WO2018038623A1

WO2018038623A1 - Improvements in parasite treatments

Info

Publication number: WO2018038623A1
Application number: PCT/NZ2017/050111
Authority: WO
Inventors: Karen Yeritsyan
Original assignee: Donaghys Ltd
Current assignee: Donaghys Ltd
Priority date: 2016-08-23
Filing date: 2017-08-17
Publication date: 2018-03-01
Anticipated expiration: 2019-02-23

Abstract

Described herein are formulations and methods of manufacture providing levamisole in a salt form with an additional anthelmintic having a different class of activity. The formulation uses a multi- solvent system to produce a topically applied formulation with all compounds in solution. In one aspect a formulation is described comprising in solution a mixture of a therapeutically effective amount of levamisole salt dissolved in at least one inorganic solvent; and a therapeutically effective amount of at least one additional anthelmintic compound with a different class of activity to levamisole, the at least one additional anthelmintic compound being substantially lipophilic and being dissolved in at least one organic solvent. A related veterinary medicament and method of treatment of parasites are also described.

Description

IMPROVEMENTS IN PARASITE TREATMENTS

TECHNICAL FIELD

Described herein are improvements in parasite treatments. More specifically, there are described formulations and methods of manufacture providing levamisole in a salt form, and an additional anthelmintic with a different class of activity, formulated using a solvent system to produce a topically applied formulation with all compounds in solution.

BACKGROUND ART

Anthelmintics are widely used to prevent and treat parasite infections or infestations in animals, particularly in farmed foraging animals such as sheep, cattle, dairy cows and deer to name a few examples.

Anthelmintics are challenging to formulate since they have quite varied physical and chemical properties.

Combining of anthelmintics from different families has become a more desirable and common practice since many parasites are developing resistance. Combinations of anthelmintics from different families, (and hence activities) means that treatments tend to be more effective at addressing parasite infection. Combinations do however increase formulation complexity since, a solvent system that works for one active may not be compatible with the solvent system used for another active.

The above difficulties often lead to complex formulations using sometimes undesirable compounds that may be hard to source or expensive. Further, the final formulation may be difficult to manufacture and require specific handling or processing parameters to achieve the end result. Further, the final formulation may present only a compromise between preferred end characteristics and active delivery - that compromise not necessarily meeting all objectives e.g. potentially irritating the skin and having other unwanted side effects.

Levamisole is a commonly used anthelmintic. Despite being water soluble and generally cheaper, levamisole salts are not widely used in topically applied veterinary art formulations as an active, the base form normally being used. The art describes considerable variability in levamisole salt uptake into the animal bloodstream from topical administration which is unwanted, typically due to slow dissolution, but sometimes also due to the solvent system used. In addition, the low/acidic pH of levamisole salt solutions presents formulating challenges particularly when other desired anthelmintics are added such as macrocyclic lactones that prefer alkaline solutions. By contrast to the above, the base form of levamisole is well transferred hence the base form has seen widespread adoption for topical treatments.

Some workarounds to the above can be to use levamisole salt in suspension or emulsion for example along with a benzimidazole. Suspensions and emulsions may be acceptable in oral drenches or injectables but are not as useful in topically applied formulations since they either do not transfer through the skin barrier or only transfer poorly. Solutions are general ly preferable for topical formulations.

Another work-around is the use of high amounts of solvent in order to achieve solubility. This is usually to the detriment of the formulation efficacy since a lower rate of active(s) is only possible. Further, high solvent concentrations tend to increase cost and potential handling issues particularly if the solvent is not biocompatible. A further disadvantage is that the solvents used may be hazardous and/or difficult, or sometimes dangerous, to handle and use. In addition, if substantial amounts of organic solvent are used, these solvents may often irritate the skin and therefore be less desirable for both animal and user.

Further aspects and advantages of the above described formulations and methods will become apparent from the ensuing description that is given by way of example only.

SUMMARY

Described herein are formulations and methods of manufacture providing levamisole in a salt form and an additional anthelmintic with a different class of activity formulated using a solvent system to produce a topically applied formulation with all compounds in solution.

In a first aspect, there is provided a formulation comprising in solution:

a therapeutically effective amount of levamisole salt;

a therapeutically effective amount of at least one additional anthelmintic compound with a different class of activity to levamisole, the at least one additional anthelmintic compound being substantially lipophilic;

the levamisole salt and at least one additional compound being dissolved in a solvent system comprising a plurality of solvents, to form a solution, wherein at least one of the solvents is an inorganic polar solvent.

