WO2013043064A1

WO2013043064A1 - Veterinary anthelmintic delivery system

Info

Publication number: WO2013043064A1
Application number: PCT/NZ2012/000170
Authority: WO
Inventors: Robert William Lachlan Holmes; Mark William DUDDING
Original assignee: Alleva Animal Health Limited
Priority date: 2011-09-23
Filing date: 2012-09-24
Publication date: 2013-03-28

Abstract

A two part container (10) for veterinary products enabling two different but mixable liquid formulations to be stored separately in one pack having dual chambers (11) and (12) and mixed prior to application. One of the liquid formulations is a stable formulation containing at least one macrocyclic lactone anthelmintic and the other formulation is a stable liquid formulation containing one or more second anthelmintics, including levamisole. One of the chambers has a void space equivalent to the volume of the other chamber. The two chambers are separated by a barrier which can be broached to allow them to be mixed together immediately prior to use, without exposing either liquid separately to the user. The chambers (11) and (12) have screw threads so that they can be attached to the internal threads of a waisted intermediate portion (15) which can be attached to different sized chambers depending upon the product ratios and volume requirements.

Description

VETERINARY ANTHELMINTIC DELIVERY SYSTEM

FIELD OF THE INVENTION

This invention relates to a veterinary anthelmintic delivery system capable of delivering two or more actives.

BACKGROUND OF THE INVENTION

The control of gastrointestinal parasites is an important aspect of modern livestock fanning. Typically these parasites are controlled by specific chemical agents developed to meet certain criteria. These criteria include:

High effectiveness against the target parasites - this could either be via broad spectrum efficacy in which a wide range of parasites are controlled or alternatively narrow spectrum of activity in which a more limited selection of parasites are controlled.

Wide margin of safety to the host animal

Low potential to cause toxic residues that could cause harm to humans consuming meat or milk products from the animal

Over the past 50-60 years there have been 5 major classes of broad spectrum anthelmintic developed. These 5 classes are as follows:

Benzimidazoles.

The first chemical class of modern anthelmintics developed was the benzimidazoles (BZD). The first drug in this class, thiabendazole (TBZ) was introduced in 1961. Other members of the benzimidazole class include fenbendazole, albendazole and oxfendazole.

Benzimidazole based anthelmintics interfere with the worm's energy metabolism on a cellular level. They bind to a specific building block called beta tubulin and prevent its incorporation into certain cellular structures called microtubules, which are essential for energy metabolism. Interfering with energy metabolism is a much more basic mode of activity than that which occurs with other classes of anthelmintics. For this reason, benzimidazoles are also able to kill worm eggs. Benzimidazoles have a wide margin of safety and broad spectrum activity.

Nicotinic agonists

Nicotinic agonists comprise the next class of anthelmintics. They include imidazothiazoles and tetrahydropyrimidines. The imidazothiazole group includes levamisole, while the tetrahydropyrimidine group includes pyrantel pamoate, pyrantel tartrate, and morantel tartrate.

The tetrahydropyrimidines mimic the activity of acetylcholine, a naturally occurring neurotransmitter that initiates muscular contraction. The worm is unable to feed and quickly starves. Tetrahydroyrimidines only affect adult populations of worms. They do not have activity against the larval stages and are ineffective against cestodes (tapeworms) and trematodes (liver flukes).

Imidazothiaoles have a similar mode of action causing spastic paralysis of the worms. The group includes the drug levamisole discovered in 1966.

Compared to other anthelmintics, levamisole has the narrowest margin of safety, though toxicity is usually the result of excess dosage. Levamisole has a broad spectrum of activity and is effective against many larval stages of parasites, though not arrested larvae.

Macrocyclic lactones

The next anthelmintic class to be developed was the macrocyclic lactones (MLs) developed from the same genus of soil dwelling-organisms (genus Streptomyces). The first drug of the class, ivermectin, was introduced in the early 1980s.

Macrocyclic lactones consist of two closely related chemical groups: avermectins and milbemycins. The avermectins include abamectin, ivermectin doramectin and eprinomectin. The milbemycin group is represented by milbemycin oxime and moxidectin, introduced in 1997.

All of the macrocyclic lactone anthelmintics have the same mode of action. They interfere with GABA-mediated neurotransmission, causing paralysis and death of the parasite. Macrocyclic lactones are the most potent killer of worms and are more persistent in their effect. The duration of persistent activity varies according to the drug and formulation.

Macrocyclic lactones also have the unique quality of also killing several types of external parasite such as lice, mites, and ticks. They have a wide margin of safety for livestock and are effective against all stages of worms, including inactive forms.

Amino-acetonitrile derivatives

In 2009 the first of this new class of anthelmintics was introduced. Monepantel acts by paralyzing worms by attacking a previously undiscovered receptor HCO-MPTL-1, present only in nematodes.

Spiroindoles.

In 2010 Derquantel (2- deoxoparaherquamide), the first of yet another new class of anthelmintic was introduced.

All of the above anthelmintics have application in the control of a wide variety of ecto- and endo-parasites. Of particular concern are those parasites classified under the group of worms known as helminths. Helminthiasis is a prevalent and serious economic problem with domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats and poultry. Among the Helminths, the group of worms described as nematodes cause widespread, and at times serious infection in various species of animals.

Nematodes that are contemplated to be treated by the anthelmintics include, the following genera:

Acanthocheilonema, Aelurostrongylus, Ancylostoma, Angiostrongylus, Ascaridia, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma, Dictyocaulus, Dioctophyme, Dipetalonema, Diphyllobothrium, Diplydium, Dirofilaria, Dracunculus, Enterobius, Filaroides, Haemonchus, Heterakis, Lagochilascaris, Loa, Mansonella, Muellerius, Nanophyetus, Necator, Nematodirus, Oesophagostomum, Opisthorchis, Ostertagia, Oxyuris, Parafilaria, Paragonimus, Parascaris, Physaloptera, Protostrongylus, Setaria, Spirocerca, Spirometry Stephanofilaria, Strongyloides, Strongylus, Thelazia, Toxascaris, Toxocara, Trichinella, Trichonema, Trichostrongylus, Trichuris, Uncinaria, and Wuchereria.

Of the above, the most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nemaodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylo stoma, Unicinaria, Toxascaris and Parascaris. Certain of these, such as Nematodirus, Cooperia and Oesophagostomum attack primarily the intestinal tract while others, such as Haemonchus and Ostertagia, are more prevalent in the stomach while others such as Dictyocaulus are found in the lungs. Still other parasites may be located in other tissues such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like.

While there have been many anthelmintics developed over the years, of great concern is the development of resistance to anthelmintics belonging to the benzimidazole, nicotinic agonist and macrocyclic lactone classes and the high probability that it will similarly develop to anthelmintics from the more recently developed amino-acetonitrile and spiroindole classes. Resistance refers to the process by which exposure of the parasite population to an anthelmintic leads to genetic selection of those parasites able to tolerate it.

While resistance can naturally be expected to occur at a certain rate the problem is exacerbated by over-exposure of the parasite population to the anthelmintic or by sub-lethal dosing of the parasite through inaccurate dose administration.

Of particular relevance to this application is the development of resistance to those classes of anthelmintics widely used in cattle.

Resistance to benzimidazole-based cattle drenches is widespread throughout the world. Cases have been reported that involve resistance in all three major cattle parasites species: Ostertagia, Trichostrongylus and Cooperia.

Resistance to the nicotinic agonist derivative class (levamisole/morantel) is well known but is less widespread than benzimidazole resistance.

Resistance to the more recent macrocyclic lactone class is also becoming much more common. This is particularly troublesome given that it is by far the most popular form of parasite treatment for farmed cattle. To prevent and manage the problem of anthelmintic resistance farmers have relied on various strategies including:

1. Minimizing anthelmintic use by only treating at strategically important times

2. Alternating the type of anthelmintic used

3. Using combinations of anthelmintics from different classes to reduce the potential of parasites to survive the treatment.

The present application describes a solution to aid farmers in the application of the third strategy by providing a novel delivery system that delivers a combination of anthelmintics selected from two or more different anthelmintic classes. The solution also has application in cases where farmers wish to extend the spectrum of activity of treatments by combining incompatible anthelmintics capable of controlling different parasite species.

From the perspective of ease of administration it is most desirable that any combination of anthelmintics is able to be applied in one simple treatment that requires no additional effort or change of routine on the part of the farmer. It would also be desirable that the formulation contained a macrocyclic lactone active ingredient and at least one second anthelmintic. Preferably this at least one second anthelmintic would be levamisole, as a combination of macrocyclic lactone and levamisole would help ensure the best efficacy against the major gastrointestinal parasites of domestic animals. However other anthelmintic combinations are envisaged.

PRIOR ART

NZ 336139 (Novartis) represents a recent attempt to formulate a combination product containing a macrocyclic lactone anthelmintic and levamisole.

Based on emulsion technology, the formulation described includes levamisole in an aqueous acidic phase and macrocyclic lactone in a lipophilic phase. A third active such as a benzimidazole could potentially be suspended in particulate form in the aqueous phase.

The disadvantage of this formulation is the need for the formulation to be shaken or agitated into an emulsion. In addition, the product is chemically complicated including 2 or 3 different phases. The formulation method also does lend itself to use for topical or injectable formulations.

The complicated nature of the formulation in NZ 336139 is due in part to the different formulation requirements of the actives. Macrocyclic lactone active ingredients are substantially insoluble in water whereas levamisole is highly water soluble. Macrocyclic lactone active ingredients are most stable at a pH of about 6.6 while levamisole is most stable at a pH of less than about 4.

As will be appreciated, in addition to the need to be physically stable during storage anthelmintic formulations also need to be safe to administer so that they do not cause excessive skin or tissue irritation.

A more recent attempt to provide a stable formulation of a macrocyclic lactone anthelmintic combined with levamisole is suggested in NZ520295 (Merial). In this patent a pyrrolidone solvent (N methyl pyrrolidone) was used to dissolve both active ingredients. This resulted in a formulation that was simple to prepare and demonstrated improved stability of the two actives.

Yet another attempted solution is suggested in NZ552040 (Bomac). In the proposed formulation the macrocyclic lactone and levamisole active ingredients are solubilized in a combination of a glyceryl acetate solvent (triacetin) and glycerol formal. However this formulation does not offer improvement in shelf stability when compared to the prior art and the data presented in the patent indicates that it is potentially more poorly absorbed when compared to the formulation described in NZ520295.

