NZ550279A

NZ550279A - Medicament

Info

Publication number: NZ550279A
Application number: NZ55027906A
Authority: NZ
Inventors: Alawi Fadil Al; Kin-Wai Mok; William Ernest Pomroy; Karthigeyan Nanjan
Original assignee: Bomac Research Ltd
Priority date: 2006-09-29
Filing date: 2006-09-29
Publication date: 2008-01-31
Also published as: ZA200708369B; AU2007221747A1; AU2007221747B2; AU2007221747C1

Abstract

Disclosed is an anthelmintic preparation for oral administration, specifically relating to the treatment of worms in equine species. The medicament comprises at least one compound selected for its activity against strongyles, at least one macrocyclic lactone, praziquantel and if required, at least one thickening agent, wherein the medicament is formulated to within a viscosity range of 100,000 to 800,000 cp at 20oC by the addition of at least one thickening agent. The viscosity range specified ensures that once administered orally the medicament spreads readily into the mouth of the subject.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 550279 PATENTS FORM NO. 5 Fee No. 4: $250.00 PATENTS ACT 1953 COMPLETE SPECIFICATION After Provisional No: 550279 Dated: 29 September 2006 MEDICAMENT WE Bomac Research Limited, a New Zealand company of 102 Wiri Station Road and Hobill Avenue, Manukau City, Auckland, New Zealand, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement: | Office of N.Z. I I 3 )AUG 2007 i l_REC E I V £ !*"* ' James S Wells Ref: 127174/55 V MEDICAMENT TECHNICAL FIELD This invention relates to a medicament. More specifically this invention relates to an anthelmintic preparation. 5 More specifically this invention relates to the oral treatment of worms in equine species, such as horses and other animals. BACKGROUND ART Anthelmintics are widely used in aqueous suspension formulations for the control of parasitic helminths, namely round worms (nematodes), tapeworms (cestodes), 10 or flukes (trematodes). Anthelmintics have been used in a variety of animal species including sheep, cattle, goats, deer, horses, cats, dogs, llama, buffalo and poultry. Benzimidazole anthelmintic compounds are widely used in veterinary medicine. Common forms include oxfendazole, mebendazole, fenbendazole, albendazole 15 and the probenzimidazoles febantel and netobimin, which are metabolised to the active benzimidazole moiety within the animal. In general, benzimidazole compounds are sparingly soluble in aqueous solutions. Pour-on solutions utilizing these compounds for the treatment of parasitic helminths are well known, for example British Patent Specification No. 1527584 20 discloses a pour-on formulation. This is characterised in that the active compound is dissolved, emulsified or suspended in a suitable solvent or solvent mixture which is tolerable to the skin and applied with the aid of a suitable device, for example a measuring cup or spray bottle to the skin of the animal to 2 James & Wells Ref: 127174/55 be treated. The active ingredients disclosed are Tetramisole and Levamisole. The current applicant has previously developed a liquid pour on product making use of benzimidazole anthelmintics such as oxfendazole, thiabendazole, albendazole, cambendazole, fendendazole, flubendazole, mebendazole, 5 oxibendazole, parbendazole, thiophanate, febantel and netobimin. Horses have a high work load and high energy requirements, and regular worming of horses is important. Untreated parasitic infestations can result in a number of health problems, including tail rubbing, colic, loss of condition, poor performance, coughing, anemia, diarrhoea, and in very extreme cases death. 10 Worming horses can be a difficult exercise, despite the large number of worming products currently available and attempts to increase the palatability of products. For the treatment of horses, drenches pour-on products, granular products put into feed, and pastes have been used with varying success. Drenches have traditionally been administered to horses directly into the 15 stomach through a tube that was inserted through the mouth into the proximal oesophagus. This method of administration, which is colloquially known as 'tubing', allows dosing of low strength high volume anthelmintics. This method also has the advantage that it maximizes the chances of the full dose of the drench being delivered to the site of action and/or the site of absorption. The 20 major disadvantage is that this administration method usually has to be carried out by a vet due to the risk of administering the product via the trachea into the lung. This method also requires a reasonable level of co-operation from the horse and therefore administering an anthelmintic in this way can be extremely difficult in factious animals. 3 James & Wells Ref: 127174/55 Pour-on products, granular products put into feed, and pastes also have significant disadvantages. These are discussed in turn below. Pour-on solutions are not a preferred method of administration of worming formulations to horses. Pour-on solutions will often rub off on covers, when the 5 horse rolls, or be consumed by other horses during grooming after administration. The use of pour-on formulations therefore requires isolation of the horse for a period of time after administration to ensure that the dosage has been absorbed. Granules, powders or pellets containing worming formulations can be mixed with 10 a horse's feed. The significant disadvantage with this method is the requirement to ensure that the entire dosage has been eaten. Many horses will carefully separate their feed from the wormer, leaving the drug in the bottom of the feed container. This method also has significant problems if a number of horses are feed in the same area or paddock, as the varying appetite of the horses will 15 result in unpredictable dosage. Alternatively