In a second aspect, there is provided a formulation comprising in solution:

a therapeutically effective amount of levamisole salt;

the levamisole salt and at least one additional compound being dissolved in a solvent system comprising a plurality of solvents, to form a solution, wherein at least one of the solvents is characterised by having: organic solvent function, penetrant function, and/or degreasing function. In a third aspect, there is provided a formulation comprising in solution a mixture of: a therapeutically effective amount of levamisole salt dissolved in at least one inorganic solvent; a therapeutically effective amount of at least one additional anthelmintic compound with a different class of activity to levamisole, the at least one additional anthelmintic compound being substantially lipophilic and being dissolved in at least one organic solvent.

In a fourth aspect, there is provided a veterinary medicament formulated for topical administration to a non-human animal, the medicament comprising at least one of the formulations substantially as hereinbefore described.

In a fifth aspect, there is provided a method of prevention and/or treatment of a parasite infection or infestation in a non-human animal, the method comprising the steps of:

selecting at least one formulation substantially as described herein; and

applying the formulation topically to the non-human animal in need thereof.

In a sixth aspect, there is provided the use of a formulation substantially as described above in the manufacture of a medicament for the treatment of internal and/or external parasites in or on an animal in need thereof.

In a seventh aspect, there is provided a method of manufacturing a veterinary medicament, the method comprising the steps of:

mixing levamisole salt with at least one inorganic polar solvent to form a first solution;

separately mixing together at least one additional anthelmintic compound with at least one organic solvent to form a second solution, the additional anthelmintic solvent having a different spectrum of activity as levamisole and being substantially lipophilic;

combining the first and second solutions to form a combined formulation.

Advantages of the above formulations and methods may include at least one of:

Minimises use of organic solvents and hence risk of irritation to the skin of the animal or user; - Avoids use of compounds requiring special handling;

Is quick to manufacture with no special handling steps required;

Is generally biocompatible;

Is stable to the extent required for commercial use;

Provides a therapeutically effective amount of actives to the animal within the time period required;

Overcomes compatibility issues between levamisole and other anthelmintics therefore allowing the actives to be combined into a single formulation. DETAILED DESCRIPTION

As noted above, described herein are formulations and methods of manufacture providing levamisole in a salt form and an additional anthelmintic with a different class of activity formulated using a solvent system to produce a topically applied formulation with all compounds in solution.

For the purposes of this specification, the term 'about' or 'approximately' and grammatical variations thereof mean a quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length.

The term 'substantially' or grammatical variations thereof refers to at least 50%, for example 75%, 85%, 95% or 98%.

The term 'comprise' and grammatical variations thereof shall have an inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements.

The term 'therapeutically effective amount' or grammatical variations thereof refers to the amount or dosage of an active agent or agents sufficient to cause a desired level of anti-parasite prevention or treatment effect in an animal post administration of the active agent or agents.

The term 'topical' refers to administration on an external skin area of an animal.

The term 'hydrophilic' or grammatical variations thereof refers to a compound that is attracted to and tends to be dissolved in water, the compound having an HLB value greater than or equal to 10 using Griffin's Method.

The term 'lipophilic' or grammatical variations thereof refers to a compound that is attracted to and tends to be dissolved in fats, oils, lipids and non-polar solvents, the compound having an HLB value less than or equal to 7 using Griffin's Method.

The term 'solvent system' or grammatical variations thereof in the context of this specification refers to a plurality of solvents, the solvent comprising both inorganic and organic solvents.

The term 'solvent' or grammatical variations thereof refers to a substance that dissolves a solute (typically an active compound in the context of this specification) to form a homogenous solution.

The term 'solution' or grammatical variations thereof refers to a homogenous mixture of two or more substances.

In a first aspect, there is provided a formulation comprising in solution:

a therapeutically effective amount of levamisole salt;

In a second aspect, there is provided a formulation comprising in solution:

a therapeutically effective amount of levamisole salt;

the levamisole salt and at least one additional compound being dissolved in a solvent system comprising a plurality of solvents, to form a solution, wherein at least one of the solvents is characterised by having: organic solvent function, penetrant function, and/or degreasing function.

In a third aspect, there is provided a formulation comprising in solution a mixture of:

a therapeutically effective amount of levamisole salt dissolved in at least one inorganic solvent; a therapeutically effective amount of at least one additional anthelmintic compound with a different class of activity to levamisole, the at least one additional anthelmintic compound being substantially lipophilic and being dissolved in at least one organic solvent.

selecting at least one formulation substantially as described herein; and

applying the formulation topically to the non-human animal in need thereof.

combining the first and second solutions to form a combined formulation.