NZ542955 discloses combination anthelmintic topical formulations containing a macrocyclic lactone anthelmintic and a second anthelmintic selected from the group comprising praziquantel, morantel and pyrantel.

Although not referring to formulations containing a macrocyclic lactone and levamisole this patent does refer to the many formulation aspects which need to be addressed to develop a formulation suitable for delivering two actives transdermally in combination. In this patent the solvents used include combinations of propylene glycol, dimethyl isosorbide, benzyl alcohol, glycerol formal, oleoyl macroglycerides, isopropanol, dimethylacetamide, Propylene Glycol Dicaprylate/Dicaprate. WO2011027333 discloses a method whereby macrocyclic lactone based anthelmintics as well as other classes of anthelmintic can be granulated and stored as a dry mix ready for dilution prior to use. This method provides a possible means of overcoming shelf storage limitations but it relies on the user having readily available clean supplies of water or solvents to enable the formulation to be prepared for use. Clean supplies of water are not always available to the user, nor are mixing instructions necessarily likely to be followed exactly. This could result in inadequate mixing, under-dosing, or even worse, overdosing to the point where animal safety is compromised.

In the art there are many systems proposed for the admixing of fluids. There are however great difficulties in utilizing these systems as part of the invention. The materials from which they are constructed are generally not compatible with the kinds of organic solvents used in many veterinary formulations. They are also typically used to dilute very small volumes of powder or liquid into a larger volume of diluent. This is usually achieved by having a recess under the main cap or in an inner vessel within the main body of a chamber. Examples of such devices are found in US20050173271, US20G601 15858, US20040112770, US7503453, 6926138, 6921087, 6886686, 6772910, 6513650, 6138821, and 4195730.

Construction of a veterinary delivery system (particularly for topical use) according to such methods would not be desirable given the large volume of liquid which would generally be required to be diluted. Scaling up such a device could result in a bulbous container of impractical proportions. It would also result in a device with an extremely large lid opening which could expose the user to hazards associated with the contents.

Other problems are encountered when trying to manufacture dual system packages for sterile formulations. These difficulties are generally associated with the need to maintain sterility and avoid cross contamination of each material. Generally the kinds of systems proposed would make it very difficult to avoid cross contamination, particularly where powder/diluent systems are to be produced. In most such injectable systems it would not be permitted to use systems in which plastic, foil or other such material were torn or punctured to permit the contents of each chamber to freely mix.

PRIOR REFERENCES All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications may be referred to herein; this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art, in New Zealand or in any other country.

DEFINITIONS

It is acknowledged that the term 'comprise' may, under varying jurisdictions, be attributed with either an exclusive or an inclusive meaning. For the purpose of this specification, and unless otherwise noted, the term 'comprise' 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. This rationale will also be used when the term 'comprised' or 'comprising' is used in relation to one or more steps in a method or process.

THE PROBLEM

Despite the various advancements in formulation technology shelf storage stability is still a limiting factor to widespread availability of macrocyclic lactone combination formulations. It is simply not possible to provide macrocyclic lactone combination formulations to many parts of the world given the current state of the art. This is because high temperatures cause rapid degradation of the combination and also because many regulatory agencies tightly control the permissible degree of degradation of the active ingredient/s allowed within the approved shelf life of a veterinary product. A further reason for the lack of such formulations is that there are only a limited number of solvents approved for use in veterinary formulations.

Indicative of the difficulty of this formulation task is the fact that over the past twenty years only three topical or injectable macrocyclic lactone/levamisole containing formulations have been commercially released (two topical and one injectable), despite there being a significant need for such formulations.

Also of note is that these products have very short shelf lives at the recommended 25 °C maximum storage temperature. The topical products rely on a significant overage of the macrocyclic lactone component to achieve this shelf life, while the injectable product must be kept in a refrigerated condition to prolong its shelf life.

In Australia, ECLIPSE Pour-On, the only combination product available in that market carries the following storage recommendation, "Store below 25°C (Air Conditioning)". Given the lack of air conditioning storage facilities on most farming properties this recommendation is highly impractical. Temperatures often exceed 40°C at times, and more commonly are 30°C for long durations.

Realistically the ideal veterinary formulation designed for on-farm use should have a shelf life of at least 12 months and preferably 24 months at 30°C, with no overage required to attain that shelf life.

The lack of definitive solutions in the prior art and the limited number of commercially available topical and injectable macrocyclic lactone/levamisole combination products is an indication of the degree of difficulty in developing such formulations. The previously proposed and currently available solutions would not meet the requirement for a prolonged shelf-life in many parts of the world.

Accordingly, there remains a substantial need for improved macrocyclic lactone combination formulation delivery systems that provide improved shelf storage stability and that: are easy to manufacture are safe for the farmer to handle, require no additional effort for the farmer to administer.

OBJECT OF THE INVENTION It is a first object of the present invention to provide improved combination anthelmintic formulations containing a macrocyclic lactone active ingredient and at least one or more second active ingredients, including levamisole in a delivery system; or which will at least provide the public with a useful choice.

It is an alternative object of the present invention to provide an improved veterinary formulation delivery system which is capable of storing two active-ingredient containing solutions, or an active ingredient and a diluent in a separated state and then mixing them immediately prior to use.

STATEMENT OF INVENTION

FIRST ASPECT - THE BINARY FORMULATIONS IN A CONTAINER

In a first aspect the invention relates to a an anthelmintic delivery system comprising;

(a) a first formulation contained in a first chamber of a container, comprising a liquid macrocyclic lactone formulation,

(b) a second formulation contained in a second chamber of the same container, comprising a liquid levamisole formulation with or without other anthelmintics; and in which the contents of the first chamber are easily admixed with the contents of the second chamber, and

(c) the delivery system being such that the two formulations can be mixed together within the container prior to use and before the user can gain physical access to either formulation in its unmixed condition.

The invention is designed to overcome the problem of lack of storage stability of unitary macrocylic lactone/levamisole combination formulations, while also ensuring the two solutions are mixed before the user is able to access either solution in its undiluted highly concentrated state.

Preferably the second chamber is larger than the first chamber and has a void space equivalent to the volume of the first chamber to facilitate mixing. Preferably the one or more macrocyclic lactone anthelmintic is selected from the group including abamectin, doramectin, eprinomectin, ivermectin and moxidectin.

Preferably the two chambers are adjacent to one another with neither chamber being enclosed within the neck or body portion of the second chamber at any time; the first chamber containing the liquid macrocyclic lactone formulation, and the second chamber containing the liquid levamisole formulation; and in which the two chambers are separated by a barrier that is capable of being broached by a broaching mechanism to permit mixing of the contents of the chambers before the user has access to the contents of either chamber.

Preferably, but not necessarily the two chambers are manufactured separately before being joined together in a post manufacturing assembly operation.

Preferably the two chambers are joined together via a threaded arrangement on each chamber.

Preferably the device once assembled has no accessible opening greater than 60mm in diameter.

Preferably the delivery system incorporates a system to prevent inadvertent mixing of the two components during storage or transport, or before the user is ready to administer the mixed formulation.

Preferably the openings between the two chambers are sealed by organic solvent compatible barrier chosen from the group comprising rubber, aluminum foil, thinly molded plastic membranes or some other material compatible with the materials contained within.

Preferably the device has a transit cap that upon rotation causes the barrier between the two chambers to be broached thereby permitting the contents of the two chambers to mix.

Preferably the upper chamber contains a barrier broaching rod that, upon rotation of the transit cap, moves in a downward direction. This rod can be any elongate member capable of fitting within the upper chamber and capable of piercing or breaking or displacing the barrier/s between the chambers but without unduly impeding the egress of the mixed liquids. It can be solid or hollow, although in the examples it is shown as a hollow tube. Preferably the barrier broaching rod broaches the barrier/s between the two chambers by either piercing the barrier/s or pushing the barrier/s free from the locating mechanism which holds the barrier/s in place.

Preferably when the device is designed for use with sterile formulations it has a thin deformable rubber stopper located between the cap and the barrier broaching rod. This stopper is designed to seal the outer opening and flex downwardly upon rotation of the cap so that the movement of the barrier broaching rod in a downward direction is not impeded but the sterility of the contents of the device is maintained.

More preferably the macrocyclic lactone anthelmintic is present in the range of between 0.01 - 5% w/v.

Preferably the second active ingredient is levamisole in the hydrochloride, phosphate or base form.

Preferably the levamisole is present in the range of between 1 - 30% w/v.

Preferably the volume of the macrocyclic lactone containing solution before mixing is from 1/10^th to ½ of the volume of the levamisole containing solution.

Preferably one or both of the formulations additionally includes at least one further medicament selected from the group comprising anthelmintics, dietary supplements, vitamins, mineral and other beneficial agents.

More preferably one or both of the formulations additionally includes excipients including preservatives, stabilizers and co solvents.

Most preferably if the admixed formulation is designed for topical use one or both of the formulations will additionally contain a viscosity modifier designed to reduce the potential for the admixed formulation to run from the back of the animal being treated.

Most preferably if the admixed formulation is designed for injectable use one or both of the formulations will additionally contain a surfactant designed to make the two formulations easier to mix. In a further related aspect the invention comprises a method of preparing a topical or injectable anthelmintic delivery system containing at least one macrocyclic lactone active and levamisole.

In yet a further aspect the invention relates to a method of treating animals with a topical or injectable anthelmintic using a delivery system consisting of two parts; the first part being a formulation containing at least one macrocyclic lactone active, and the second part being a formulation containing levamisole; and in which immediately prior to application the two parts are admixed together within a container that permits mixing to occur before the user can gain physical access to either formulation in its unmixed condition.

In yet a further aspect the invention relates to a method of treating or preventing infection of animals with Cooperia or Ostertagia by administering a treatment from a topical or injectable anthelmintic delivery system consisting of two parts; the first part being a formulation containing at least one macrocyclic lactone active, and the second part being a formulation containing levamisole; and in which immediately prior to application the two parts are admixed together within a container that permits mixing to occur before the user can gain physical access to either formulation in its unmixed condition.

In a further aspect the invention provides a veterinary anthelmintic delivery system comprising:

(a) A container consisting of at least two chambers;

(b) At least one macrocyclic lactone dissolved in a first solvent or solvent system stored in a first chamber;

(c) Levamisole dissolved in a second solvent or solvent system and stored in a second chamber; with the contents of the first chamber being freely miscible with the content of the second chamber;

(d) A mechanism which causes the contents of the two chambers to be mixed together before the user gains physical access to either solution in its unmixed condition; and

(e) In which the volume of solvent in which the macrocylic lactone is dissolved is from 1/10* to ½ of the volume of the solvent in which levamisole is dissolved.

