NZ553144A - Anthelmintic formulations comprising triclabendazole and a liquid polyethylene glycol - Google Patents

Abstract

Disclosed is a veterinary anthelmintic formulation containing a stable solution of triclabendazole, wherein the solution contains an effective amount of triclabendazole, or a pharmaceutically acceptable moiety thereof, dissolved in a solvent system, wherein the solvent system contains at least 60% by volume of one or more of the liquid polyethylene glycols.

Description

New Zealand Paient Spedficaiion for Paient Number 553144 INTELLECTUAL FHUHERTYI OFFICE OP N Z- I 11 FEB 2007 I r f r. e i v E p] DIVISIONAL OUT OF APPLICATION # 530286 ANTE-DATING REQUESTED TO 19 May 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: 130577NZA_Divpat_20070208_1049_TDT.doc FEE CODE-1010 FIELD OF THE INVENTION This invention relates to liquid solutions of thiabendazole and in particular to veterinary anthelmintic formulations including triclabendazole in liquid solution, it has particular, though no sole, application to liquid pour-on formulations. This is a divisional out of application 530286 which claims formulations containing 2-pyrrolidone.

BACKGROUND OF THE INVENTION Diseases caused by parasitic helminths such as nematodes, cestodes and trematodes (liver fluke) can cause severe economic losses in the farming of ruminants and other animals. Fasciolisis, a disease caused by parasitic liver flukes, is commonly contracted by domestic herbivorous animals such as sheep, cattle and goats. The liver flukes Fasciola hepatica and Fasciola gigantica are flat worms which live in the bile ducts (in the liver) of their hosts.

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 fasciola hepatica (miracidia). The miracidia develop and multiply and eventually leave the snail host and 20 encyst on vegetation forming metacercarial (infective stage of fasciola hepatica). When the vegetation is consumed by a grazing animal, the metacercarial excysts in the small intestine releasing the young parasite. These immature flukes penetrate the intestinal wall and enter the abdominal cavity. From there they migrate to the liver. Acute infections can result from the immature flukes burrowing through the liver substance. Death often follows as a result 25 of concomitant blood loss.

It has been estimated that around the world at least 40 million sheep and 6 million cattle graze on pastures contaminated with fasciola hepatica (liver fluke). 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Because ruminants, such as sheep, cattle and goats, are susceptible to fasciolisis, it is of critical importance that formulations effective against the disease are available.

Until recently, the treatment of fasciolisis has been less than optimal. The drug previously used, bithionol, had to be administered orally over five days at a dosage of 30 mg/kg of body 5 weight. Praziquantel, a very effective drug against most trematode infections, is inactive against Fasciola species.

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.

Of all the benzimidazoles 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 following structural formula: Other active agents within the benzimidazole class of actives such as albendazole are only effective against adult fluke.

In general for ease of application to large numbers of animals, farmers and veterinary 20 surgeons prefer to treat farm animals with pour-ons rather than oral drenches or injectables.

Pour-ons are typically relatively viscous liquids applied in small doses to the neck or back line of the animal. In the case of sheep pour on, the applicator guns 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 60ml. Most pour-ons have the active in solution, and the solvent or I30577NZA DIVISIONAL SPEC 20080813 by JP.DOC 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 the farmer and the animal, stable, non-toxic, non-carcinogenic, and capable of being used in a pour-on applicator gun. Because of the 5 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 standard. Thus a 10ml dose of a pour-on would normally supply sufficient active to treat a 100kg sheep, 50ml would supply normally enough active to treat a 500kg 10 cattle beast.

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.

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 15 route of administration, and solutions are usually far more stable than suspensions when stored in bulk. However, if the active is known to be sparingly soluble in water or most practical solvents then the formulator will favour a suspension for use as an oral drench.

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 20 way of a pour-on.

It has been difficult to provide liquid formulations containing triclabendazole in solution. Indeed, until recently it has only been available as a suspension formulation for oral administration.