The levamisole salt is a levamisole HCI but other hydrophilic salt forms (e.g. phosphate, acetate, fluoride, sulphate forms) may also be used.

The levamisole salt may be present in the formulation at a rate of approximately: 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30% by weight. The levamisole salt may be present at a rate of approximately: 10 to 30% or 10 to 20% or 20 to 30% or 15 to 25% or 20 to 30% by weight. This level of concentration may be sufficient based on application rates of 1ml per 10 to 20kg animal live weight however these figures are provided by way of illustration only and may be increased or decreased depending on the dose volume desired and the level of efficacy needed (prevention or treatment for example where a higher dose may be desirable for treatment versus prevention).

The levamisole salt may be in powder form prior to production of the formulation and mixed with the inorganic polar solvent to provide the levamisole salt solution . This salt solution is then mixed with at least one additional solvent and active to form the formulation described herein.

The at least one additional anthelmintic compound may be a macrocyclic lactone compound. The macrocyclic lactone compound or compounds may be selected from the group of avermectins or milbemycins. Examples of macrocyclic lactone compounds that may be used include for example: abamectin, ivermectin, moxidectin, eprinomectin, doramectin, selamectin, and combinations thereof. Macrocyclic lactones have a potent, broad antiparasitic spectrum at low dose levels. They are active against many immature nematodes (including hypobiotic larvae) and arthropods. The published literature contains reports of use to treat infections of >300 species of endo- and ectoparasites in a wide range of hosts. Moreover, a single therapeutic dose can persist in concentrations sufficient to be effective against new nematode infections for prolonged periods after treatment.

Where macrocyclic lactones are used as the at least one additional active, they may be present at a rate of approximately: 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1.0, or 1.1, or 1.2, or 1.3, or 1.4, or 1.5% by weight. The additional active may be present at a rate of approximately: 0.5 to 1.5%, or 0.5 to 1.0%, or 1.0 to 1.5%, or 0.75 to 1.25% by weight. This level of concentration may be sufficient based on application rates of 1ml per 10 to 20kg animal live weight however these figures are provided by way of illustration only and may be increased or decreased depending on the dose volume desired and the level of efficacy needed (prevention or treatment for example where a higher dose may be desirable for treatment versus prevention).

Despite the above discussion, the same formulation may be used to deliver other anthelmintics from different classes, the anthelmintic having lipophilic properties. The above discussion should not therefore be seen as limiting. The inorganic polar solvent noted above may be a substantially aqueous solution. The inorganic polar solvent may be water. The inorganic polar solvent may be present in the formulation at a rate of approximately: 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30, or 31, or 32, or 33, or 34, or 35, or 36, or 37, or 38, or 39, or 40, or 41, or 42, or 43, or 44, or 45, or 46, or 47, or 48, or 49, or 50% by weight. The inorganic polar solvent may be present in the formulation at a rate of approximately: 15-50%, or 15-45%, or 20-35%, or 15-35%, or 35-50%, or 20-30%, or 15-25%, or 25-35% by weight.

As noted above, the formulation described is present in the form of a solution. Providing actives with very different solubility's and properties in a common solubilised formulation were challenging and the final results went against what the art might suggest is possible. Specifically, levamisole salt is water soluble but traditionally only poorly transferred via the topical route of administration. Historically, it is used in base form for topical administration so as to provide greater transfer into the blood stream of an animal to which the levamisole base is administered. Salt forms of levamisole have largely only been used in drenches where emulsions and suspensions are acceptable. Topically applied formulations generally need to be solutions as different phases or suspended solids can be poorly transferred through the skin barrier.

In addition to achieving the production of a solution, it is also important to produce a formulation that is biocompatible. The term 'biocompatible' refers to the formulation as a whole or at least one compound or ideally most if not all of the compounds being:

(a) physiologically and pharmaceutically acceptable; and

(b) ideally Generally Recognised as being Safe (GRAS).

The at least one additional solvent may be an organic solvent. The at least one additional solvent may have solvent properties as well as other properties or functions selected from: humectant properties, penetrant properties, degreasing properties and combinations thereof. The at least one organic solvent may be characterised by having: an organic solvent function; and a penetrant function; and a degreasing function.

The at least one additional solvent may be at least one sulfoxide. The at least one additional solvent may be dimethyl sulfoxide (DMSO).

