AU2010101389C4

AU2010101389C4 - Anthelmintic formulation

Info

Publication number: AU2010101389C4
Application number: AU2010101389A
Authority: AU
Inventors: Kai Lau
Original assignee: Jurox Pty Ltd
Current assignee: Jurox Pty Ltd
Priority date: 2010-12-08
Filing date: 2010-12-08
Publication date: 2017-03-02
Anticipated expiration: 2018-12-08
Also published as: AU2010101389A4; AU2010101389B4

Abstract

Abstract Anthelmintic compositions in the form of micellar solutions, their associated methods and uses.

Description

i 2010101389 08 Dec 2010

I 1

AUSTRALIA

Jurox Pty Ltd

Anthelmintic formulation

\ I 2010101389 08 Dec 2010 2

Anthelmintic formulation

The disclosure of the present application relates to pesticidal compositions, their preparations and use. More particularly the invention relates to liquid anthelmintic compositions comprising multiple actives. 5

Parasites in farm animals are a widespread problem throughout Australia and New Zealand. Scientists are exploring many avenues in trying to develop new options for graziers to deal with parasites and the escalating dilemma of resistance in animals to drenches. 10

Drench is the common name for an anthelmintic, a chemical specifically designed to kill parasites such as worms. Drenches can be "broad spectrum" which means they are suitable for treating a wide range of internal parasites or can target multiple stages of the parasites lifecycle, or "narrow spectrum", which means that they treat a restricted 15 range of internal parasites. "Combination drenches" are mixes of two or more of these drench classes.

Examples of broad spectrum drenches that are available include benzimidazole drenches or "white" drenches, and levamisole or "clear" drenches. Macrocyclic 20 lactones drenches are the newest group of broad spectrum drenches.

Drenches are usually administered orally using a drenching gun.

When drenching it has been found to be important to shake the drench container first as 25 most combination drenches settle out, meaning that the active ingredients settle into various phases in the container in which they are stored. It is important that the animals to which the drench is administered receive sufficient amounts of each of the active ingredients, otherwise there is an increased chance that the animals to which the drench is administered may develop resistance to one or more of the active ingredients. 30

Triton, registered trade mark of Merial (hereinafter Triton), is one example of a triple combination drench. In work leading to the development of Triton (as described in PCT/NZ00/00087) it was the intention of the inventors to address problems relating to stability and degradation, flocculation and curdling of the active ingredients. In one 2010101389 08 Dec 2010 3 aspect of the composition described in PCT/NZ00/00087, the composition is a partitioned composition comprising, in a first liquid phase (preferably organic) a first active ingredient and in a second liquid phase (preferably aqueous at acid pH) a second active ingredient, said active ingredient in said first liquid phase being unstable 5 chemically in the conditions of said second liquid phase. The third active ingredient is suspended preferably in the aqueous phase. More specifically, according to Example 15 and the claims of PCT/NZ00/00087, a macrocyclic lactone is carried in the organic liquid phase, levamisole is carried in the aqueous phase and albendazole is particulate and is at least in part in the aqueous phase, with the levamisole. The organic liquid 10 carrier is preferably an oil, and more preferably includes a co-solvent.

According to PCT/NZ00/00087 the presence of an emulsifying agent and/or anti-flocculant agent was found to be necessary to ensure stability of the two phases with the first phase with its first active ingredient as an emulsion within said second phase. 15

The Triton formulation and the formulation described in PCT/NZ00/00087 is an emulsion formulation, more particularly a suspo-emulsion. Emulsions consist of two immiscible phases, being an oil phase and an aqueous phase, which are generally considered to be thermodynamically unstable. After time or at elevated temperatures 20 an emulsion becomes unstable and separates into two phases. As soon as phase separation occurs, the active which is protected in the oil phase of the emulsion will start to contact with the aqueous phase and the active contained in the aqueous phase will start to contact with the oil phase. The degradation will be enhanced further once the emulsion is broken down. A known technique in slowing an emulsion from 25 breaking down is the use of a viscosity modifier to increase the viscosity of the formulation. Although this will slow down the separation of the two phases, it also gives the final formulation an undesirably high viscosity that makes the formulation extremely difficult to push through the drench gun at low temperature. A high viscosity product also has the disadvantage of being difficult to redisperse. Since an 30 emulsion will separate into phases with time, the user is required to "shake up" the product well before use to ensure that the animal receives the adequate dose of the active. AU2010100349 discloses compositions in the form of a micellar solution comprising at 35 least three active ingredients selected from a macrocyclic lactone, a benzimidazole and an imidazothiazole. 2010101389 08 Dec 2010 4

