NZ549424A

NZ549424A - Anthelmintic formulations

Info

Publication number: NZ549424A
Application number: NZ549424A
Authority: NZ
Inventors: Majid Hameed Abdul Razzak; Ranjith Srilal Gamage; Bantupalli Rao
Original assignee: Merial Ltd
Priority date: 2002-12-12
Filing date: 2002-12-12
Publication date: 2010-02-26

Abstract

Disclosed is a multiple active veterinary formulation comprising: at least one first active; at least one second active which has incompatible formulation requirements to the first active(s); a liquid carrier; a solvent; and a sorbing medium, wherein the first active or each of the first actives is compatible with and carried in the liquid carrier, and the second active or each of the second actives is compatible with the solvent, and the sorbing medium contains both (a) the second active(s) and (b) the solvent, to form a chemically stable suspension in the liquid carrier.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 549424 Patents Form # 5 5 4 9 4 2 4 *10056615790* DIVISIONAL OUT OF APPLICATION NO. 540499 ANTE-DATING REQUESTED TO 29 JANUARY 2004 NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION Title: ANTHELMINTIC FORMULATIONS We, ASHMONT HOLDINGS LIMITED Address: First Floor, 17 Shea Terrace, Takapuna, Auckland, New Zealand Nationality: A New Zealand company do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - OOW926NZC_Divpat_20060823_1400_SEP.doc FEE CODE - 1010 2 Pharmaceutical Formulation and a Method of Making Same FIELD OF THE INVENTION This invention relates to pharmaceutical formulations, their preparation and their use in veterinary applications. 5 More specifically, the present invention relates to methods of making multi-active formulations which are capable of stably integrating multiple actives. BACKGROUND It is often desirable to administer a combination of actives. A mixture may be required for effective management of a condition, or the combination may provide an advantageous result 10 over the administration of a single active. In most human health situations the administration of multiple formulations containing a single active is acceptable. However, in circumstances where mass administration of a number of different actives is required, it is advantageous if a combination of the actives can be administered in the same formulation. This is especially the case when inoculating a large 15 proportion of the population or in the case of veterinary applications where a herd of animals may require treatment. In some cases, the actives to be co-administered will have overlapping formulation requirements and therefore should be able to co-exist stably in the formulation. However, in many cases, the actives to be co-administered will have conflicting formulation 20 requirements or may actively degrade each other. By way of example, levamisole is soluble in water-based formulations and requires an acidic pH for stability. By contrast avermectins are substantially insoluble in water. If formulated in water based formulations avermectins require a neutral pH for stability. Therefore, in the acidic pH required by levamisole the avermectins are likely to degrade. G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual property office of n.z 2 u K3V mi RECEIVf 1 3 In addition to the need for finding a formulation in which each of the actives can be stably integrated, it is important that the formulation is practical to use. That is, it should be able to be stored for say up to a year without significant physical or chemical changes taking place. The relative proportions of the components should not change significantly over time. In addition, 5 while some sedimentation is to be expected, the sediment should be easily re-dispersed on shaking. In addition, it is important that the formulation does not cause excessive side effects in the animal. The formulation should be relatively easy to administer and should be of suitable flowability to allow delivery by injection and drench. 10 Various attempts have been made to produce effective combined active formulations with limited success. One such attempt is set out in New Zealand Patent Application No. 336139 (a New Zealand equivalent of International Patent Application No. PCT/NZ00/00087, published as WO 00/074489), which relates to a storage stable veterinary composition in the form of an emulsion, 15 comprising an aqueous phase containing a first active agent such as levamisole and an organic phase containing a further anthelmintic active agent wherein the organic phase is emulsified in the aqueous phase. However, this suspo-emulsion method, as it is known, tends to result in a formulation that is highly viscous and flows poorly. As such, it is difficult to administer. Accordingly there is a need for an improved formulation capable of integrating a number of 20 actives together and a method of manufacturing the same. OBJECT It is an object of the present invention to provide an improved multi-active formulation and a method of making the same or one that will at least provide the public with a useful choice. STATEMENT OF THE INVENTION 25 In one aspect the invention comprises a method of manufacturing a stable multiple active veterinary formulation comprising the steps of: a) Dissolving an active in a solvent; G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual propertv office of n.z I U kUV Ml RECEIVED, 4 b) Sorbing the solvent containing active composition on to a sorbing medium; and c) Dispersing the sorbing medium loaded with the solvent composition in a liquid to form a suspension, wherein the liquid contains at least one further active dissolved or suspended therein. 5 The method requires the dissolving of a first active in a suitable solvent. This solution is sorbed onto a sorbing medium such as silicon dioxide (e.g. Aerosil R972). This active loaded medium is then dispersed in a liquid to form a suspension. "Solvent" means an oil or water immiscible liquid having good solubility for the active(s) and being able to sorb onto the silica or other sorbing medium to physically separate the active(s) 10 from the liquid. "Sorb and sorbing" is used to include the absorption and adsorption processes. "Active" includes compounds which provide a health advantage or benefit to an animal to which the formulations referred to herein are administered. Active includes vitamins, minerals, anthelmintics, antigens and the like. 15 "Liquid" refers to a liquid carrier including one or more actives dissolved or suspended therein. The liquid may be a water or oil based liquid depending on the nature of the actives/solvent and sorbing medium to be used in the formulation. In a preferred formulation the liquid will be an aqueous vehicle, that is, it will be water based and will include a water soluble active dissolved therein. It is envisaged however that the liquid 20 may also include a further active suspended therein. The liquid may also include excipients such as defoaming agents, buffering agents, suspension aids, or viscosity inducing agents such as sodium carboxy methylcellulose, guar gum, karaya gum or xanthan gum. In addition, preservatives, such as methyiparaben, propylparaben and their salts may be used to prevent degradation of the formulation. A defoamer, such as a silicon 25 emulsion can be used as a lubricant. G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual property office of n.z 2 5 KOI/ sag i IV E r* "Sorbing medium" refers