DMSO may be found particularly useful in this formulation for a variety of reasons. DMSO is a naturally occurring compound presents in many vegetables, fruits, grains and animal products. Therapeutic applications for DMSO began in 1963 when it was reported to penetrate through skin and produce analgesia, reducing pain and promoting tissue healing. According to one source, one of the most significant properties of DMSO is its low toxicity, another source describing DMSO as practically nontoxic. These properties may make DMSO a useful compound in the present formulations to introduce greater biocompatibility and safer use for both the animal to which the formulation is to be applied and for the operator/user. Besides being very safe to use and having penetrant properties, DMSO also provides a combination of organic solvent, penetrant and degreasing properties.

Where DMSO is used, the DMSO may be present in the formulation at a rate of approximately 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10% by weight. The DMSO may be present in the formulation at a rate of approximately 1-10%, or 1-5%, or 5-10%, or 3-7% by weight.

In addition to DMSO or, as an alternative to DMSO, the at least one additional solvent may be: at least one sugar alcohol, examples including sorbitol and glycerol although other sugar alcohols may also be used; isopropyl myristate; D-limonene; at least one aromatic solvent, (examples including benzene or naptha blends and derivatives, one commercially available product being marketed under the name A150 solvent); at least one water miscible solvent; and combinations thereof.

These compounds may all be useful candidates as organic solvents due to their having organic solvent and penetrant and/or degreasing and/or humectant properties making them advantageous for the formulations described herein.

The water miscible solvent, if used, may be present in the formulation to volume of total formulation. One example of a water miscible solvent may be at least one form of glycol ether. The glycol ether may be diethylene glycol monobutyl ether although other glycol ethers may be used. Glycol ethers may be useful as they have organic solvent, diluent and penetrant properties plus they act to bridge water and oil solutions and may prevent separation.

As may be appreciated, the compounds noted above are generally non-irritant compounds. Further, through use of one or more of these compounds, no special additional treatments or pre-treatments are required before or during administration of the formulations e.g. agitation prior to use or heating prior to use. The selection of biocompatible compounds also reduces handling risk for the person administering the formulation and avoids additional handling steps and/or special equipment.

The formulation may further comprise at least one additional active compound. The additional active compound may for example comprise: at least one anthelmintic, at least one vitamin, at least one mineral, at least one antigen, at least one ectoparasiticide, and combinations thereof. As may appreciated, co-administration of the above formulation along with other actives may be useful in order to minimise labour and time needed to maintain the wellbeing and/or treat animals.

The at least one additional anthelmintic may be an anthelmintic with a further different spectrum of anti-parasite activity to levamisole and the additional anthelmintic e.g. a macrocyclic lactone already noted above. The at least one additional anthelmintic may be selected from the benzimidazole family of compounds.

The at least one vitamin may be vitamin B12. The at least one mineral may be selenium. Vitamin B12 and selenium are commonly supplemented vitamins and minerals to farmed animals, at least in New Zealand. Co-administration with other actives may be beneficial at least in terms of labour and handling requirements. The at least one antigen may be a vaccine.

The at least one ectoparasiticide may be deltamethrin.

The rate at which the additional actives or actives are incorporated may be related to the concentration needed for that active to be therapeutically effective which varies dependent on active type. In the inventor's experience it is quite easy to adjust the solvent system and other compound amounts present to suit the addition of a further active or actives yet retain the stability and efficacy desired.

The formulation may comprise at least one additional non-active agent or carrier compound.

In one embodiment the at least one additional non-active agent may be at least one surfactant and/or wetting agent. The at least one surfactant and/or wetting agent may be present in the formulation at a rate of approximately 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30% by weight. The at least one surfactant and/or wetting agent may be present in the formulation at a rate of approximately 0.1-30%, or 0.1-1%, or 1- 10%, or 10-20%, or 20-30%, or 0.5 to 1.5%, or 5-15%, or 15-25% by weight. The at least one surfactant and/or wetting agent may be at least one ionic or non-ionic surfactant. The at least one surfactant and/or wetting agent may be polysorbate. The polysorbate may be polysorbate 80.

The formulation may also comprise at least one preservative or antioxidant compound. One example may be butylated hydroxytoluene (BHT), this being a common preservative used in many anthelmintic containing formulations although other preservatives may also be used. The preservative if used, may be included at a rate of approximately: 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1, or 1.1, or 1.2, or 1.3, or 1.4, or 1.5% by weight of the total formulation. The preservative may be present at a rate of approximately 0.5-1.5%, or 0.5-1, or 1-1.5, or 0.8-1.2, or 0.9-1.1% by weight. The rates described may be varied to suit the preservative used.