Preferably the first chamber of the two chambered container contains a solution containing one or more macrocyclic lactone active ingredients, and the second chamber contains a solution containing levamisole in its base, hydrochloride or phosphate form; and in which the contents of both chambers can be mixed together to form a unitary solution before the user is able to gain physical access to either solution in its unmixed condition.

Preferably the macrocyclic lactone containing solution contains at least one macrocyclic lactone anthelmintic selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin and moxidectin.

Preferably the macrocyclic lactone anthelmintic is present in the first chamber at a range of between 1 - 20% w/v.

Preferably the levamisole is present in the second chamber in the range of between 10 - 50% w/v.

Preferably the ratio of macrocylic lactone active ingredient contained in the first formulation is between 1/15^th and l/25^th of the weight per volume of the levamisole contained in the second container or chamber.

Preferably either the macrocyclic lactone or the levamisole is present in a solution containing one or more solvents selected from Diethyl carbonate, Diethyl phthalate, Diethyl sebacate, Dimethyl acetamide, Dimethyl phthalate, Dimethyl isosorbide, Dimethyl sulphoxide, Glycerol formal, C1-C20 alcohols or esters thereof, fatty acid esters or alcohols, Carboxylic acid esters, Glycerol & derivatives & esters, Glycol ethers & Glycol esters, Glycerine carbonate and Alkylene carbonates, Lactone solvents, Propylene glycol & derivatives (including esters, diesters and fatty acids), Polyethylene glycols & derivatives (including esters, diesters and fatty acids), Ketones, Vegetable oil and derivatives, Mineral Oils, Silicone oils, Aliphatic and Aromatic hydrocarbons, Pyrollidone based solvents, Aliphatic lactones and Water.

Preferably either the macrocyclic lactone or levamisole active ingredient is dissolved and stored in a solution containing one or more solvents selected from glycol ethers and glycol esters, dimethyl acetamide, dimethyl isosorbide, dimethyl phthalate, diethyl phthalate, N- methyl pyrrolidone, 2-pyrrolidone, glyceryl triacetate, glycerol formal, gamma hexalactone, polyethylene glycol, propylene glycol, benzyl alcohol, propylene glycol Dicaprylate/Dicaprate, water.

In another aspect the invention provides a two part anthelmintic formulation system in which a macrocyclic lactone and a levamisole active ingredient are independently stored in solvents solutions designed for mixing immediately prior to use and in which either the macrocylic lactone or levamisole active ingredient is dissolved and stored in a solution containing one or more solvents selected from glycerol formal, and glycol based solvents.

In another aspect the invention provides a two part anthelmintic formulation system in which a macrocyclic lactone and a levamisole active ingredient are independently stored in solvents solutions designed for mixing immediately prior to use and in which the macrocyclic lactone is dissolved and stored in a formulation system including glycerol formal or glycol based solvents and the levamisole component is stored in a formulation system including a glycol based solvent.

Preferably either one or both formulations contain a stabilising antioxidant material.

Preferably the stabilising antioxidant material is selected from BHT and BHA.

Preferably either one or both solutions contains one or more additional anthelmintics selected from benzimidazoles (including albendazole, fenbendazole, mebendazole, oxfendazole, oxibendazole, ricobendazole, triclabendazole), clorsulon, closantel, derquantel, febantel, monepantel, morantel, netobimin, nitroxynil, oxyclozanide, praziquantel, pyrantel and rafoxinide.

Preferably either one or both solutions contain one or more additional, minerals, supplements or therapeutic elements, either dissolved or suspended in the solution/s.

Preferably the volume of the macrocyclic lactone containing solution prior to mixing is from between 1/3 to 1/10^th of the volume of the levamisole component.

Preferably one or both formulations includes a viscosity modifying agent designed to reduce run-off of the formulation from the back of an animal. Preferably the viscosity modifying agent is selected from the group comprising ppolymers (including Linear, Branched or Cross-linked polymers, Acrylic Polymers, Cross-linked Acrylic Polymers), Cellulose & Cellulose derivatives, Organoclays, 01igomer,Aluminum stearates/isostearates/myristates/laurates/palmitates, inorganic polymer and its modified silicate materials, natural waxes and glycerides.

Preferably one or both of the unmixed formulations includes water and/or a surfactant.

Preferably the surfactant is selected from non-ionic, cationic, anionic and amphoteric surfactant classes.

Preferably the formulation which included water is the formulation containing levamisole.

In another aspect the invention provides a method of manufacturing an anthelmintic delivery system containing levamisole and at least one macrocylic lactone anthelmintic according to the following steps:

(a) A first levamisole or macrocyclic lactone liquid formulation is manufactured in a vessel by dissolving the active ingredient in one or more solvents;

(b) The first levamisole or macrocylic lactone formulation is filled into a first container or chamber;

(c) The first container or chamber is sealed either by sealing with an induction seal or some other sealing means, or by attaching a second container or chamber over the opening of the first container or chamber;

(d) A second levamisole or macrocyclic lactone liquid formulation is manufactured in a vessel by dissolving the active ingredient in one or more solvents; >

(e) The second container or chamber is filled with the second formulation and then sealed with a sealing means;

(f) If the first container or chamber and the second container or chamber are still in a separated state the two container or chambers are joined together into a final use configuration either at the manufacturing site, or by the user prior to use.

Alternatively the method of manufacturing an anthelmintic delivery system containing levamisole and at least one macrocylic lactone anthelmintic would be according to the following steps: (a) A formulation containing at least one macrocyclic lactone active ingredient is manufactured in a first vessel, and a second formulation containing levamisole is manufactured in a second vessel;

(b) The first formulation is filled into a first container chamber;

(c) The first chamber is sealed either by sealing with an induction seal or some other sealing means, or by attaching the second chamber of the container to the first chamber of the container over the opening of the first chamber;

(d) The second chamber is filled with the second formulation and then sealed with a sealing means;

(e) If the first chamber and second chamber are still in a separated state the two chambers are joined together into a final configuration before use either at the manufacturing site, or by the user prior to use.

In another aspect the invention provides a method of treating cattle or sheep by using a veterinary delivery system prepared according to any one of the preceding paragraphs.

In another aspect the invention provides a method of prolonging the shelf life of a veterinary delivery system containing levamisole and at least one macrocylic lactone anthelmintic by supplying the two parts in a separated condition with a label recommendation to mix the two parts together immediately prior to use and then to store under refrigerated conditions any mixed formulation remaining after use.

The formulations contained within the present invention must be stable in their non-mixed condition to be of commercial use. In this specification, a commercially acceptable product is one in which both anthelmintic formulations contained within the containment system are stable at room temperature for a period of at least 6 months. In conditions of accelerated testing, at 40° C, this requires the potency of the actives within each formulation to remain within specified and acceptable limits for 3 months.

When used in this invention macrocyclic lactone anthelmintics refer to a class of active ingredients having anthelmintic activity. They are derived from soil microorganisms belonging to the genus Streptomyces. The class includes by way of example; abamectin, ivermectin, doramectin, eprinomectin and moxidectin.

The chemical structure of each is as follows: Ivermectin Bi_a & Ivermectin Bi_b

Eprinomectin

Levamisole is an anthelmintic belonging to a class of synthetic imidazothiazole derivatives. When used in this specification it includes levamisole hydrochloride, levamisole base, levamisole phosphate together with other salts and forms.

Levamisole

Other anthelmintics of particular note that may be used in the invention include albendazole, fenbendazole, mebendazole, oxfendazole, oxibendazole, ricobendazole, triclabendazole, clorsulon, closantel, derquantel, febantel, monepantel, morantel, netobimin, nitroxynil, oxyclozanide, praziquantel, pyrantel and rafoxinide.

The first aspects of this invention are advantageous as they provide stable formulations including a macrocyclic lactone anthelmintic and levamisole each in their own unique solvent system but which are admixed simply and easily immediately prior to administration and before the user can gain access to either formulation in an unmixed state.

In the preferred embodiments relating to the formulations, each of the formulations are monophasic and suitable to manufacture on a commercial scale. In addition, as both actives are in solution the formulations are physically stable in that they do not separate out into separate phases; either aqueous or lipophilic phases or liquid and solid phases. This also enables the formulations that are the subject of this application to be easily admixed prior to use.

The following description will describe the invention in relation to preferred embodiments of the invention, namely admixable solutions of one or more macrocyclic lactone active ingredients and one or more second anthelmintic, including levamisole and methods of manufacture and use therein. The invention is in no way limited to these preferred embodiments as they are purely to exemplify the invention only and that possible variations and modifications would be readily apparent without departing from the scope of the invention.

ALTERNATIVE ASPECT - THE CONTAINER

In an alternative aspect the invention relates to a delivery system comprising two substance containing chambers with neither chamber being enclosed within the neck or body portion of the second chamber at any time; the first chamber containing a liquid, and the second chamber containing a powder or liquid; and in which the two chambers are separated by a barrier that is capable of being broached by a broaching mechanism to permit mixing of the contents of the chambers before the user has access to the contents of either chamber.

Preferably the two substances are as defined above - namely a levamisole formulation and a macro cyclic lactone formulation.

Preferably the openings between the two chambers are sealed by organic solvent compatible rubber, aluminum foil, thinly molded plastic membranes or some other material compatible with the materials contained within.

Preferably the upper chamber contains a barrier broaching rod that, upon rotation of the transit cap, moves in a downward direction. This rod can be any elongate member capable of fitting within the upper chamber and capable of piercing or breaking or displacing the barrier/s between the chambers but without unduly impeding the egress of the mixed liquids. It can be solid or hollow, although in the examples it is shown as a hollow tube.

Preferably the barrier broaching rod broaches the barrier/s between the two chambers by either piercing the barrier/s or pushing the barrier/s free from the locating mechanism which holds the barrier/s in place.

In a further related aspect the invention comprises a method of preparing a veterinary formulation delivery system comprising two chambers; the first chamber containing a first liquid, and the second chamber containing a powder or liquid.