wormers can be in the form of a paste which is administered orally using a syringe. Worming in this way can be difficult. The paste must be administered far enough to the back of the horses mouth/throat to ensure that it is swallowed and not spat out. This usually involves holding the horses tongue in 20 one hand and administering the paste as far back in the mouth as possible. While this approach might be attractive in theory, much of the paste often ends up on the ground or person administering the dosage. This common loss of part (often a significant part) of the dosage decreases the accuracy with which the actual dosage administered can be determined, and also decreases the dose 25 administered. Under dosing can commonly lead to a build up of resistance of a worm species to that particular active compound. This is highly undesirable. It 4 James & Wells Ref: 127174/55 can also be a time consuming and messy process. This method can also lead to injury of the person administering the dosage through unpredictable behavior of un-cooperative animals. A further complicating factor is that some worm species have developed 5 resistance to a number of commonly used worming drugs. The more frequently worms are exposed to the drug, the greater the chance of resistance developing. Treating or preventing worms in horses is not as simple as giving a dose of wormer which results in the host's helminth population being killed. Horses 10 travel to different events and eat from different pastures in the presence of different horses with high frequency and are therefore exposed to a wide variety of parasites including different strains of the same species. Frequent worming is necessary and issues of drug resistant worms are critical. It is therefore an object of the present invention to provide a product which is 15 easily administered to horses or other equine species, and overcomes the above mentioned problems. 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 20 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 are 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 25 country. 5 James & Wells Ref: 127174/55 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. It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice. Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only. DISCLOSURE OF INVENTION According to one aspect of the present invention there is provided a medicament for oral administration to a subject, which includes at least one compound which is selected for its activity against strongyles, at least one macrocyclic lactone (or pharmaceutical equivalents thereof), and praziquantel (or pharmaceutical equivalents thereof), the medicament characterised in that the medicament is within a viscosity range that ensures that once administered orally the medicament spreads readily into the mouth of the subject. In a preferred embodiment the medicament of the present invention may be used to treat parasitic helminths, namely round worms (nematodes), tapeworms 6 James & Wells Ref: 127174/55 (cestodes), or flukes (trematodes), and shall be referred to as such herein. However, this should not be seen as limiting, as the active ingredients, or the combination used herein may also be active against other parasitic species. In this instance, these additional parasitic species should be considered to be 5 covered by the present application. In a preferred embodiment the medicament may include at least three active ingredients. In a preferred embodiment the compound which is selected for its activity against strongyles may be a benzimidazole compound (or a pharmaceutical equivalent 10 thereof). In an alternative embodiment the compound which is selected for its activity against strongyles may be a tetrahydropyrimidine compound (or a pharmaceutical equivalent thereof). However, this should not be seen as limiting as any other compound which is 15 active against strongyles, and which is compatible with the subject species may be utilised with the present invention. Another example of a compound which is active against strongyles is levamisole. Levamisole is toxic to equine species, and therefore would not be utilised when the medicament is prepared for equine use. However, levamisole could be utilised if the medicament was for use in 20 another species, such as cattle, or camel. Therefore, in one preferred embodiment the medicament may include: at least one anthlemintically active benzimidazole compound (or pharmaceutical equivalent thereof), at least one macrocyclic lactone compound (or pharmaceutical equivalent 7 James & Wells Ref: 127174/55 thereof), and praziquantel (or pharmaceutical equivalents thereof). In an alternative embodiment the medicament may include: at least one anthlemintically active tetrahydropyrimidine compound (or 5 pharmaceutical equivalents thereof) at least one macrocyclic lactone compound (or pharmaceutical equivalents thereof), and praziquantel (or pharmaceutical equivalents thereof). One skilled in the art would however realise that the above combinations are not 10 limiting, and that combinations including both a benzimidazole and tetrahydropyimidine compounds may be utilised with the present invention. One skilled in the art would also appreciate that the medicament may also include additional active ingredients in addition to the three anthelminitically active compounds selected from the classes above. 15 It should be appreciated that each of the three classes of active components in the medicament act on different parasitic helminths, for example: • Macrocyclic lactones are active against most parasitic helminth species, except tapeworms and some species of strongyles which have built up resistance to macrocyclic lactones, for example p. equorum. 