NZ616160B2

NZ616160B2 - Veterinary pharmaceutical formulations and methods

Info

Publication number: NZ616160B2
Application number: NZ616160A
Authority: NZ
Inventors: Grant Halligan Douglas; Gary Robert Harrison
Original assignee: Nexan Corporation Limited
Filing date: 2013-10-01
Publication date: 2014-09-30

Abstract

Disclosed is a method of veterinary treatment, the method including the step of administration of a formulation including: at least one veterinary pharmaceutical compound selected from any one or more of: a macrocyclic lactone, an anthelmintic nicotinic receptor agonist, an amino-acetonitrile derivative, an imidazothiazole, a benzimidazole, a spirodioxepinoindole, a salicylanilide, a benzenedisulfonamide, a spinosyn, a chloronicotinyl, a pyrethrin, a synthetic pyrethroid, an organophosphate, a carbamate, a formamidine, a phenylpyrazole, a semicarbazone; a cyclic depsipeptide, an anti-inflammatory, analgesic, ntiemetic an antihyperthyroid, an antihypothyroid; and methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate. Also disclosed is a veterinary formulation and a method of producing a veterinary formulation comprising methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate. tive, an imidazothiazole, a benzimidazole, a spirodioxepinoindole, a salicylanilide, a benzenedisulfonamide, a spinosyn, a chloronicotinyl, a pyrethrin, a synthetic pyrethroid, an organophosphate, a carbamate, a formamidine, a phenylpyrazole, a semicarbazone; a cyclic depsipeptide, an anti-inflammatory, analgesic, ntiemetic an antihyperthyroid, an antihypothyroid; and methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate. Also disclosed is a veterinary formulation and a method of producing a veterinary formulation comprising methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate.

Description

KAE509143NZPR 303137968 VETERINARY PHARMACEUTICAL FORMULATIONS AND METHODS Field of Invention The invention relates to veterinary pharmaceutical formulations, their preparation and their use.

More particularly, the invention relates to veterinary pharmaceutical formulations including methyl 5-(dimethylamino)methyloxopentanoate, their preparation and their use in veterinary methods for the treatment of non-human animals (“veterinary methods”).

Background It is desirable to be able to treat non-human animals using formulations which are suitably non- toxic, suitably non-irritant and are capable of delivering one or more actives in a single formulation. Irritancy is particularly of concern for oral and topical delivery.

Topical formulations have advantages for ease of administration. They can cut down on time required to administer drugs, which is particularly important for large numbers of livestock.

Administration of topical formulations requires little training of the administrator. They also generally cause less distress in the animal than administration by oral (drench), rectal or by injection. They also require less handling/manipulating of the animal, which can be a particular advantage for larger animals, for example cattle and deer. In the case of domestic animals there is also greater convenience and less distress for the pet owner, which results in greater compliance with dosage regimes. However, formulations for topical delivery have a tendency to cause skin irritation in the subject, which can result in the need to treat the skin, or to discontinue use of the formulation. For example, NZ520295 to Merial Limited discloses the use of pyrrolidone solvents, in particular N-methylpyrrolidone, in a pour-on veterinary formulation containing levamisole and an avermectin or milbemycin. However, this formulation has been found to cause skin irritation in some cases.

Topical formulations are preferred for many purposes because of their ease of use. However, there is a perception that orals may be more effective and faster acting (although there is little evidence that this is the case). Orals are therefore preferred in some instances, particularly for smaller commercial animals, such as sheep. In addition, orals can be more effective than topicals for unshorn sheep due to the difficulty of getting the formulation through the wool. Oral KAE509143NZPR 303275309-1 formulations are required to be sufficiently non-toxic as they are consumed by the subject. They must also be sufficiently non-irritant, such that they do not cause damage to the mouth and throat of the subject.

It is highly desirable to have high stability in veterinary formulations. Low stability results in wastage of product and the need to safely dispose of product which is out of date. Consumers prefer products with longer expiry dates for these reasons. A product with a shorter expiry date than equivalent products is less likely to be commercially successful. Further a product with a longer expiry date than equivalent products is likely to have a significant commercial advantage.

It is an object of the invention to provide a method of veterinary treatment and/or formulations for such treatments. Alternatively, it is an object of the invention to at least provide a useful choice to the public.

Summary of the Invention According to a first aspect of the invention, there is provided a method of veterinary treatment, the method including the step of administration of a formulation including: at least one veterinary pharmaceutical compound selected from any one or more of: a macrocyclic lactone, an anthelmintic nicotinic receptor agonist, an amino-acetonitrile derivative, an imidazothiazole, a benzimidazole, a spirodioxepinoindole, a salicylanilide, a benzenedisulfonamide, a spinosyn, a chloronicotinyl, a pyrethrin, a synthetic pyrethroid, an organophosphate, a carbamate, a formamidine, a phenylpyrazole, a semicarbazone; a cyclic depsipeptide, an anti-inflammatory, analgesic, antiemetic an antihyperthyroid, an antihypothyroid; and methyl 5-(dimethylamino)methyloxopentanoate.

Preferably, the formulation is administered topically.

Preferably, the formulation is administered orally.

Preferably, the formulation is non-aqueous.

KAE509143NZPR 303275309-1 Preferably, the veterinary pharmaceutical compound is an anthelmintic selected from any one or more of: a macrocyclic lactone, an anthelmintic nicotinic receptor agonist, an amino- acetonitrile derivative (AAD), an imidazothiazole, a benzimidazole, a spirodioxepinoindole, a salicylanilide, a benzenedisulfonamide.

Preferably, the macrocyclic lactone is selected from: abamectin, ivermectin, doramectin, eprinomectin, selamectin, moxidectin, milbemycin oxime, selamectin.

Preferably, the benzimidazole is triclabendazole.

Preferably, the veterinary pharmaceutical compound is a pesticide selected from any one or more of: a spinosyn, a chloronicotinyl, a pyrethrin, a synthetic pyrethroid, an organophosphate, a carbamate, a formamidine, a phenylpyrazole, a semicarbazone.