to a solid preferably in the form of a powder or particulate matter (or which solid can be processed into powder or particulate matter) which is capable of adsorbing or absorbing a liquid or gas. The sorbing medium may be hydrophobic or hydrophilic in nature depending on the nature of 5 the active(s) and solvent(s) to be sorbed thereon. Suitable sorbing mediums include, by way of example, magnesium aluminometasilicate, cellulose, microcrystalline cellulose, diatomaceous earth, montmorillonite, bentonite, titanium dioxide, amorphous silicon dioxide, colloidal silicon dioxide, calcium carbonate, talc (SiQ2+MgO), attapulgite (silicon, aluminium and iron oxides clay) and kaolin (aluminum 10 silicate). These sorbing mediums are hydrophobic and/or hydrophilic to different degrees. Suppli ers will usually specify the degree of hydrophobicity or hydrophilicity of the medium. These sorbing mediums exhibit large specific surface area and have high adsorption or absorption capacity and can be used to sorb the solvent-containing active. Hydrophobic fumed silica is also suitable for this application, as it tends to produce a less 15 viscous product when mixed with oil. The oil adsorption capacity is very good and the resulting mix is free flowing and can be dispersed easily within the bulk of the aqueous formulation. It is important when arriving at the combination of actives and solvents to be used that the active and solvent that is sorbed on to the sorbing medium should be incompatible with the liquid in which the active loaded sorbing medium is dispersed. By way of example if a 20 lipophilic active, such as an avermectin is dissolved in a lipophilic solvent such as Capmul MCM and loaded onto Aerosil, the liquid should be an aqueous based liquid. The inventive step is therefore in the new technique or method of "packaging" actives which have different formulation requirements and which would otherwise be incompatible with each other and with the medium in which they are carried. For example, a first active is dissolved in 25 a first liquid and then sorbed onto or into a particular sorbing medium which is then dispersed to form a suspension in a second liquid in which the first active would otherwise have been incompatible. The second liquid includes a second active which has different formulation requirements to the first active. Therefore, the new technique or method of "packaging" the first active using a sorbing medium allows it to be included in a stable formulation with the G:\OOW926NZC Amended Spec clean copy 27Nov07.doc IMTFI I FPTII Al DDnp'i intellectual property office of n.z 2 £ M'OV 2C27 second active. In this manner, stable formulations containing multiple actives (that is, two or more) can be produced. Although the first active is dissolved in a first liquid, it is effectively a solution "hidden" inside a solid which is effectively suspended in the second liquid. The invention encompasses two different versions of a formulation. The first version of the formulation includes at least one lipophilic active dissolved in a lipophilic solvent, then packaged in such a way that the resulting lipophilic solution is carried by a lipophilic (i.e. hydrophobic) sorbing medium which is dispersed to form a suspension in an aqueous solution containing at least one hydrophilic active dissolved or suspended therein. The second version of the formulation includes at least one hydrophilic active dissolved in an aqueous solvent, then packaged in such a way that the resulting hydrophilic solution is carried by a hydrophilic sorbing medium which is dispersed to form a suspension in a lipophilic (i.e. hydrophobic) solution containing at least one lipophilic active dissolved or suspended therein. Accordingly, in a further aspect the invention relates to a multiple active veterinary formulation comprising: at least one first active; at least one second active which has incompatible formulation requirements to the first active(s); a liquid carrier; a solvent; and a sorbing medium, wherein the first active or each of the first actives is compatible with and carried in the liquid carrier, and the second active or each of the second actives is compatible with the solvent, and the sorbing medium contains both (a) the second active(s) and (b) the solvent, to form a chemically stable suspension in the liquid carrier. Preferably, the first active or each of the first actives is a hydrophilic active; the second active or each of the second actives is a lipophilic active; the liquid carrier is an aqueous liquid; and the solvent is a lipophilic solvent G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual property office of n.z. 2 8 NOV 2007 7 Alternatively, the first active or each of the first actives is a lipophilic active; the second active or each of the second actives is a hydrophilic active; the liquid carrier is a non-aqueous liquid; and the solvent is an aqueous solvent. 5 In still a further aspect the invention relates to a multiple active veterinary formulation comprising: a non-aqueous liquid carrier; at least one lipophilic active in solution with the non-aqueous liquid carrier; at least one hydrophilic active; 10 an aqueous solvent; and a sorbing medium, wherein the sorbing medium is hydrophilic and is adapted to contain both (a) the hydrophilic active(s) and (b) the aqueous solvent, to form a chemically stable suspension of the sorbing medium in the non-aqueous liquid carrier. 15 In still a further aspect the invention relates to a multiple active veterinary formulation comprising: an aqueous liquid carrier; at least one hydrophilic active in solution with the aqueous liquid carrier; 20 at least one lipophilic active; a lipophilic solvent; and a sorbing medium, wherein the sorbing medium is hydrophobic and is adapted to contain both (a) the lipophilic active(s) and (b) the lipophilic solvent to form a chemically stable suspension of the sorbing medium in the aqueous liquid 25 carrier. Preferably, the lipophilic active or each of the lipophilic actives is selected from the group comprising avermectins and milbemycins. 30 Preferably, the non-aqueous liquid carrier is selected from the group comprising oils and organic solvents. G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual property office of n.z 2 S K3V 2007 RECEIVED 8 Preferably, the lipophilic solvent is selected from the group comprising oils and organic solvents. More preferably, the lipophilic solvent is selected from the group comprising medium chain mono-/di-glycerides. 