Preferably the two chambers are manufactured separately before being joined together in a post manufacturing assembly operation

If the formulation is intended to be a non-sterile product intended for topical or oral use it is preferably prepared in the following manner:

(a) the two chambers are manufactured as separate parts

(b) the caps, barrier/s, barrier broaching rod, etc. are manufactured

(c) the lower chamber is filled with a first formulation and then the opening is sealed with an aluminum foil barrier. The chamber is then put aside to await preparation of the upper chamber

(d) the upper chamber has an aluminum foil barrier placed over the lower opening that will be aligned with the opening of the lower chamber when the two chambers are joined together.

(e) the upper chamber is then filled with a second formulation

(f) the barrier broaching rod is placed in the upper opening of the upper chamber (g) the transit cap is screwed into place over the barrier broaching rod

(h) the lower chamber and the upper chamber are then joined together

(i) an optional reinforcing shroud is then wrapped around the joined portion of the two chambers so that the join between the two chambers is strengthened; alternatively the upper and lower chambers are mated together using the reinforcing shroud as a mating mechanism.

Alternatively the device may be prepared in the following manner:

(a) the two chambers are manufactured as separate parts

(b) the caps, barrier/s, barrier broaching rod, etc. are manufactured

(c) the lower chamber is filled with a first formulation and then the opening is sealed with an aluminum foil barrier

(d) The upper chamber is joined to the lower chamber

(e) the upper chamber is then filled with a second formulation

(f) the barrier broaching rod is placed in the upper opening of the upper chamber

(g) the transit cap is screwed into place over the barrier broaching rod

(h) the lower chamber and the upper chamber are then joined together

(i) an optional reinforcing shroud is then wrapped around the joined portion of the two chambers so that the join between the two chambers is strengthened

Alternatively the device may be prepared in the following manner if the two chambers are molded together in one unit with a second opening in the lower chamber and a plug or molded but frangible barrier located in a neck space between the two chambers:

(a) the chambers are manufactured as a one piece molding

(b) the caps, hollow barrier broaching rod are manufactured (c) the lower chamber is filled through the second opening with a first formulation and then the opening is sealed with a non-openable cap

(d) the upper chamber is then filled with a second formulation

(e) the barrier broaching rod is placed in the upper opening of the upper chamber

(f) the transit cap is screwed into place over the barrier hollow barrier broaching rod

Optionally with each of these methods of manufacture the barrier portion may be molded as part of one or both chambers by making the barrier portion simply a very thin part of the wall section of the chamber.

If the formulation is manufactured as a sterile product intended for injectable use it is preferably prepared in the following manner:

The two chambers are molded together in one unit with a first opening in the upper chamber and a second opening in the lower chamber and a plug or molded but frangible barrier located in a neck space between the two chambers:

(a) the container with two chambers, caps, barrier broaching rod are manufactured, with at least one chamber being sealed before the contents are filled into it. Preferably this is the upper chamber with the barrier broaching rod being located in the upper chamber before the opening is sealed with a rubber stopper and aluminum seal

(b) the device is gamma irradiated to assure sterility

(c) the lower chamber is filled through the lower opening and then sealed with a permanent seal (most preferably composed of a compatible and pharmaceutically acceptable rubber material) and non-removable aluminum overcap

(d) the upper chamber is filled with an acceptable method such as that offered by Aseptic Technologies, Crystal^®Closed Vial Technology.

(e) the transit cap is screwed into place over the rubber stopper. It is also envisaged that both chambers might be sealed and that the two chambers could be filled with a technique such as that offered by Aseptic Technologies, Crystal^®Closed Vial Technology. With this method a needle is used to insert the formulation into the chamber through the closed rubber stopper. Once the needle is withdrawn the stopper is resealed by laser. The advantage of such a methodology is that there is a much reduced risk of inadvertent contamination.

Alternatively if the nature of the materials in the formulation permitted it the device could be prepared in the following manner:

(a) two chambers are molded together in one unit with a first opening in the upper chamber and a second opening in the lower chamber and a plug or molded but frangible barrier located in a neck space between the two chambers

(b) the chambers, caps, barrier broaching rod are manufactured, with both chambers being open

(c) the barrier (and optionally barrier broaching rod) are located in place

(d) the device is gamma irradiated to assure sterility

(e) the upper chamber is filled and then sealed with a permanent seal (most preferably composed of a compatible and pharmaceutically acceptable rubber material) and aluminum overcap

(f) The optional transit cap is screwed into place over the rubber stopper

(g) the lower chamber is filled and sealed with a permanent non-removable aluminium overseal.

THIRD ASPECT - INTERACTION OF THE CONTAINER AND FORMULATIONS

In another aspect the invention provides an anthelmintic delivery system comprising:

(a) A container consisting of at least two chambers;

(b) A first liquid formulation containing at least one macrocyclic lactone stored in a first chamber; (c) A second liquid formulation containing at least Levamisole stored in a second chamber; with the contents of the first chamber being freely miscible with the content of the second chamber;

(d) And wherein the contents of both chambers can be mixed together to form a unitary formulation before the user is able to gain physical access to either formulation in its unmixed condition.

Preferably the first formulation comprises the at least one macrocyclic lactone dissolved in a first solvent or solvent system, and the second formulation comprises levamisole dissolved in a second solvent or solvent system and the volume of the first solvent/solvent system in which the macrocylic lactone is dissolved is from 1/10^th to ½ of the volume of the second solvent/solvent system in which levamisole is dissolved.

Preferably the first solution contains at least one macrocyclic lactone anthelmintic selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin and moxidectin.

Preferably the macrocyclic lactone anthelmintic is present in the first chamber at a range of between 1 - 20% w/v of the first solvent/solvent system.

Preferably the levamisole is present is present in the second chamber in the range of between 10 - 50% w/v of the second solvent/solvent system.

(d) A second levamisole or macrocyclic lactone liquid formulation is manufactured in a vessel by dissolving the active ingredient in one or more solvents;

In another aspect the invention provides a formulation delivery system comprising two chambers, a first chamber capable of containing a first liquid or powder formulation and a second chamber capable of containing a second liquid or powder formulation, and wherein:

(a) neither chamber is enclosed within the neck or body portion of the second chamber at any time; There is a barrier between the two chambers which must be broached to cause mixing of the contents of the two chambers before the contents of either chamber become accessible to the user;

(b) either the first or second chamber contains a barrier broaching rod designed to cause an interaction between an outer cap and the barrier between the chambers thereby causing the barrier to be broached; and

(c) the outer cap and barrier broaching rod are distinct and separate parts of the device, rather than being formed as one single unitary part. Preferably the first chamber wherein the available volume of the first chamber is smaller than the available volume of the second chamber.

Preferably the first chamber wherein the first chamber contains a first liquid formulation comprising at least one macrocyclic lactone dissolved in a first solvent or solvent system, and the second chamber contains a second liquid formulation comprising levamisole dissolved in a second solvent or solvent system, and the volume of the first solvent/solvent system in which the macrocylic lactone is dissolved is from 1/10* to ½ of the volume of the second solvent/solvent system in which levamisole is dissolved.

In another aspect the invention provides a method of treating a domestic animal using a delivery system as described in any one of the preceding paragraphs.

The invention the subject of the present application is advantageous as it provides a means to supply stable formulations of veterinary drugs each in their own unique formulation but which are capable of being admixed simply and easily immediately prior to administration.

Each of the formulations can therefore be monophasic and suitable to manufacture on a commercial scale.

The following description will describe the invention in relation to preferred embodiments of the invention, namely a Container for Veterinary Products and formulations for use therein. The invention is in no way limited to these preferred embodiments as they are purely to exemplify the invention only and that possible variations and modifications would be readily apparent without departing from the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described, by way of example only, by reference to the accompanying drawings:

Figure 1 shows a side view of the first embodiment of the container. Figure 2 shows a cut away view of the container of Figure 1. Figure 3 shows a cut away view of a second embodiment of the container, in the form of a smaller two part bottle.

Figure 4 shows an exploded side view of the upper compartment of the bottle of Figure

3.

Figure 5 shows an exploded perspective view of the components of Figure 4.

Figure 6 is an expanded view of the barriers between the two chambers of the bottles of this invention.

Figure 7 is a side view of the intermediate member capable of connecting two pre- barriered chambers together.

Figure 8 is a perspective view of the intermediate component of Figure 7.

Figure 9 shows the side view of Figure 4 and the perspective view of Figure 5 side by side.

Figure 10 is a side view of the intermediate portion and the barriers.

Figure 11 is a perspective view of the intermediate portion and barriers of Figure 10.

Figure 12 is a side view of a larger bottom chamber for use with the components of

Figures 9 through 11.

Figure 13 is a perspective view of this lower chamber.

Figure 14 is an exploded side elevation of the upper and lower chambers of different sizes connectable together by the intermediate portion.

Figure 15 is an exploded perspective view of these components of Figure 14.

Figure 16 is a perspective view of a larger two chamber veterinary pack.

Figure 17 is a perspective view of an intermediate two chamber veterinary pack.

Figure 18 is a perspective view of a smaller bottle like two part veterinary pack.

Figure 19 is an end elevation corresponding to Figure 16. Figure 20 is an end elevation corresponding to Figure 17.

Figure 21 is an end elevation corresponding to Figure 18.

Figure 22 is a front view corresponding to the container of Figure 16.

Figure 23 is a front view corresponding to the container of Figure 17.

Figure 24 is a front view corresponding to the container of Figure 18.

Figure 25 is an exploded perspective (shaded) view of an alternative two chamber veterinary pack.

Figure 26 is an exploded front view of the veterinary container of Figure 25.

Figure 27 is a complete perspective view of the container of Figures 25 and Figures 26.

Figure 28 is a view of the container illustrating an embodiment with a secondary opening in the lower chamber.

Figure 29 is an embodiment of the container designed for use with sterile injectable products.

Figure 30 is a cross section view of the container for use with sterile injectable products.

Figure 31 is a cross section view of an alternative embodiment of a container designed for use with sterile injectable products.

Figure 32 is an overcap designed for use with a container used for sterile injectable products.

Figure 34 is an embodiment of a barrier broaching rod for use with the sterile product container.

Figure 35 is chart showing Part 1 of the manufacturing steps for the first formulations. Figure 36 is chart showing Part 2 of the manufacturing steps for the first formulations. Figure 37 is chart showing the combined manufacturing steps for the first formulations. Figure 38 is chart showing Part 1 of the manufacturing steps for the second preferred formulations.

Figure 39 is chart showing Part 2 of the manufacturing steps for the second preferred formulations.