The above described formulation was found to be unexpectedly stable unlike what the art would suggest. Stability for the purposes of this specification refers to the various formulation components and compounds remaining in solution when stored for at least approximately 1, or 2, or 3, or 4 weeks, or at least 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 months at ambient temperature and pressure and when subjected to UV light or sunlight. The term 'ambient temperature' refers to diurnal outdoor temperatures that, depending on climate may range from -20^°C-50^°C, or -20^°C-40^°C, or -10^°C- 40^°C, or 0^°C-40^°C, or 0^°C-35^°C, or 0^°C-30^°C. Stability further refers to the active compounds being present after storage at a rate substantially the same as that at manufacture. Stability also may refer to the formulation being able to withstand moisture, typically from humid ambient conditions and/or condensation.

In selected embodiments, the rate of active post storage in the formulation may remain at: 90, or 91, or 92, or 93, or 94, or 95, or 96, or 97, or 98, or 99% by weight of that present at manufacture when stored for at least 1, or 2, or 3 months. The rate of active post storage in the formulation may remain above approximately: 90-99%, or 90-95%, or 95-99%, or 97-99% by weight of that present at manufacture. These stability rates were unexpectedly high compared to art predictions particularly for levamisole salt. Art tends to suggest that levamisole salt in solution deteriorates during storage, often with greater than 10% by weight concentration decrease over only 1-3 months. By contrast, the formulation described herein did not show any decrease of significance after test accelerated aging time periods of 3 weeks.

A further unexpected outcome of the above described formulation was that the transfer of actives into the animal bloodstream post topical administration was fast enough to be comparable to other commercially available formulations (topical or oral) or, at least to a level that is still therapeutically effective. For levamisole salt, this result was contrary to the art that generally shows a much slower - to the point of being un-commercial - rate of uptake into the animal bloodstream. By contrast, the inventor found that the rate of uptake post administration for the formulation described herein using levamisole salt was comparable (greater than approximately 70% by weight) of that observed for a levamisole base formulation. The slower rate of uptake is one reason for commercialised formulations using levamisole base instead of levamisole salt. The combination of compounds described in the formulation noted herein achieved results contrary to that taught by the art.

In addition, based on trials completed by the inventor, the rate of transfer of macrocyclic lactone to the animal bloodstream was also comparable to other commercially available formulations (topical or oral) or, at least to a level that is still therapeutically effective.

A problem with art formulations using anthelmintic combinations is that the combination may, as a result of the solvent system chosen, become too viscous to be administered topically or at least not used with some special pre-treatment handling step such as heating. Achieving a viscosity with Newtonian flow and shear properties that is also sufficiently low to be administered using art equipment e.g. a backpack tank and applicator gun, is essential to the commercial success of new products. The formulation embodiments described herein all easily fall with maximum practical viscosity levels when subjected to extremes in temperature and storage time. The formulations produced had substantially Newtonian flow and shear properties. The formulation may have a viscosity of less than approximately: 6000cps, or 5500cps, or 5000cps, or 4500cps, or 4000cps, or 3500cps, or 3000cps, or 2500cps, or 2000cps. The viscosity may be approximately equivalent to that measured for water at 20°C and atmospheric pressure.

As noted above, a challenge in formulating mixtures of levamisole and macrocyclic lactones may be the opposing solubility of each compound with respect to pH. That is, levamisole (the salt form in particular) is more soluble in acidic conditions (pH less than 6). By contrast, macrocyclic lactones are more stable in alkaline conditions (pH up to 9). Simply mixing the two actives is therefore not possible without accounting for relative pH. To the inventor's surprise, the combination of actives and solvent systems noted overcame the relative acid/alkaline challenge and both actives remain in solution together despite this basic incompatibility. It is envisaged this may due to the mixing of separate inorganic and organic solutions prior to complete mixing. In the inventor's experience, the final formulation may have a pH of approximately: 4, or 4.5, or 5, or 5.5, or 6. The pH may be from approximately: 4 to 6 or 4 to 5, or 5 to 6, or 4.5 to 5.5, or 4.5 to 6, or 4 to 5.5.

The above formulation is formulated for topical administration. That is, the formulation is applied to the skin and the actives pass through the skin barrier and into the blood stream. For ease of reference in this specification, the term 'topical' or grammatical variations thereof is used however, as may be appreciated, this encompasses other terms such as 'transdermal administration', 'pour-on' treatment and 'spot-on' treatment. Reference to one term or the other should not be seen as limiting.