Commercial drench formulations of triclabendazole are known in which triclabendazole is 25 suspended in a liquid carrier. Such formulations are administered 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 (or 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC 240g/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 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 5 formulation often requires a suitably experienced/qualified person to 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 10 the farming community but attempts to produce pour ons containing benzimidazoles have been unsuccessful until the applicant invented a formulation for a triclabendazole pour on. The applicant had previously tried unsuccessfully to formulate an oxfendazole pour on.

In W095/23590 (Bomac), a pour-on formulation is described in which a benzimidazole, selected from oxfendazole and/or albendazole, is formulated in a suspension. Suspensions of 15 albendazole in accordance with formulations described in 'Bomac' 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.

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. Anthelmintic 20 formulations are known which contain oxfendazole; tetramisole and levamisole 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-ionic surfactant and a polymer. As stated earlier, 25 however, such anthelmintics are not effective in the treatment of early immature and immature fasciola hepatica.

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 (1) 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC efficient and sufficient absorption to provide systemic amounts of active 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 required to 5 permeate across an animal's 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.

For triclabendazole pour-on an effective dose is a dose of about 30 mg per kg animal weight. 10 If the triclabendazole is present in solution at 150mg per ml or 15%w/v, a dose of 70 ml will deliver sufficient triclabendazole to treat fasciolisis in a cow weighing 350 kg.

In PCT/NZ00/00053 we disclose certain solvents which are capable of dissolving triclabendazole. The specific solvents disclosed are benzyl alcohol, n-methyl pyrrolidone, glycol ethers including butyl dioxitol. The formulations included as examples incorporated 15 triclabendazole at 30 % w/v. Thus a dose of 35 ml will deliver sufficient triclabendazole to treat fascioliasis in a cow weighing 350 kg.

While this is a significant advance it would be useful to be able to include triclabendazole in solution with other solvents for pour-ons and for other routes of administration, and in the case of a pour on formulation preferably containing higher concentrations of triclabendazole 20 to allow an even smaller volume of formulation to be applied to the animal while still providing an effective dose.

While reference has been made to prior art in the specification it is not to be taken as an admission that the cited art forms part of the common general knowledge.

OBJECT OF THE INVENTION It is an object of the invention to provide an improved veterinary anthelmintic formulation including triclabendazole in solution, or one which will at least provide the public with a useful choice. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC SUMMARY OF THE INVENTION In one aspect the invention provides a veterinary anthelmintic formulation containing a stable solution of triclabendazole, wherein the solution contains an effective amount of triclabendazole, or a pharmaceutically acceptable moiety thereof, dissolved in a solvent 5 system consisting only of or consisting predominantly of one or more of the liquid polyethylene glycols.

We have discovered that the liquid PEGs (and in particular PEG 400) are very effective solvents for use in veterinary formulations containing triclabendazole as shown in table la. In the tables shown below the most effective solvent is PEG 400 and the next most effective 10 solvent is 2-pyrrolidone (the subject of patent application 530286).

In either case there may be excipients or other actives present but the liquid polyethylene glycols will make up the bulk of the solvent system.

By the phrase "the solvent system consisting predominately of' we mean that the named solvent(s) make up the bulk of the solvent system. This means that the "one or more of the 15 liquid polyethylene glycols" will make up at least 60% of the solvent system. In the example we show formulations containing PEG 400 making up 87% by volume of the solvent system, as well as 90%, 92% and 100% by volume.

Preferably the triclabendazole or a pharmaceutically acceptable moiety thereof is present in the range of 5 - 60% w/v (in g/lOOml).

Preferably the one or more of the liquid polyethylene glycols consists substantially of polyethylene glycol 400.

Optionally the solvent system also includes up to 10% w/v in total (in g/lOOml) of another solvent or solvents chosen from the group comprising benzyl alcohol, propylene glycol, N-methyl pyrrolidone, glycerol formal, glycol ethers, butyl dioxitol, methyl alcohol, ethyl 25 alcohol, isopropyl alcohol, 1-butanol and 1-hexanol.

Preferably the formulation includes at least one additional anthelmintic active or other medicament which is soluble in the solvent system.

Preferably the additional anthelmintic active or actives are selected from the group comprising avermectins, milbemycins, tetramisole, and levamisole. 130577NZA DIVISIONAL SPEC 20081008 BY JP002.DOC Preferably the additional anthelmintic active is an avermectin.