Preferably, the phenylpyrazole is fipronil.

Preferably, the veterinary pharmaceutical compound is a cyclic depsipeptide.

Preferably, the veterinary pharmaceutical compound is an ectoparasiticide.

Alternatively, the veterinary pharmaceutical compound is an endoparasitic.

Preferably, the veterinary pharmaceutical compound is an anti-inflammatory.

Preferably, the veterinary pharmaceutical compound is an analgesic.

Preferably, the veterinary pharmaceutical compound is an antiemetic.

Preferably, the veterinary pharmaceutical compound is an antihyperthyroid or an antihypothyroid.

According to a second aspect of the invention, there is provided a veterinary formulation including: at least one veterinary pharmaceutical compound; and KAE509143NZPR 303275309-1 methyl 5-(dimethylamino)methyloxopentanoate.

According to a third aspect of the invention, there is provided a veterinary formulation including: at least one veterinary pharmaceutical compound; and methyl 5-(dimethylamino)methyloxopentanoate; with the proviso that the veterinary pharmaceutical compound is not: propuxur, chlorpyrifos, or Fastac (alpha – cypermethrin).

Preferred embodiments of the second and third aspects include: Preferably, the veterinary formulation is suitable for topical administration to a non-human animal.

Preferably, the veterinary formulation is suitable for oral administration to a non-human animal.

KAE509143NZPR 303137968 Preferably, the veterinary pharmaceutical compound is an anthelmintic.

Preferably, the veterinary pharmaceutical compound is a macrocyclic lactone.

Preferably, the veterinary pharmaceutical compound is an anthelmintic nicotinic receptor agonist.

Preferably, the veterinary pharmaceutical compound is an amino-acetonitrile derivative (AAD).

Preferably, the veterinary pharmaceutical compound is an imidazothiazole.

Preferably, the veterinary pharmaceutical compound is a benzimidazole.

Preferably, the veterinary pharmaceutical compound is a spirodioxepinoindole.

Preferably, the veterinary pharmaceutical compound is a salicylanilide.

Preferably, the veterinary pharmaceutical compound is a benzenedisulfonamide.

Preferably, the veterinary pharmaceutical compound is a pesticide.

Preferably, the veterinary pharmaceutical compound is an IGR (insect growth regulator).

Preferably, the veterinary pharmaceutical compound is a spinosyn and/or chloronicotinyl.

Preferably, the veterinary pharmaceutical compound is a pyrethrin and/or synthetic pyrethroid.

Preferably, the veterinary pharmaceutical compound is an organophosphate.

Preferably, the veterinary pharmaceutical compound is a carbamate.

Preferably, the veterinary pharmaceutical compound is a formamidine.

Preferably, the veterinary pharmaceutical compound is a phenylpyrazole.

KAE509143NZPR 303137968 Preferably, the veterinary pharmaceutical compound is a semicarbazone.

Preferably, the veterinary pharmaceutical compound is a cyclic depsipeptide.

Preferably, the veterinary pharmaceutical compound is an ectoparasiticide.

Alternatively, the veterinary pharmaceutical compound is an endoparasiticide.

Preferably, the veterinary pharmaceutical compound is an anti-inflammatory.

Preferably, the veterinary pharmaceutical compound is an analgesic.

Preferably, the veterinary pharmaceutical compound is an antiemetic.

Preferably, the formulation further includes a preservative.

Preferably, methyl 5-(dimethylamino)methyloxopentanoate is the only solvent in the formulation.

Alternatively, the formulation further includes at least one co-solvent.

Preferably, the methyl 5-(dimethylamino)methyloxopentanoate is the major solvent.

According to a fourth aspect of the invention, there is provided a method of producing a veterinary formulation including the step of: addition of at least one veterinary pharmaceutical compound to methyl 5- (dimethylamino)methyloxopentanoate.

Preferably, the veterinary pharmaceutical compound is an anthelmintic.

KAE509143NZPR 303137968 Preferably, the veterinary pharmaceutical compound is a pesticide.

Preferably, the veterinary pharmaceutical compound is an ectoparasiticide.

Alternatively, the veterinary pharmaceutical compound is an endoparasiticide.

Preferably, the veterinary pharmaceutical compound is an anti-inflammatory.

Preferably, the veterinary pharmaceutical compound is an analgesic.

Preferably, the veterinary pharmaceutical compound is an antiemetic.

Preferably, the method further includes addition of a preservative.

Alternatively, the method further includes addition at least one co-solvent.

Further aspects of the invention, which should be considered in all its novel aspects, will become apparent to those skilled in the art upon reading of the following description which provides at least one example of a practical application of the invention.

Detailed Description of Preferred Embodiments The present invention relates to methods and formulations for the treatment of non-human animals (veterinary). In particular the methods of the invention include the step of administering a formulation including at least one veterinary pharmaceutical compound (also referred to as active or actives) and methyl 5-(dimethylamino)methyloxopentanoate.

KAE509143NZPR 303137968 The present invention also relates to veterinary formulations including at least one veterinary pharmaceutical compound and methyl 5-(dimethylamino)methyloxopentanoate and methods for producing the same.

In an embodiment of the invention the methods and formulations of the invention are for the oral delivery of the active(s) to a non-human animal.

In a particularly preferred embodiment the methods and formulations of the invention are for the topical delivery of the veterinary pharmaceutical to a non-human animal. While not wishing to be bound by theory it is believed application of the formulation topically acts by either delivering the active or actives transdermally or alternatively in other cases the formulation spreads and mixes with the natural oils (sebum) of the host’s skin, fur or feathers, and is deposited in the sebaceous glands. The sebaceous glands are believed to act as a reservoir for the active(s) that allows for the active(s) to drain back out of the glands to the follicles to reapply itself to the skin and hair. This action provides for longer periods between applications and also eliminates or ameliorates the need to reapply if the host becomes wet, for example due to rain or bathing (this form of delivery will herein after be referred to as “sebaceous deposit” or “sebaceous depositing”).

The mode of delivery of the active(s) is dependent on the compound or compounds.