5 Preferably, the hydrophilic active or each of the hydrophilic actives is selected from the group comprising vitamins, minerals, anthelmintics and antigens, or combinations thereof. More preferably, the hydrophilic active, or at least one of the hydrophilic actives is an anthelmintic and the anthelmintic is selected from the group comprising thiazole derivatives such as levamisole or a salt thereof; benzimidazole derivatives such as albendazole, oxfendazole, 10 fenbendazole, mebendazole; acylated quinoline such as praziquantel; and benzenesulphanamides such as clorsulon and closantel. Alternatively or additionally, the hydrophilic active or at least one of the hydrophilic actives is a mineral and the mineral is selected from the group comprising selenium salts, cobalt salts, 15 copper salts, zinc salts, iodine salts and their chelates. Preferably, the sorbing medium is selected from the group comprising magnesium ahiminometasilicate, cellulose, microcrystalline cellulose, diatomaceous earth, montmorillonite, betonite, titanium dioxide, amorphous silicon dioxide, colloidal silicon dioxide, calcium 20 carbonate, talc (Si02+Mg0), attapulgite (silicon, aluminium and iron oxides clay), and kaolin (aluminium silicate). More preferably, the sorbing medium is silicon dioxide, namely, Aerosil 200 or Aerosil R972. Preferably, the formulation further includes one or more excipients selected from the group 25 comprising preservatives, suspending agents, buffering agents, defoaming agents, and viscosity inducing agents. In yet a further aspect, the invention relates to a multiple active veterinary formulation comprising: 30 an aqueous vehicle; at least one hydrophilic active selected from the group comprising thiazole derivatives, benzimidazole derivatives, acylated quinoline, and benzenesulphanamides, in solution with the aqueous vehicle; G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual property office of n.z 2 ti m/ M7 9 at least one lipophilic active selected from the group comprising avermectins and milbemycins; a lipophilic solvent; and 5 a sorbing medium, wherein the sorbing medium is hydrophobic and is adapted to contain both (a) the lipophilic active(s) and (b) the lipophilic solvent to form a chemically stable suspension of the sorbing medium in the aqueous vehicle. Preferably, the hydrophilic active or each of the hydrophilic actives is selected from the group comprising levamisole or a salt thereof, oxfendazole, albendazole, fenbendazole, mebendazole, 10 praziquantel, clorsulon and closantel. .Preferably, the hydrophilic actives included in the formulation are levamisole or a salt thereof and oxfendazole. 15 More preferably, the hydrophilic actives included in the formulation are levamisole or a salt thereof, oxfendazole and praziquantel. The formulation may further include vitamins, minerals or antigens. 20 Preferably, the formulation includes one or more minerals selected from the group comprising - selenium salts, cobalt salts, copper salts, zinc salts, iodine salts and their chelates. Preferably, the lipophilic active is abamectin. 25 Preferably, the lipophilic solvent is selected from the group comprising oils and organic solvents. More preferably, the lipophilic solvent is selected from the group comprising medium chain mono-/di-glycerides. Preferably, the sorbing medium is selected from the hydrophobic members of the group 30 comprising magnesium aluminometasilicate, cellulose, microcrystalline cellulose, diatomaceous earth, montmorillonite, betordte, titanium dioxide, amorphous silicon dioxide, colloidal silicon dioxide, calcium carbonate, talc (Si02+Mg0), attapulgite (silicon, aluminium and iron oxides G:\00W926NZC Amended Spec clean copy 27Nov07.doc p f r f i v ; 10 clay), and kaolin (aluminium silicate). More preferably, the sorbing medium is silicon dioxide, namely, Aerosil R972. The formulation may further include one or more excipients selected from the group comprising 5 preservatives, suspending agents, buffering agents, defoaming agents, and viscosity inducing agents. Preferably, the formulation is suitable for administration to an animal by oral drench. 10 The present invention relates to a veterinary formulation incoiporating multiple actives and a method for making a formulation incorporating multiple actives. The formulation and method are,-advantageous as they allow the stable integration of actives which have different formulation requirements (for example, the actives may have different solubility characteristics or they may degrade each other), in the same formulation. 15 An important factor in determining suitable active and solvent combinations for loading onto the sorbing medium is the amount of active needed to provide effective treatment. Accordingly actives which provide good efficacy at relatively low dose rates are more suitable for sorption onto the sorbing medium than are actives which require administration of a relatively large dose 20 for efficacy. The constraint is a physical one, as the inclusion of a larger amount of Aerosil or other sorbing medium into a formulation can lead to difficulties in flowability. It is envisaged that more than two avermectins or other anthelmintics may be incorporated into the formulation. These additional actives may be incorporated in the suspension or sorbed onto the silica or other sorbing medium to provide for differential release of the active. 25 DETAILED DESCRIPTION The present invention provides an improved veterinary composition including two or more actives together and a method of manufacturing the same. DEVELOPMENT TRIALS The following examples numbered 1 to 13, relate to trials to determine an effective formulation. 30 These are given by way of illustration and shall not be taken to be in any way limiting to the G:V00W926NZC Amended Spec clean copy 27Nov07.doc i intellectual pro pert/ office of n.z 11 mi &j7 BJTPFiyEDl 11 spirit or scope of the invention. The flow time of each example formulation was determined by timing how long it took for a volume of 100 ml to flow through a Ford No. 4 cup. A flow time of less than about 20 seconds was desired. In addition, the chemical and physical stability of the formulation was tested. The formulations 5 were exposed to 55°C for four weeks after which the levels of the actives and then condition of the formulation was tested. Example 1 The initial trial included silicon dioxide (brand name Aerosil R972) and polyoxyl 40 hydxogenated castor oil. 10 The formulation comprising: 1. 3.5g carboxymethyl cellulose sodium is dissolved in 150ml of water. 2. 500mg ivermectin is dissolved in 25ml of medium chain mono-/di-glycerides (Capmul MCM). 3. 900mg sodium methyl paraben and lOOmg sodium propyl paraben are dissolved in 15 250ml water, wherein 476mg sodium selenate and 6.284g cobalt EDTA are added under stirring. 4. 20g levamisole HC1 is added to the formulation from step 3 under stirring, and lOg polyoxyl 40 hydrogenated caster oil and 500mgdefoamer are added under stirring. 5. 11.35g oxfendazole is dispersed into the formulation resulting from step 4 under stirring. 20 6. Medium chain mono-/di-glycerides containing ivermectin (the formulation from step 2) is sorbed on 15g silicon dioxide (brand name Aerosil R972) using mortar and pestle. 7. The ivermectin-loaded silicon dioxide (brand name Aerosil R972) is dispersed into the formulation of step 5 under stirring. 8. The formulation of Step 1 is added to that from step 7 under stirring. 25 9. 10ml of purified water is used to rinse the beaker; this is then added to the formulation from step 8. G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual property office of n.z. 2 u K0V 2007 RECEIVED 12 10. The pH is adjusted to below 4, preferably 3.84 using 20%w/v citric acid solution. 11. Volume is made up to 500ml using purified water. The result of this combination is a physically and chemically stable formulation with a flow time through a Ford No. 4 cup of 33 seconds. 