Preferably the additional anthelmintic active is abamectin.

Preferably the formulation further includes excipients such as dyes, preservatives, stabilisers, buffers, thickeners, anti-foaming agents, spreading agents, and the like.

Preferably the solution is formulated as a pour-on formulation.

A method of treating parasites including fasciolisis in non-human animals by administering to an animal a formulation as described above.

A method of treating parasites including fasciolisis in non-human animals by providing a formulation as previously described and administering a volume of substantially 25 ml or 10 less of the pour-on formulation onto the skin surface of an animal.

A method of treating fasciolisis in non-human animals by providing a formulation as previously described in the form of a pour-on formulation and administering a volume capable of delivering at least 1 mg of triclabendazole, or a pharmaceutically acceptable moiety thereof, per 10 kg of body weight of the animal to be treated.

In another aspect the invention provides a veterinary anthelmintic formulation containing a stable solution of triclabendazole, wherein the solution contains an effective amount of triclabendazole, or a pharmaceutically acceptable moiety thereof, dissolved in a solvent system, wherein the solvent system contains at least 60% by volume of one or more of the liquid polyethylene glycols.

Preferably the triclabendazole, or a pharmaceutically acceptable moiety thereof is present in the range of 5 - 60% w/v (in g/lOOml).

Preferably the one or more of the liquid polyethylene glycols is polyethylene glycol 400.

Preferably the solvent system includes up to 10% w/v in total (in g/lOOml) of another solvent or solvents chosen from the group comprising benzyl alcohol, propylene glycol, N-methyl 25 pyrrolidone, glycerol formal, glycol ethers, butyl dioxitol, methyl alcohol, ethyl alcohol, isopropyl alcohol, 1-butanol and 1-hexanol. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Preferably the formulation includes at least one additional anthelmintic active or other medicament which is soluble in the solvent system.

Preferably the additional anthelmintic active or actives are selected from the group comprising avermectins, milbemycins, tetramisole and levamisole.

Preferably the additional anthelmintic active is an avermectin.

Preferably the additional anthelmintic active is abamectin.

Preferably the formulation further includes excipients such as dyes, preservatives, stabilisers, buffers, thickeners, anti-foaming agents, or spreading agents.

Preferably the solution is formulated as a pour-on formulation.

References to 'medicaments' include those substances such as anthelmintics, antigens, vaccines, vitamin and mineral supplements and other substances, which may be useful for promoting the health of the animal.

'Liquid polyethylene glycol' includes polyethylene glycol (PEG) that is liquid at room temperature. PEG 200 to 400 are liquid at room temperature. In addition, blends containing 15 polyethylene glycols of higher or lower molecular weight are useable if the resulting mixture is liquid at roofti temperature.

PREFERRED EMBODIMENTS Benzimidazoles are generally regarded as being difficult to dissolve, and consequently 20 commercial formulations are made up as liquid suspensions mainly for application as oral drenches.

As a comparison we conducted trials to determine the solubility of various members of the benzimidazole family in different solvents. We found that oxfendazole, albendazole and ricobendazole are all either insoluble or so insignificantly soluble that they cannot be 25 formulated as effective veterinary solutions in solvents such as benzyl alcohol, propylene glycol, NMP, 2-pyrrolidone, PEG, glycerol formal and butyl dioxitol. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC When we conducted trials with triclabendazole it was found that the triclabendazole was more soluble generally in the solvents mentioned above than the other benzimidazoles which were sparingly soluble at best, and in most cases insoluble. But more importantly we discovered that triclabendazole is extremely soluble in 2-pyrrolidone and PEG 400 with more than 500 mg of triclabendazole capable of being dissolved in a ml of these solvents. This is particularly advantageous as it allows for formulations of low volume to be formulated for delivery to cattle and other animals.

Table la: Solubility Studies of triclabendazole in different organic solvents Sample No.