20 • Praziquantel is active against tapeworms, and Compounds which are selected for their activity against strongyles, such as benzimidazole or tetrahydropyrimidine are active against species of 8 James & Wells Ref: 127174/55 strongyles which have built up resistance to macrocyclic lactones, for example p. equorum. The medicament of the present invention therefore covers and is active against a very wide spectrum of parasitic helminth species. 5 In a preferred embodiment the anthelmintically active benzimidazole compound may be oxfendazole, and shall be referred to as such herein. However, this should not be seen as limiting, as any other suitable benzimidazole such as fenbendazole, mebendazole, oxibendazole, albendazole or any other benzimidazole with anthelmintic activity may be utilised with the present 10 invention. Oxfendazole is particularly preferred when the animal to be treated is an equine. Oxfendazole is the sulfoxide form of fenbendazole, and is a broad spectrum benzimidazole anthelmintic used against roundworms, strongyles and pinworms. It is a white to grey powder; insoluble in water, slightly soluble in acetone, 15 chloroform, ether and methanol. Its chemical designation is [5-(phenylsulfinyl)-1H- benzimidazol-2-yl] carbamic acid methyl ester. In a preferred embodiment the tetrahydropyrimidine compound may be morantel or pyrantel. However, this should not be seen as limiting, as any other suitable tetrahydropyrimidines with anthelmintic activity may be utilised with the present 20 invention It should be appreciated by one skilled in the art that the replacement of a benzimidazole compound (or other active ingredient) with a tetrahydropyrimidine compound would overcome resistance, if this should build up against the benzimidazole compound. 9 James & Wells Ref: 127174/55 In a preferred embodiment the macrocyclic lactone may be a milbemycin. In a preferred embodiment the macrocyclic lactone may be one of the following: ivermectin, abamectin or moxidectin. In a particularly preferred embodiment the macrocyclic lactone may be abamectin, and shall be referred to as such herein. However, this should not be seen as limiting, as any other suitable macrocyclic lactone may be utilised with the present invention. Abamectin is a mixture of avermectins containing > 80% avermectin B1a and < 20% avermectin B1b. These two components, B1a and B1b have very similar biological and toxicological properties. The avermectins are insecticidal or anthelmintic compounds derived from the soil bacterium Streptomyces avermitilis. In an alternative particularly preferred embodiment, the macrocyclic lactone may be moxidectin. Moxidectin is a semisynthetic macrolide antibiotic, being the 23-methyloxime analogue of the milbemycin nemadectin. Praziquantel is an antiparasitic (antihelmintic) medication which is used for the treatment of intestinal tapeworms. The active ingredients should be taken to include pharmaceutical equivalents 20 thereof, which may include salts of, analogues of, or compounds having the same activity. In a preferred embodiment the subject may be a non-human mammal. 10 James & Wells Ref: 127174/55 In one preferred embodiment the subject may be an equine mammal, including horses, ponies, donkeys, mules and asses. However, this should not be seen as limiting as the medicament may also be used for other animals, including, but not limited to camels, cattle, sheep, goats 5 and deer. In the case of a medicament including a benzimidazole, a macrocyclic lactone and praziquantel as the active ingredients, these may be present in the medicament in the following concentrations. In a preferred embodiment the active ingredient benzimidazole (or a pharmaceutical equivalent thereof) may be approximately 0.1 to 50 % w/w of the medicament. In a preferred embodiment the active ingredient benzimidazole (or a pharmaceutical equivalent thereof) may be approximately 18 to 22 % w/w of the medicament. In a preferred embodiment the active ingredient benzimidazole (or a pharmaceutical equivalent thereof) may be approximately 18.9 % w/w of the medicament. In a preferred embodiment the active ingredient macrocyclic lactone (or a pharmaceutical equivalent thereof) may be approximately 0.05 to 5.0 % w/w of the medicament. In a preferred embodiment the active ingredient abamectin (or a pharmaceutical equivalent thereof) may be approximately 0.36 to 0.46 % w/w of the medicament. In a preferred embodiment the active ingredient abamectin (or a pharmaceutical equivalent thereof) may be approximately 0.42 % w/w of the medicament. 15 20 11 James & Wells Ref: 127174/55 In an alternative preferred embodiment the active ingredient moxidectin (or a pharmaceutical equivalent thereof) may be approximately 0.72 to 0.92 % w/w of the medicament. In a preferred embodiment the active ingredient moxidextin (or a pharmaceutical equivalent thereof) may be approximately 0.8 % w/w of the medicament. In a preferred embodiment the active ingredient praziquantel may make up approximately 1 to 20 % w/w of the medicament. In a preferred embodiment the active ingredient praziquantel (or a pharmaceutical equivalent thereof) may be approximately 4.5 to 5.5 % w/w of the medicament. In a preferred embodiment the active ingredient praziquantel (or a pharmaceutical equivalent thereof) may be approximately 5.1 % w/w of the medicament. It should be noted, that the ratio of the three active ingredients in the medicament may alter depending on the target animal species for treatment. This ratio may take into account the most common parasitic species in the target animal species, the resistance of those species, and the route of metabolism of each of the active ingredients in the target animal species. One skilled in the art would realize, and readily be able to determine the desired concentrations of active ingredients when these differ from above. In a preferred embodiment the medicament may also include at least one preservative. In a preferred embodiment the medicament may also include at least one thickener. 