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of 5 these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

In work leading to the present disclosure, the inventors have surprisingly found that 10 further effective anthelmintic compositions comprising two or more active ingredients may be prepared where the composition comprises a micellar solution.

Accordingly the present disclosure relates to anthelmintic compositions comprising two or more active ingredients. Preferably the active ingredients have different spectrums 15 of activity with respect to parasites and in particular nematodes. Examples of parasite species for which the composition has activity are provided in the following table:

Parasite Species

Species Common Name Haemonchus contortus Barber’s pole worm Haemonchus placei Large stomach worm Ostertagia circumcincta Small brown stomach worm Trichostrongylus axei Stomach hair worm Trichostrongylus colubriformis Trichostrongylus vitrinus Black scour worm Cooperia curticel Cooperia oncophera Small intestinal worm Nematodirus spathiger Nematodirus filicollis Thin-necked intestinal worm Chabertia ovina Large mouthed bowel worm Oesophagostomum columbianum Nodule worm Oesophagostomum venulosum Large bowel worm Trichuris ovis Whip worm Strongyloides papillosus Intestinal threadworm 5

Bunostomum spp Hookworm Oestrus ovis Dictyocaulus viviparus Large lungworm Fasciola hepatica Monezia 2010101389 16 May 2013

As used herein the term "anthelmintic" and derivatives thereof refer to a medication capable of expelling or destroying parasitic worms. Preferably the composition is particularly useful for administration to a non-human animal. The compositions 5 disclosed herein are effective when used in a variety of animals. For example, sheep, goats, ruminants (including cattle) and camelids.

Throughout this specification, and unless it is stated to the contrary, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers 10 or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Disclosed herein is a stable anthelmintic composition in the form of a micellar solution, comprising an anthelmintically effective amount of at least two anthelmintic agents, 15 wherein the anthelmintic agents at least include a macrocyclic lactone and an imidazothiazole; the composition further comprising a therapeutically acceptable carrier, at least one surfactant and one or more water miscible solvent(s); with the proviso that the composition does not comprise a macrocyclic lactone, a benzimidazole, and an 20 imidazothiazole.

Also disclosed herein is a stable anthelmintic composition in the form of a micellar solution, comprising an anthelmintically effective amount of only two anthelmintic agents selected from a macrocyclic lactone and an imidazothiazole, the composition 25 further comprising a therapeutically acceptable carrier, at least one surfactant and one or more water miscible solvent(s).

Accordingly to a first aspect, there is provided a stable anthelmintic composition in the form of a micellar solution, comprising an anthelmintically effective amount of at least 2010101389 16 May 2013

5A two anthelmintic agents, wherein the anthelmintic agents at least include a macrocyclic lactone selected from one or more of the group consisting of: abamectin, ivermectin, doramectin, moxidectin, milbemycin and/or avermectin; and an imidazothiazole selected from one or more of the group consisting of: levamisole, pyrantel pamoate 5 and/or butamisole; the composition further comprising a therapeutically acceptable carrier comprising water, at least one surfactant, and one or more water miscible solvent(s) selected from the group comprising one or more liquid polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol;and optionally further 10 comprising napthalophos and/or praziquantel; with the proviso that the composition does not comprise a macrocyclic lactone, a benzimidazole, and an imidazothiazole; and optionally with the further proviso that the composition does not comprise a salicylanilide; wherein the composition is in the form of an oral drench. 15

Accordingly to a further aspect, there is provided a stable anthelmintic composition in the form of a micellar solution, comprising an anthelmintically effective amount of only two anthelmintic agents selected from: a macrocyclic lactone selected from one or more of the group consisting of: abamectin, ivermectin, doramectin, moxidectin, 20 milbemycin and/or avermectin; and an imidazothiazole selected from one or more of the group consisting of: levamisole, pyrantel pamoate and/or butamisole, the composition further comprising a therapeutically acceptable carrier comprising water, at least one surfactant and one or more water miscible solvent(s) selected from the group comprising one or more liquid polyethylene glycols, 25 tetraglycol, ethanol, benzyl alcohol and propylene glycol.