5 Example 2 In a further trial the silicon dioxide (brand name Aerosil R972) was used alone to provide a formulation which was surfactant free. The formulation components and method are as in example 1 except: • At step 4 the defoamer is added but the polyoxyl 40 hydrogenated castor oi! is omitted; 10 and • At step 10 the pH is adjusted to 3.80 instead of 3.84 in example 1 The result of this combination is a physically and chemically stable formulation with a flow time through a Ford No. 4 cup of around 27 seconds. Example 3 15 In a further trial the silicon dioxide (brand name Aerosil 200) was used in combination with polyoxyl 40 hydrogenated castor oil. The formulation components and methods are as example 1 except: • At step 6 the medium chain mono-/di-glycerides containing ivermectin are sorbed on silicon dioxide (brand name Aerosil 200) instead of silicon dioxide (brand name Aerosil 20 R972), and • At step 10 the pH is adjusted to 3.76 instead of 3.84 in example 1. The resulting formulation was chemically stable; however it exhibited a non-homogeneous sedimentation. Accordingly it was decided to discontinue this formulation. The flow time for this formulation was 28 seconds. G:\00W926NZC Amended Spec clean copy 27Nov07.doc intellectual pro pert'/ ofrce of ivi.z 2 J fcOV 2uiii7 R E C EIV r D RECEIVED at IPONZ on 21 December 2009 13 Example 4 In a further trial silicon dioxide (brand name Aerosil 200) was used alone to provide a formulation which was surfactant free. The formulation components and methods are as in example 1. except: 5 » At step 4 the defoamer is added and the polyoxyl 40 hydrogenated castor oil is omitted, and ■ At step 6 medium chain monc-/di-glycerides containing ivermectin are sorbed on to silicon dioxide (brand name Aerosil 200) instead of silicon dioxide (brand name Aerosil R972). 10 • At step 10 the pH is adjusted to 3,81 instead of 3,§4 in example I. • The formulation has a flow time of 17 scconds. however, it did not exhibit sufficient physical stability, accordingly it was decided to discontinue this formulation. Example 5 In a further trial silicon dioxide (brand name Aerosil 200) and polyoxyl 40 hydrogenated castor 15 oil were u$ed for reconfirmation of the results in example 3. The formulation components and methods arc as example 3 exccpt: * At step 10 the pH is adjusted to 3.80 instead of 3.7(5 as in example 3, The resulting formulation was surfactant free and chemically stable, This con finned the formulation of example 3 was viable. However, it exhibited a flow time of 30 seconds. 20 Example 6 It was decidcd to use the formulation in example 2 as a base but to nse 0.5% carboxymethyl cellulose sodium. The formulation volume was increased to 1000ml. The amount of each component was increased accordingly. <3:WWM6NHC AMENDED SPEC 17 Dec WWcnni.DOC 14 The formulation in this example uses silicon dioxide (brand name Aerosil R972) alone and 0.5% carboxymethyl cellulose sodium to improve the flow time. The formulation components and methods are as follows: 1. 5g Carboxymethyl cellulose sodium is dissolved in 300ml of water. 5 2. 1.072mg Ivermectin is dissolved in 50ml of medium chain mono-/di-glycerides (Capmul MCM.) 3. 1.8mg Sodium methyl paraben and 200mg sodium propyl paraben are dissolved in 500ml water, wherein 95Smg sodium selenate and 12.568g cobalt EDTA are added under stirring. 10 4. 40g Levamisole HC1 is added to the formulation from step 3 and lg defoamer added under stirring. 5. 22.7g Oxfendazole is dispersed into the formulation resulting from step 4 under stirring. 6. Medium chain mono-/di-glycerides containing ivermectin (the formulation from step 2) is sorbed on 30g silicon dioxide (brand name Aerosil R972) using mortar and pestle. 15 7. The ivermectin-loaded silicon dioxide (brand name Aerosil R972) is dispersed into the formulation of step 5 under stirring. 8. The formulation of Step 1 is added to that from step 7 under stirring. 9. 20ml of purified water is used to rinse the beaker; this is then added to the formulation from step 8. 20 10. The pH is adjusted to below 4, preferably 3.84 using 20%w/v citric acid solution. 11. Volume is made up to 1L using purified water. Testing of this formulation revealed a flow rate of 16 seconds through a Ford No. 4 cup suggesting the defoamer had no effect on the flow rate. G:\00W926NZC Amended Spec clean copy 27Ncrv07.doc 2 s m m 15 Example 7 In a further trial silicon dioxide (brand name Aerosil R972) was used and 0.5% carboxymethyl cellulose sodium was added for changing stability. The formulation components and methods are as example 6 except: instead of 20%w/v in example 6. • At step 11 the volume is made up to 1000ml using purified water. Testing of this formulation revealed a flow rate of 16 seconds confirming the defoamer had no effect on the flow rate. 10 Example 8 The following trial included ivermectin and xanthan gum. The formulation components and methods comprised: 1. 6g Xanthan dissolved in 600ml water. 2. 3.216g Ivermectin dissolved separately in 150ml medium chain mono-/di-glycerides. 15 3. 5.4g Sodium methyl paraben and 600mg sodium propyl paraben sodium dissolved in 1800ml of water, to this 2.941g sodium selenate and 37.704g cobalt EDTA (14%) were added under stirring. 4. 120g Levamisole HCL was added to the formulation of step 3 under stirring, to this 60g defoamer was added. 20 5. 68. lg Oxfendazole was dispersed into the formulation of step 4 under stirring. 6. The medium chain mono-/di-glycerides containing ivermectin was sorbed onto 90g silicon dioxide (brand name Aerosil R972) using mortar and pestle. 7. Ivermectin loaded silicon dioxide (brand name Aerosil R972) was dispersed into the formulation from step 5 under stirring. 5 • At step 10 the pH is set at 3.79 instead of 3.84 and 30%w/v citric acid solution is used G:\OOW926NZC Amended Spec clean copy 27Nov07.doc RECEIVED at IPONZ on 21 December 2009 16 S, The formulation from Step 1 was added to that from step 7 under stirring. 9, 50ml of purified water was used to rinse the beaker. This was then added to the formulation of step 8. 10 The pH was adjusted lo below 4 preferably 3.71 using 30%w/v citric acid solution. 5 11. . The volume was made up to 3000ml using purified water. The resulting formulation had a reduccd flow time of around 12 seconds. Example 9 In a further trial abamectin and 0,2% xanthan gum was used. The formulation components and methods are as example 8 cxcept: 10 • At step 2, 3g abamectin4* dissolved in 150ml medium chain mono-/di-glyceride$. (instead of ivermectin as in example 8) • At step 7 the abamectin loaded silicon dioxide {brand name Aerosil R972) is dispersed into the formulation of step 5, • At step 10 the pH is set at 3.81 instead of 3.71 as in example 8. 15 Testing of (his formulation revealed an easily dispersed composition wilh a. reduced flow time of 12 seconds. Example 10 In a further trial, a decreased amount of medium chain mcno-Zdi-glycerides and silicon dioxide (brand name Aerosil R972) was used in combination with sodium benzoate and xanthum gum. 20 The formulation components and methods are as example 8 except; • At step 1 xanthan gum was dissolved in 150ml of water instead of 600ml as in example S. aWWKtWZC AMENDED SPEC 17 Dm 09 <clam).DOC RECEIVED at IPONZ on 21 December 2009 17 • At step 1 ivermectin was dissolved in 15ml of medium chain tnono-/di-glyceridcs instead of 150ml as in example 8, • At step 3 sodium benzoate was added with sodium methyl paraben and sodium propyl paraben and dissolved in 250ml of water instead of 1800ml as in example 8. 5 • At step 9 10ml of purified water was used to rinse the beaker instead of 50ml as in example 8. • At step 11 the volume was made up to 500ml as opposed to 3000ml as in example 8. Testing of this formulation revealed an incompatibility between tine sodium benzoate and one of the ingredients in the formula. 