Figure 40 is chart showing the combined manufacturing steps for the second preferred formulations.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

Formulations:

In many of the extensive grassland markets in which anthelmintic products might be used it is necessary for such formulations to be capable of shelf stability of 18 months to 2 years when stored at temperatures of 30°C and 70% relative humidity.

When stored and tested under these conditions the commercially available macrocyclic lactone/levamisole formulations, ECLIPSE® Pour-On (Merial), ECLIPSE-E Injection and SATURN® Pour-On (Bayer), rapidly deteriorate thereby demonstrating that they could not be registered or sold in high temperature markets without considerable limitations on recommended storage conditions.

A larger number of tests were conducted to try to find a set of solvents that might offer performance improvements from those currently used as the main solvents in commercially available macrocyclic lactone/nicotinic agonist combination topical formulations (ECLIPSE®Merial, SATURN®Bayer).

In the trials formulations were prepared containing 1% abamectin, 20% levamisole base and 0.1% BHT with all materials dissolved in the selected solvent. Table 1 - Results of testing were as follows:

dissolved.

1.15g abamectin added. Took

Ethyl L-lactate 0.96 0.42 -56.2% 5minutes to dissolve. Levamisole dissolved (time taken not recorded)

1.14g abamectin added. Took less than 5minutes to dissolve.

2-Propanol 1.32 0.62 -53.0%

Levamisole took 5minutes to dissolve.

1.15g abamectin added. Took less

N,N- than 5minutes to dissolve.

1.19 0.8 -32.7%

Dimethylformamide Levamisole took lOminutes to

dissolve.

1.13g abamectin added. Took

Butyl carbitol

1.13 0.62 -45.1% 1 Ominutes to dissolve. Levamisole (DGBE)

took 15minutes to dissolve.

As might be expected the two major solvents used in the marketed products, ECLIPSE® and SATURN® performed better than most of the other solvents tested. Surprisingly however three other solvents performed equally well. One in particular, Dimethyl isosorbide, performed best of all in terms of enhancing the stability of abamectin.

Table 2 - In order of performance:

Despite the fact that the solvents offered potential for a formulation that was an improvement on those currently available further testing determined that the solvents could not meet the criteria for prolonging the shelf life of the macrocyclic lactone formulation that would be required in a very hot climatic region. Various other approaches were then tried, such as pack purging with nitrogen, enhanced barrier packaging and other methods known to the general pharmaceutical industry.

Results of the studies concluded that the stability problem would also not be solved by using the approaches commonly adopted in the prior art. It was therefore concluded that it would not be possible to develop a unitary solvent based macrocyclic lactone/levamisole formulation capable of being shelf stable at the temperature and humidity conditions experienced in some parts of the world.

The current invention is based on a completely novel formulation & packaging approach in which the two actives are stored under separate formulation conditions and in such a form that they are designed to be readily mixed immediately prior to use and before the user can gain access to either formulation in its unmixed condition. The invention meets the following criteria:

• the two anthelmintics are each dissolved in their own easy to manufacture formulations;

• the two formulations are stored separately prior to use so as to maximize their shelf-lives and prevent degradation of the active ingredients contained within them

• the anthelmintics in their pre-mixed condition remain stable for a prolonged period of time;

• the concentration of each active ingredient in the separated state is such that once mixed with the second solution it will be at the generally accepted use concentration;

• the two formulations are easily miscible without the need for vigorous shaking;

• the admixed formulation is non-irritant to the animal;

• the admixed formulation has an acceptable broached shelf life that permits the user to use all the container contents without waste. A shelf life at ambient temperature/humidity of 1-3 months would be required; • the formulations are admixed within the containment system so that the user cannot access them in their unmixed highly concentrated state.

A further benefit of the proposed solution is that it also offers potential shelf-life enhancement for other macrocyclic lactone combination formulations.

PREFERRED FORMULATION EMBODIMENTS

The two formulations used in the preferred device must be stable when stored, easy to mix and non-irritant when used in their admixed condition on animals. They must also not be accessible to the user in their unmixed condition.

Formulation studies were conducted to develop basic preferred formulations that would not only offer a long shelf life for the formulations but would also provide a longer shelf life to each active ingredient when the formulations were mixed.

In a series of injectable formulation studies eprinomectin was used as the representative macrocyclic lactone active, whilst levamisole, in its phosphate form, was used as the representative levamisole anthelmintic. By using eprinomectin a valid comparison could be made with the commercially available Merial Ancare ECLIPSE® E Injection product.

In a series of topical studies abamectin was used as the representative macrocyclic lactone active, whilst levamisole, in its base form, was used as the representative levamisole anthelmintic. By using abamectin a valid comparison could be made with commercially available ready to use abamectin/levamisole blended products (Merial Ancare ECLIPSE® Pour-On and Bayer Bomac SATURN® Pour-On)

Injectable Studies

The shelf life stability of a ready to use, commercially available eprinomectin/levarnisole injection (Merial Ancare ECLIPSE® E Injection) was compared with that of a two part formulation designed to be mixed immediately prior to use. Storage condition was 55°C/75% r.h. for 3 weeks with assay content of eprinomectin and levamisole being reported at the conclusion of the period and compared to initial levels. Test materials were: a) Merial Ancare ECLIPSE® E Injection Eprinomectin component of experimental two part injection:

c) Levamisole Phosphate component of experimental two part injection:

Experimental two part injection in mixed condition:

Table 3 - Stability results:

The results demonstrated that it would be possible to achieve a substantially longer shelf life with a two component injectable than with a ready mixed formulation. In the mixed condition the stress results for the two part injection were comparable to the ECLIPSE E Injection. Such a result indicated that it should be possible to store the two separate components at room temperature until time of mixing. This would represent a considerable advance over the refrigerated shelf storage requirement for the ready mixed ECLIPSE E formulation.

Topical Studies

The shelf life stability of two ready to use, commercially available abamectin/levamisole pour-on formulations (Merial Ancare ECLIPSE® Pour-On & Bayer Bomac SATURN® Pour-On) were compared with that of various two part formulations designed to be mixed immediately prior to use. Storage condition was 55°C/75% r.h. for 3 weeks with assay content of abamectin and levamisole being reported at the end of the period and compared to initial levels. Test materials were: a) Merial Ancare ECLIPSE® Pour-On (1% abamectin & 20% levamisole base) b) Bayer Bomac SATURN® Pour-On (1 % abamectin & 20% levamisole base) c) Potential abamectin formulation components of two part pour-on. The formulations tested were either 2.5% or 5% abamectin + 0.1% BHT dissolved in:

• Benzyl alcohol

• Diethylene glycol monobutyl ether

• Dimethyl isosorbide

• Dimethyl sulphoxide

• Glycerol formal

• N-methyl pyrrolidone

• Propylene Glycol

Potential levamisole formulation component of two part pour-on. The formulations were 25% levamisole + 0.1% BHT dissolved in:

Benzyl alcohol

Diethylene glycol monobutyl ether Dimethyl isosorbide Dimethyl sulphoxide Glycerol formal

N-methyl pyrrolidone

Propylene Glycol

Table 4 - Study Results

25% Levamisole in Propylene Glycol

When stored separately from the levamisole component it was clear that the abamectin component was substantially more stable than it was when dissolved together as in the ECLIPSE formulation.

Upon the conclusion of this test phase further tests were conducted to determine the broached shelf-life acceptability of these various two-part formulations when they were admixed as they would be prior to use: The chosen combinations were tested for 3 weeks at 55°C/75% r.h. with assay content of abamectin and levamisole being reported at the end of the period and compared to initial levels.

Table 5 - Test formulations were:

Table 6 - Results were:

The results demonstrated that it would be possible to achieve a substantially longer shelf life with a two component topical formulation than with a ready mixed formulation. In the mixed condition some of the stress results for the two part topical formulation were comparable to the ECLIPSE Pour-On formulation. Such a result indicated that it should be possible to store the two separate components at 30°C until time of mixing. After mixing a shelf life equivalent to the entire shelf life of the ECLIPSE Pour-On test formulation might be possible. This would represent a considerable advance over the relatively short 25° shelf storage requirement for the ready mixed ECLIPSE Pour-On formulation.

The results of both sets of studies clearly demonstrated that the shelf-life stability of a macrocyclic lactone/levamisole product could be enhanced by separating the two components and then mixing immediately prior to use. Stability of the macrocyclic lactone component in particular was considerably enhanced when compared to the stability of this active in ready- mixed solutions. Stability of the two actives when the two components were mixed would also be of sufficient duration to give an acceptable broached shelf-life. Solvent Selection

A variety of solvents were tested to determine those that were capable of achieving good storage stability of macrocyclic lactone and levamisole active ingredients when stored separately at the desired concentrations. It is clear that many solvents could be used within the framework of the invention to give shelf stable injectable, oral and topical anthelmintic combination formulations. These solvents may be found, for example, in Remington Pharmaceutical Sciences, 16^th Edition (1986).

Of particular usefulness are solvents selected from Aliphatic lactones, Diethyl carbonate, Diethyl phthalate, Diethyl sebacate, Dimethyl acetamide, Dimethyl phthalate, Dimethyl isosorbide, Dimethyl sulphoxide, Glycerol formal, C1-C20 alcohols or esters thereof, fatty acid esters or alcohols, Carboxylic acid esters, Glycerol & derivatives & esters, Glycol ethers & Glycol esters, Glycerine carbonate and Alkylene carbonates, Propylene glycol & derivatives (including esters, diesters and fatty acids), Polyethylene glycols & derivatives (including esters, diesters and fatty acids), Ketones, Vegetable oil and derivatives, Mineral Oils, Silicone oils, Aliphatic and Aromatic hydrocarbons, Pyrollidone based solvents, and Water.

More specifically the solvents of most use are aromatic hydrocarbons, glycol ethers and glycol esters, dimethyl acetamide, dimethyl isosorbide, dimethyl phthalate, diethyl phthalate, dimethyl sulfoxide, N-methyl pyrrolidone, 2-pyrrolidone, glyceryl triacetate, glycerol, glycerol formal, gamma hexalactone, glycofurol, isopropyl alcohol, isopropyl myristate, polyethylene glycol, propylene glycol, benzyl alcohol, propylene glycol dicaprylate/dicaprate and water.

Of most usefulness are glycerol formal, dimethyl isosorbide, dimethyl acetamide, benzyl alcohol, diethylene glycol monobutyl ether, and propylene glycol dicaprylate/dicaprate and water.

These solvents would be capable of providing long-term stability of a macrocyclic lactone or levamisole active ingredient when each active ingredient were stored independently rather than together in the same formulation.