In a further embodiment, the anthelmintic composition further comprises praziquantel. 2010101389 08 Dec 2010 6

In a yet further embodiment, the anthelmintic composition further comprises napthalophos.

In a yet further embodiment, the anthelmintic composition additionally does not 5 comprise a salicylanilide.

In a yet further embodiment, the anthelmintic composition additionally does not comprise napthalophos. 10 In a yet further embodiment, the anthelmintic composition additionally does not comprise praziquantel.

In a yet further embodiment, the anthelmintic composition additionally does not comprise abamectin and levamisole HC1. 15

The composition does not comprise a separate organic liquid phase. In this way, the formulation now described is advantageous since the formulation is a single phase and the actives can be protected from interacting. The formulation of the present invention is more stable and is less prone to separation. This may help to provide a longer shelf 20 life for the product. Furthermore, in comparison to prior art emulsion based compositions, this increased stability means that the less thickening agent is required to maintain an adequate shelf life for the product. This leads to a decrease in the viscosity of the formulation which has advantages in both manufacture and administration, especially administration at low temperature which can be particularly difficult with 25 viscous emulsion based formulations.

In a second aspect, the present disclosure relates to a method of treating helminth or suspected helminth infections in a non-human animal comprising administering an anthelmintically effective amount of the compositions as disclosed herein, to an 30 infected animal or an animal suspected to be infected with at least one helminth.

In a third aspect, the present disclosure relates to the use of a composition as disclosed herein to treat helminth or suspected helminth infections in a non-human animal. 35 As used herein the term "micellar solution" refers to a thermodynamically stable single phase system. 2010101389 08 Dec 2010 7

As used herein the term "stable" refers to a composition which is chemically and physically stable to a commercially acceptable level for a period of at least 6 months and preferably at least 12 months. 5

The therapeutically active compounds disclosed herein are preferably incorporated into formulations in the range of concentrations as follows (g/L): macrocyclic lactones: 0.1-20.0 g/L, preferably 0.5-1.5 g/L imidazothiazoles: 1-100 g/L, preferably 30-50 g/L. 10

The anthelmintic composition disclosed herein can be formulated and administered in a number of ways, including for example as a drench, a pour-on transdermal formulation, a slow release bolus or an injectable formulation. Preferably the composition is a drench. More preferably the composition is an oral drench. 15

Preferably the amount of surfactant present is in the range of less than 200 g/L, preferably about 5 to less than about 200 g/L, preferably in the range of about 120 -165 g/L. Examples of suitable surfactants include, for example, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, and ethoxylated caster oil. Teric 380 (Teric is 20 a registered trademark of Huntsman Corporation Australia Pty Ltd) is an example of an alcohol ethoxylate surfactant. Preferably the surfactant is polysorbate 80. Polysorbate 80 is a nonionic surfactant or emulsifier derived from polyethoxylated sorbitan and oleic acid. 25 Most surprisingly, the inventors have found that a micellar solution can be formulated comprising at least one each of a macrocyclic lactone and imidazothiazole even when the concentration of surfactant is less than 200g/L. This is surprising and advantageous since the novel composition has an improved viscosity and it is easy to keep and administer the composition to an animal in need. Preferably the viscosity is improved 30 even at lower temperatures. An advantage for the manufacturer of having less surfactant is a decrease in cost of the ingredient.

Therefore, the composition now disclosed is a single phase micellar solution and it comprises lower amounts of surfactant than would be expected in a formulation 35 comprising the actives described here. The composition described here preferably comprises less than 200g/L surfactant. 2010101389 16 May 2013 8

The composition has a low viscosity which makes the product easy to administrate to the animal using a drench gun. The composition is not greatly affected by temperature. This micellar solution based formulation provides a product wherein the actives can be 5 resuspended readily and remain in suspension for a long time during use without it being necessary to further shake the formulation.