As may be appreciated, topical administration can be challenging particularly for anthelmintic compounds where the skin barrier tends to repel such actives (especially those that are hydrophilic as skin oils tend to prevent movement across the skin barrier). In addition and as noted above, levamisole salts are often acidic and macrocyclic lactones are alkaline presenting considerable compatibility issues. The formulation described herein unexpectedly delivers both of the actives to the animal at therapeutically effective levels, well above what the art would suggest is possible. It is the inventor's understanding that this outcome is a result of the selection of actives/agents used.

The above formulation need not be diluted or otherwise subjected to any preparatory steps before use. This may be of benefit to minimise labour and time needed during administration and is often a useful commercial success factor as well. Despite not requiring dilution, the formulation may be diluted at time of use as desired and reference to not diluting should not be seen as limiting.

The formulation described herein may be manufactured by mixing levamisole salt with the inorganic polar solvent to form a first solution and separately mixing the further anthelmintic active with the remaining solvent or solvents to form a second solution and then simple mixing the first and second solutions to form the formulation described with both anthelmintic agents dissolved in solution. The first solution may be an inorganic solution and the second solution may be an organic solution. As may be appreciated from the above, no special heating, use of pressure or other modified atmospheric conditions are required. Use of compounds requiring special handling are also avoided. This method differs considerably to many art processes that require special handling or processing cond itions that all add to the cost and complexity of manufacturing.

The above formulation is intended for veterinary use to prevent or treat a parasite infection or infestation. Parasite infection can be a key issue in farmed animals, particularly those that are grass fed and hence, anthelmintic treatments are commonly used in agriculture. Anthelmintics are a group of anti-parasitic active compounds that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them without causing significant damage to the host animal. Due to resistance, formulations that contain more than one anthelmintic active may be beneficial particularly when the actives have differing spectrum of activity.

The animal to which the formulations are applied may be of various farmed livestock species including but not limited to those from the genus: bovine, ovine, cervine, porcine. Despite these examples, the formulation may be used for many other farmed animals e.g. Llamas, and may also be used for companion animals such as cats and dogs. Reference to farmed livestock should not be seen as limiting.

As noted above, the formulations described herein are generally designed for use in topical treatments. That is, they are coated, painted, spot applied, poured, sprayed or otherwise administered to the skin of an animal in need thereof. Despite reference to topical administration, the formulations described could also be administered orally as a drench and via injection. Despite non-topical modes of administration being possible, they may not be as commercially valuable or viable as existing alterative art oral or injectable anthelmintic containing products. Topical treatments are however highly valued particularly where many animals require treatment since the mode of administration avoids the need for a trained user (e.g. a vet for injections) and minimises animal handling and therefore minimises trauma on the animal and reduces labour and time needed from the person applying the formulation.

Advantages of the above formulations and methods may include at least one of:

Minimises use of organic solvents and hence risk of irritation to the skin of the animal or user; Avoids use of compounds requiring special handling;

- Is quick to manufacture with no special handling steps required;

Is generally biocompatible;

Is stable to the extent required for commercial use;

- Overcomes compatibility issues between levamisole and other anthelmintics therefore allowing the actives to be combined into a single formulation.

The embodiments described above 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, and any or all combinations of any two or more said parts, elements or features.

Further, where specific integers are mentioned herein which have known equivalents in the art to which the embodiments relate, such known equivalents are deemed to be incorporated herein as of individually set forth.

WORKING EXAMPLES

The above described formulations and methods are now described by reference to specific examples.

EXA M P LE 1

A possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight. Table 1 - Formulation 1

EXA M P LE 2

A possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight.

Table 2 - Formulation 2

EXA M P LE 3

Table 3 - Formulation 3

EXA M P LE 4

Table 4 - Formulation 4

Butylated hydroxytoluene (BHT) Preservative/ Antioxidant 1.1

Water Inorganic Solvent 32

Vitamin B12 Additional active 0.04-0.05

Polysorbate 80 Emulsifier, penetrant, surfactant, 5

wetting agent

Diethylene glycol monobutyl ether Organic solvent, diluent, penetrating q.s. / to volume 100%

agent

EXA M P LE 5

Table 5 - Formulation 5

EXA M P LE 6

A possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 10kg animal live weight. Table 6 - Formulation 6

Compound Mode of Action Concentration (weight %)

Levamisole HCI Active - levamisole salt 12

Abamectin Active - macrocyclic lactone 0.5

DMSO Organic Solvent / Penetrant / 10

Degreasing agent

Butylated hydroxytoluene (BHT) Preservative / Antioxidant 0.5

Water Inorganic Solvent 16

Deltamethrin Additional active 0.75-1.12

Polysorbate 80 Emulsifier, penetrant, surfactant, 7.5

wetting agent

agent

EXA M P LE 7

A possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight and the formulation in this case has a further anthelmintic from the benzimidazole family in fine suspension with the dissolved levamisole salt and macrocyclic lactone.