10 Example It In this trial the formulation of example 10 was used to give a reduced quantity of medium chain mono-/di-glycerides, silicon dioxide (brand name Aerosil R972) and xanthan gum. The sodium benzoate was omitted. The formulation components and method are a® example IC except: 15* At step 3 sodium benzoate is omitted, • At step 10 the pH is adjusted to 3.55 instead of 3.71 in example 10. Testing this formulation revealed small oil droplets stuck to the inside of the walls of the container indicating not enough silicon dioxide (brand name Aerosil R972) was added to sorb the oil. 20 Example 12 Tn this trial the formulation is the same as example 11 except: • At step 7 9g of silicon dioxide (Aerosil R972) was added. • At step 10 the pl-I is adjusted to 3.71 instead of 3.65 as in example 11. G:\DW94GNZC AMEWnro SPEC 17 Dec 09 (cIcm).DOC RECEIVED at IPONZ on 21 December 2009 IS Testing of this formulation revealed an easily dispersed formulation with a flow time of 14 seconds. Example 13 In this trial the formulation is the same as example 12 except; 5 • At step 2 ivermectin is dissolved in 10ml medium chain mono-/di-glyeeri des instead of 15 ml as it) example 12. * At step 7 6g of silicon dioxide (Aerosil R972) was added Testing of this formulation revealed an easily dispersed formulation with a flow time of 14 seconds. 10 RESULTS The result of the trials determined example 12 was the best formulation on the basis that it stably integrated two pharmaceutical actives in the formulation. The suspension was surfactant free and had a low sedimentation rate resulting in a formulation that can be stored without significant physical change. The formulation also had a reduccd flow rate of around 15 seconds 15 through a Ford No. 4 cup to allow for easy and effective administration of the formulation to animals. Tn the examples a lipophilic activc, ivermectin is firstly solubilised and then sorbed on a hydrophobic grade of silica. The surrounding aqueous solution contains levamisole. art active more stable at low pH. Levamisole salts (Levamisole HC1) are easily soluble: in water. This 20 method provides a physical and chemical separation between the sorbed ivcrmectin/siliea and the surrounding solution or suspension containing the second or more active ingredients. It is envisaged that other materials may also be used as the sorbing medium. It will be appreciated that other combinations of aetives may be used. 25 PREFERRED FORMULATIONS G:\C0WS2STJZC AMENDED SPEC 17 Of [eltsn).TTOC RECEIVED at IPONZ on 21 December 2009 19 Based on the development work desctibed above, the following preferred formulations were developed. These illustrate the use of the method to make formulations incorporating 2, 3 or 4 actives together with optional mineral additives. These preferred formulations are administered to the animals orally at a rate of 1 ml per 5 kg live animal weight. Oral Drench Containing Two Actives and Minerals Name: ABAMECTIN- PRAZIQUANTEL DRENCH Materials Amomi/batch (g) Abamectin 500mg Praziquantel 9,40gms Sodium Selenate 47«Smg Cobalt EDTA 6.284gm Capmul MCM 15ml Aerosil R972 9gms Xanthan gum l.25Cgms Nipagin Sod. 900mg Nipasol Sod. lODmg Defoamer IOgms Citric acid anhydrous 5Q0mg P. Water Q.S. 500ml Procedure: 1 Dissol ve Xanthan gum in 150 ml of water 2 Dissolve Abamectin in Capmul MCM. 3 Dissolve Nipagfn sodium arid Ntpasol sodium in water under heating separately. To this add sodium selenatef Cobalt EDTA and defoamer under stirring. 4 Disperse Praziquantel in step 3 under stirring. 5 Adsorb Capmul MCM containing Abamectin solution on Aerosil R972 using mortar and pestle. 6 Disperse Abamectin loaded Aerosil in step 4 under stirring. 7 Add formulation of step 1 to that of step 6 under stirring. £ Add Citric acid to step 7 under stirring. 9 Make the volume with water. G:MWK!GNZC AMENDED SPEC 17 Dnc.(»Cdsanli.DtK: RECEIVED at IPONZ on 21 December 2009 20 10 Check the pH. Oral Drench Containing Two Actives without Minerals Name: ABAMECTIN - PRAZIQUANTEL DRENCH Materials Amount/hatch (g) Abamectin 500mg Praziquantel 9.40gms Capmul MCM 15.0ml Aerosil R972 9,0gms Xanthan gum l„250gms Nipagin Sod. 900mg Nipasol Sod. IGOmg Defoamer IGgins Citric acid anhydrous 500mg P. Water Q.S. 500ml Procedures 1 Dissolve Xanthan gum in 150 ml of water. 2 Dissolve Abamectin in Capmul MCM 3 Dissolve "Nipagin sodium and Nipasol sodium in 250 ml of water under heating separately. To this add defoamer under stirring. 4 Disperse Praziquantel in step 3 under stirring 5 Adsorb Cepmul MCM containing Abamectin solution on Aerosil R972usmg mortar and pestle. 5 Disperse Adsorbed abamectin in step 4 under stirring. 7 Add formulation of step 1 to that of step 6 under stirring. 8 Add Citric acid to step 7 under stirring. 9 Make the vol umc with water. 10 Check the pH Oral Drcnch Containing Three Actives and Minerals CMJ0W926NZC AMENDED SPEC 17 Da; 09 (cIcsmVDQC RECEIVED at IPONZ on 21 December 2009 21 Name: 3 COMPONENT DRENCH Materials Amount/batch (g) Levamisole HCt 20gms Oxfendazole 11.35gms Abamectin 500mg Sodium Selenate eqt to selenium 0,2gms Cobalt EDTA eq. to cobalt O.SSgms Capmul MCM 15ml Aerosil R972 9gms Xanthan Gutn 1,5gms Nipagin Sod- 9(Mmg Nipasol Sod. IGOmg Defoamer 30gm Citric acid anhydrous 1.4gm P. Water Q„S. to 500ml PROCEDURES 1 Dissolve Xanthan Oiim in 150ral of water 2 Dissolve Abamectin in Capmul MCM separately 3 Dissolve Nipagin sodium and Nipasol sodium m 250ml of water under heat. To this add Sodium Selenate and cobalt EDTA under stirring. 4 Add Levamisole HC1 to step 3 under stirring. To this add Defoamer under stirring. 5 Disperse Oxfendazole in step 4 under stirring. 6 Adsorb Capmul MCM containing Abamectin on Aerosil R.972 using mortar and pestle. 7 Disperse Abamectin loaded Aerosil in step 5 order stirring. 8 Add step 1 to step 7 under stirring. 9. Add Citric acid anhydrous to step 8 under stirring and check the pH. 10 Make tbe volume up to 500ml using purified water and stir further 30 minutes. Orai Drench Containing Four Actives and Minerals Name: 4 COMPONENT DRENCH Materials Amount/batch (g) O:1(10W925NZC AMENDED SPEC 17 Dec 09 (cfosn).DOC RECEIVED at IPONZ on 21 December 2009 22 Levamisole HC1 40gms Oxfendazole 22.70gms Abamectin l.OOOgm Praziquantel 18,$0gms Sodium Selenate eq> to selenium 0,4gms Cobalt EDTA eq. to cobalt 1,76gtro Capmul MCM 30.00ml Aerosil R972 ] S.OOgms Xanthan Gum 2.500gms Defoamer 20gms Nipagin. Sod. l.Sgm Nipasol Sod. 200mg Citric acid anhydrous 2,8gms P. Water Q.S. 1000ml Procedures 1 Dissolve Xanthan Gum in 300ml of ■water 2 Dissolve Abamectin in Capmul MCM separately 3 Dissolve Nipagin .sodium arid Nipasol sodium in 500ml of water under heat. To this add Sodium selenate and cobalt EDTA under stirrin g. 4 Add Levamisole HC1 to step3 under stirring. To this add Defoamer under stirring, 5 Disperse Oxfendazole in step 4 under stirring. To this add Praziquantel under stirring. 6 Adsorb Capmul MCM containing Abamectin sofurion on Aerosil R.972 using mortar and pestle. 7 Disperse Abamectin loaded Aerosil in step 5 under stirring. 8 Add step 1 to step 7 under stirring. « 9 Add citric acid anhydrous to step 8 and chcck the pH. Make volume up to 1000ml using purified water and stir further 30 minutes. The flow time of the 3 and 4 way drench disclosed above and the Triton™ 3-way dreuch marketed by Nuferm was compared, Flow time was determined using Sheen 406/4; ASTM D1200 cup, S, No, Sample . Flow Time (Seconds) A MENDED SPEC 17 Dec <» ft lean ).