Solvent Name Quantity dissolved in 10 ml solvent Total Volume occupied Amount dissolved (mg/ml) 1 Benzyl Alcohol .0 g (Max solubility) 14 ml 357.14 2 Propylene Glycol 1.5 g (Max solubility) 11.0 ml 136.36 3 NMP" 4.5 g (Max solubility) 14.0 ml 321.43 4 2-pyrrolidone .0 g (flowable in nature) 17,5-18.0 ml 555.55 PEG400 .0 g (flowable in nature) 17.5 ml 571.43 6 Glyceryl Formal Ig (Max solubility) 90.91 7 DGBE (butyl dioxitol) 2.0 g (Max solubility) 166.66 "NMP -N-methyl pyrrolidone 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Table lb: Solubility studies of triclabendazole in different alcohols Sample No.

Solvent Name Triclabendazol e taken in 10 ml solvent. Day 0 Triclabendazole aftded to previous system. Day 1 Triclabendazo le added to previous system. Day 7 Solvent added to the previous system.

Day 12 Solvent added to the previous system.

Day 15 1 Methyl alcohol 500 mg 500 mg lg ml ml 2 Ethyl alcohol 500 mg 500 mg 1 g ml ml 3 Isopropyl alcohol 500 mg 500 mg 1 g ml 4 1-butanol 500 mg 500 mg 1 g ml 1- hexanol 500 mg 500 mg 1 g ml Table lc: Solubility Studies of Triclabendazole is various alcohols Sample No.

Solvent Name Quantity dissolved in solvent) Total volume occupied Amount dissolved (mg/ml) 1 Methyl alcohol 2 gm/20 ml 22.5 ml 88.88 2 Ethyl alcohol 2 gm/20 ml 22.5 ml 88.88 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC 3 Isopropyl alcohol 2 gm/15 ml 17.0 ml 117.5 4 1-butanol 2 gm/15 ml 17.0 ml 117.5 1-hexanol 2 gm/15 ml 17.0 ml 117.5 Based on the above solubility data various formulations containing 2-pyrrolidone or PEG were proposed. The formulations were prepared and stored at room temperature and refrigeration temperature for 30 days. The formulations showed no deposition at room 5 temperature or under refrigeration. The formulations based on 2-pyrrolidone are claimed in our earlier application 530286. The formulations having a solvent system consisting predominately of a liquid PEG show from 5% to 40% of triclabendazole dissolved in the solvent system. Example 2 is similar to Example 1 of our earlier PCT/NZ00/00053 as DGBE is the main solvent. The solvent system contains less than 50% by volume of PEG 10 400, and hence it is not claimed in this application.

In field use these formulations would be highly desirable as they could provide the flexibility to deliver high concentrations of triclabendazole to the animal in a relatively small amount of solvent. The ideal would be to deliver concentrated quantities of triclabendazole in a solvent delivered at the rate of as low as 1ml per 20kg bodyweight.

After conducting a number of solubility studies of benzimidazoles in general and triclabendazole in particular it has now been found that triclabendazole is extremely soluble in 2-pyrrolidone and liquid polyethylene glycol (particularly PEG 400), with more than 500 mg of triclabendazole dissolving In a millilitre of each of these solvents.

It has been found that stable liquid formulations containing triclabendazole in solution with 20 these solvents can be prepared and that these actives can be absorbed through the skin to control parasitic diseases, including fasciolisis in warm blooded animals. The use of these particular solvents is advantageous as it allows high concentrations of triclabendazole to be dissolved so that doses of low volume can be administered to cattle and other animals. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Based on the solubility studies various formulations containing 2-pyrrolidone or liquid polyethylene glycol were prepared in accordance with the following examples.

The example formulations below are particularly suitable for administration as pour-ons. However, the solutions of the present invention are useable in different dosage forms. By way of example the triclabendazole solution may be incorporated into oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations) and drenches. Other topical administration forms such as spot-ons are useable. The various dosage forms are well known to those of ordinary skill in the pharmaceutical and veterinaiy arts.

Example 1 (not claimed in this application) Ingredients Quantity Triclabendazole g 2-pyrrolidone 50 g DGBE (butyl dioxitol) q. s. to 100 ml To prepare the formulation add the triclabendazole and 2-pyrrolidone. Warm to 60°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with DGBE.