12 James & Wells Ref: 127174/55 In a preferred embodiment the medicament may also include at least one dispersing and/or suspending agent. The following are given by way of example only, and one skilled in the art would be aware that other agents with the same or similar properties may be utilized in the present invention. In a preferred embodiment the medicament may also include the following agents. The following approximate concentrations are given by way of example only: Agent Purpose Amount (%w/w) Diethylene Glycol Stearate Helps in dispersion 8.0 Cellogen 7A Thickener 1.5 Benzyl Alcohol Technical Solubilizing agent 2.0 Plasdone K 25 Helps in dispersion 2.0 Tween 80 Wetting agent 1.5 Sodium Metabisulphite Antioxidant 0.1 Sorbitol 70 % Bulking agent 5.0 Propyl paraben Preservative 0.005 Methyl paraben Preservative 0.05 Wacker silica Thickener 1.0 Deionised water Solvent/bulking agent 52.425 In a preferred embodiment the medicament may also include at least one flavoring agent to increase the palatability of the medicament. In a preferred embodiment the flavoring may be apple flavor. This is especially palatable for equines. However, this should not be seen as limiting, as a number of flavorings may be utilized with the present invention, depending on the target 13 James & Wells Ref: 127174/55 animal species for treatment, for example, peach or other fruit flavoring. In a preferred embodiment the apple flavoring may be present at an approximate concentration of 2% w/w. In a preferred embodiment the medicament may be administered orally, this may be via a syringe as in preferred embodiments the present invention is administered as a single dosage. Tubing on the other hand, is more suitable for presentation of multiple doses. In a preferred embodiment the medicament may be within the viscosity range of any of the following: • Viscosity at 20 °C (Helipath spindle T-F at 0.6 rpm) - within the range of 100,000 to 800,000 cp • Viscosity at 20 °C (Helipath spindle T-F at 6 rpm) - within the range of 20,000 to 150,000 cp • Thixotropic Index (Helipath spindle T-F, 0.6rpm/6 rpm) - within the range of 1.0 to 8.0. In a preferred embodiment the pH of the medicament may be within the range of 5.5 to 6.5 at 20°C for a 10% aqueous solution. This is suitable to ensure the stability of abamectin, moxidectin, or other macrocyclic lactone. This viscosity range provides the following characteristics and advantages to the medicament of the present invention: • The viscosity is sufficiently creamy to adhere to the inner surface of the subject's mouth or checks, including the buccal membrane. 14 James & Wells Ref: 127174/55 This allows quick and easy absorption of the medicament both through the buccal membrane and through the gut when the medicament is swallowed. The spreading of the medicament in the mouth of the animal leads in part to a coating of the medicament over the buccal mucosa and may lead to some absorption through same. This is one manner in which the medicament of the present invention may be absorbed into the animal. However, this should not be seen as limiting, as a significant amount, or most of the medicament may, or is likely to be swallowed by the animal, as the medicament is washed off the buccal membrane into the saliva, or as the medicament is administered. The viscosity is low enough that the animal cannot gather the medicament in its tongue and spit it out. In contrast, this is possible with paste like formulations. One of the main advantages of the formulation having the stated degree of viscosity is that it allows the medicament to disperse in the buccal cavity in such a way that the animal cannot spit it out. The medicament spreads easily and reliably throughout the mouth of the subject. It does not clump together, like more viscous pastes, which are commonly used. This is a distinct advantage of the medicament of the present invention. It is anticipated by the applicants that while some absorption through the buccal membrane may occur, the majority of the active administered is absorbed or performs its action within the gastrointestinal tract. The temporary coating of the buccal membrane has the advantageous effect 15 James & Wells Ref: 127174/55 of facilitating the flushing of the medicament into the saliva where it will then be swallowed by the subject. The clumping tendency of more viscous pastes allows the subject to easily spit the accumulated paste out. This is both a waste of the medicament, and decreases the accuracy with which the dosage can be applied. The viscosity is high enough that the medicament is not too fluid, an overly fluid medicament is likely to naturally collect within areas of the animal's mouth, which will result in it being easily spat out. Similarly, if the medicament is too fluid, it may dribble out of the animal's mouth of its own accord; again this may lead to wastage of the medicament and a decrease in the accuracy with which a dosage of the medicament may be administered. Further, if the medicament is too fluid there may be leaks of the medicament from the syringe prior to or during administration. Often, the user may have a struggle to administer the medicament to an animal which is not co-operating, if the medicament is too fluid, it can easily be lost during this process by accidental triggering of the syringe by the user. Further, if the medicament is too fluid, there is a danger of separation of the active ingredients from the liquid carrier. It will be appreciated by those skilled in the art that suitable physiologically acceptable thickeners or thinners may be required to obtain the desired viscosity. These may be any known compounds which are suitable for administration to the subject, and which will preferably not affect the active ingredients of the medicament. 