Anthelmintics, endoparasitics, anti-inflammatories, analgesics, antiemetics, antihyperthyroids or antihypothyroids will generally be delivered orally or transdermally. However, active(s) for the treatment of ectoparasites will generally by delivered by “sebaceous depositing”, for example the use of fipronil for the treatment or prevention of fleas and ticks.

Water is preferably not added to the formulations as water can impede the ability of the formulation to spread across the skin of the animal. In addition, water may also affect the ability of many of the actives (such as the macrocyclic lactones) to stay in solution. The formulations and the formulations used in the methods of the invention are therefore preferably non- aqueous. When the formulations are in the preferred non-aqueous form, they may include trace amounts of water (less than about 1% w/w) which naturally occurs in the solvent or actives. For example, the product data sheet for one source of commercially available methyl 5- (dimethylamino)methyloxopentanoate (solvent) indicates it can include 0-0.1% water.

KAE509143NZPR 303137968 Therefore the invention in a preferred form will include a method of veterinary treatment, the method including the step of administration of a formulation comprising at least one veterinary pharmaceutical compound and methyl 5-(dimethylamino)methyloxopentanoate; wherein the formulation is non-aqueous. The method will preferably be topical or oral treatment. Further, the invention in a preferred form includes a veterinary formulation including at least one veterinary pharmaceutical compound and methyl 5-(dimethylamino)methyloxopentanoate; wherein the formulation is non-aqueous. Still further the invention preferably includes a method of producing a veterinary formulation including the step of addition of at least one veterinary pharmaceutical compound to methyl 5-(dimethylamino)methyloxopentanoate, and wherein water is not added to the formulation.

As will be readily apparent to the skilled person, in some circumstances a user or manufacturer may decide to add water to the formulation. While the inclusion of water into formulations of the invention is not needed and could be detrimental, the inclusion of water to the formulations is not excluded from the scope of the invention. Non-aqueous formulations and veterinary methods using such formulations are very much preferred however. it is a particular advantage that the formulations for topical use can be non-aqueous due to resultant spreading, transdermal and stability advantages.

Oral delivery is typically performed in larger animals with the use of a drench gun which delivers a set dose of the liquid veterinary formulation into the throat/mouth of the subject.

However, it is also possible to have a single dose tube/bottle to deliver the liquid formulation into the mouth/throat of the subject. This option may be more likely for small animal/domestic animal purposes. The formulation may also be contained in a capsule (for example a soft gelatine capsule), or formed into a paste, for delivery into the mouth of the subject.

Topical delivery methods include (but are not limited to) spot-on, pour-on, backliner and spray.

Topical formulations are typically applied to the back of the subject, but may alternatively or in addition be applied to other areas of the body. The liquid formulation may be applied with the use of an applicator, straight from the container or following dilution. In some cases it is particularly convenient to have a single dose bottle/tube where the whole of the contents are applied to the subject, for example flea treatment of a domestic animal. The formulation may also be contained in a patch which is applied to the skin of the subject. In such cases the KAE509143NZPR 303137968 formulation is typically incorporated into a reservoir in the patch.

The solvent, methyl 5-(dimethylamino)methyloxopentanoate, has previously been disclosed in AU2009207634 (from WO2009/092795) to be useful as a solvent for phytosanitary compositions, cleaning, degreasing or stripping compositions. Use as part of a veterinary formulation was never considered and, given the previously disclosed use in phytosanitary compositions, it is particularly surprising the inventors have been able to formulate veterinary formulations capable of delivering veterinary compounds, orally and topically, to a non-human animal using methyl 5-(dimethylamino)methyloxopentanoate. The ability of the solvent to transport active(s) though the dermal layer or to spread over the dermal layer and deposit in sebaceous glands would be a disadvantage in phytosanitary compositions, as it would be potentially dangerous to the user mixing and applying the compositions to crops and other plants. AU2009207634 particularly discloses the use of propuxur, chlorpyrifos, or Fastac (alpha – cypermethrin) in those phytosanitary formulations. In a preferred embodiment therefore, a veterinary formulation of the invention includes at least one veterinary pharmaceutical compound and methyl 5-(dimethylamino)methyloxopentanoate; with the proviso that the veterinary pharmaceutical compound is not: propuxur, chlorpyrifos, or Fastac (alpha – cypermethrin). However, as stated above, veterinary uses (and in particular oral and topical veterinary uses) were never envisioned by this publication.

AU2013100468, published 16 May 2013, describes the use of a solvent system requiring both methyl 5-(dimethylamino)methyloxopentanoate and organic acid solvents, such as C -C carboxylic acids (in particular lactic acid), in veterinary formulations that must also include an IGR. The inventors of the present invention have discovered that methyl 5-(dimethylamino) methyloxopentanoate may be used as the only solvent in veterinary formulations that include IGRs and/or other actives (as described in detail below) and that a solvent system that also includes C -C carboxylic acids is not needed. AU2013100468 specifically teaches IGR containing formulations and refers broadly to the requirement of organic acids as part of the solvent system. The document actually only demonstrates the use of C -C carboxylic acids and, in particular lactic acid, as being able to produce the IGR containing formulations described.

AU2013100468 also refers to the possible inclusion of any one or more of synthetic pyrethroids, piperonyl butoxide, chloronicotinyls (for example imidacloprid), phenylpyrazoles KAE509143NZPR 303137968 (for example fipronil) with the required IGRs (for example (S)-methoprene). AU2013100468 does not recognise that other veterinary actives (as described in more detail below), including any one or more of synthetic pyrethroids, piperonyl butoxide, chloronicotinyls (for example imidacloprid), phenylpyrazoles (for example fipronil), can be formulated without the need for a C -C carboxylic acid as part of a solvent system together with methyl 5-(dimethylamino) methyloxopentanoate. AU2013100468 also does not recognise that any one or more of synthetic pyrethroids, piperonyl butoxide, chloronicotinyls (for example imidacloprid), phenylpyrazoles (for example fipronil) can be formulated without an IGR using a solvent system including methyl 5-(dimethylamino)methyloxopentanoate and a C -C carboxylic acid.