Preferably the viscosity of the composition is in the range of less than about 300 cps, less than about 250 cps, less than about 200 cps, less than about 150 cps, about 50-300 10 cps, about 50-250 cps, about 50-200 cps, about 100-200 cps, about 50-150 cps, or about 100-150 cps, as determined by a Brookfield viscometer using a spindle 3 at a speed of 60 rpm at 25 degrees centigrade.

The micellar solution is thermodynamically stable and the macrocyclic lactone inside 15 the micelles is well protected from reacting with other actives in the formulation. Stability results are provided in the Examples.

Preferably the therapeutic composition can comprise multiple combinations of actives to expand the spectrum of available treatments. 20

Preferred examples of the active ingredients are as follows:

Macrocyclic lactone Imidazothiazole abamectin levamisole ivermectin pyrantel pamoate doramectin butamisole moxidectin milbemycin avermectin

The macrocyclic lactone compound is selected from the group comprising abamectin, ivermectin, doramectin, moxidectin, milbemycin and avermectin. In one example the 25 macrocyclic lactone is abamectin. Avermectin is understood to be a mixture of abamectins. 2010101389 16 May 2013 9

Preferably the macrocyclic lactone is present in an amount in a range of about 0.1-20.0 g/L, preferably 0.3-5 g/L, preferably 0.5-1.5 g/L, preferably about 1 g/L. In one example the macrocyclic lactone is present in an amount of about lg/L. 5 The imidazothiazole is selected from the group comprising levamisole, pyrantel pamoate and butamisole.

Preferably the imidazothiazole is levamisole. Preferably the levamisole is present in the form of a water soluble salt, more preferably the levamisole is present as a 10 hydrochloride salt, that is levamisole hydrochloride.

Preferably the imidazothiazole is present in an amount in the range of about 1-100 g/L, preferably 20-60 g/L preferably 30-50 g/L preferably about 40 g/L. In one example the imidazothiazole is present in an amount of about 40g/L. 15

The therapeutically active compounds used in the invention are preferably incorporated into formulations in the range of concentrations as follows (g/L): avermectin: 0.1-20.0 g/L, preferably 0.3-5 g/L, preferably 0.5-1.5 g/L, preferably about 1 g/L; 20 levamisole: 1-100 g/L, preferably 20-60 g/L preferably 30-50 g/L preferably about 40 g/L.

According to a preferred embodiment of the present invention, the macrocyclic lactone is protected from interacting or reacting with the imidazothiazole by forming a stable 25 micellar solution. A stable micellar solution is formed by the presence of an amount of surfactant that is suitable to form a micellar solution. Preferably the amount of surfactant is less than 200g/L.

In a preferred embodiment the composition comprises surfactant at about 5 to less than 30 about 200 g/L, preferably, about 100-190g/L, preferably about 110-180g/L, preferably about 120-170 g/L, most preferably about 120g/L, 130g/L, 140g/L, 150g/L, 160g/L, or 170g/L.

Most preferably the surfactant is polysorbate 80. 35 2010101389 08 Dec 2010 ίο

In the present invention the composition further comprises a solvent system, and one or more anti-caking agents.

In a preferred embodiment of the composition, the macrocyclic lactone is in a solvent 5 system. The solvent system is preferably miscible with water to form a single phase.

In one embodiment the solvent system includes one or more solvents selected from the group comprising one or more liquid polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol. 10 In one preferred embodiment the solvent system comprises an amount of benzyl alcohol. In another preferred embodiment the solvent system comprises an amount of propylene glycol. In yet another embodiment, the solvent system comprises amounts of benzyl alcohol (about 1 - 40 g/L) and propylene glycol (about 5 - 400 g/L). 15 In one embodiment the solvent systems comprises: benzyl alcohol: 1-50 g/L, preferably 1-40 g/L, preferably 20-40 g/L; propylene glycol: 5-250 g/L, preferably 175-225 g/L.