16 James & Wells Ref: 127174/55 In summary: • The medicament is easy to handle and produce. • The medicament spreads readily into the mouth as defined above. • The combination of at least three different active components decreases the risk of the relevant parasitic species becoming resistant to a particular active ingredient. • The combination of at least three different active components also ensures that any parasitic species which have become resistant to one active ingredient may be removed or killed with one of the other active components, thus ensuring more complete and efficient treatment. In a preferred embodiment the medicament may be administered at a dosage rate suitable for the particular animal species being treated. The dosage rate may vary considerably between species. In one preferred embodiment, for equine use, the medicament may be administered at a dosage rate of 1 g per 20 kg body weight. According to another aspect of the present invention there is provided a method for the treatment of a subject for parasitic helminths, characterised by the step of administering to a subject a sufficient dosage of a medicament substantially as previously described. According to another aspect of the present invention there is provided the use of a medicament substantially as herein described for the treatment of an animal. 17 James & Wells Ref: 127174/55 According to another aspect of the present invention there is provided a method for manufacturing a medicament, including the steps of: a) mixing the active ingredients, and b) adding sufficient additional ingredients in the proportion and type to ensure that the medicament has a viscosity within the range specified herein. In one preferred embodiment the medicament may be manufactured via the following method: 1. Dissolve sodium metabisulphate in deionised water, and then mix in cellogen 7A, Tween 80 and Sorbitol 70% with stirring. Suspend praziquantel and oxfendazole and mix well. 2. In a separate manufacturing vessel, dissolve methyl parabens, propyl parabens and abamectin in benzyl alcohol. Add to the main bulk (1) and mix well. 3. Add the apple flavor to the main bulk and mix well. 4. Add wacker silica and then mix plasdone K 25 to the main bulk and mix well. 5. Heat diethylene glycol stearate at 50-60°C, and then add it to the main bulk and mix well. Homogenise for 20-30 minutes until a smooth and homogenous paste is obtained. One skilled in the art would realise that this method may vary depending on the preservative, thickening, dispersing and suspending agents utilised. 18 James & Wells Ref: 127174/55 BEST MODES FOR CARRYING OUT THE INVENTION The following experimentation is given by way of example only: Objective: To develop a medicament which has a viscosity or texture which allows the 5 medicament to coat the horses (or other animal's) mouth after administration, and prevent the animal from spitting out the medicament. Coating of the animal's mouth prevents clumping of the medicament and minimizing the ability of the animal to spit out the product. The objective was that the medicament was an oral broad spectrum wormer and 10 boticide paste for horses containing three bioactives: Abamectin, Praziquantel and Oxfendazole (or pharmaceutical equivalents thereof) for the treatment and control of tapeworms, roundworms and bots. Background of product development: Two medicaments were trialed, (herein referred to product 1 and product 2 15 respectively). Conclusions: The medicament of the present invention is product 1. The creaminess, texture (viscosity) and pH of this formulation gave it preference to product 2. 20 Results of the physical and chemical assays of 5 weeks accelerated stability trial indicated that this product was stable over the studied period. 19 James & Wells Ref: 127174/55 10 15 Further stability trials over 18 months on samples of this formulation confirmed stability over 18 months. Product 1 has a viscosity within the desired range, whereas product 2 was a thick paste, this is undesirable as it facilitates the animal spitting out the formulation. Product 1 also has the following advantages over product 2: • It does not form a clump or form a hard ribbon when delivered, • It spreads easily within the mouth of the animal, and • It does not facilitate the animal spitting the medicament out, These characteristics are shown in Table 1, this table also includes the same characteristics for some common creams and pastes such as ketchup, mayonnaise. Table 1: Characteristics of some common creams/pastes and comparison with product 1 and 2. Parameters Ketchup Mayonnaise Bomazeal Skin & Coat Oral Paste Product 1 Product 2 Description Thin Creamy Soft Creamy paste Thick slurry paste paste paste paste Formation of Hard Paste Ribbon No No Yes No Yes Ease of Spreading in Mouth Easy Easy Easy Easy Not easy Subjectable to Spitting No No No No Yes Viscosity, cp @ 20°C (Helipath Spindle T-F at 0.6rpm) 140,000 250,000 760,000 250,000 >1,600,00 0 Viscosity, cp @ 20°C (Helipath Spindle T-F at 6rpm) 23,000 75,000 140,000 83,000 >160,000 Thixotropic Index (Helipath Spindle T-F, 0.6rpm/6rpm) 6.2 3.3 5.3 3.0 - 20 James & Wells Ref: 127174/55 Figure 1: Graph showing viscosity of compositions provided in Table 1. Q. O W O O </> 10000000 1000000 100000 - 10000 1000 - 100 0 2 4 6 Helipath Spindle T-F Speed (rpm) Product 1 Mayonnaise Ketchup Bomazeal Skin & Coat 5 Development Trials: Development Trial 1: The following formulation of product 1 (as shown in Table 2). 