In one embodiment the formulation of the invention includes two formulations each independently dissolved and stored in their own solvent system. The pharmaceutically or veterinarily acceptable carrier for each active ingredient is a solvent commonly used in the formulation art.

Accordingly a first aspect of the invention comprises an anthelmintic delivery system consisting of a multi-chambered container and two formulations, each independently dissolved and stored in their own solvent system; the two formulations presented as follows:

(a) A first part consisting of a macrocyclic lactone active ingredient dissolved in a solvent system and stored in a first chamber of the multi-chambered container; the solvent consisting of one or more solvents selected from Aliphatic lactones, Diethyl carbonate, Diethyl phthalate, Diethyl sebacate, Dimethyl acetamide, Dimethyl phthalate, Dimethyl isosorbide, Dimethyl sulphoxide, Glycerol formal, C1-C20 alcohols or esters thereof, fatty acid esters or alcohols, Carboxylic acid esters, Glycerol & derivatives & esters, Glycol ethers & Glycol esters, Glycerine carbonate and Alkylene carbonates, Lactone solvents, Propylene glycol & derivatives (including esters, diesters and fatty acids), Polyethylene glycols & derivatives (including esters, diesters and fatty acids), Ketones, Vegetable oil and derivatives, Mineral Oils, Silicone oils, Aliphatic and Aromatic hydrocarbons, Pyrollidone based solvents and Water.

(b) A second part consisting of a levamisole active ingredient dissolved in a solvent system and stored in a second chamber of the same container; the solvent consisting of one or more solvents selected from Aliphatic lactones, Diethyl carbonate, Diethyl phthalate, Diethyl sebacate, Dimethyl acetamide, Dimethyl phthalate, Dimethyl isosorbide, Dimethyl sulphoxide, Glycerol formal, C1-C20 alcohols or esters thereof, fatty acid esters or alcohols, Carboxylic acid esters, Glycerol & derivatives & esters, Glycol ethers & Glycol esters, Glycerine carbonate and Alkylene carbonates, Lactone solvents, Propylene glycol & derivatives (including esters, diesters and fatty acids), Polyethylene glycols & derivatives (including esters, diesters and fatty acids), Ketones, Vegetable oil and derivatives, Mineral Oils, Silicone oils, Aliphatic and Aromatic hydrocarbons, Pyrollidone based solvents and Water.

A mechanism in which the contents of the two chambers are able to be mixed togethi before the user gains physical access to either solution in its unmixed condition. One or both parts may contain additional materials such as further anthelmintic/s and other therapeutic agents, viscosity modifying agents, surfactants, stabilisers and the like.

The use of the two part formulation results in an anthelmintic delivery system in which the anthelmintics are highly shelf stable when stored and are easily mixed.

It was also noted during the development of the invention that when prepared as a topical formulation and applied to the back of the animal, solvent based levamisole containing topical formulations have a significant tendency to run-off due to their low viscosity.

Accordingly when prepared as a topical delivery system the preferred formulation includes a viscosity modifying material in either one or both parts.

The following examples also provide evidence that the invention also has scope for use with a range of macrocyclic lactone active ingredients.

EXAMPLE FORMULATIONS

In the preferred embodiment the formulations of the invention include;

Component A - a macrocyclic lactone active ingredient dissolved in a first solvent system comprising predominantly a solvent or solvents suited to the long-term shelf stability of the macrocyclic lactone active ingredient. This is the smaller volume in the first chamber of the pack.

Component B - a levamisole active ingredient dissolved in a second solvent system comprising predominantly a solvent or solvents suited to the long-term shelf stability of the levamisole active ingredient. This is the larger volume in the second chamber of the pack. In practice the second chamber is large enough to accept the volume of both component A and component B so that component A can drop into the chamber containing component B and mix together before the combined formulation is expelled from the container.

In the formulation development studies a variety of macrocyclic lactone active ingredients were used while levamisole, in its base or phosphate form, was used as the representative levamisole anthelmintic. The administration rates for administration of these formulations are generally in the order of 1 ml per 5kg to 1 ml per 50 kg; preferably 1ml per 10kg to 1ml per 30kg, and when in a topical formulation most preferably 1ml per 10kg to 1ml per 20kg, and when in an injectable formulation most preferably lmL per 15kg to lmL per 40kg.

EXAMPLE TOPICAL FORMULATIONS Configuration 1 :

Upon mixing the formulation resulting from the mixing of these two parts would contain 10% levamisole and 0.5% abamectin, to be administered at a dose rate of lmL per 10kg.

Configuration 2:

Constituents of Part B % /v

Levamisole 25%

BHT 0.1%

Diethylene glycol monobutyl ether q.v.

Upon mixing the formulation resulting from the mixing of these two parts would contain 20% levamisole and 1% ivermectin, to be administered at a dose rate of ImL per 20kg.

Configuration 3:

Upon mixing the formulation resulting from the mixing of these two parts would contain 10% levamisole and 0.5% eprinomectin, to be administered at a dose rate of ImL per 10kg.

Configuration 4:

Constituents of Part B %w/v

Levamisole 12.5%

BHT 0.1%

Diethylene glycol mono butyl ether q.v.

Upon mixing the formulation resulting from the mixing of these two parts would contain 10% levamisole and 0.5% moxidectin, to be administered at a dose rate of ImL per 10kg.

Configuration 5:

Upon mixing the formulation resulting from the mixing of these two parts would contain 10% levamisole and 0.5% eprinomectin, to be administered at a dose rate of ImL per 10kg. Configuration 6:

Upon mixing the formulation resulting from the mixing of these two parts would contain 10% levamisole and 0.5% ivermectin, to be administered at a dose rate of ImL per 10kg.

Configuration 7:

Upon mixing the formulation resulting from the mixing of these two parts would contain 20% levamisole and 1% moxidectin, to be administered at a dose rate of ImL per 20kg. Configuration 8:

Upon mixing the formulation resulting from the mixing of these two parts would contain 10% levamisole, 0.5% doramectin and 20% triclabendazole, to be administered at a dose rate of lmL per 10kg.

Configuration 10:

Upon mixing the formulation resulting from the mixing of these two parts would contain 10% levamisole, 0.5% eprinomectin and 20% triclabendazole, to be administered at a dose rate of lmL per 10kg.

It is generally accepted in most regulatory jurisdictions that the broached shelf life of anthelmintic packs should not exceed 30-60 days. The performance of the preferred formulations is such that these criteria could easily be achieved. More importantly the unopened pack shelf life would be considerably lengthened when compared to currently available products.

Particularly preferred topical formulations are those in which the macrocyclic lactone component is dissolved in glycerol formal or glycol ethers and the levamisole component is dissolved in glycol ether based solvents such as DGBE. Also preferred are formulations in which one or both formulations include a viscosity modifying agent designed to prevent runoff of the formulation from the back of the animal. Further experiments were conducted to determine that the preferred formulations would also have application across a range of macrocyclic lactone forms and that there would be no rapid crystallisation when subjected to refrigeration:

Table 7 - Observation: Batches with Ivermectin

Table 8 - Observation: Batches with Moxidectin

Table 9 - Observation: Batches with Eprinomectin

Table 10 - Method of Preparation of the Preferred Formulation:

Example Injectable Formulations

Injectable formulations of the invention are contemplated. In the preferred formulation Part I contains 3.5% of the macrocyclic lactone component, and part II contains 27.9% levamisole phosphate. Immediately prior to use part I is mixed with part II to make up an injectable formulation comprising 0.7% of the macrocyclic lactone component and 22.3 % of the levamisole component. The two formulations are easily mixed. Of particular note with the injectable formulation prepared in two parts is that one or both parts may contain a surfactant to enable easier mixing of the two parts.

Table 11 - Observation: Batches with Ivermectin

Table 12 - Observation: Batches with Moxidectin

Table 13 - Observation: Batches with Eprinomectin

Assembly of the Preferred Device Configuration

The two formulations can be packed in the preferred delivery system comprising a two chambered device.

The steps involved in packing a delivery system with topical and oral non-sterile formulations in this system are:

Step 1 : Fill the first chamber with the levamisole solution

Step 4: Seal the first chamber with an aluminium induction seal or other sealing means and then affix the upper chamber to the lower chamber which may at this point contain a seal broaching rod.

Step 5: Insert the seal broaching rod in the upper chamber if not already present: Step 6: Fill the upper chamber with the macrocyclic lactone solution Step 7: Cap the upper chamber with the transit cap device

Alternatively both chambers can be filled and then sealed before the two chambers are joined together into their final pre-use configuration.

A second alternative is that the two chambers can be sold as a package and the end user joins the two chambers together immediately prior to use.

In a particularly preferred embodiment of the delivery system designed for topical use in large herds the lower chamber is of 5000mL in volume while the upper chamber is lOOOmL. The lower chamber is filled with 4000mL of levamisole solution containing 500g levamisole base (12.5%). The upper chamber is filled with lOOOmL of ivermectin solution containing 25g ivermectin (2.5%). Thus the fill ratio is 1 :4 of ML to levamisole liquid volumes. In other words the ML formulation is ¼ of the volume of the levamisole formulation.

Upon broaching the barrier between the two chambers the lOOOmL of ivermectin solution contained in the top chamber would be free to flow down into the lOOOmL empty space within the lower chamber. Upon mixing the 5000mL of mixed solution would contain 500g levamisole base (10%) and 25g ivermectin (0.5%). This could then be administered to the animal being treated at a dose rate of lmL per 10kg. Such a dose rate would mean the animal received 200mcg/kg ivermectin and lOmg/kg levamisole base.

The steps involved in packing a sterile delivery system with a sterile formulation in this system are:

Step 1 : Fill the lower chamber with the levamisole solution

Step 4: Seal the lower chamber with a rubber stopper.

Step 5: Fill the upper chamber with the macrocyclic lactone solution

Step 6: Insert the seal broaching spike into the neck of the upper chamber

Step 7: Cap the upper chamber with the rubber stopper

In a particularly preferred embodiment of the injection pack the lower chamber is of 500mL in volume while the upper chamber is 1 OOmL. The lower chamber is filled with 400mL of levamisole solution containing 111.6g levamisole phosphate (27.9%). The upper chamber is filled with lOOmL of ivermectin solution containing 3.5g ivermectin (3.5%).