Example 2 (not claimed in this application) Ingredients Quantity Triclabendazole g PEG 400 50 g DGBE (butyl dioxitol) q. s. to 100 ml 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC To prepare the formulation add the triclabendazole and PEG 400 (polyethylene glycol 400). Warm to 60°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with DGBE.

Example 3 (not claimed in this application) Ingredients Quantity Triclabendazole 60g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, and 2-pyrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 4 (not claimed in this application) Ingredients Quantity Triclabendazole 60g N-methyl pyrrolidone 10g 2-pyrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, NMP and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 5 (not claimed in this application) Ingredients Quantity Triclabendazole 60g Benzyl Alcohol 10g 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, Benzyl Alcohol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 6 (not claimed in this application) Ingredients Quantity Triclabendazole 60g DGBE 10g 2-pyrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, DGBE and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 7 (not claimed in this application) Ingredients Quantity Triclabendazole 60g Glycerol Formal 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, Glycerol Formal and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 8 Ingredients Quantity Triclabendazole 40 g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 9 Ingredients Quantity Triclabendazole 40g DGBE 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, DGBE and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 10 (not claimed in this application) Ingredients Quantity Triclabendazole 40g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 11 (not claimed in this application) S. No.

Ingredients Quantity 1 Triclabendazole 40g 2 NMP 10g 3 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, NMP and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 12 (not claimed in this application) S. No.

Ingredients Quantity 1 Triclabendazole 40g 2 Benzyl alcohol 10g 3 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, benzyl alcohol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 13 (not claimed in this application) Ingredients Quantity Triclabendazole 40g Glycerol formal 10g 2-pyrrolidone q. s. to 100 ml 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC To prepare the formulation add the triclabendazole, glycerol formal and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 14 (not claimed in this application) Ingredients Quantity Triclabendazole 40g Propylene glycol 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, propylene glycol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 15 (not claimed in this application) .

Ingredients Quantity Triclabendazole 20g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 16 (not claimed in this application) Ingredients Quantity Triclabendazole 20g 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC NMP lOg 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, NMP and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 17 (not claimed in this application) Ingredients Quantity Triclabendazole 20g Benzyl alcohol 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, benzyl alcohol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 18 (not claimed in this application) Ingredients Quantity Triclabendazole 20g Glycerol formal 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, glycerol formal and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 19 (not claimed in this application) Ingredients Quantity Triclabendazole 20g Propylene glycol 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, propylene glycol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 20 (not claimed in this application) Ingredients Quantity Triclabendazole 20g Ethyl alcohol 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, ethyl alcohol and 2-pyrrolidone, Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 21 (not claimed in this application) Ingredients Quantity Triclabendazole 10g 2-pyrrolidone q. s. to 100 ml 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC To prepare the formulation add the triclabendazole, and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 22 (not claimed in this application) Ingredients Quantity Triclabendazole lOg NMP 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, NMP and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 23 (not claimed in this application) Ingredients Quantity Triclabendazole lOg Benzyl alcohol lOg 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, benzyl alcohol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 24 (not claimed in this application) Ingredients Quantity Triclabendazole 10g 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Glycerol formal 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, glycerol formal and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 25 (not claimed in this application) Ingredients Quantity Triclabendazole lOg Propylene glycol lOg 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, propylene glycol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 26 (not claimed in this application) Ingredients Quantity Triclabendazole 10g Ethyl alcohol 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, ethyl alcohol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 27 (not claimed in this application) Ingredients Quantity Triclabendazole 5g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 28 (not claimed in this application) Ingredients Quantity Triclabendazole 5g NMP 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, NMP and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 29 (not claimed in this application) Ingredients Quantity Triclabendazole 5g Benzyl alcohol 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, benzyl alcohol and 2-pyrrolidone. Warm 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 30 (not claimed in this application) Ingredients Quantity Triclabendazole 5S Glycerol formal 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, glycerol formal and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 31 (not claimed in this application) Ingredients Quantity Triclabendazole 5s Propylene glycol lOg 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, propylene glycol and 2-pyrrolidone, Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 32 (not claimed in this application) Ingredients Quantity Triclabendazole 5g 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Ethyl alcohol 10g 2-pyrrolidone q. s. to 100 ml To prepare the formulation add the triclabendazole, ethyl alcohol and 2-pyrrolidone. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with 2-pyrrolidone.