Table 7 - Formulation 7

Polysorbate 80 Emulsifier, penetrant, surfactant, 10

wetting agent

agent

EXA M P LE 8

The stability of Formulation 1 in Example 1 was tested by storing samples of Formulation 1 at 4^°C, 25^°C and 40^°C storage temperature conditions and testing the relative active concentrations on

commencement of the trial (day 1) and subsequently on day 8, day 16 and day 24. As can be seen in Table 8 below the findings indicated minimal changes if any in measured concentration in that the concentrations at day 24 were 98% to 100% of that at day 1, a result unexpected given art papers that suggest levamisole salt in particular tends to deteriorate.

Table 8 - Active Stability Test

EXA M P LE 9

The efficacy of the formulation was tested by administering Formulation 1 from Example 1 to cattle and then subsequently measuring the presence of levamisole in the blood stream (plasma) of the animal (cattle) at 6 and 12 hour intervals post administration. As shown below in Table 9, levamisole is clearly present in the bloodstream even at the earliest time interval of 6 hours post administration. Table 10 below shows the results obtained from a commercially available levamisole base formulation, traditionally thought of as being a more rapid way to deliver levamisole to the animal bloodstream. Comparing the averaged results of Table 9 and 10, Formulation 1 using levamisole salt has a concentration of levamisole in the bloodstream of the animals after 6 hours that was around 73% of that observed using the levamisole base formulation. After 12 hours the levamisole salt formulation has somewhat higher levels still present in the bloodstream versus that seen for the base formulation. The trials showed more than adequate efficacy as measured by transfer into the bloodstream both after 6 and 12 hours and a longer acting effect possible also using the salt form. These results are contrary to the art that tends to indicate poor transfer at any time interval let alone after 6 hours.

Table 9 - Formulation 1 - Efficacy Test

EXA M P LE 10

A further trial was completed using Formulation 1 above to test the efficacy in terms of macrocyclic lactone transfer as measured by testing for abamectin. As shown in Table 11 below, therapeutically effective quantities of abamectin were detected in the animal (cattle) blood stream (plasma) post administration.

Table 11 - Formulation 1 - Efficacy in Terms of Abamectin Found in Cattle Plasma

2 18.14 6.19

3 3.72 3.81

4 5.41 4.34

Average 34.09 5.96

EXA M P LE 11

As noted above, it is possible to manufacture the formulation described herein within minimal if any special mixing steps or special processing parameters. By way of example one method of preparation of the formulations described in Examples 1-7 can be presented as process consisting of the steps:

1. Levamisole salt is dissolved in water to form a first liquid solution;

2. Macrocyclic lactone and BHT (if used) are dissolved in an organic solvent, for example in DMSO, and then diethylene glycol ether is added to form a second liquid solution;

3. The two solutions are then mixed together under agitation 5-10 minutes;

4. Surfactant and other compounds as desired may then be mixed in, agitation continuing until a homogenous clear solution is formed, in the inventor's experience being less than 5-10 minutes.

The final formulations are clear solutions with no observable particles suspended or otherwise in the solution. The solution is flowing at ambient conditions within viscosity limits suitable for art pour on equipment.

As can be seen from the above, no special temperatures or pressures are required. Only simple mixing equipment is necessary and the process may be completed relatively quickly.

Aspects of above described formulations and methods have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope of the claims herein.

Claims

WHAT IS CLAIMED IS:

1. A formulation comprising in solution a mixture of:

a therapeutically effective amount of levamisole salt dissolved in at least one inorganic solvent;

a therapeutically effective amount of at least one additional anthelmintic compound with a different class of activity to levamisole, the at least one additional anthelmintic compound being substantially lipophilic and being dissolved in at least one organic solvent.

2. The formulation as claimed in claim 1 wherein the levamisole salt is present in the formulation at a rate of approximately: 10 to 30% by weight.

3. The formulation as claimed in claim 1 or claim 2 wherein the levamisole salt is present as levamisole HCI.

4. The formulation as claimed in claim 1 of claim 2 wherein the levamisole salt is present as hydrophilic salt forms selected from: phosphate, acetate, fluoride, sulphate forms and combinations thereof.