10 Table 2: Formulation of the medicament of the present invention (product • 1) No Ingredients %w/w Function 1 Diethylene glycol stearate 8 Helps in dispersion 2 Abamectin 0.42 Active Ingredient 3 Praziquantel 5.10 Active Ingredient 4 Oxfendazole (micronised) 18.9 Active Ingredient 5 Cellogen 7A 1.5 Thickener 6 Benzyl alcohol technical 2 Solublizing agent 7 Plasdone K25 2 Helps in dispersion 21 James & Wells Ref: 127174/55 8 Tween 80 1.5 Wetting agent 9 Sodium Metabisulphite 0.1 Antioxidant 10 Sorbitol 70% solution 5 Bulking agent 11 Propyl paraben 0.005 Preservative 12 Methyl paraben 0.05 Preservative 13 Wacker Silica 1 Thickener 14 Apple Flavour (MTO) 2 Flavouring 15 Deionised water 52.425 Solvent / Bulking agent I Total 100.00 Manufacturing Procedure of product 1 (medicament of the present invention): 1. Dissolve sodium metabisulphate and cellogen 7 A in 52.425% (wlw) water, then mix in tween 80 and Sorbitol70%. Suspend praziquantel and oxfendazole and mix well. 2. Dissolve methyl and propyl parabens and abamectin in benzyl alcohol by heating at 40°-50°C. Add to (1) whilst mixing. 3. Add the apple flavor to (2). 4. Add and mix in plasdone K 25 and wacker silica. 5. Heat diethylene glycol stearate at 50-60°C, then add to (4). Mix well until a smooth and homogenous suspension is obtained. Development Trial 2: The following formulation (given in Table 4) was (product 2). 22 James & Wells Ref: 127174/55 Table 4: Formulation of product 2 No Ingredients %w/w Function 1 Diethylene glycol state 8 Helps in dispersion 2 Glycerine formal stabilized 6 Solvent 3 PEG 400 6 Viscosity increasing agent - 4 Benzyl alcohol technical 1 Solubilizing agent 5 Abamectin 0.42 Active Ingredient 6 Praziquantel 5.10 Active Ingredient 7 Oxfendazole (micronised) 18.9 Active Ingredient 8 Sorbitol 70% solution 12 Bulking agent 9 Sodium Metabisulphite 0.1 Antioxidant 10 Methyl paraben 0.05 Preservative 11 Propyl paraben 0.005 Preservative 12 Oat flour-collodial 2 Flavouring and thickener 13 Wacker Silica 1 Thickener 14 Apple Flavour 2 Flavouring 15 Deionised water 37.42 Solvent/ Bulking agent Total 100.00 Manufacturing Procedure of product 2 1. In a clean and dry beaker, add the required quantity of PEG 400, glycerin formal stabilized and benzyl alcohol. Mix well. Add methyl paraben and propyl paraben then heat at 50 - 60°C to dissolve. Add abamectin. Mix well and leave to cool to room temperature. Add praziquantel and mix well. Add sorbitol 70% and mix well. 23 James & Wells Ref: 127174/55 2. Dissolve sodium metabisulphate in 37.4gms of deionised water. Then mix in the oat flour to form a collodial mixture. 3. Heat diethylene glycol stearate to 50 - 60°C 4. Add (2) to (1). Add apple flavour and mix well. Add oxfendazole and mix well. Add wacker silica and mix well. Add the heated diethylene glycol (step 3) to the mixture and mix well. Homogenise until a smooth homogenous paste is obtained. Results: NB: The oxfendazole content in tables 6 and 7 was amended from 18.4 to 20.4 % w/w to provide a dosage rate of 1 g / 20 Kg body weight. Table 6: Results of accelerated stability trial of product 1 Active Initial (% w/v) !fl Wi«te % 40®C (% w/v) Abamectin 0.49 0,49 Praaquentel 5,72 5.75 Oxfendazole 20.9 20,9 pH@20°C 10% aqueous suspension 5.8 | 5.7 24 James & Wells Ref: 127174/55 Table 7: Results of accelerated stability trial of product 2 Active Initial (% w/v) S weeks @409C (%W/¥> Abamectin 0.51 0.50 Praziquantel 5.92 5.87 Oxfendazole 21.7 21.6 pH @ 20* C (10%) aqueous suspension 3.91 3.6 Table 8: Results of stability trial of product 1 Storage Conditions: 25°C 60%RH Test Specifications Initial 3 Months 6 Months 9 Months 12 Months 18 Months Description A smooth off white paste Complies Complies Complies Complies Complies Complies pH 5.0-6.5 @20°C 5.6 5.53 5.6 5.4 5.4 5.5 Apparent density 1.050-1.150 @20°C 1.097 1.104 1.098 1.100 1.105 1.050 Syringibility Passes through a 7mm nozzle to form a soft ribbon Complies Complies Complies Complies Complies Complies Abamectin 0.36-0.46%w/w by HPLC 0.42 0.42 0.44 0.46 0.45 0.44 Oxfendazole 16.7-20.4%w/w by HPLC 19.78 18.76 18.5 18.8 18.3 19.25 Praziquantel 4.50-5.50%w/w by HPLC 4.82 5.25 5.16 5.34 4.96 5.15 25 James & Wells Ref: 127174/55 Final preparation and manufacturing method of product 1: FORMULATION Quantity (%w/w) Active Constituent Abamectin 0.42* Praziquantel 5.10** Oxfendazole Micronised 20.4** Excipients Diethylene Glycol Sterate 8.00 Sodium Carboxymethyl Cellulose (Cellogen 7A) 1.50 Benzyl Alcohol Technical 2.00 Plasdone K25 (Povidone K25) 2.00 Polysorbate 80 (Tween 80) 1.50 Sodium Metabisulphate 0.10 Sorbitol 70% Solution 5.00 Propyl Paraben 0.005 Methyl Paraben 0.05 Colloidal Silicon Dioxide (Wacker Silica) 1.00 Apple Flavour (MTO) 2.00 Deionised Water 50.93 * 5%w/v manufacturing overages added **2%w/v manufacturing overages added MANUFACTURING METHOD Dissolve sodium metabisulphate in deionised water, and then mix in cellogen 7A, tween 80 and sorbitol 70% with stirring. Suspend praziquantel and oxfendazole and mix well. 26 James & Wells Ref: 127174/55 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> In a separate manufacturing vessel, dissolve methyl parabens, propyl parabens and abamectin in benzyl alcohol. Add to the main bulk and mix well. Add apple flavour to the main bulk and mix well. Add wacker silica and then mix plasdone K25 to the main bulk and mix well. Heat diethylene glycol stearate at 50° - 60 °C, and then add it to the main bulk and mix well. Homogenise for 20 - 30 minutes until a smooth and homogenous paste is obtained. It will be appreciated by the skilled addressee in relation to the above final formulation, should the abamectin be substituted for moxidectin in the range of 7.2 -9.2%w/w it will be necessary to increase the amount of benzyl alcohol required in order to solubilize the moxidectin from about 2% w/w to about 4% w/w. Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims. 27 James & Wells Ref: 127174/55 WHAT l/WE CLAIM IS:

1. A medicament for oral administration to a subject, which includes at least one compound which is selected for its activity against strongyles, and at least one macrocyclic lactone (or pharmaceutical equivalent thereof), and praziquantel (or pharmaceutical equivalent thereof),

if required, at least one thickening agent to provide the required viscosity, characterised in that the medicament is formulated to within a viscosity range of 100,000 to 800,000 cp at 20°C when measured on a Helipath spindle T-F at 0.6 rpm by the addition of at least one thickening agent which ensures that once administered orally the medicament spreads readily into the mouth of the subject.

2. A medicament as claimed in claim 1 wherein the medicament is for the treatment of parasitic helminths.

3. A medicament as claimed in either claim 1 or claim 2 wherein the compound selected for its activity against strongyles is benzimidazole (or pharmaceutical equivalents thereof).

4. A medicament as claimed in claim 3 wherein the benzimidazole is oxfendazole.

5. A medicament as claimed in any one of claims 1 to 4 wherein the active ingredient benzimidazole (or a pharmaceutical equivalent thereof) is present at a

Intellectual Property Office of M.Z.

22 NOV 2007

RECEIVED

28 James & Wells Ref: 127174/55

concentration of approximately 18 to 22 % w/w of the medicament.

6. A medicament as claimed in any one of claims 1 to 4 wherein the active ingredient benzimidazole (or a pharmaceutical equivalent thereof) is present at a concentration of approximately 18.9 % w/w of the medicament.

7. A medicament as claimed in either claim 1 or claim 2 wherein the compound selected for its activity against strongyles is tetrahydropyrimidine (or pharmaceutical equivalents thereof).

8. A medicament as claimed in any one of claims 1 to 7 wherein the macrocyclic lactone is a milbemycin.

9. A medicament as claimed in any one of claims 1 to 7 wherein the macrocyclic lactone is abamectin.

10. A medicament as claimed in claim 9 wherein the active ingredient macrocyclic lactone is abamectin (or a pharmaceutical equivalent thereof) and is present at a concentration of approximately 0.36 to 0.46 % w/w of the medicament.