Example 33 Ingredients Quantity Triclabendazole 40 g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 34 Ingredients Quantity Triclabendazole 40g Glycerol formal 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, glycerol formal and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

I30577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 35 Ingredients Quantity Triclabendazole g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 36 Ingredients Quantity Triclabendazole 20g Glycerol formal 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, glycerol formal and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 37 Ingredients Quantity Triclabendazole 20g Benzyl alcohol 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, benzyl alcohol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 38 Ingredients Quantity Triclabendazole 20g Propylene glycol 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, propylene glycol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 39 Ingredients Quantity Triclabendazole 20g Ethyl alcohol 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, ethyl alcohol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 40 Ingredients Quantity Triclabendazole g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 41 Ingredients Quantity Triclabendazole 10g Glycerol formal lOg PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, glycerol formal and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 42 Ingredients Quantity Triclabendazole 10g Benzyl alcohol 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, benzyl alcohol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 43 Ingredients Quantity Triclabendazole lOg Propylene glycol 10g PEG 400 q. s. to 100 ml 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC To prepare the formulation add the triclabendazole, propylene glycol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 44 Ingredients Quantity Triclabendazole lOg Ethyl alcohol lOg PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, ethyl alcohol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 45 Ingredients Quantity Triclabendazole g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 46 Ingredients Quantity Triclabendazole 5g Glycerol formal 10g 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, glycerol formal and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 47 Ingredients Quantity Triclabendazole 5g Benzyl alcohol 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, benzyl alcohol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

Example 48 Ingredients Quantity Triclabendazole 5g Propylene glycol 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, propylene glycol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC Example 49 Ingredients Quantity Triclabendazole 5g Ethyl alcohol 10g PEG 400 q. s. to 100 ml To prepare the formulation add the triclabendazole, ethyl alcohol and PEG 400. Warm to 70°C and stir to dissolve. Cool mix to less than 25°C and dilute to volume with PEG 400.

It will be appreciated that the above formulations are examples only and that other formulations are contemplated wherein the solvent system may include any combination of liquid polyethylene glycol with additional solvents selected from the group comprising 2-pyrrolidone, benzyl alcohol, propylene glycol, N-methyl pyrrolidone, glycerol formal, glycol ethers, butyl dioxitol, methyl alcohol, ethyl alcohol, isopropyl alcohol, 1-butanol and 1-hexanol.

Furthermore, it will be appreciated that the formulation may further include additional anthelmintic actives or other medicaments which are soluble in the solvent system. For example, the additional anthelmintic active or actives may be selected from the group comprising avermectins, milbemycins, tetramisole and levamisole. Abamectin has been 15 found to be particularly suitable.

The formulation may also further include excipients such as dyes, preservatives, stabilisers, buffers, thickeners, anti-foaming agents, spreading agents and the like.

Stability Trials Various formulations containing 2-pyrrolidone or PEG were prepared and stored at room temperature and refrigeration temperature for 30 days. The • formulations showed no deposition at room temperature or under refrigeration. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC ADVANTAGES The triclabendazole formulations of the present invention are advantageous as they allow the inclusion of triclabendazole in solution at significantly higher concentrations than previously known. This is advantageous as it allows the administration of an effective amount of 5 triclabendazole in a low volume dose.

By way of example, pour-on formulations including triclabendazole in solution at about 40% w/v or greater will deliver an effective dose of triclabendazole to a 350 kg cow in about 25 ml of formulation. This smaller volume is particularly advantageous as it marries with the amount of liquid a pour-on gun can deliver. In addition, it increases the number of animals 10 that may be treated out of the same pack thereby decreasing the need to change packs. The lower volume also further decreases the risk of the triclabendazole running off the back of the animal.

In field use these formulations would be highly desirable as they could provide the flexibility to deliver high concentrations of triclabendazole to an animal in a relatively small amount of 15 solvent. Concentrated quantities of triclabendazole in solution could be delivered at a rate of as low as 1 ml per 20 kg of body weight, which equates to as little as 17.5 ml of formulation for a 350 kg cow.