An advantage of the formulations and methods of the present invention is the reduction in irritation caused by delivery of the formulations either orally or topically over prior formulations.

For example, formulations based on pyrrolidone solvents are basic (high pH) and can therefore be caustic. The formulations of the present invention preferably do not include components, such as co-solvents or stabilising agents, which are caustic or which will cause skin irritation.

Therefore the formulations of the invention will preferably not include organic acid solvents, such as C -C carboxylic acids (as described in AU2013100468), or pyrrolidone solvents. This is particularly preferred where the formulations and methods of the invention are applied topically, particularly in the case of “spot on” formulations for treatment of domestic animals.

While dermal irritation is an animal welfare concern for all animals, skin irritation following treatment is particularly of concern to domestic animal owners who are less likely to be compliant with medication if they believe there is any dermal irritation caused to the skin of their animal by the treatment, even if it is merely cosmetic.

In a particularly preferred embodiment, when the formulations, and methods, of the invention include an IGR (for example (S)-methoprene), alone or together with any one or more of synthetic pyrethroids, piperonyl butoxide, chloronicotinyls (for example imidacloprid), phenylpyrazoles (for example fipronil), the formulations, and methods, do not include a C -C carboxylic acid(s) in a solvent system with methyl 5-(dimethylamino)methyl oxopentanoate.

In a further preferred embodiment, when the formulations, and methods, of the invention include any one or more of synthetic pyrethroids, piperonyl butoxide, chloronicotinyls (for example imidacloprid), phenylpyrazoles (for example fipronil), the formulations, and methods, KAE509143NZPR 303137968 do not include a C -C carboxylic acid(s) in a solvent system with methyl 5-(dimethylamino) methyloxopentanoate.

In a further preferred embodiment, when the formulations, and methods, of the invention include any one or more of synthetic pyrethroids, piperonyl butoxide, chloronicotinyls (for example imidacloprid), phenylpyrazoles (for example fipronil), and the formulations, and methods, include a C -C carboxylic acid in a solvent system with methyl 5-(dimethylamino) methyloxopentanoate, the formulations, and methods do not include an IGR.

Therefore, the invention preferably relates to a method of veterinary treatment, the method including the step of administration of a formulation at least one veterinary pharmaceutical compound and methyl 5-(dimethylamino)methyloxopentanoate; wherein when the formulation includes an IGR the formulation does not include a C -C carboxylic acid as part of the solvent system.

Further the invention preferably relates to a veterinary formulation including at least one veterinary pharmaceutical compound and methyl 5-(dimethylamino)methyloxopentanoate; wherein when the formulation includes an IGR the formulation does not include a C -C carboxylic acid as part of the solvent system.

Still further the invention preferably relates to a method of producing a veterinary formulation including the step of adding at least one veterinary pharmaceutical compound to methyl 5- (dimethylamino)methyloxopentanoate; wherein when the formulation includes an IGR a C -C carboxylic acid solvent is not added to the formulation.

In addition, solvents, such as pyrrolidone solvents in particular, can have a malodour which is unpleasant for the administrator and the subject. Methyl 5-(dimethylamino)methyl oxopentanoate for use in the formulations and methods of the invention has little or no odour which results in more pleasant experience for the administrator and subject (particularly with oral formulations), and allows for greater ease of storage (with less requirement for ventilation).

In addition, methyl 5-(dimethylamino)methyloxopentanoate has surprisingly been found to be sufficiently non-toxic to allow use in veterinary formulations of the invention.

KAE509143NZPR 303137968 In a preferred embodiment of the invention, the veterinary pharmaceutical compound is an anthelmintic, more preferably, a macrocyclic lactone and/or anthelmintic nicotinic receptor agonist and/or an amino-acetonitrile derivative (AAD) and/or an imidazothiazole and/or a benzimidazole and/or a spirodioxepinoindole and/or a salicylanilide and/or a benzenedisulfonamide.

Macrocyclic lactones for use in the invention include any or more of the avermectins and/or milbemycins, for example, but not limited to, abamectin, ivermectin, doramectin, eprinomectin, selamectin, moxidectin, milbemycin oxime. In some cases, macrocyclic lactones have broader pesticidal activity (rather than just use as anthelmintic), for example, selamectin is used to treat various types of worms, as well as scabies, fleas, ear mites and ticks and may therefore be considered both an anthelmintic and a pesticide.

Anthelmintic nicotinic receptor agonist for use in the invention may be selected from any one or more of levamisole, pyrantel, morantel.

Amino-Acetonitrile Derivatives (AADs) for use in the invention include, but are not limited to, monepantel.

Imidazothiazoles for use in the invention include, but are not limited to a tetramisole, more preferably levamisole.

Benzimidazoles for use in the invention include, but are not limited to albendazole, oxfendazole, fendendazole, mebendazole, rycobendazole, parrbendazole, triclabendazole, febantel, netobimin, thiabendazole, cambendazole.

Spirodioxepinoindoles for use in the invention include, but are not limited to, 2- desoxoparaherquamide.

Salicylanilides for use in the invention include closantel.

Benzenedisulfonamides for use in the invention include clorsulon.

In a further preferred embodiment of the invention, the veterinary pharmaceutical compound is KAE509143NZPR 303137968 a pesticide, even more preferably an ectoparasiticide or an endoparasiticide. Examples of pesticides for use in the invention include, but are not limited to IGRs (insect growth regulators), spinosyns and/or chloronicotinyls, pyrethrins and/or synthetic pyrethroids, organophosphates, carbamates, formamidines, phenylpyrazoles, semicarbazone. However, and as stated previously, when the formulation includes an IGR, a C -C carboxylic acid is not included as part of the solvent system.

IGRs for use in the invention include, but are not limited to benzoylphenyl ureas (for example fluazuron, diflubenzuron, flufenoxuron), triazine and pyrimidine derivatives (for example, cyromazine and dicyclanil), juvenile hormone analogs (for example (S)-methoprene).

Spinosyns and/or chloronicotinyls for use in the invention include, but are not limited to imidacloprid, spinosad.

Pyrethrins and/or synthetic pyrethroids for use in the invention include, but are not limited to bioallethrin, cypermethrin, deltamethrin, fenvalerate, flumethrin, lambdacyhalothrin, phenothrin, permethrin, including isomers and mixtures of isomers thereof, for example alpha-cypermethrin.

Piperonyl butoxide is optionally used in conjunction with the pyrethrins and pyrethroids due to its synergistic action.

Organophosphates for use in the invention include, but are not limited to coumaphos, diazinon, dichlorvos, famphur, fenthion, malathion, trichlorfon, stirofos (tetrachlorvinphos), phosmet, chlorpyrifos, haloxon, metriphonate, cythioateand, propetamphos. In some cases organophosphates are also used as anthelmintics, for example haloxon and metriphonate.

Carbamates for use in the invention include, but are not limited to carbaryl and/or propoxur.

Formamidines for use in the invention include, but are not limited to amitraz.

Phenylpyrazoles for use in the invention include, but are not limited to fipronil.

Semicarbazones for use in the invention include, but are not limited to metaflumizone, In a further preferred embodiment of the invention, the veterinary pharmaceutical compound is KAE509143NZPR 303137968 a cyclic depsipeptide. Cyclic depsipeptides for use in the invention include, but are not limited to cyclosporine, valinomycin. Cyclic depsipeptides have a number of uses, for example, cyclosporine is used for the treatment of atopic dermatitis in dogs. Valinomycin may be used as an insecticide and/or a nematocide (see for example US3,520,973).

In a further preferred embodiment of the invention, the veterinary pharmaceutical compound is an anti-inflammatory and/or an analgesic. Examples of analgesics and/or anti-inflammatories for use in the invention include, but are not limited to fentanyl, non-steroidal anti-inflammatories (NSAID) (eg. ketoprofen). In some cases, compounds used as analgesics may, when used in alternative dose rates, also be used as anaesthetics and/or sedatives.

In a further alternative preferred embodiment of the invention, the veterinary pharmaceutical compound is an antiemetic, for example (but not limited to) metoclopramide, maropitant, ondansetron.

In a further alternative preferred embodiment of the invention, the veterinary pharmaceutical compound is an antihyperthyroid or an antihypothyroid, for example (but not limited to) methimazole, levothyroxine sodium.

In some embodiments the formulation will include more than one veterinary pharmaceutical compound. The invention should be taken to include such embodiments. In particular, two or more veterinary pharmaceutical compounds for the same indication (for example, anthelmintics) are included in the same formulation when there is the risk of resistance building up to a single active, or where resistance is already an issue. It is also beneficial to include two or more veterinary pharmaceutical compounds for different indications in the same formulation (for example, an anthelmintic and an ectoparasiticide) to allow treatment or prophylaxis of more than one condition in a single application. Such formulations save time in administration and decrease distress to the animal by allowing a single treatment in place of two or more treatments. The formulations and methods of the invention are particularly suited to providing two or more actives in a single formulation, as methyl 5-(dimethylamino)methyl oxopentanoate is capable of forming a stable formulation with a wide range of actives.

Accordingly the methods and formulations of the invention at least one veterinary pharmaceutical compound and methyl 5-(dimethylamino)methyloxopentanoate, wherein the veterinary pharmaceutical compound is selected from any one or more of: a macrocyclic KAE509143NZPR 303137968 lactone, an anthelmintic nicotinic receptor agonist, an amino-acetonitrile derivative, an imidazothiazole, a benzimidazole, a spirodioxepinoindole, a salicylanilide, a benzenedisulfonamide, an Insect Growth Regulator, a spinosyn, a chloronicotinyl, a pyrethrin, a synthetic pyrethroid, an organophosphate, a carbamate, a formamidine, a phenylpyrazole, a semicarbazone a cyclic depsipeptide, an anti-inflammatory, an analgesic, an antiemetic, an antihyperthyroid, an antihypothyroid.

The amount of any one or more active used in the methods and formulations of the invention will be dependent on the type of active, the method of administration and the type of (non- human) animal being treated. The standard dose rates under Government standards are dependent on all of these factors. The concentration of the formulation is also dependent on user preference as in some cases a more concentrated formulation is desired so that there is less need to administer a large volume of formulation. Examples of quantities of actives in the formulations of the invention are as follows: about 0.1-10 %w/v, macrocyclic lactone, about 0.1- 40% w/v levamisole, about 0.1-20%w/v fipronil, 0.1-20%w/v IGR (for example (S)-methoprene), about 0.1-20%w/v formamidine (for example Amitraz), about 0.1-20%w/v chloronicotinyl (for example imidacloprid), about 0.1-40%w/v benzimidazole (for example triclabendazole); however, as noted above these can be varied depending on user preference and intended use.

Accordingly preferred formulations include (1) about 0.1-10%w/v macrocyclic lactone and about 50-99.9%w/v methyl 5-(dimethylamino)methyloxopentanoate; (2) about 0.1-10%w/v macrocyclic lactone, about 0.1-40% w/v levamisole and about 50-99.8%w/v methyl 5- (dimethylamino)methyloxopentanoate; (3) about 0.1-20%w/v fipronil and about 50- 99.9%w/v methyl 5-(dimethylamino)methyloxopentanoate; (4) about 0.1-20%w/v chloronicotinyl and about 50-99.9%w/v methyl 5-(dimethylamino)methyloxopentanoate; (5) about 0.1-10%w/v macrocyclic lactone, about 0.1-20%w/v chloronicotinyl and about 50- 99.8%w/v methyl 5-(dimethylamino)methyloxopentanoate; (6) about 0.1-10%w/v macrocyclic lactone, about 0.1-40%w/v benzimidazole and about 99.8%w/v methyl 5- (dimethylamino)methyloxopentanoate. Any one of formulations (1) to (6) can optionally include one or more preservatives (for example but not limited to BHA and/or BHT), one or more co-solvents (for example but not limited to diethyl-glycol monobutyl ether).

