticeable change in appearance, such as precipitation formation, coagulation of dispersed particles or separation of phases was noted confirming ample stability for proposed applications of the formulation.

EXAMPLE 12

Preparation of the formulation described herein was also found to be easier and faster than other art formulations.

Depending on end purpose of the alcohol based formulation described herein, different particle sizes can be employed. Further, it is possible to formulate the product to suit the scenario where dilution occurs prior to application or instead where an undiluted formulation is applied. As may be appreciated, the particle size may vary depending on whether or not dilution is to occur. By way of example only, the inventor has found that for dilution, a particle size range of 1-5 micron may be preferable while drench formulations may have a particle size range from 1 to 50 microns.

As a further example, a formulation, (Formulation A) was prepared and milled by using a laboratory ball mill. Formulation A included the compounds noted in Table 9 below.

Table 9 - Formulation A compounds

The process of manufacture involved the following two step process:

(a) all ingredients were loaded in mixing vessel and mixed for 15-20 minutes;

(b) the mixture was added into a ball mill and wet milling was carried until a desirable consistency of suspension was achieved.

The formed suspension was of a more coarse particle size (5 to 50 micron) which proved excellent for administration via a drench applicators and can be used without dilution.

To produce a product better suited to dilution applications, the method above may be completed in the same manner however, milling may be completing using a laboratory scale Dyno-Mill™ mill. The product may be re-milled multiple times until a desired particle size is reached. In this example, the product obtained from the mill (less than 5 micron) shows excellent stability, making it suitable for both drench application and for administration via dilution methods such as in a drinking trough.

Another type of mill that may be used for fine milling is a colloid mill.

As can be seen from the above example, the processing method does not require any special steps, is a one mixing vessel process and occurs relatively quickly. EXAMPLE 13

An alternative method of preparation is described.

Broadly, the alternative method involves the steps of:

(a) ionophore antibiotic weighed and milled with at least one surfactant in presence of benzyl alcohol until a homogenous paste forms and the and particle size is less than 20 microns;

(b) the formed paste is then added to a mixing vessel which has been filled up with 2/3 of calculated amount of sugar alcohol;

(c) stabilsing agent, if has not been included in milling step, is weighed and added to the mixing vessel;

(d) the mixture is agitated for 10-15 minutes or until it is completely homogenous;

(e) the required amount of water is then added and the mixture brought up to required volume with sugar alcohol;

(f) the product is then mixed for 10-15 minutes or until the desired viscosity is achieved.

Optionally, the particle size noted in step (a) may be as low as 1 micron depending on the final characteristics desired.

Due to the small amount of water utilised, it is possible to not have to be concerned about longer mixing time. Water based formulations by contrast are time critical where over mixing may result in a rapid increase in viscosity to the point where the product is not able to be used in pouring type applications.

As should be appreciated, the above method (and that described in Example 12 above) are less complicated to manufacture than art water-based or oil based formulation methods.

Aspects of the formulations, methods of manufacture, methods of treatment and uses thereof have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope of the claims herein.

Claims

WHAT IS CLAIMED IS:

1. An alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase including at least one polyol and benzyl alcohol and at least one or more of the following agents:

i. at least one anionic and/or non-ionic surfactant;

ii. at least one stabilising agent;

iii. water in an amount of less than or equal to 15% v/v of the total formulation.

2. An alcohol based suspension formulation including:

and

(b) 3-40% w/v of at least one anionic and/or non-ionic surfactant;

(c) 0.1 to 4% w/v of at least one stabilising agent;

(d) 5 to 15% w/v water.

3. An ionophore antibiotic formulation including at least one ionophore antibiotic in an alcohol based suspension wherein the suspension includes: at least one stabilising agent, at least one non-ionic and/or anionic surfactant, at least one polyol, benzyl alcohol and water;

4. The formulation as claimed in any one of the above claims wherein the formulation is diluted with water.

5. A drench including the formulation as claimed in any one of claims 1 to 3 or the diluted formulation as claimed in claim 4.

6. A method of manufacturing an alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase, said method including the steps of:

(b) adding water and/or at least one stabilising agent to the mixture of step (a); (c) adding at least one polyol to volume to the mixture of step (b).

7. A method of manufacturing an alcohol based suspension formulation including a therapeutically effective amount of at least one ionophore antibiotic in an organic liquid phase, said method including the steps of:

(b) mix the paste with at least one polyol;

(d) add water and mix.

8. A method of treatment and/or prevention of bloat, ketosis, coccidiosis and combinations thereof in an animal by oral administration of a formulation as claimed in any one of claims 1 to 4 or the drench as claimed in claim 5.

9. A method of enhancing milk production from a lactating animal by oral administration of a formulation as claimed in any one of claims 1 to 4 or the drench as claimed in claim 5.

10. A method of:

(a) enhancing mineral uptake of an animal,

(b) increasing the feed efficiency of an animal,

(c) increasing weight gain by an animal,

(d) enhancing reproduction by an animal,

(e) and combinations of the above;

by the step of orally administering a formulation as claimed in any one of claims 1 to 4 or the drench as claimed in claim 5; or

by the step of co-administration of the formulation as claimed in any one of claims 1 to 4 or the drench as claimed in claim 5 with a mineral supplement formulation.

11. Use of a formulation as claimed in any one of claims 1 to 4 or the drench as claimed in claim 5 in the production of an orally administered medicament for the treatment and/or prevention of conditions selected from: bloat, ketosis, coccidiosis, and combinations thereof.

12. Use of a formulation as claimed in any one of claims 1 to 4 or the drench as claimed in claim 5 in the production of an orally administered medicament for enhancing milk production from a lactating animal.

13. Use of a formulation as claimed in any one of claims 1 to 4 or the drench as claimed in claim 5 in the production of an orally administered medicament for:

(a) enhancing mineral uptake of an animal,

(b) increasing the feed efficiency of an animal,

(c) increasing weight gain by an animal,

(d) enhancing reproduction by an animal,

(e) and completing combinations of the above.

Donaghys Industries Limited

By their attorneys

CreatelP

Per: