NZ548401A

NZ548401A - Stable liquid antihelmintic solution comprising triclabandazole dissolved in at least one solvent

Info

Publication number: NZ548401A
Application number: NZ54840100A
Authority: NZ
Inventors: Colin Manson Harvey
Original assignee: Ashmont Holdings Ltd
Priority date: 1999-04-14
Filing date: 2000-04-14
Publication date: 2007-11-30

Abstract

Disclosed is a pour-on veterinary anthelmintic formulation containing one or more anthelmintic actives wherein one of the anthelmintic actives is triclabendazole in a stable liquid solution, wherein the solution contains at least 10% w/v of triclabendazole and a solvent system containing one or more of solvents selected from the group consisting of benzyl alcohol, glycerol formal, n-methyl-2-pyrrolidone, and glycol ethers and its use in treating parasites including liver flukes and fasciolisis in non-human animals.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 548401 Patents Form # 5 548401 *10052008638* DIVISIONAL OUT OF APPLICATION NO. 537450 ANTE-DATING REQUESTED TO 14 APRIL 2000 NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION Title ANTHELMINTIC COMPOSITIONS We, ASHMONT HOLDINGS LIMITED, of First Floor, 17 Shea Terrace, Takapuna, Auckland, New Zealand, 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 - 00T210NZE_DIVISIONAL_OF_CONV_PAT_APP_20060707_1204_SEP.doc FEE CODE - 1050 INTELLECTUAL PROPERTY OFFICE OF N.Z. ~ 7 JUL 2006 MCBIVKo 2 FIELD OF THE INVENTION This invention relates to novel anthelmintic formulations and in particular it relates to stable veterinary formulations containing the anthelmintic triclabendazole. 5 BACKGROUND In general for ease of application to large numbers of animals, farmers and veterinary surgeons prefer to treat farm animals with pour-ons rather than oral drenches or injectables. Pour-ons are typically relatively thick liquids applied in small doses to the neck or back line of the animal. In the case of sheep pour-on, the applicator guns 10 are adapted to supply a dose of about 5ml to 10ml, and in the case of cattle the dose (depending upon the product) is typically about 40ml to about 60ml. Most pour-ons have the active in solution, and the solvent or solvent system is chosen to allow the active to pass through the dermal layer and provide a sufficiently high systemic amount of the active quickly enough. The solvent system needs to be non-irritant to 15 the farmer and the animal, stable, non-toxic, non-carcinogenic, and capable of being used in a pour-on applicator gun. Because of the small volume of each dose (too much would result in liquid running off the animal's back) the pour-on formulation is typically designed so that sufficient active is contained within the solvent system that a typical designed dose rate of 1ml of pour on for each 10kg of animal live weight is 20 the standard. Thus a 10ml dose of a pour on would supply sufficient active to treat a 100kg sheep. Parasitologists on the other hand recommend the use of oral drenches as there is usually a better take up of active from an oral drench than a pour-on. 25 Formulators prefer to design solutions rather than suspensions for veterinary purposes, as solutions can normally be used for either the pour-on route of administration or the oral route of administration, and solutions are usually far more stable than suspensions when stored in bulk. But if the active is known to be 30 sparingly soluble in water or most practical solvents then the formulator will favour a suspension for use as an oral drench. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 3 It is particularly advantageous to provide liquid formulations which contain a sufficient quantity of an active anthelmintic agent in a solution which can be easily administered by way of a pour-on. 5 The benzimidazole class of active agents are known for their anthelmintic activity. They are known to be sparingly soluble and are either made up in tablet or powder form (for use with small animals) or typically made up as suspensions for use in oral drenches. 10 Of all the benzimidazole's known, triclabendazole, which is a halogenated benzimidazole, is highly effective against liver flukes (fasciolisis) at all stages of their life cycle. Triclabendazole is known as 5-Chloro-6-(3,3-dichlorophenoxy)-2-methylthio-lH-benzimidazole, and is represented by the structural Formula 1. 15 Other active agents within the benzimidazole class of actives such as albendazole are only effective against adult fluke. 20 Diseases caused by parasitic helminths such as nematodes, cestodes and trematodes (liver fluke) can cause severe economic losses in ruminants and other animals. It has been estimated that 40 million sheep and 6 million cattle graze on pastures contaminated with fasciola hepatica (liver fluke). 25 Ruminants, such as sheep, cattle and goats, are susceptible to fasciolisis, the disease caused by parasitic liver flukes and it is of critical importance that formulations effective against the disease are available. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 4 Fasciola hepatica infection is widespread and is generally associated with low lying wet or water-covered areas. Areas where the average annual rainfall is at or above about 600mm and irrigation areas in particular, tend to create ideal living/propagating environments for aquatic snails which serve as intermediate hosts for first larvae of 5 fasciola hepatica (miracidia). The miracidia develop and multiply and eventually leave the snail host and encyst on vegetation forming metacercarial (infective stage of fasciola hepatica). When the vegetation is consumed by a grazing animal the metacercarial excyst in the small intestine. The metacercarial eventually releases immature flukes that penetrate the intestinal wall into the abdominal cavity. Acute 10 infections can result from the immature flukes burrowing through the liver substance. Death often follows as a result of concomitant blood loss. It has been difficult to provide liquid formulations containing triclabendazole in solution due to the highly insoluble nature of the compound. This has resulted in 15 anthelmintic formulations containing triclabendazole being prepared as suspensions for oral administration. Commercial drench formulations of triclabendazole are known in which triclabendazole is suspended in a liquid carrier. Such formulations are administered 20 orally via an appropriate drenching apparatus or by subcutaneous injection. Oral triclabendazole suspension formulations are commercially available and marketed under the trade name 'Fasinex'120 or 240. Such formulations can have a triclabendazole concentration in the order of 120g/l (or240g/l), which equates to 12% w/v (24% w/v). A 50 ml (25ml) dose of Fasinex 120 (240) equates to a dose of 6g 25 triclabendazole/500kg beast (12mg/kg). While oral (drench) suspension formulations containing triclabendazole have been available and successful in treating fasciolisis, the method of administering a suitable volume of oral formulation often requires a suitably experienced/qualified person to 30 administer a dose. Dosing a herd of animals can therefore be laborious, time consuming and place a severe economic strain on a conventional farm. Treatment of fasciolisis by way of a single injection represents an even less practical option for a farmer. Pour-on formulations containing a benzimidazole compound are therefore desirable within the farming community. INTELLECTUAL PROPERTY OFFICE OF N.2. 2 6 MAR 2007 n i- /n r" i II I" l"> 5 To date only one benzimidazole pour-on formulation has reached the market and it is based on a suspension, which is not particularly effective. In W095/23590 (Bomac), a pour-on formulation is described in which a benzimidazole, selected from 5 oxfendazole and/or albendazole, is formulated in a suspension. Suspensions of albendazole in accordance with formulations described in W095/23590 have not been effective in the treatment of a parasitic burden. In any case as stated earlier albendazole is not the preferred active for treatment of liver fluke. 10 Generally suspension pour-on formulations have suffered from insufficient/inefficient permeation across an animal's dermal layer. Consequently the amount of an active agent in a suspension form which is available for absorption is extremely low and can expose an animal to sub-optimal therapeutic drug concentrations. This is clearly undesirable since drug resistant strains of a parasite may develop. For this reason 15 there is a general aversion within the parasitology community to adopt a pour-on dosage form. Other pour-on formulations have been suggested in patent literature in which an active agent is dissolved; emulsified; or suspended in a solvent/solvent mixture. 20 Anthelmintic formulations are known which contain oxfendazole; tetramisole and levatnisole that exhibit anthelmintic action as a pour-on comparable to that of analogous oral or injectable treatments. French patent registration no. 96 14068 teaches a formulation for topical administration including oxfendazole in an amount of 5% w/v dissolved in a non-aqueous 'vehicle', a non-aqueous co-solvent, a non-25 ionic surfactant and a polymer. As stated earlier however such anthelmintics are not effective in the treatment of early immature and immature fasciola hepatica. Benzimidazoles in general and triclabendazole in particular are insoluble in water. Benzimidazoles and in particular triclabendazole have only been supplied in a 30 suspension formulation for dosing by oral administration. Suspensions are less able to be absorbed when applied by way of a pour-on. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 6 Pour-ons must be formulated to penetrate the animal's dermis which is the body's natural barrier. While a suspension may be absorbed from the digestive tract the same formulation applied to the skin would be less able to be absorbed. 5 Pour-on formulations have been used to deliver easily soluble actives such as synthetic pyrethroids and active agents in the class of 'avermectins' one such product containing the active ivermectin is marketed under the trade name 'Ivomec pour-on'. With most of the actives applied as pour-ons to the dermis, the dose rate at which it is applied is increased when compared to an oral or injectable formulation. This is to 10 offset less efficient absorption through skin tissues. The concept of increasing the drug loading of a single active formulation is generally not a preferred approach by conventional parasitology as a method of combating drug resistance and offsetting poor dermal absorption characteristics. Indeed increasing 15 drug loading in a pour-on formulation to offset exposure to sub-optimal drug concentration is viewed counter to current attempts to overcome increasing development of drug resistant parasitic strains. Parasitologists in contradistinction have attempted to address developing resistance by trialling combinations of active agents in attempts to find a synergistic combination. 20 The solubility characteristic of triclabendazole makes formulating an effective triclabendazole pour-on extremely difficult. A number of rate limiting barriers are faced in formulating active ingredient(s) in a commercially effective dosage form including (i) efficient and sufficient absorption to provide systemic amounts of active 25 quickly; (ii) minimal exposure of an animal to a toxic dosage form; and (iii) stability of formulation. These and other limitations are amplified given the characteristics of triclabendazole and the desire to provide a triclabendazole pour-on formulation, which is additionally 30 required to permeate across an animals dermis, and be sufficiently absorbed and transported to the site of infection (liver). Even further barriers exist to the extent that a sufficient kill rate of liver fluke needs to be achieved to substantially minimise potential development of drug resistant parasitic strains. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 7 While reference has been made to prior art in the specification it is not to be taken as an admission that art forms part of the common general knowledge. OBJECT 5 One object of the invention is therefore to obviate at least one of the disadvantages of the prior art. It is a further object of the invention to provide an improved stable liquid anthelmintic solution containing an effective amount of triclabendazole which is suitable for administration to warm blooded animals or one which at least provides the public with a useful choice. 10 STATEMENT OF INVENTION In one aspect the invention provides a pour-on veterinary anthelmintic formulation containing one or more anthelmintic actives wherein the anthelmintic active or one of the anthelmintic actives is triclabendazole and the triclabendazole is in a stable liquid 15 solution, and wherein the solution contains at least 10% w/v of triclabendazole and a solvent system containing one or more of solvents selected from the group consisting of benzyl alcohol, glycerol formal, n-methyl-2-pyrrolidone, and glycol ethers. The present invention provides a liquid formulation which solubilises triclabendazole 20 in high concentrations that can be easily administered by way of a pour-on. The solvent system of the present invention can contain at least one of benzyl alcohol and glycerol formal. The solvent system can contain at least two or more of the solvents selected from the group consisting of benzyl alcohol, glycerol formal, n-25 methyl-2-pyrrolidone, and glycol ethers. The majority solvent in the solvent system can be a glycol ether. Preferably the glycol ether can be butyl dioxitol. The solvent system can include benzyl alcohol as a second solvent. 30 The triclabendazole in the pour-on formulation can be present in the range 10-40% w/v. INTELLECTUAL PROPERTY OFFICE OF N.2. 2 6 MAR 2007 RECEIVED 8 The pour-on veterinary formulation can include at least one additional anthelmintic selected from the group of avermectins, milbemycins, tetramisole and levamisole, and which is soluble in the solvent system as previously defined. The additional anthelmintic is preferably an avermectin. The avermectin can be present in the range 5 0.25 to 2% w/v. There is further disclosed a pour-on veterinary formulation including: a solution of triclabendazole substantially dissolved in a solvent system of at least one 10 solvent selected from the group benzyl alcohol, glycerol formal, n-methyl-2-pyrollidone, and glycol ethers, the triclabendazole being present in an amount equal to or greater than 10%w/v. The solvent system can include a major proportion of a glycol ether and a minor 15 proportion of benzyl alcohol. The glycol ether can be butyl dioxitol and butyl dioxitol and benzyl alcohol may be present in an amount ranging between about 40% w/v to 60% w/v and about 5% w/v to 15% w/v respectively, and preferably 50% w/v and 5% w/v respectively. 20 The solvent system can further include a solubilisation agent selected from polyethylene glycols (PEG's) class of compounds. The PEG compound can be PEG 400 and can be present in an amount of about 14.5% w/v. The triclabendazole can be present in an amount of about 30% w/v. 25 The pour-on formulation of the present invention is effective in treating ruminants with the disease fasciolisis. The present invention provides a pour-on formulation in which at least 10% w/v triclabendazole is available for permeation of the dermal layer and subsequent absorption. 30 The pour-on formulation can be administered to an animal in an amount of up to about 50ml. The solvent system of the present invention is able to solubilise a sufficiently high amount of triclabendazole such that the formulation can be INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 9 10 15 administered from a conventional pour-on dosing gun substantially reducing the need for multiple dosing. In an embodiment of the present invention there is described a pour-on formulation for treatment of parasitic diseases including fasciolisis in warm blooded animals including: a solution of triclabendazole substantially dissolved in a solvent system, the triclabendazole being present in an amount of about 30%w/v; abamectin in an amount of about 0.5% w/v; wherein the solvent system includes butyl dioxitol; benzyl alcohol; and PEG 400 in an amount of about 50% w/v; 5% w/v; and 14.5% w/v respectively. In a related aspect of the present invention there is provided a method of treating warm blooded animals for parasites including liver flukes and fasciolisis by administering to the animal a pour-on formulation containing one or more anthelmintic actives wherein the anthelmintic active or one of the anthelmintic actives 20 is triclabendazole or a pharmaceutically acceptable salt thereof and the triclabendazole is in a stable liquid solution, and wherein the solution contains at least 10% w/v of triclabendazole and a solvent system containing one or more of solvents selected from the group consisting of benzyl alcohol, glycerol formal, n-methyl-2-pyrrolidone, and glycol ethers. 25 One advantage of the present invention is that triclabendazole is provided in a pour-on solution in high concentrations. The high concentration of triclabendazole in the pour-on formulation allows a farmer to administer manageable doses directly onto an animal's hide. This substantially obviates the need for oral dosing. A further 30 advantage is that the solvent system of the invention aids permeation of triclabendazole across an animal's dermal layer and subsequent absorption into the bloodstream for efficient transport to the diseased site. INTELLECTUAL PROPERTY OFFICE OF N.Z. 26 MAR 2007 RECEIVED 10 PREFERRED EMBODIMENTS It has now been found that stable liquid formulations containing the active triclabendazole in solution can be prepared and that these actives can be absorbed 5 through the skin to control the infection of liver in animals in particular cattle. The above, and other aspects of the invention, which should be considered in all its novel aspects will be apparent from the following examples. EXAMPLE 1 The formulation of this example is shown in table 1. It is suitable for administration 10 as a pour-on, in particular to cattle. The recommended dose rate is: Table 1 INGREDIENT G/lOOmL Abamectin 0.5 Triclabendazole 30.0 Butyl dioxitol 50.0 Benzyl Alcohol 5.0 PEG 400 to volume To prepare the formulation add the abamectin and benzyl alcohol. To this add butyl dioxitol and the triclabendazole. Warm to 40°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400. It will be apparent to the skilled 15 addressee if filtering is necessary at this point. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 11 TRIALS Stability Trials A stability trial was conducted to ensure that the triclabendazole solution was stable. 5 A formulation made as described in example I ("Formulation 1") was stored at ambient for 11 months. At the conclusion of the storage period samples were tested for total abamectin and triclabendazole levels. The results are presented in table 2 below. Table 2: Stability Trial Formulation 1 Abamectin Bla Abamectin Blb Total Abamectin Triclabendazole Date of manufacture Dayl 0.48 0.02 0.50 31.3 End of trial Day 345 0.48 0.008 0.49 28.9 10 Method Reference Technique Abamectin H127/01V3 HPLC Triclabendazole In House HPLC The results clearly show that the triclabendazole remained in solution. There was no loss in activity for either abamectin or triclabendazole. Efficacy Trials 15 Trials were conducted comparing the efficacy of the Formulation 1 with two other treatments and a control. The trial included twenty animals all confirmed infected INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 12 with Fasciola spp. The animals were divided into four groups of five animals. The animals were ranked on the basis of faecal fluke egg counts, and divided into blocks of four. Animals from each block were randomly allocated to one of the four treatment groups. Egg counts were performed twice on animals a week prior to the 5 trial to confirm all animals had a Fasciola spp burden. At day zero of the trial all animals were treated according to the protocol set out in Table 3. Group 1 animals were left untreated as controls. Group 2 received Formulation 1. Group 3 were the positive control group and received a commercial flukacide Fasinex 50 (Novartis). Group 4 received triclabendazole oral formulations at levels shown in table 3. 10 During the course of the trial all animals were grazed as a single group grazing on fluke infested pastures up to treatment and then removed to fluke free pastures post treatment. Table 3 15 At 14 days post treatment all animals were sacrificed. Total worm counts were performed using the following procedures: 1. Faecal egg counts 2. Fasciola hepatica liver counts. The liver counts were performed by 20 collecting the entire liver (ensuring thegall bladder remained intact) at necropsy. The liver was then labelled and transported (within 4 hours) on ice to laboratory facilities. INTELLECTUAL PROPERTY OFFICE OF N.2. 2 6 MAR 2007 RECEIVED Group 1 No treatment Group 2 At 5ml per 50 kg topically with the pour-on of Formulation 1 Group 3 At 12ml per 50 kg orally with Fasinex 50 50mg per ml of triclabendazole Group 4 At 12ml per 50 kg orally with the triclabendazole oral drench containing 50 mg per ml of triclabendazole 13 3. The liver was laid on a smooth surface and was evaluated for gross pathological changes according to the morbid pathology score sheets. 4. Large bile ducts and gallbladder were dissected allowing the mature and larger immature fluke if present to be seen. These were counted and 5 recorded on sheets. The balance of the liver tissue is dissected into 1cm thick slices and gently squeezed between the fingers. Any immature fluke appearing from the tissue were retrieved and countered. Remaining tissue was homogenised in a tissue "Stomacher" and washed over a 20 micron mesh such that any remaining immature flukes were recovered. The total worm 10 counts were collated into the treatment groups. Effective control was obtained against an established natural Fasciola hepatica burden with all formulations. The results are summarised on table 4 below. Table 4: Total Worm Counts Treatment Adult Fasciola Immature Fasciola hepatica hepatica Control mean 20 4.3 - n/a n/a Formulation 1 mean 0 0 % reduction 100 100 Fasinex 50 mean 0 0 % reduction 100 100 TCB formulation mean 0 0 % reduction 100 100 15 It can be clearly seen from the trials that the formulations of the present invention provide effective treatment of infection by the parasite Fasciola hepatica. In addition the formulations of the present invention provide the advantage of increased stability over the previous suspension formulations. 20 The combination of increased stability and effective treatment against all stages of Fasciola hepatica is a real advantage. It allows the storage of formulation for long INTELLECTUAL PROPERTY OFFICE OF N.2. 2 6 MAR 2007 14 periods as may arise in veterinary practises or on the farm eliminating wastage. In addition it eliminates the problems caused by settling of actives. The maintenance of the actives in solution and therefore maintaining a uniform concentration across the formulation ensuring an effective safe dose on application at the recommended 5 dosage. ADVANTAGES It is advantageous to be able to provide triclabendazole in stable solutions which can be more easily and effectively administered by pour-on. These solutions also allow 10 the use of triclabendazole in combination with other anthelmintics resulting in broader spectrum of activity, and consequently a reduction in the number of treatments required. Now that triclabendazole can be dissolved to form a stable pour-on solution the opportunities for combining this effective anthelmintic with other actives in stable solutions have substantially increased. 15 Comparative Example Pour-on formulations are generally administered in small volumes; indeed conventional dosing guns for administering a pour-on usually deliver up to about 50ml quantities of a formulation. For treatment of fasciolisis by triclabendazole pour-20 on, a dosage form of 50ml can require a drug loading of at least 10% w/v. It is known that triclabendazole has solubility in absolute ethanol of about 0.2g per 25ml (i.e.0.8% w/v). In order to achieve a suitable systemic concentration of triclabendazole, a 12% w/v drug loading would require dosing an animal with about 750 ml of ethanol including 6g of triclabendazole. At such volumes the dosing form may no longer 25 constitute an effective pour-on since such dosing with such quantities has the effect of exiting the skin. In view of the comparative example, the present invention allows farmers to substantially avoid the need for administering an unpractically large single dose or 30 repeated administration of a smaller dosage form. In any case farmers seek to avoid the need for multiple dosing and the exposure of animals to excessive volumes of carrier which may cause skin irritations. In addition with usage of larger volumes of a pour-on formulation it is difficult to prevent the dose from running off an animals hide. " • - .-i INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 15 The pour-on formulation of the present invention provides effective permeation through an animal's dermal layer without exposing the animal to excessive volumes of solvent. Indeed the present invention allows for administration of manageable 5 dosing quantities without causing skin irritation, while achieving therapeutic concentrations of triclabendazole at the liver. Hence the possibility for developing drug resistance is substantially obviated. VARIATIONS 10 It is envisaged that the formulations are the subject of the invention may be modified by the inclusion of additional excipients without departing from the spirit and scope of the invention. In particular it may be desirable to include dyes in the formulation to allow easy 15 identification of treated animals. Alternately other excipients such as buffers, thickeners, spreading agents may be included to modify the formulation to specific animals. In this specification the words "includes", "including" and the like and "comprises", 20 "comprising" and the like should be considered synonymous and be given a non-exhaustive meaning. Finally it will be appreciated that various other alterations and modifications may be made to the foregoing without departing from the scope of the invention. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 16 CLAIMS:

1. A pour-on veterinary anthelmintic formulation containing one or more anthelmintic actives wherein the anthelmintic active or one of the anthelmintic actives is triclabendazole and the triclabendazole is in a stable liquid solution, and wherein the solution contains at least 10% w/v of triclabendazole and a solvent system containing one or more of solvents selected from the group consisting of benzyl alcohol, glycerol formal, n-methyl-2-pyrrolidone, and glycol ethers.

2. A pour-on veterinary formulation as claimed in claim 1, wherein the solvent system contains at least one of benzyl alcohol and glycerol formal.

3. A pour-on veterinary formulation as claimed in claim 1 wherein the solvent system contains at least two or more of the solvents selected from the group claimed in claim 1.

4. A pour-on veterinary formulation as claimed in claim 3, wherein the majority solvent in the solvent system is a glycol ether.

5. A pour-on veterinary formulation as claimed in claim 4, wherein the glycol ether is butyl dioxitol.

6. A pour-on veterinary formulation as claimed in any one of claims 3 to 5, wherein a second solvent in the solvent system is benzyl alcohol.

7. A pour-on veterinary formulation as claimed in any one of claims 1 to 6, wherein the triclabendazole is present in the range 10-40% w/v.

8. A pour-on veterinary formulation as claimed in any one of claims 1 to 7 which includes at least one additional anthelmintic selected from the group of avermectins, milbemycins, tetramisole and levamisole, and which is soluble in the solvent system as previously claimed. INTELLECTUAL PROPERTY OFFICE OF HZ 2 6 MAR 2007 Dcr>eiv/en 17

9. A pour-on veterinary formulation as claimed in claim 8, wherein the additional anthelmintic is an avermectin. 5

10. A pour-on veterinary formulation as claimed in claim 9, wherein the avermectin is present in the range 0.25 to 2% w/v.

11. A pour-on veterinary formulation for the treatment of parasitic diseases including fasciolisis in warm blooded animals including: 10 15 20 a solution of triclabendazole substantially dissolved in a solvent system of at least one solvent selected from the group consisting of benzyl alcohol, glycerol formal, n-methyl-2-pyrollidone, and glycol ethers, the triclabendazole being present in an amount equal to or greater than 10%w/v.

12. A pour-on formulation for the treatment of parasitic diseases including fasciolisis in warm blooded animals as claimed in claim 11 wherein the solvent system includes a major proportion of a glycol ether; and a minor proportion of benzyl alcohol.

13. A pour-on formulation for the treatment of parasitic diseases including fasciolisis in warm blooded animals as claimed in 12 in which the glycol ether is butyl dioxitol and wherein butyl dioxitol and benzyl alcohol are present in amount of between about 40 to 60% w/v and about 5% to 15% w/v respectively.

14. A pour-on formulation for the treatment of parasitic diseases including fasciolisis in warm blooded animals as claimed in claim 13 wherein butyl dioxitol and benzyl alcohol are present in amount of about 50% w/v and 5% w/v respectively. 30

15. A pour-on formulation for the treatment of parasitic diseases including fasciolisis in warm blooded animals as claimed in any one of claims 11 to 14 wherein the solvent system further includes a solubilisation agent selected from polyethylene glycols (PEG's) class of compounds. 25 INTELLECTUAL PROPERTY OFFICE OF N.2. 2 6 MAR 2007 RECEIVED 18

16. A pour-on formulation for the treatment of parasitic diseases including fasciolisis in warm blooded animals as claimed in claim 15 wherein the PEG compound is PEG 400 and is present in an amount of about 14.5% w/v. 5

17. A pour-on formulation for the treatment of parasitic diseases including fasciolisis in warm blooded animals as claimed in any one of claims 11 to 16 wherein the triclabendazole is present in an amount of about 30% w/v.

18. A pour-on formulation for the treatment of parasitic diseases including fasciolisis 10 in warm blooded animals as claimed in any one of claims 11 to 17 wherein the pour-on formulation is administered to an animal in an amount of up to 50ml.

19. A pour-on veterinary formulation including: 15 a solution of triclabendazole substantially dissolved in a solvent system, the triclabendazole being present in an amount of about 30%w/v; abamectin in an amount of about 0.5% w/v; 20 wherein the solvent system includes butyl dioxitol; benzyl alcohol; and polyethylene glycol 400 in an amount of about 50% w/v; 5% w/v; and 14.5% w/v respectively.

20. A method of treating parasites including liver flukes and fasciolisis in non-25 human animals, said method comprising administering to said animal a pour-on formulation as claimed in any one of the previous claims. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 MAR 2007 RECEIVED 54 84 To- The Commissioner *10052008616* The Intellectual Property Office of New Zealand Our reference: A/SEP/00T210NZE Patent Form #2 Patents Act 1953 CONVENTION APPLICATION FOR A PATENT

1. We: ASHMONT HOLDINGS LIMITED Address: First Floor, 17 Shea Terrace, Takapuna, Auckland, New Zealand Nationality: A New Zealand company hereby declare that an application for protection for an invention or inventions has been made in the following country or countries and on the following official date or dates, namely: In: New Zealand on: 14 April 1999 by: Ashmont Holdings Limited and that the said application or each of the said applications was the first application in a convention country in respect of the relevant invention by us or by any person from whom we derive title.

2. We hereby declare that the true and first inventor of the invention disclosed in the accompanying complete specification is: Name: Colin Manson Harvey Nationality: A New Zealand citizen Address: 55 Beach Road, Castor Bay, Auckland, New Zealand and that our right to apply for a patent for the invention is as follows: We are the assignee of the said inventor by virtue of an assignment.

3. We declare that to the best of our knowledge and belief there is no lawful ground of objection to the grant of a patent to us on this application, and pursuant to subsection (2) and subsection (3) of Section 7 of the Patents Act 1953 We pray that a patent may be granted to us with priority founded on the above-mentioned application in a Convention country as provided by subsection (4) of section 11 of that Act, for the invention described in the accompanying complete specification under the title : ANTHELMINTIC COMPOSITIONS

4. ANTE-DATING is requested for this application and the attached complete specification to the date of filing of Application No. 537450 of 14 April 2000. 00T210NZE DIVISIONAL OF CONV PAT APP 20060707 1204 SEP.doc FEE CODE-1050 INTELLECTUAL PROPERTY OFFICE OF N.Z. - ? JUL 2006 RECEIVED 54 840

5. AND We request that all notices, requisitions, and communications relating to this application may be sent to: Postal Address: PIPERS, DX RP 42029, Lower Hutt, NEW ZEALAND PIPERS, PO Box 30-495, Lower Hutt 5040, NEW ZEALAND Address for Service: PIPERS, Level 1,29 Waterloo Road, Lower Hutt 5010, NEW ZEALAND who are hereby appointed to act for us. Dated: 7 July 2006 or PIPERS Attorneys for the Applicant ASHMONT HOLDINGS LIMITED 00T21QNZE DIVISIONAL OF_CONV PAT APP_20060707J204_SEP.doc FEE CODE-1050 - ? JUL 2006 received </div>