[]()€ RECEIVED at IPONZ on 21 December 2009 23 1 Triton 33-36 2 3-way drench 14-17 3 4-way drench 16-18 The 3-way and 4-way drench formulations are suspension dosage forms. Some sediment formed upon standing at room temperature. However, the sedvmsnted portion was easily rcdispersed upon shaking. There was no sign of cake formation. 5 FIELD TRIALS The preferred formulations have atso been shown lo be highly efficacious in Field use. The formulations were administered to animals as a drench at a rale of 1 ml per 5 kg animal weight Tables 1 and 2 below show the arithmetic and geometric mean total worm counts respectively for group of sheep treated with the 3 aid 4 active drenches. Tables 3 and 4 show the efficacies 10 of each of the treatments relative to the controls using arithmetic and geometric means respectively. Species identification indicated that the following species were present in the untreated control group: Cooper ict species: 94% C. curticei, 4% C. oncophora, 2% C. punctata Trickostrongylus species; 100% T, colubriformis. 15 Results demonstrate that both the 3 and 4 active drenches were highly effective against all species present in the trial. Efficacies of >99.9% were achieved against ail parasites that were present Worm numbers in the control animals were high for all species that were present demonstrating that the animals were exposed to a very high parasite challenge. Table 1: Arithmetic mean total warm counts for control and treated groups wmmmm ■■■MB 0 Ostertagia (mature) 8275 0 Osleriagia (immature) 692 0 0 T. axei (mature) 1350 0 0 71 axei (immature) 67 0 0 H. contortus (mature) 5292 0 0 i H. contarlus (immature) 2150 0 0 G:V»W«fi!srzt? AMENDED SF15C ] 7 lJco 09 (tleim}. UOC RECEIVED at IPONZ on 21 December 2009 24 Trichostrangylus spp (mature) 26985 0 0 Trichostrortgylus spp (immature) 75 0 0 Cooperia (mature) 225S 0 0 Cooperia (immature) 58.4 0 0 Strangytoides (mature) 66.7 0 0 Nematodirus (mature) 267 0 0 Nematodirus (immature) 133.4 0 0 Oesophagostomum 38 0 0 Chabertia 12 0 0 Trichuris 17 0 0 Table 2: Geometric mean total worm counts for control and treated groups iilllllllis Ostertcfgia (raature) 7660a ob ob Ostertngia (immature) 140" ob oh T. axei (mature) 858" 0* oh T. axei (immature) 21" ob ob H. contortus (mature) 3343" Qb oh H contortus (immature) 10C9'1 01' oh Trkhostrongylus spp (mature) 2G254* o" ob Trichastrongylus spp (immature) 19.T o13 o" Cooperia (mature) 1281* oh ofc Cooperia (immature) 11* 0" 0B Strongyloses (mature) 18.7" o" oh Nematodirus (mature) 20.6* o" oh Nematodirus (immature) 53. S11 oh oh Oesophagosiomum 33n o51 ob Chabertia 6' o* & Trichuris 15* oh ob C:\D0WS26NZC AMENOHP SPEC I? Beef© (stain),DOC RECEIVED at IPONZ on 21 December 2009 25 = means with different superscripts within the same row are statistically different from each other. Table 3: Treatment efficacies based on group arithmetic mean total worm counts. SHISIiilli MMNNMNNi Ostertetgici (mature) >99.9% >99.9% Osiertagia (immature) >99.9% >99.9% T. axei (mature) >99.9% >99.9% T. axei (immature) >99.9% >99.9% H. contortus (mature) >99,9% >99.9% H comorfus (immature) >99.9% >99.9% Trichostrongylus spp (mature) >99.9% >99.9% Trichoxiroftgyhis spp (immature) >99,9% >99.9% Cooperia (mature) >99.9% >99.9% Cooperia (immature) >99.9% >99,9% Strongyloides (mature) >99.9% >99.9% Nematodirus (mature) >99.9% >99.9% Nematodirus (immature) >99.9% >99.9% Oesophagostomum >99.9% >99.9% Chabertia >99,9% >99.9% Trichuris >99.9% >99.9% Table 4; Treatment efficacies based on group geometric mean total "worm counts> HHHHI Ostertagia (mature) >99.9% >9 9.9% Outertagia (immature) >993% >99.9% T. axei (mature) >99.9% >9 9.9% T. axei (immature) >99.9% >99.9% H. contortus (mature) >99.9% >99.9% H contortus (immature) >99,9% >99.9% Trichastrongyhts spp (mature) >99.9% >99.9% Trichostrangylus spp (immature) >99.9% >99,9% Cooperia (mature) >99.9% >99.9% GMCWOSNZC AMENDED SPEC r J Tec £» (ctairO.DUC RECEIVED at IPONZ on 21 December 2009 26 Cooperia (immature) >99.9% >99.9% Strongyloides (mature) >99.9% >99.9% Nematadlrus (mature) >99.9% >99.9% N&matodirus (immature) >99.9% >99.9% Oesophagostomum >99.9% >99.9% Chabcrtia >99.9% >99.9% Trickum >99.9% >99.9% STABILITY TRIALS It has also been dcnionstxated that the formulations made according to this method are stable using accelerated testing in elevated temperature conditions. Batch samples were tested for 2S 3, and 4 active drenches. Stability results summary of trials Stress conditions: 55°C for 2, 4 weeks Batch No, CanditicH First Active % Recovery Oxfendazole % Recaveiy Levamisole HCt % Recovery Example I 5S°C, 4\veek 0.083 93% 2M 109% 3.78 97% 55eC, 2weck 0,088 99% 2.07 10S% 3.90 101% 4°C 0.089 100% 1.91 100% 3.88 100% Example 2 55°C, 4wcek 0.087 95% 2.06 99% 3.88 99% 55°C? 2wcek 0.090 98% 2.06 100% 3.99 102% 4°C 0.092 100% 1.73 100% 3,91 100% Example 3 55°C. 4week 0.095 97% 2.33 110% 4,15 100% 55°C, 2week 0.096 9B% 2.24 106% 4.18 101% 4°C 0.09? 100% 2,12 100% 4.13 100% Example 4 5SDC, 4week 0,079 93% 1.85 97% 3.91 102% CM0W92SN"ZC AMENDED SPEC 17D&3 on (cUan>.IX)C RECEIVED at IPONZ on 21 December 2009 27 y; -oft | , j 0.079 2week \ 96% 1.75 98% 3.97 104% 4°C 0.088 100% 1.91 100% 3.82 100% Example 5 55°Cf 4week 0.087 99% 2.12 104% 3.80 98% 55QC) 2\yeek 0.090 102% 2.13 104% 4.05 104% 4CC 0.088 100% 2.04 100% 3.89 100% Example 6 55°C, 4week 0.087 84% 2,4(5 102% 3,84 96% 556C, 2\veek 0.090 87% 2.42 100% 3.76 94% 4°C 0.103 100% 2.41 100% 4.00 100% Example 7 55QC; 4weck 0.096 93% 2.39 102% 3.63 95% 55°C, 2week 0,099 96% 2.36 101% 3.79 99% 4°C 0.103 100% 234 100% 3.83 100% Example 8 4°C 0.107 100% 2.36 100% 4.02 100% S5°C» 2week 0,103 96% 2.37 100% 3.97 99% 55°C: 4week 0.099 93% 2.38 101% 3.95 98% Example 12 4°C 0,109 100% 2.51 100% 4.23 100% 55°C 2week 0.105 96% 2.50 100% 4.17 99% S5aC, 4week 0.101 93% 2.58 103% 4.25 100% Example 13 4°C 0.100 100% 2,39 100% 4.22 100% 55T, 2week 0.099 99% 2.43 | 102% 4.12 98% 55DC, 4week 0.098 9&% 2.43 102% 4.05 96% Example 9 4CC 0.103 100% 2.43 100% 4.17 100% 55°C, Sweek 0.101 98% 2.40 99% 4,08 98% 55°C. 0.096 93% 2.45 101% 3.99 96% ri:VW926HZC AMENDED SPEC 1? Dec OS {clfflm).riOC RECEIVED at IPONZ on 21 December 2009 28 4wcek PREFERRED FORMULATIONS STABILITY RESULTS Stability results of 2 actives drench Stress conditions: 55 °C for 2-4 weeks Batch No. Condition Abamectin % Recovery Praziqumtei % Recovery 011202 (Without Minerals) 4eC 0.089 100% 1.97 100% 55°C,2weck 0.089 100% 1.97 100% 55°C. 4week 0.089 100% 1.94 99% 011202 (With Minerals) 4°G 0.079 100% t .S3 100% 55°C,2weck 0.079 100% .1.77 97% 55°Cr 4week 0.079 100% 1,79 98% Stability results of 3 actives drench Stress conditions: 55°C for 2-4 weeks Batch iWo. Condition Abamectin % Recovery OxfmdQzole % Recovery Levamhofe HCi % Rec. oveiy DRE001 ^04 4°C o.ioa 100% 2.55 100% 4.71 100% 55 °C, 2week 0.102 94% 2.55 100% 4,67 100% 55*C, 4wcck 0,099 92% 2.60 102% 3.71 100% Stability results of 4 actives drench Stress conditions: 556C for 2-4 weeks Patclf No. Condition Ivermectin % Rscavsty Oxfendazole a Recovery Lcvami-xak MCI % iteiwvecy Prasl-qtitoUef % Recovery 050802 4C 0.124 100% 2.60 100% 4,47 100% 1.99 100% 5SCf 2week 0.133 105% 2.52 97% 4.42 99% 1.96 9S% 5SC, 4week 0.139 107% 2.62 101% 4.42 99% 1.96 98% 060802 4C 0,111 100% 2.33 100% 4.10 100% 1.87 100% 55C, 0.100 90% 2.33 100% 4.05 99% 1.S6 99% Cr:ttX7W92GNZC AMENDED SPEC 17 Dk 09 fClfiCm>.DOC </div>