In preferred cases the active(s) will dissolve or substantially dissolve in methyl 5- (dimethylamino)methyloxopentanoate. In some cases, one or more co-solvent(s) may be used. In such cases, the major solvent (i.e. the solvent in the formulation with the greatest KAE509143NZPR 303137968 volume) is preferably methyl 5-(dimethylamino)methyloxopentanoate. As will be apparent to a skilled person, as methyl 5-(dimethylamino)methyloxopentanoate can be used as the only, or major, solvent for veterinary formulations. It can also be used as a co-solvent if desired, (i.e. a minor portion of the solvent system used); this is not the preferred use however. In some cases the active may be micronized (ground to fine particles) and suspended in methyl 5- (dimethylamino)methyloxopentanoate. Where there is a combination to two or more actives, one or more of the actives may be dissolved while others are suspended. Co-solvents for use in the invention include (but are not limited to) glycol ethers, for example diethylene glycol monobutyl ether, benzyl alcohol, butyl dioxitol, mineral and vegetable oils, glycerol formal/acetates, Miglycols (triglycerides of the fractionated plant fatty acids C8 and C10). Other co-solvents commonly used in veterinary formulations will be known to a person skilled in the art.

Where co-solvent(s) are used, they may be added to the methyl 5-(dimethylamino)methyl oxopentanoate prior to the active(s), or after addition of the active(s). Alternatively, one or more of the actives may be dissolved in the co-solvent prior to addition to the methyl 5- (dimethylamino)methyloxopentanoate.

Preferably, the methyl 5-(dimethylamino)methyloxopentanoate makes up from about 50% w/v to about 100% w/v of the solvent in the formulation, more preferably from about 60% w/v to about 100% w/v of the solvent in the formulation, more preferably from about 70% w/v to about 100% w/v, even more preferably from about 80% to about 100% w/v of the solvent in the formulation.

While a C -C carboxylic acid co-solvent could optionally be used in formulations for some actives (but not IGRs), they would be an unnecessary additional expense and complication to the formulations. In addition, like pyrrolidone solvents, they may also have irritancy issues.

Therefore in a preferred embodiment, the veterinary formulations do not include C -C carboxylic acids.

In preferred embodiments of the invention, methyl 5-(dimethylamino)methyl oxopentanoate will be the only solvent. Such formulations are particularly preferred, as a single solvent (and therefore less components in the formulation) result in ease of manufacture (and therefore lower manufacture costs) and simplified application process for regulatory approval.

KAE509143NZPR 303137968 The formulations of the invention optionally include additional components, for example, but not limited to, preservatives, anti-oxidants, colourings, surfactants, minerals, vitamins, thickeners and/or buffers. Preservatives for use in the invention include (but are not limited to) butylated hydroxyanisole, formalin and/or butylated hydroxytoluene. Surfactants may be used in oral formulations in particular to aid in suspension and wettability.

Where preservatives, anti-oxidants, surfactants, thickeners and/or buffers are used, these may be added to the methyl 5-(dimethylamino)methyloxopentanoate prior to the active(s), or at the same time as the active(s), or alternatively after the active(s). It is preferred to add the preservatives to the methyl 5-(dimethylamino)methyloxopentanoate prior to one or more of the active(s). Where components are used which will colour the formulation, for example colourings, minerals, it is preferred these are added to the formulation after the actives, to allow clear visualization while dissolving the actives. However, these may be added to the formulation at any time.

The formulations of the invention are surprisingly stable, which is particularly beneficial for the commercial use of the formulations. The stability of the formulations allows extended shelf lives, which are highly desirable to consumers (including veterinarians, wholesalers, and farmers). An extended shelf life results in longer effective use periods, as well as lower waste due to having to dispose of product which is out of date. An extended shelf life also reduces the need to safely dispose of out of date product.

A common meaning of “stable” formulations is that the actives in the formulation decompose by less than 10% after 12 months of storage in a suitable container at room temperature, more preferably 24 months, more preferably 36 months even more preferably over 36 months.

However, as will be apparent to a person skilled in the art the stability will be at least partially dependent on the active in the formulation. Some actives inherently have lower stability. The formulations of the invention have at least comparable stability to prior art formulations.

KAE509143NZPR 303137968 EXAMPLES Example 1 – Topical Anthelmintic Formulation 1 Table 1 gives an example of an anthelmintic pour on formulation for use on cattle.

Table 1 Component Function of component Concentration Levamisole Base (97.0%) Active 206 g/L Abamectin Technical (95.0%) Active 11 g/L Methyl 5-(dimethylamino)methyl- Solvent 853 g/L -oxopentanoate Manufacturing method 1. Add actives to methyl 5-(dimethylamino)methyloxopentanoate in a mixing vessel. 2. Stir at room temperature (or optionally warm) until actives dissolved and a clear solution is obtained.

Example 2 – Ectoparasiticide formulations for use on cats and dogs - Formulations 2 to Table 2 gives Examples of ectoparasiticidal formulations for administration to cats and dogs.

Formulations 4-7 in the table provide examples of formulations with more than one veterinary pharmaceutical compound.

The manufacturing method of formulations 2-7 is per Example 1 above. The preservatives butylated hydroxyanisole and butylated hydroxytoluene were added after the active (or actives).

However, where preservatives are used these may be added to the solvent prior to, at the same time, or after the actives.

Table 2 Formulation 2 Formulation 3 Formulation 4 Formulation 5 Formulation 6 Formulation 7 Component Fipronil 95% 105.3 g/L 105.3 g/L 105.3 g/L 65.9 g/L - 65.9 g/L (active) (S)-methoprene - 90 g/L 56.4 g/L - - (active) KAE509143NZPR 303137968 Amitraz (active) - - 74.8 g/L - 74.8 g/L Imidacloprid - - - 103.1 g/L 56.4 g/L 97% (active) Butylated - 0.2 g/L 0.2 g/L 0.2 g/L 0.2 g/L 0.2 g/L hydroxyanisole (preservative) Butylated - 0.1 g/L 0.1 g/L 0.1 g/L 0.1 g/L 0.1 g/L hydroxytoluene (preservative) Methyl 5- 974.7 g/L 974.4 g/L 904.4 g/L 904.4 891.3 g/L 904.4 g/L (dimethylamino) methyl oxopentanoate (solvent) Total 1080 1080 1100 1100 1100 1100 Example 3 – Anthelmintic formulations for use on cats and dogs – Formulations 8 and 9 Table 3 gives examples of anthelmintic formulations for administration to cats and dogs.