VARIATIONS It is envisaged that the formulations 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 identification of treated animals. Alternately other excipients such as preservatives, stabilisers, buffers, thickeners, anti-foaming agents, spreading agents and the like may be 25 included to modify the formulation to specific animals.

Also, additional excipients may be included within the formulations of the present invention to tailor them to suit a specific administration method. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC In this specification the words "includes", "including" and the like and "comprises", "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. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC

Claims (17)

WHAT WE CLAIM IS:

1. A veterinary anthelmintic formulation containing a stable solution of triclabendazole, wherein the solution contains an effective amount of triclabendazole, or a pharmaceutically acceptable moiety thereof, dissolved in a solvent system, wherein the solvent system contains at least 60% by volume of one or more of the liquid polyethylene glycols.

2. A veterinary anthelmintic formulation as claimed in claim 1, wherein the triclabendazole or pharmaceutically acceptable moiety thereof is present in the range of 5 - 60% w/v (in g/lOOml).

3. A veterinary anthelmintic formulation as claimed in claim 1 or claim 2, wherein the one or more of the liquid polyethylene glycols is polyethylene glycol 400.

4. A veterinary anthelmintic formulation as claimed in any one of claims 1 to 3, wherein the solvent system includes up to 10% w/v in total (in g/lOOml) of another solvent or solvents chosen from the group comprising 2-pyrrolidone, benzyl alcohol, propylene glycol, N-methyl pyrrolidone, glycerol formal, glycol ethers, butyl dioxitol, methyl alcohol, ethyl alcohol, isopropyl alcohol, 1-butanol and 1-hexanol.

5. A veterinary anthelmintic formulation as claimed in any one of the previous claims, wherein the formulation includes at least one additional anthelmintic active or other medicament which is soluble in the solvent system.

6. A veterinary anthelmintic formulation as claimed in claim 5, wherein the additional anthelmintic active or actives are selected from the group comprising avermectins, milbemycins, tetramisole and levamisole.

7. A veterinary anthelmintic formulation as claimed in claim 5, wherein the additional anthelmintic active is an avermectin.

8. A veterinary anthelmintic formulation as claimed in claim 5, wherein the additional anthelmintic active is abamectin. 130577NZA DIVISIONAL SPEC 20080813 by JP.DOC -35-

9. A veterinary anthelmintic formulation as claimed in any one of the preceding claims wherein the formulation further includes excipients such as dyes, preservatives, stabilisers, buffers, thickeners, anti-foaming agents, or spreading agents.

10. A veterinary anthelmintic formulation as claimed in any one of the preceding claims wherein the solvent system contains at least 87% by volume of one or more of the liquid polyethylene glycols.

11. A veterinary anthelmintic formulation as claimed in any one of the preceding claims wherein the solvent system contains at least 90% by volume of one or more of the liquid polyethylene glycols.

12. A veterinary anthelmintic formulation as claimed in any one of the preceding claims wherein the solvent system contains at least 92% by volume of one or more of the liquid polyethylene glycols.

13. A veterinary anthelmintic formulation as claimed in any one of the preceding claims wherein the solvent system contains 100% by volume of liquid polyethylene glycol 400.

14. A veterinary anthelmintic formulation as claimed in any one of the preceding claims, wherein the solution is formulated as a pour-on formulation.

15. A method of treating parasites including fasciolisis in non-human animals by administering to an animal a formulation as claimed in any one of claims 1 to 14.

16. A method of treating parasites including fasciolisis in non-human animals by providing a formulation as claimed in claim 14 and administering a volume of substantially 25 ml or less of the pour-on formulation onto the skin surface of an animal.

17. A method of treating fasciolisis in non-human animals by providing a formulation as claimed in claim 1 in the form of a pour-on formulation and administering a volume 130577NZA DIVISIONAL SPEC 20081008 BY JP002.DOC -36- capable of delivering at least 1 mg of triclabendazole, or a pharmaceutically acceptable moiety thereof, per 10 kg of body weight of the animal to be treated. PIPERS Attorneys for MERIAL LIMITED 130577NZA DIVISIONAL SPEC 20081008 BY JPQ02.DOC