Claims

<div class="application article clearfix printTableText" id="claims"> RECEIVED at IPONZ on 21 December 2009 29 2week 55C. 4wcek 0,100 <50% 2,37 102% 4.01 98% 1.88 101% 070802 4C 0.114 100% 2.13 100% 4.68 100% 2.09 100% 55C, 2\veek 0.116 102% 2.15 101% 4.65 99% 2.10 100% 55C, 4wcek 0.1] 3 99% 2.14 ioo% 4.63 99% 2.09 100% 080802 4C 0.099 100% 2.08 100% 3,95 100% 1.84 100% 55C, 2week Q.09R 99% 2.07 100% 3.98 101% 1.63 95% 55C, 4week 0.098 99% 2.06 99% 4.01 102% 1.59 93% 090802 4C 0.104 100% 2.46 100% 3.21 100% 2.05 100% 55C, 2"week 0.104 100% 2.42 98% 3.19 99% 2.06 100% S5C, 4week 0.099 95% 2.34 95% 3.20 100% 2.00 98% 100S02 AC 0.082 100% 3.85 100% 4.07 100% 1,85 100% 550, 2-week 0.081 99% 3.85 100% 4.04 99% 1.80 97% 55C, 4week 0.083 101% 3.95 103% 4.04 99% 1.85 100% 110802 4C 0.086 100% 2.52 100% 4.39 100% 2.01 100% 55C, 2week 0.086 100% 2.53 100% 4.32 98% 2.01 100% S5C, 4week 0.088 102% 2.59 103% 4.30 98% 2,05 102% As can be seen from the above trials the methods of the present invention and the formulations made from those methods, allow the stable integration of multiple actives within a single formulation. The solubllisation of the active in a solvent and the subsequent sorption onto a sorbing medium provides effective protection for the active from any adverse conditions within the liquid in which the active-loaded sorbing medium is dispersed. As a result the liquid can be formulated to suit the requirements of the activcs that may be included therein. As a result the actives may be stably integrated within the formulation. This allows the co-administration of the actives and the resultant benefits in terms of cost savings and convenience to be enjoyed. G:\DDW26N2C AMENDED SPEC IT Dec 00 (dcati).OOC 30 We Claim:

1. A multiple active veterinary formulation comprising: at least one first active; at least one second active which has incompatible formulation requirements to the 5 first active(s); a liquid carrier; a solvent; and a sorbing medium, wherein the first active or each of the first actives is compatible with and carried in the liquid carrier, and the second active or each of the second 10 actives is compatible with the solvent, and the sorbing medium contains both (a) the second active(s) and (b) the solvent, to form a chemically stable suspension in the liquid earner.

2. A multiple active veterinary formulation as claimed in claim 1 wherein the first active or 15 each of the first actives is a hydrophilic active; the second active or each of the second actives is a lipophilic active; the liquid carrier is an aqueous liquid; and the solvent is a lipophilic solvent.