The manufacturing method of formulations 8 and 9 is as described in Example 2 above.

Table 3 Component Formulation 8 Formulation 9 (cats) (dogs) Moxidectin 92% (active) 10.9 g/L 27.2 g/L Butylated hydroxyanisole 0.2 g/L 0.2 g/L (preservative) Butylated hydroxytoluene 0.1 g/L 0.1 g/L (preservative) Methyl 5-(dimethylamino)methyl 1038.8 1022.5 g/L oxopentanoate (solvent) Total 1050 1050 Example 4 – Combination anthelmintic and ectoparasiticide formulations for use on cats and dogs – Formulations 10 and 11 Table 4 gives examples combination formulations i.e. an anthelmintic and an ectoparasiticide, for administration to cats and dogs.

KAE509143NZPR 303137968 The manufacturing method of formulations 10 and 11 is as described in Example 2 above.

Table 4 Component Formulation 10 Formulation 11 (cats) (dogs) Moxidectin 92% (active) 10.9 g/L 27.2 g/L Imidacloprid 97% (active) 103.1 g/L 103.1 g/L Butylated hydroxyanisole 0.2 g/L 0.2 g/L (preservative) Butylated hydroxytoluene 0.1 g/L 0.1 g/L (preservative) Methyl 5-(dimethylamino)methyl 965.7 g/L 949.4 g/L oxopentanoate (solvent) Total 1080 1080 Example 5 –Topical and oral combination anthelmintic formulation – Formulation 12 Table 5 gives an example of a topical and/or oral combination anthelmintic formulation useful for the treatment of liver fluke.

The manufacturing method of formulation 12 is per Example 1 above.

Table 5 – Formulation 12 Component Concentration Avermectin (active) 5 Triclabendazole (active) 300 Methyl 5-(dimethylamino)methyl Qs to 1L oxopentanoate (solvent) Example 6 - Combination anthelmintic formulation including co-solvent – Formulation 13 Table 6 gives an example of a formulation of the invention including a co-solvent (diethylene glycol monobutyl ether) with the major solvent (methyl 5-(dimethylamino)methyl oxopentanoate).

KAE509143NZPR 303137968 Table 6 – Formulation 13 Component Concentration %w/v Avermectin (active) 1.158 Levamisole (active) 21.01 diethylene glycol monobutyl ether 25 (co-solvent) Methyl 5-(dimethylamino)methyl 60 oxopentanoate (solvent) The manufacturing method is as Example 1 (above) with the addition of the co-solvent prior to addition of the actives.

Example 7 – Stability testing (fipronil active) – Formulation 14 Formulation 14 (shown in table 7) was stored at room temperature in Neopac – Polyfoil PF containers for 12 months then tested for the quantity of active ingredient. Results are shown in Table 8. The decomposition of the veterinary pharmaceutical compound (Fipronil) was 0.8% after 12 months.

No change in appearance or specific gravity was noticeable after 12 months. Further no distortion of the packaging was noticeable after 12 months.

Table 7 – Formulation 14 Component Function of component Concentration (g/L) Fipronil (active) Active 100 BHA (preservative) Preservative 0.2 BHT (preservative) Preservative 0.1 Methyl 5-(dimethylamino) Solvent to 1L methyloxopentanoate Table 8 – (Stability data Formulation 14) Time period Fipronil (g/L) Test method Time zero 100.2 HPLC ATM-1023 12 months 99.4 HPLC ATM-1023 KAE509143NZPR 303137968 Example 8 - Stability testing Formulations 1, 6, 9, 11, 12, 13 and 15 Table 9 shows stability trial data for Formulation 1 stored at ambient temperature and at 40ºC.

In all stability trials the amount of active at the start of the trial is measured in order to take into account the purity of the active that went into the formulation.

Table 9 – (Stability data Formulation 1) Time period Temperature Abamectin (g/L) Levamisole (g/L) 0 days Ambient 10.6 199.6 365 days Ambient 10.1 197.2 0 days 40ºC 10.6 199.6 28 days 40ºC 9.8 199.1 Table 10 shows stability trial data for Formulation 6 stored at ambient temperature.

Table 10 - (Stability data Formulation 6) Time period Temperature Imidacloprid (g/L) 0 days Ambient 101.8 365 days Ambient 101.2 Table 11 shows stability trial data for Formulation 9 stored at ambient temperature.

Table 11 - (Stability data Formulation 9) Time period Temperature Moxidectin (g/L) 0 days Ambient 24.8 365 days Ambient 24.3 Table 12 shows stability trial data for Formulation 11 stored at ambient temperature.

Table 12 - (Stability data Formulation 11) Time period Temperature Moxidectin (g/L) Imidacloprid (g/L) 0 days Ambient 25.2 100.9 365 days Ambient 24.8 100.5 KAE509143NZPR 303137968 Table 13 shows stability trial data for Formulation 12 stored at ambient temperature and at 40ºC.

Table 13 – (Stability data Formulation 12) Time period Temperature Abamectin (g/L) Triclabendazole (g/L) 0 days Ambient 5.1 298.3 365 days Ambient 5 288.8 0 days 40ºC 5.6 302.1 28 days 40ºC 5.2 296.5 Table 14 shows stability trial data for Formulation 13 stored at ambient temperature and at 40ºC.

Table 14 – (Stability data Formulation 13) Time period Temperature Abamectin (g/L) Levamisole (g/L) 0 days Ambient 10.4 200.6 365 days Ambient 9.8 198.8 0 days 40ºC 10.4 200.6 28 days 40ºC 9.6 200.4 Example 9 – Topical and oral anthelmintic formulation and stability testing Table 15 gives an example of a topical and/or oral anthelmintic formulation useful for the treatment of liver fluke (Formulation 15).