11. A medicament as claimed in claim 9 wherein the active ingredient macrocyclic lactone is abamecitn (or a pharmaceutical equivalent thereof) and is present at a concentration of approximately 0.42 % w/w of the medicament.

12. A medicament as claimed in any one of claims 1 to 7 wherein the macrocyclic lactone is moxidectin.

13. A medicament as claimed in claim 12 wherein the active ingredient macrocyclic lactone is moxidectin (or a pharmaceutical equivalent thereof) and is present at a concentration of approximately 0.72 to 0.92 % w/w of the medicament.

Intellectual Property Office of /

2 2 NOV 2007

_ _ _ f 29 James & Wells Ref: 127174/55

RECElveol

14.

15

16

17

18.

19.

20.

21.

22.

23.

A medicament as claimed in claim 12 wherein the active ingredient macrocyclic lactone is moxidectin (or a pharmaceutical equivalent thereof) and is present at a concentration of approximately 0.42 % w/w of the medicament.

A medicament as claimed in any one of claims 1 to 14 wherein the active ingredient praziquantel is present at a concentration of approximately 4.5 to 5.5 % w/w of the medicament.

A medicament as claimed in any one of claims 1 to 14 wherein the active ingredient praziquantel (or a pharmaceutical equivalent thereof) is present at a concentration of approximately 5.1 % w/w of the medicament.

A medicament as claimed in any one of claims 1 to 16 wherein the subject is a non-human mammal.

A medicament as claimed in any one of claims 1 to 17 wherein the subject is an equine mammal.

A medicament as claimed in any one of claims 1 to 18 which also includes at least one preservative.

A medicament as claimed in any one of claims 1 to 19 which also includes at least one thickener.

A medicament as claimed in any one of claims 1 to 20 which also includes at least one dispersing agent.

A medicament as claimed in any one of claims 1 to 21 which also includes at least one suspending agent.

A medicament as claimed in any one of claims 1 to 22 which also includes at least one flavouring agent.

Intellectual Property

Office iV ?

2 2 NOV 2007

RECEI .

30 James 8 Wells Ref: 127174/55

24.

A medicament as claimed in claim 23 wherein the flavouring agent is apple flavour.

25. A medicament as claimed in either claim 23 or 24 wherein the flavouring agent is present at a concentration of approximately 2% w/w of the medicament.

26. A medicament as claimed in any one of claims 1 to 25 wherein the pH is within the range of 5.5 to 6.5 at 20'C for a 10% aqueous solution.

27. A method of treating a non-human subject for parasitic helminths, characterised by the step of administering to a subject a sufficient dosage of a medicament as claimed in any one of claims 1 to 26.

28. A method of manufacturing a medicament as claimed in any one of claims 1 to 26, including the steps of:

a) mixing the active ingredients, and b) adding sufficient additional ingredients in the proportion and type to ensure that the medicament has a viscosity within the viscosity range that ensures that once administered orally the medicament spreads readily into the mouth of the subject.

29. A method of manufacturing a medicament as claimed in any one of claims 1 to 26, including the steps of:

a) mixing the active ingredients, and b) adding sufficient additional ingredients in the proportion and type to ensure that the medicament has a viscosity within the required viscosity range.

Intellectual Property Office of N Z.

22 NOV 2007

RECEIVED

31

James Swells Ref: 127174/55

30. A method of manufacturing a medicament as claimed in any one of claims 1 to 26, including the steps of:

a) dissolving sodium metabisulphate in deionised water,

b) mixing in cellogen 7A, Tween 80 and Sorbitol 70% with the dissolved sodium metabisulphate,

c) suspending praziquantel and oxfendazole, and d) mixing the suspended praziquantel and oxfendazole from c) with the solution from b),

e) in a separate manufacturing vessel, dissolving methyl parabens, propyl parabens and abamectin in benzyl alcohol,

f) adding the solution from e) into the solution from d),

g) adding wacker silica into the solution from f),

h) mixing plasdone K 25 into the solution from g),

i) heating diethylene glycol stearate at 50-60°C,

j) adding the heated diethylene glycol stearate it to the solution from h),

k) homogenizing the mixture from j) for 20-30 minutes until a smooth and homogenous paste is obtained.

31. A medicament substantially as herein described with reference to the accompanying example formulations of product 1 and product 2 provided in the best modes section.

Intellectual Property

Office of N.Z.

2 2 NOV 2007

RECEIVED

32 James & Wells Ref: 127174/55

A method of manufacturing a medicament substantially as herein with reference to the accompanying example formulations of product 1 and product 2 provided in the best modes section.

Intellectual Property Office of n.Z.

22 NOV 2007

RECEIVED 33

James & Wells Ref: 127174/55

</div>