5. The formulation as claimed in any one of the above claims wherein the at least one additional anthelmintic compound is a macrocyclic lactone compound.

6. The formulation as claimed in claim 5 wherein the macrocyclic lactone compound is selected from: abamectin, ivermectin, moxidectin, eprinomectin, doramectin, selamectin, and combinations thereof.

7. The formulation as claimed in claim 5 or claim 6 wherein the macrocyclic lactone compound is present in the formulation at a rate of approximately: 0.5 to 1.5% by weight.

8. The formulation as claimed in any one of the above claims wherein the inorganic polar solvent is a substantially aqueous solution.

9. The formulation as claimed in any one of the above claims wherein the inorganic polar solvent is water.

10. The formulation as claimed in any one of the above claims wherein the inorganic polar solvent is present in the formulation at a rate of approximately: 15 to 50% by weight.

11. The formulation as claimed in any one of the above claims wherein the at least one organic solvent also has properties or functions selected from: humectant properties, penetrant properties, degreasing properties, and/or combinations thereof.

12. The formulation as claimed in any one of claims 1 to 10 wherein the at least one organic solvent is selected from: at least one sulfoxide; at least one sugar alcohol; isopropyl myristate; D-limonene; at least one aromatic solvent; at least one water miscible solvent; and/or combinations thereof.

13. The formulation as claimed in claim 12 wherein the at least one sulfoxide is dimethyl sulfoxide (DMSO).

14. The formulation as claimed in claim 12 wherein the at least one sugar alcohol is selected from

sorbitol, glycerol, and/or combinations thereof.

15. The formulation as claimed in claim 12 wherein the at least one aromatic solvent is selected from benzene or naptha blends and derivatives.

16. The formulation as claimed in claim 12 wherein the water miscible solvent is glycol ether.

17. The formulation as claimed in claim 12 wherein the glycol ether is diethylene glycol monobutyl ether.

18. The formulation as claimed in any one of the above claims wherein the composition further

comprises at least one additional active compound selected from: at least one additional anthelmintic with a further spectrum of anti-parasitic activity to levamisole and macrocyclic lactones, at least one vitamin, at least one mineral, at least one antigen, at least one

ectoparasiticide, and/or combinations thereof.

19. The formulation as claimed in claim 18 wherein the additional anthelmintic is selected from the benzimidazole family.

20. The formulation as claimed in any one of the above claims wherein the formulation comprises at least one surfactant and/or wetting agent at a rate of approximately 0.1 to 30% by weight.

21. The formulation as claimed in any one of the above claims wherein the formulation comprises at least one preservative or antioxidant compound at a rate of approximately: 0.5 to 1.5% by weight of the total formulation.

22. The formulation as claimed in any one of the above claims wherein the formulation viscosity has Newtonian flow and shear properties with a viscosity of less than approximately 6000cps.

23. The formulation as claimed in any one of the above claims wherein the formulation viscosity has a pH of approximately 4 to 6.

24. The formulation as claimed in any one of the above claims wherein the rate of active post storage in the formulation remains at 90 to 99% by weight of that present at manufacture when stored for at least 1 month.

25. A veterinary medicament formulated for topical administration to a non-human animal, the

medicament comprising at least one of the formulations as claimed in any one of the above claims.

26. Use of a formulation as claimed in any one of claims 1 to 24 in the manufacture of a medicament for the treatment of internal and/or external parasites in or on an animal in need thereof.

27. A method of prevention and/or treatment of a parasite infection or infestation in a non-human animal, the method comprising the steps of: selecting at least one formulation as claimed in any one of claims 1 to 19; and

applying the formulation topically to the non-human animal in need thereof.

28. The method as claimed in claim 27 wherein the rate of uptake post administration of the levamisole salt formulation is greater than approximately 70% by weight of that observed for a levamisole base formulation.

29. A method of manufacturing a veterinary medicament, the method comprising the steps of:

combining the first and second solutions to form a combined formulation.

30. The method as claimed in any one of claims 27 to 29 wherein the non-human animal is selected from the genus: bovine, ovine, cervine, porcine.

31. A formulation comprising in solution:

a therapeutically effective amount of levamisole salt;

32. A formulation comprising in solution:

a therapeutically effective amount of levamisole salt;

the levamisole salt and at least one additional compound being dissolved in a solvent system comprising a plurality of solvents, to form a solution, wherein at least one of the solvents is characterised by having: organic solvent function; penetrant function; and/or degreasing function.