Table 15 – Formulation 15 Component Concentration g/L Triclabendazole (active) 300 Methyl 5-(dimethylamino)methyl Qs to 1L oxopentanoate (solvent) Table 16 shows stability trial data for Formulation 15 stored at ambient temperature.

KAE509143NZPR 303137968 Table 16 - (Stability data Formulation 15) Time period Temperature Triclabendazole (g/L) 0 days Ambient 308.1 365 days Ambient 296.5 The stability date in Examples 7, 8 and 9 show the formulations of the invention are surprisingly stable. All of the actives in the formulations tested decompose by less than 10% after 12 months stored at ambient temperature. In most cases the decomposition is far less than 10% after 12 months at ambient temperature. It is therefore expected the products will have extended shelf lives of 2-3 years.

Example 10 – Animal Trial A trial was conducted in Cattle to evaluate efficacy and safety of Formulation 1 against a commercially available product containing the same active ingredients at the same levels.

The trial was performed on 18 month old cattle at a farm located in the Waikato, New Zealand.

The Cattle were selected into groups of 8, based on their FEC. The products were applied topically using a large plastic syringe. The dose volumes were determined from the weight of each animal.

Results Table 17- Results from trial group treated with Formulation 1 of the invention Animal ID Initial Faecal Egg Faecal Egg Count Count (epg) Day 14 (epg) 146 blue 300 0 484 300 0 82 250 0 483 300 0 85 150 0 1721 400 50 469 700 0 482 200 0 KAE509143NZPR 303137968 Table 18 - Results from control trial group Animal ID Initial Faecal Egg Faecal Egg Count Count (epg) Day 14 (epg) 456 200 400 1719 100 450 89 250 200 459 200 300 460 300 150 457 150 300 470 150 250 481 200 200 Table 19 – Comparative example - Results from trial group treated with commercially available product Animal ID Initial Faecal Egg Faecal Egg Count Count (epg) Day 14 (epg) 199 400 0 190 150 0 45 100 0 192 100 0 50 100 0 54 400 100 2840 200 50 2842 300 0 The results of the trail show the formulation of the invention has comparable or potentially better efficacy than the commercially available product. The results also show the actives are effectively delivered to the subject when applied topically.

The results also show that methyl 5-(dimethylamino)methyloxopentanoate can be used to prepare stable and effective veterinary formulations that contain multiple actives or single actives with, and without, the use of additional preservatives. The invention therefore can also be seen to be the use of methyl 5-(dimethylamino)methyloxopentanoate in the KAE509143NZPR 303137968 manufacture of topical and oral veterinary formulations containing at least one veterinary active compound. In a more preferred embodiment, the invention can be seen to be the use of methyl -(dimethylamino)methyloxopentanoate in the manufacture of topical and oral veterinary formulations containing at least one veterinary active compound with the proviso that where the veterinary active compound is an IGR, the formulation does not also include a C -C carboxylic acid (organic acid) as part of the solvent system.

General The entire disclosures of all applications, patents and publications cited above and below, if any, are herein incorporated by reference.

Reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that that prior art forms part of the common general knowledge in the field of endeavour in any country in the world.

The invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, in any or all combinations of two or more of said parts, elements or features.

Wherein the foregoing description reference has been made to integers or components having known equivalents thereof, those integers are herein incorporated as if individually set forth.

It should be noted that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be included within the scope of the invention.

KAE509143NZPR 303275309-1

Claims

1. A method of veterinary treatment, the method including the step of administration of a formulation including: 5 at least one veterinary pharmaceutical compound selected from any one or more of: a macrocyclic lactone, an anthelmintic nicotinic receptor agonist, an amino-acetonitrile derivative, an imidazothiazole, a benzimidazole, a spirodioxepinoindole, a salicylanilide, a benzenedisulfonamide, a spinosyn, a chloronicotinyl, a pyrethrin, a synthetic pyrethroid, an organophosphate, a carbamate, a formamidine, a phenylpyrazole, a semicarbazone; a 10 cyclic depsipeptide, an anti-inflammatory, analgesic, antiemetic an antihyperthyroid, an antihypothyroid; and methyl 5-(dimethylamino)methyloxopentanoate.

2. The method of claim 1, wherein the formulation is administered topically.

3. The method of claim 1, wherein the formulation is administered orally.

4. The method of any one of claims 1 to 3, wherein the veterinary pharmaceutical compound is an anthelmintic selected from any one or more of: a macrocyclic lactone, an 20 anthelmintic nicotinic receptor agonist, an amino-acetonitrile derivative, an imidazothiazole, a benzimidazole, a spirodioxepinoindole, a salicylanilide, a benzenedisulfonamide.

5. The method of claim 4, wherein the macrocyclic lactone is selected from: abamectin, 25 ivermectin, doramectin, eprinomectin, selamectin, moxidectin, milbemycin oxime, selamectin.

6. The method of claim 4, wherein the benzimidazole is triclabendazole. 30

7. The method of any one of claims 1 to 3, wherein the veterinary pharmaceutical compound is a pesticide selected from any one or more of: a spinosyn, a chloronicotinyl, a pyrethrin, a synthetic pyrethroid, an organophosphate, a carbamate, a formamidine, a phenylpyrazole, a semicarbazone. KAE509143NZPR 303275309-1

8. The method of claim 7, wherein the phenylpyrazole is fipronil.

9. The method of any one of claims 1 to 3, wherein the veterinary pharmaceutical compound is a cyclic depsipeptide.

10. The method of any one of claims 1 to 3, wherein the veterinary pharmaceutical compound is an anti-inflammatory.

11. The method of any one of claims 1 to 3, wherein the veterinary pharmaceutical compound 10 is an analgesic.

12. The method of any one of claims 1 to 3, wherein the veterinary pharmaceutical compound is an antiemetic. 15

13. The method of any one of claims 1 to 3, wherein the veterinary pharmaceutical compound is an antihyperthyroid or an antihypothyroid.

14. A method of veterinary treatment as claimed in claim 1, substantially as hereinbefore described with particular reference to any one of the Examples.