Preferably the composition comprises an anti-caking agent. Preferably the anti-caking 20 agent is present in an amount effective to prevent the micronized material from agglomeration or forming large particles or forming a hard "cake", particularly on the bottom surface of a container. In a preferred embodiment of the invention the anticaking agent is a kaolin and / or colloidal silicon dioxide. A variety of anti-caking agents are known. 25

Preferably the composition comprises a buffering system. A variety of buffer systems may be used. Preferably the pH of the composition is about 5.0 - 5.5.

Examples of suitable buffering systems for the present invention include for example 30 phosphate buffers based on combinations of varying amounts of monobasic and dibasic sodium phosphate to achieve the desired pH. One example of a suitable phosphate buffer is monosodium phosphate anhydrous.

In one example of the invention the composition comprises about 15-20g/L 35 monosodium phosphate anhydrous, more preferably about 18g/L monosodium phosphate anhydrous. 2010101389 08 Dec 2010 11

Preferably the composition comprises an antifoaming agent. An antifoaming agent is used to minimise foaming during manufacturing and use of the composition. In one embodiment the antifoaming agent is a silicone oil, for example a hydrophobic silicone 5 oil antifoaming agent. For example, Antifoam AF. A preferred range of the antifoaming agent is about 0.01 - 1.0 g/L.

Preferably the composition comprises a dispersing or suspending agent. Preferably the dispersing or suspending agents can be selected from, for example, the group 10 comprising glyceryl palmitostearate, bentonite, colloidal silica, xanthan gum and polymeric pyrrolidones. In a preferred example the dispersing/suspending agent is a colloidal silica.

The dispersing or suspending agent can also be used as viscosity agents. Preferred 15 viscosity agents can be selected from, for example, colloidal silica, xanthan gum and polymeric pyrrolidones.

In a preferred embodiment of the composition described herein, the dispersing or suspending agent(s) / viscosity agent(s) are present in an amount of about 10-50 g/L, 20 preferably about 15-45 g/L. In one example the composition comprises about 18, 20, 25, 30, 35, 40 or 45g/L dispersing or suspending agent. Examples of dispersing agents include, for example, Terasperse 2500 (polymeric dispersant) or Aerosil 200 (amorphous fumed silica, Aerosil is a registered trade mark of Evonik Industries). Examples of viscosity agents include, for example, colloidal silica, xanthan gum and 25 polymeric pyrrolidones.

Methods of formulation

In another aspect, the present invention provides methods for formulating a product. In work leading to the formulation of the product, the inventors found that a superior 30 product is formulated in a micellar solution. Furthermore, the inventors found that a superior product is formulated with lower amounts of surfactant than would be expected for this type of formulation.

To ensure proper formation of a stable micelle it is most preferred that the macrocyclic 35 lactone is first mixed with and dissolved in the surfactant and water miscible solvent. Preferably, water is then added slowly to the surfactant-macrocyclic lactone solution. 2010101389 08 Dec 2010 12

The inventors found that this method minimises an instant dilution effect of water which can cause instability of micelles. The inventors were able to keep the micelles stable even using smaller amounts of surfactant than would be expected. The pH of the formulation is preferably adjusted before adding, an imidazothiazole to ensure that it is 5 buffered to remain as an acidic water soluble salt.

In order to better understand the nature of the compositions described herein examples will now be described as follows: 10 Example 1 FORMULATION:

NAMES OF SUBSTANCES QUANTITY (g/U Monosodium Phosphate anhydrous 18 g Antifoam AF 3_g__ Benzyl Alcohol 30 g Polysorbate 80 150g Propylene Glycol 200 g Disodium Phosphate anhydrous Abamectin __ 1 g Aerosil 200 18 g Levamisole Hydrochloride o ora Water q.s. to 1 L 15 Example 2

NAMES OF SUBSTANCES QUANTITY (g/Li Monosodium Phosphate anhydrous 18 g Antifoam AF _Ls__ Benzyl Alcohol 30 g Polysorbate 80 120g Propylene Glycol 300 g Disodium Phosphate anhydrous Ai__ Abamectin 1 g Aerosil 200 40 g Levamisole Hydrochloride 40 g Water q.s. to 1 L