Upon broaching of the barrier between the two chambers the lOOmL of ivermectin solution contained in the top chamber would be free to flow down into the lOOmL empty space within the lower chamber. Upon mixing the 500mL of mixed solution would contain 1 1 1.6g levamisole phosphate (22.3%) and 3.5g ivermectin (0.7%). This could then be administered to the animal being treated at a dose rate of lmL per 35kg. Such a dose rate would mean the animal received 200mcg/kg ivermectin and 6.4mg/kg levamisole phosphate.

Advantages of the preferred binary formulation embodiments:

(a) Stability on shelf is far better than would be achieved if the actives were mixed and stored in a ready to use condition.

(b) The method of manufacture is simple with no complicated formulation processes.

(c) The formulations are of low cost. (d) The formulations are easily admixed and require no special admixing conditions.

(e) Users do not require special solvents, water or other materials to prepare the formulation.

INDUSTRIAL APPLICABILITY

Each of the formulations is monophasic and can be manufactured on a commercial scale.

ALTERNATIVE DESCRIPTION OF THE PREFERRED TYPE OF CONTAINER

This part of the description is concerned with the new form of delivery system in which two separate materials can be stored and then mixed immediately prior to use. It has application to the two different actives described above but can also be used with other veterinary actives or formautions.

The invention fulfills a number of design criteria: the two materials may be stored separately prior to use and if each is a liquid they can be formulated in unique solvent systems that maximize their shelf-lives.

The delivery system in which the two materials are stored is robust and only permits the materials to be mixed immediately prior to use.

The delivery system is not bulky with all openings and shapes similar to what the user would currently encounter when using a standard veterinary delivery system.

The materials in their pre-mixed condition are able to remain stable and within their expiry specification for the duration of the proposed shelf-life. PREFERRED DEVICE EMBODIMENT

A variety of devices were proposed during development - it became apparent in testing that while some devices were capable of holding fluids in a separated condition they failed on issues of usability and robustness. The preferred device configurations have the advantages that they can be readily manufactured and many parts are interchangeable between pack sizes.

The preferred device embodiments are also advantageous in that the overall device size is similar to existing one chamber packs. At no time is the smaller substance containing chamber enclosed within the neck or body portion of the second substance containing chamber at any time; - this means the overall device dimensions are smaller and all orifices in the chambers are of a similar size to standard packs.

Container 1

Figures 1 and 2 shows a first embodiment of the container of this invention comprising a two chambered bottle 10 having a first upper chamber 11 and a somewhat larger lower chamber 12 suitable for the delivery of a veterinary topical or oral mixture. The two chambers are separated by an intermediate portion 15 (discussed below) and each chamber is capable of being filled, and sealed before being assembled into the finished bottle.

Each chamber preferably has a barrier portion so that after it is filled with the required material, it can be sealed during manufacture, and then the two chambers can be abutted together through the medium of the intermediate member 15.

In most cases it is preferable that the intermediate member 15 shown in more detail in Figures 7 and 8, has a pair of sockets, and an internal thread, enabling each of the chambers 11 and 12 to be secured to the intermediate member 15 by engaging the appropriate threads, and screwing them into place. Of course other connection means can be used, such as bayonet fittings, snap locks and the like but in these examples we have made use of a common intermediate member 15, for the different size containers, and have standardized on a common thread to enable different types of chambers to be screwed together.

Looking at Figures 2 and 3, the upper chamber 11 has an aperture for reception of a suitable cap 20, and the cap has contained within it a hollow barrier broaching rod 21. The neck of the bottle and the cap are configured so that the barrier broaching rod is fully retracted (i.e. above the foil barriers) when the cap is screwed tight as in figure 3, but the barrier broaching rod is moved downwardly as the cap is unscrewed in the counter clockwise direction as in figures 1 and 2. As best seen in figure 3 the neck of the bottle has a thread on its inside to engage a threaded portion of the hollow barrier broaching rod. This thread is in the opposite sense to the thread on the outside of the neck which engages with the cap. To mix the two components the cap is grasped with one hand and rotated counter clockwise. Due to the direction of the thread on the outside of the neck of the bottle the cap is forced to move in an upwards direction as it is rotated. There is also a protrusion (or series of protrusions) under the cap. These protrusions loosely interact with corresponding guides on the inner diameter of the hollow barrier broaching rod. As the cap is rotated counter clockwise the interacting protrusions cause the hollow barrier broaching rod to also turn in the same counter clockwise manner. However due to the cut of the thread on the inside of the neck of the bottle the hollow barrier broaching rod is forced to move in a downward direction thereby resulting in the broaching of the barrier between the two chambers whilst the cap is still in place (this depends on the relative length of thread so that the foil barriers are broached before the cap is able to be removed), allowing mixing of the two materials inside the container.

In an alternative configuration the broaching rod could be fixed in a position to directly interact with the barrier between the chambers during storage. When the transit cap is being removed in an upward direction the broaching rod could also be set to move in an upward direction thereby causing the barrier to either be displaced or broached.

Mixing is best achieved by allowing a larger lower chamber than is required for the initial contents of the lower chamber - so that it contains the material (powder or liquid) and an empty space of volume greater than the contents of the upper chamber. In practice this means the empty space will be of a volume equal to or greater than the volume of the upper chamber. This allows all of the liquid from the upper chamber to drop into the lower chamber to allow complete mixing of the two materials inside the lower chamber before the cap is fully removed.

The actual size of each chamber and the fill volumes of each chamber can be varied to suit different combinations of materials. The following measures are given by way of example only to help explain the operation of the invention. For example the fill volumes & mixing ratios for all three container sizes are suited to 1 :4 liquid mixing ratios as follows:

Small size

1L bottom (800mL fill) & 200mL top bottle with 200mL fill Medium Size

2.5L bottom container (2L fill) & 500mL top bottle with 500mL fill Large Size

5L bottom container (with 4L fill) & 1L top bottle with 1L fill

All of the examples presented are designed to conform to these 1 to 4 mixing ratios but of course the container volumes and fill sizes can be varied for different applications. This 1 : 4 mixing ratio is particularly suited to the liquid formulations described below.

Preferably the barrier broaching rod is moulded of a plastics material with the lower end ending in a sharp point. This can be achieved by suitably moulding the hollow barrier broaching rod, to a knife point. In essence the lower most edge of the barrier broaching rod is sloping rather than flat.

Alternatively the lower most edge of the barrier broaching rod could be provided by a metallic cutter, or a cutter made from glass, or some other hard material. Nevertheless the moulded plastics hollow barrier broaching rod is preferred, as we have found that this can be moulded to a sufficiently sharp point that it will puncture the foil barriers, when depressed.

In the first embodiment of the container shown in Figure 2, the hollow barrier broaching rod can have two rods 34 and 35 of different lengths and locations so that the barriers can be puncture in at least two different locations. This results in a passageway 32 being tapered towards its bottom edge and with the body 33 of the rod 35 off to one side of the passageway.

This type of double chambered container is especially suited for the preparation of different formulations that can each be stored in individually sealed chambers but then mixed immediately prior to the time of use. When delivery is required the depression of the barrier broaching rod 21 causes the barrier between the two chambers to be broken, thereby allowing the components to be mixed together, and dispensing can occur by removing the upper cap 20, and either pouring or pumping the mixed liquids out of the container. Selection of appropriate solvents for the two non-mixed materials would result in the two materials readily admixing.

Preferably the barrier broaching rod can be depressed by unscrewing the cap 20 away from the top of the upper chamber, so that as the outer cap 20 moves from the position shown in Figure 3 to the position shown in Figure 2 (noting that Figure 3 has a slightly smaller second chamber than that of Figure 2) the barrier broaching rod will be forced downwardly to puncture the barrier as described above.

Container 2

Figure 3 shows a related embodiment, in which the upper chamber 11 and the lower chamber 12A are of comparable size. There are many examples where the two different materials will need to be mixed in a one to one ratio prior to application.

The chambers 11 and 12A are connected together by the intermediate portion 15 in a similar fashion to that shown in Figures 1 and 2. In this case the cross sectional view of the container of Figure 3 shows the hollow barrier broaching rod in its retracted position above the two foil barriers (shown in more detail in expanded view of Figure 6).

Figures 4 and 5 show exploded views of the upper portion of the container of Figure 3, showing that the barrier broaching rod 21 is an elongate hollow tube, with a tapered point 30 at the lower end, which his adapted to puncture the foil barriers.

This barrier broaching rod 21 is capable of moving downwardly within the upper chamber, when the cap 20 is suitable rotated.

Figure 6 shows the foil barriers 24 and 26 which are preferably induction barriers, being applied to the relevant openings in the chambers 1 1 and 12 or 12 A, during filling and prior to assembly. In addition, an appropriate sealing washer 27 or 28 is positioned between the foil barriers, and the intermediate portion 15 to prevent any leakage or exposure of the contents to atmosphere. These barriers are shown in Figures 10 and 11 as well as in Figure 6.

Figure 9 shows the different views of the components of the upper chamber and barrier broaching rod as noted above. Container 3

Figures 12 and 13 show a larger lower chamber 12B having the appropriate threaded portion 30 for engagement with a thread of the intermediate portion 15. Such a larger lower chamber 12B has an aperture 32 in the top thereof, of the same dimensions as the apertures used on the previous chambers, so that a standard size barrier can be used, and a standard size intermediate member can be used regardless of the size of the upper or lower chamber.

Figure 14 shows this larger lower chamber 12B in exploded side view with the upper components comparable to the upper components of containers 1 or 2. Similarly Figure 15 is an exploded perspective view of the container 3, showing a small upper chamber and a larger lower chamber 12B. This means it is possible to mix and match the size of the upper and lower chambers depending upon the ration of the liquids to be mixed.

Figures 16 through 27 shows how the container of this invention can be adapted to large or small pack sizes, particularly flat packs suitable for use in the dispensing of larger volumes of veterinary products.

By using the common intermediate member 15 (described below), and using a shroud 40 around that intermediate member, it is possible to conceal the interconnection between the two chambers and provide a smooth exterior as shown in Figure 27, whilst providing a smaller upper chamber 11 A and a much larger lower chamber 12C

Intermediate member: Intermediate member 15 is shown throughout the drawings, and is essentially a collar best shown in Figure 8, having a narrowed waist surrounded by larger diameter sockets 51 and 52 each of which has a thread 53 on the inner surface of the respective sockets. The sockets are spaced apart by radial fins 54 as shown throughout the drawings. Some of the views the container has been rotated, so more or less of the radial fins are shown as for example in Figure 8.