3. A multiple active veterinary formulation as claimed in claim 1, wherein the first active 20 or each of the first actives is a lipophilic active; the second active or each of the second actives is a hydrophilic active; the liquid carrier is a non-aqueous liquid; and the solvent is an aqueous solvent.

4. A multiple active veterinary formulation comprising: 25 a non-aqueous liquid carrier; at least one lipophilic active in solution with the non-aqueous liquid carrier; at least one hydrophilic active: an aqueous solvent; and a sorbing medium, wherein the sorbing medium is hydrophilic and is adapted to contain both (a) the hydrophilic active(s) and (b) the aqueous solvent, to form a chemically stable suspension of the sorbing medium in the non-aqueous liquid 30 earner. G:\0DW926NZC Amended Spec dean copy 27Nov07.doc intellectual property OFFICE of N.Z 2 0 NOV 2007 RE.CE IV ED 31

5. A multiple active veterinary formulation comprising: an aqueous liquid carrier; at least one hydrophilic active in solution with the aqueous liquid carrier; at least one lipophilic active; a lipophilic solvent; and a sorbing medium, wherein the sorbing medium is hydrophobic and is adapted to contain both (a) the lipophilic active(s) and (b) the lipophilic solvent to form a chemically stable suspension of the sorbing medium in the aqueous liquid

6. A multiple active veterinary formulation as claimed in any one of claims 2 to 5 wherein the lipophilic active or each of the lipophilic actives is selected from the group comprising avermectins and milbemycins.

7. A multiple active veterinary formulation as claimed in claim 3 or 4 wherein the nonaqueous liquid carrier is selected from the group comprising oils and organic solvents.

8. A multiple active veterinary formulation as claimed in claim 2 or 5 wherein the lipophilic solvent is selected from the group comprising oils and organic solvents.

9. A multiple active veterinary formulation as claimed in claim 8 wherein the lipophilic solvent is selected from the group comprising medium chain mono-/di-glycerides.

10. A multiple active veterinary formulation as claimed in any one of claims 2 to 5 wherein the hydrophilic active or each of the hydrophilic actives is selected from the group comprising vitamins, minerals, anthelmintics and antigens, or combinations thereof.

11. A multiple active veterinary formulation as claimed in claim 10 wherein the hydrophilic active, or at least one of the hydrophilic actives is an anthelmintic and the anthelmintic is selected from the group comprising thiazole derivatives such as levamisole or a salt thereof; benzimidazole derivatives such as albendazole, oxfendazole, fenbendazole, earner. G:\OOW926NZC Amended Spec clean copy 27Nov07.doc intellectual property office of im.z 2 3 my 2007 32 Received at IPONZ on 13/8/08 mebendazole; acylated quinoline such as praziquantel; and benzenesulphanamides such as clorsulon and closantel.

12. A multiple active veterinary formulation as claimed in claim 10 wherein the hydrophilic 5 active or at least one of the hydrophilic actives is a mineral and the mineral is selected from the group comprising selenium salts, cobalt salts, copper salts, zinc salts, iodine salts and their chelates.

13. A multiple active veterinary formulation as claimed in any one of the previous claims 10 wherein the sorbing medium is selected from the group comprising magnesium aluminometasilicate, cellulose, microcrystalline cellulose, diatomaceous earth, montmorillonite, betonite, titanium dioxide, amorphous silicon dioxide, colloidal silicon dioxide, calcium carbonate, talc (Si02+Mg0), attapulgite (silicon, aluminium and iron oxides clay), and kaolin (aluminium silicate). 15

14. A multiple active veterinary formulation as claimed in claim 13 wherein the sorbing medium is silicon dioxide.

15. A multiple active veterinary formulation as claimed in any one of the previous claims 20 wherein the formulation further includes one or more excipients selected from the group comprising preservatives, suspending agents, buffering agents, defoaming agents, and viscosity inducing agents.

16. A multiple active veterinary formulation comprising: 25 an aqueous vehicle; at least one hydrophilic active selected from the group comprising thiazole derivatives, benzimidazole derivatives, acylated quinoline, and benzenesulphanamides, in solution with the aqueous vehicle; at least one lipophilic active selected from the group comprising avermectins and 30 milbemycins; a lipophilic solvent; and G:\00W926NZC Amended Claims 13August08.doc 33 a sorbing medium, wherein the sorbing medium is hydrophobic and is adapted to contain both (a) the lipophilic active(s) and (b) the lipophilic solvent to form a chemically stable suspension of the sorbing medium in the aqueous vehicle.

17. A multiple active veterinary formulation as claimed in claim 16 wherein the hydrophilic active or each of the hydrophilic actives is selected from the group comprising levamisole or a salt thereof, oxfendazole, albendazole, fenbendazole, mebendazole, praziquantel, clorsulon and closantel.

18. A multiple active veterinary formulation as claimed in claim 16 or 17 wherein the hydrophilic actives included in the formulation are levamisole or a salt thereof and oxfendazole.

19. A multiple active veterinary formulation as claimed in claim 16 or 17 wherein the hydrophilic actives included in the formulation are levamisole or a salt thereof, oxfendazole and praziquantel.

20. A multiple active veterinary formulation as claimed in any one of claims 16 to 19 wherein the formulation further includes vitamins, minerals or antigens.

21. A multiple active veterinary formulation as claimed in claim 20 wherein the formulation includes one or more minerals selected from the group comprising selenium salts, cobalt salts, copper salts, zinc salts, iodine salts and their chelates.

22. A multiple active veterinary formulation as claimed in claim 16 wherein the lipophilic active is abamectin.

23. A multiple active veterinary formulation as claimed in claim lo wherein the lipophilic solvent is selected from the group comprising oils and organic solvents.

24. A multiple active veterinary formulation as claimed in claim 23 wherein the lipophilic solvent is selected from the group comprising medium chain mono-/di-glycerides. G:\00W926NZC Amended Spec clean copy 27Nov07.doc 34 Received at IPONZ on 13/8/08 10 15

25. A multiple active veterinary formulation as claimed in claim 16 wherein the sorbing medium is selected from the hydrophobic members of the group comprising magnesium aluminometasilicate, cellulose, microcrystalline cellulose, diatomaceous earth, montmorillonite, betonite, titanium dioxide, amorphous silicon dioxide, colloidal silicon dioxide, calcium carbonate, talc (Si02+Mg0), attapulgite (silicon, aluminium and iron oxides clay), and kaolin (aluminium silicate).

26. A multiple active veterinary formulation as claimed in claim 25 wherein the sorbing medium is silicon dioxide.

27. A multiple active veterinary formulation as claimed in any one of claims 16 to 26 wherein the formulation further includes one or more excipients selected from the group comprising preservatives, suspending agents, buffering agents, defoaming agents, and viscosity inducing agents.

28. A multiple active veterinary formulation as claimed in any one of the previous claims wherein the formulation is suitable for administration to an animal by oral drench. G:\Q0W926NZC Amended Claims 13August08.doc </div>