Example 3 13

NAMES OF SUBSTANCES QUANTITY (g/L) Monosodium Phosphate anhydrous 18 g Antifoam AF 1 g Benzyl Alcohol 30 g Polysorbate 80 120g Propylene Glycol 300 g Disodium Phosphate anhydrous 2g Moxidectin 1 g Aerosil 200 40 g Levamisole Hydrochloride 40 g Water q.s. to 1 L 2010101389 16 May 2013

Method

Examples 1 and 2 were prepared as follows : 1. Dissolve avermectin in benzyl alcohol and propylene glycol. 5 2. Add polysorbate 80 to step 1. 3. Add water to the solution from step 2 and mix until homogeneous. 4. Dissolve phosphate buffer salts in the solution from step 3. 5. Add levamisole hydrochloride. Mix until fully dispersed. 6. Add Aerosil to the suspension and mix until fully dispersed. 10

The stability of Example 3 was evaluated at 30 °C with the following results:

Initial 6 months Levamisole HC1 39.8 g/L 40.1 g/L Moxidectin 1.05 g/L 1.03 g/L 15 In addition, it was noted that after centrifugation of a sample of Example 1 to 3 at 4000 g for 1 hour, the sample did not separate but remained as a single phase.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments 20 without departing from the scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

CLAIMS:

1. A stable anthelmintic composition in the form of a micellar solution, comprising an anthelmintically effective amount of at least two anthelmintic agents, wherein the anthelmintic agents at least include a macrocyclic lactone selected from one or more of the group consisting of: abamectin, ivermectin, doramectin, moxidectin, milbemycin and/or avermectin; and an imidazothiazole selected from one or more of the group consisting of: levamisole, pyrantel pamoate and/or butamisole; the composition further comprising a therapeutically acceptable carrier comprising water, at least one surfactant, and one or more water miscible solvent(s) selected from the group comprising one or more liquid polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol;and optionally further comprising napthalophos and/or praziquantel; with the proviso that the composition does not comprise a macrocyclic lactone, a benzimidazole, and an imidazothiazole; and optionally with the further proviso that the composition does not comprise a salicylanilide; wherein the composition is in the form of an oral drench.
2. A stable anthelmintic composition in the form of a micellar solution, comprising an anthelmintically effective amount of only two anthelmintic agents selected from: a macrocyclic lactone selected from one or more of the group consisting of: abamectin, ivermectin, doramectin, moxidectin, milbemycin and/or avermectin; and an imidazothiazole selected from one or more of the group consisting of: levamisole, pyrantel pamoate and/or butamisole, the composition further comprising a therapeutically acceptable carrier comprising water, at least one surfactant and one or more water miscible solvent(s) selected from the group comprising one or more liquid polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol.
3. The composition of any preceding claim wherein the pH of the composition is about 5.0 - 5.5.
4. Use of a composition according to any one of claims 1 to 3 in the treatment of helminth or suspected helminth infection in a non-human animal, wherein the helminth is selected from the group consisting of: Haemonchus contortus (Barber's pole worm); Haemonchus placei (Large stomach worm); Ostertagia circumcincta (Small brown stomach worm); Trichostrongylus axei (Stomach hair worm); Trichostrongylus colubriformis; Trichostrongylus vitrinus (Black scour worm); Cooperia curticel; Cooperia oncophera (Small intestinal worm); Nematodirus spathiger; Nematodirus filicollis (Thin-necked intestinal worm); Chabertia ovina (Large mouthed bowel worm); Oesophagostomum columbianum (Nodule worm); Oesophagostomum venulosum (Large bowel worm); Trichuris ovis (Whip worm); Strongyloides papillosus (Intestinal threadworm); Bunostomum spp (Hookworm); Oestrus ovis; Dictyocaulus viviparus (Large lungworm); Fasciola hepatica; and/or Monezia. and/or the helminth or suspected helminth infection in the animal is by parasites resistant to at least one or both of the groups macrocyclic lactones, and imidazothiazoles.
5. A composition substantially as hereinbefore described with reference to the accompanying examples, wherein the animal is a non-human animal.