In each socket, there are a plurality of indentations 58 surrounding the aperture 59 connecting the upper and lower sockets. As can be seen from Figure 3, each of the chambers 11 and 12 A have external threads capable of engaging with the internal threads 53 of the socket. Each of the chambers 11 and 12A are suitably shaped, so that their barriered apertures, fit within the narrow portion 50, and the barriers engage as shown in Figure 6. Note that the lower chamber 12A has only one aperture which is covered by the foil barrier after filling but that the upper chamber 11 has two apertures - the lower one covered by its foil barrier, and the upper one closed by cap 20.

Alternatively the container can have a secondary opening in lower chamber - this opening is simply to facilitate filling. Once the lower chamber was filled it would be permanently sealed.

Container 4

In some cases it may not be necessary to use a sterile filling arrangement - in which case the following non- sterile container can be used.

Assembly of the Optional Non-Sterile Device Configuration

Two active ingredient containing formulations can be simply packed in the preferred delivery system comprising the two chambered device. The steps involved in packing the formulations in this system are:

Step 1 : Fill the lower chamber with a first formulation

Step 4: Seal the lower chamber with an aluminium induction barrier and then affix the upper chamber to the lower chamber.

Step 5: Fill the upper chamber with the second formulation

Step 6: Insert the barrier broaching rod into the neck of the upper chamber

Step 7: Cap the upper chamber with the transit cap

In a particularly preferred embodiment of the container for use in bulk use situations the lower chamber is of 5000mL in volume while the upper chamber is lOOOmL. The lower chamber is filled with 4000mL of a first active ingredient containing solution. The upper chamber is filled with lOOOmL of a second active ingredient containing solution.

Upon broaching the barrier between the two chambers the lOOOmL of solution contained in the top chamber would be free to flow down into the lOOOmL empty space within the lower chamber. Upon mixing the 5000mL of mixed solution would contain a mixture of both solutions. This could then be administered to the animal being treated at the required dose rate. Of course the concentrations of active ingredient in each solution would be set to ensure the appropriate concentrations of each were present in the final mixed solution.

More preferably the invention is used with a sterile filling option.

Assembly of this Preferred Sterile Device Configuration

Packaging of sterile formulations is a significant challenge due to the need to maintain sterility and avoid contamination. This challenge is even more acute when the formulation involves a sterile powder and liquid diluent. Typically such formulation are supplied to users in two vials, so that the user is required to draw up the diluent from one vial then inject it into the powder vial. Once this is done the user shakes the now admixed vial and uses the syringe to draw off the admixture. The invention reduces the time and effort involved in preparing the admixture.

The two chambers are molded, preferably together in one unit; with a first opening in the upper chamber and a second opening in the lower chamber, and a plug or molded but frangible barrier located in a neck space between the two chambers: Step 1 : The chambers are molded as a one-piece molding, optionally with the barrier between the two chamber also located in position;

Step 2: The barrier and barrier broaching rod are manufactured and then placed in position within the device with at least one chamber then being sealed with a stopper and seal before the contents are filled into it. Preferably this is the upper chamber with the barrier broaching rod being located in the upper chamber before the opening is sealed with a rubber stopper and aluminum seal

Step 3: The components are gamma irradiated Step 4: The lower chamber is filled through the lower opening and then sealed with a permanent seal (most preferably composed of a compatible and pharmaceutically acceptable rubber material) and non-removable aluminum overcap.

Step 5: The upper chamber is filled with an acceptable method such as that offered by Aseptic Technologies, CrystafClosed Vial Technology (Registered Trade Mark)

Step 6: The transit cap is screwed into place over the rubber stopper.

Alternatively both chambers can be unsealed until each is filled.

In a particularly preferred embodiment of the container for use in large herd situations the lower chamber is of 500mL in volume while the upper chamber is lOOmL. The lower chamber is filled with 400mL of a first active ingredient containing solution. The upper chamber is filled with lOOmL of a second active ingredient containing solution.

Upon broaching the barrier between the two chambers the lOOmL of solution contained in the top chamber would be free to flow down into the lOOmL empty space within the lower chamber. Upon mixing the 500mL of mixed solution would contain a mixture of both solutions. This could then be administered to the animal being treated at the required dose rate. Of course the concentrations of active ingredient in each solution would be set to ensure the appropriate concentrations of each were present in the final mixed solution.

Advantages of the preferred device embodiment:

(a) The provision of a special container for veterinary products enabling two different liquid formulations to be store separately yet mixed together at the time of administration without exposing either liquid to atmosphere.

(b) The provision of two active ingredients each in their own unique shelf stable formulation but which are capable of being admixed simply and easily immediately prior to administration.

(c) The preferred device configuration is readily manufactured and has the added benefit that many parts are interchangeable between pack sizes.

(d) The filling of the device is simple and able to fit within the framework of existing veterinary manufacturing operations. (e) The preferred device embodiment is also advantageous in that the overall device size is similar to existing one chamber packs. At no time is the smaller substance containing chamber enclosed within the neck or body portion of the larger second substance containing chamber - this means the overall dimensions are smaller and all orifices are of a similar size to standard packs.

(f) The user is not exposed to the materials during the mixing process

INDUSTRIAL APPLICABILITY

The special container can be manufactured by blow moulding or injection moulding from suitable plastics material.

VARIATIONS

Although in most cases it is preferable to have a single barrier broaching rod 21 which punctures both barriers, and allows the liquids to mix in the larger lower chamber which has sufficient empty space to receive all of the upper liquid, it is also possible to allow an empty space in the upper chamber and to invert the container to effect mixing.

In most cases it is preferable that the barrier broaching rod moves downwardly with rotation to thereby cut through the foil barriers creating a greater opening, but in other cases it may be preferable to cause the downward movement without rotation.

In yet other cases it may be preferable that the barrier broaching rod is directly interactive with the barriers during transit and that upon unscrewing of the transit cap the barrier broaching rod moves upwardly with rotation to cause broaching or displacement of the barriers.

In the examples the barrier broaching rod is shown as a hollow tube but it could also be a solid rod. It need not have a sharp edge as it could be a blunt rod capable of displacing the barrier/s. The two formulations may additionally include other active ingredients such as anthelmintics, nutritional materials etc.

It will of course be realised that while the foregoing has been given by way of illustrative example of this invention, all such and other modifications and variations thereto as would be apparent to persons skilled in the art are deemed to fall within the broad scope and ambit of this invention as is hereinbefore described.

Claims

CLAIMS:

1. An anthelmintic delivery system comprising:

(a) a container consisting of at least two chambers;

(b) a first liquid formulation containing at least one macrocyclic lactone stored in a first chamber;

(c) a second liquid formulation containing at least 10% w/v levamisole stored in a second chamber; with the contents of the first chamber being freely miscible with the content of the second chamber;

2. An anthelmintic delivery system as claimed in claim 1 wherein the second chamber is larger than the first chamber and has a void space equivalent to the volume of the first chamber to facilitate mixing.

3. An anthelmintic delivery system as claimed in claim 2 wherein the first formulation comprises the at least one macrocyclic lactone dissolved in a first solvent or solvent system, and the second formulation comprises levamisole dissolved in a second solvent or solvent system and the volume of the first solvent/solvent system in which the macrocylic lactone is dissolved is from 1/10^th to ½ of the volume of the second solvent/solvent system in which levamisole is dissolved.

4. An anthelmintic delivery system as claimed in claim 3, wherein the first solution contains at least one macrocyclic lactone anthelmintic selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin and moxidectin.

5. An anthelmintic delivery system as claimed in claim 4, wherein the macrocyclic lactone anthelmintic is present in the first chamber at a range of between 1 - 20% w/v of the first solvent/solvent system.

6. An anthelmintic delivery system as claimed in claim 5, wherein the levamisole is present is present in the second chamber in the range of between 10 - 50% w/v of the second solvent/solvent system.

7. An anthelmintic delivery system as claimed in any one of claims 1-5 , wherein the ratio of macrocylic lactone active ingredient contained in the first formulation is between 1/15^th and l/25^th of the weight per volume of the levamisole contained in the second container or chamber.

8. An anthelmintic delivery system as claimed in any one of claims 1-6, wherein either the macrocyclic lactone or the levamisole is present in a solution containing one or more solvents selected from Diethyl carbonate, Diethyl phthalate, Diethyl sebacate, Dimethyl acetamide, Dimethyl phthalate, Dimethyl isosorbide, Dimethyl sulphoxide, Glycerol formal, C1-C20 alcohols or esters thereof, fatty acid esters or alcohols, Carboxylic acid esters, Glycerol & derivatives & esters, Glycol ethers & Glycol esters, Glycerine carbonate and Alkylene carbonates, Lactone solvents, Propylene glycol & derivatives (including esters, diesters and fatty acids), Polyethylene glycols & derivatives (including esters, diesters and fatty acids), Ketones, Vegetable oil and derivatives, Mineral Oils, Silicone oils, Aliphatic and Aromatic hydrocarbons, Pyrollidone based solvents, Aliphatic lactones and Water.

9. A formulation delivery system comprising two chambers, a first chamber capable of containing a first liquid or powder formulation and a second chamber capable of containing a second liquid or powder formulation, and wherein:

(b) either the first or second chamber contains a barrier broaching rod designed to cause an interaction between an outer cap and the barrier between the chambers thereby causing the barrier to be broached; and (c) the outer cap and barrier broaching rod are distinct and separate parts of the device, rather than being formed as one single unitary part.

10. A formulation delivery system as claimed in claim 9 wherein the available volume of the first chamber is smaller than the available volume of the second chamber.

1 1. A formulation delivery system as claimed in claim 9 or 10 wherein the first chamber contains a first liquid formulation comprising at least one macrocyclic lactone dissolved in a first solvent or solvent system, and the second chamber contains a second liquid formulation comprising levamisole dissolved in a second solvent or solvent system, and the volume of the first solvent/solvent system in which the macrocylic lactone is dissolved is from 1/10^th to ½ of the volume of the second solvent/solvent system in which levamisole is dissolved.

12. A method of treating a domestic animal using a delivery system as claimed in any one of the preceding claims.

13. A method of manufacturing an anthelmintic delivery system containing levamisole and at least one macrocylic lactone anthelmintic according to the following steps:

(e) The second container or chamber is filled with the second formulation and then sealed with a sealing means; (f) If the first container or chamber and the second container or chamber are still in a separated state the two container or chambers are joined together into a final use configuration either at the manufacturing site, or by the user prior to use.