AU2007334747A1 - Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents - Google Patents
Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents Download PDFInfo
- Publication number
- AU2007334747A1 AU2007334747A1 AU2007334747A AU2007334747A AU2007334747A1 AU 2007334747 A1 AU2007334747 A1 AU 2007334747A1 AU 2007334747 A AU2007334747 A AU 2007334747A AU 2007334747 A AU2007334747 A AU 2007334747A AU 2007334747 A1 AU2007334747 A1 AU 2007334747A1
- Authority
- AU
- Australia
- Prior art keywords
- tablet
- compound
- levamisole
- compounds
- animal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
WO 2008/075984 PCT/NZ2007/000383 TABLET FORMULATION STATEMENT OF CORRESPONDING APPLICATIONS This application is based on the Provisional specification filed in relation to New Zealand 5 Patent Application Number 552293, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The invention relates to a tablet formulation. More specifically, the invention relates to a 10 tablet formulation containing at least one macrocyclic lactone compound with anthelmintic activity dissolved in at least one organic solvent along with levamisole and optionally at least one further anthelmintic compound for use in treatment of animal parasites. BACKGROUND ART 15 Anthelmintic chemical compounds are widely known agents that are destructive to worms and used for treating internal and external parasitic infestations in animals including humans. There are many different types of anthelmintic compound, each with varying degrees of 20 parasitic activity and chemical properties. A difficulty in formulating such compounds is that many are extremely insoluble in aqueous environments such as extracellular'fluids thus they need to be formulated to ensure they are bioavailable. In addition, in order to make these compounds soluble, different conditions 25 may be required resulting in situations where one compound may be solubilized by for example, by reducing pH. This change can cause other compounds in the formulation to become insoluble, or the change may cause physical or chemical degradation of another compound in the formulation. In addition, the change may cause adverse side effects in the animal. 30 Stabilising and providing combinations of anthelmintic agents for oral administration have been considered in the prior art. A wide variety of advantages may be obtained by such combinations and these are discussed in prior art patent specifications including WO 00/74489 and WO 02/09764, incorporated herein by reference. 35 In the present invention, an aim is to provide a tablet formulation containing at least two different anthelmintic compounds ideally from different families of anthelmintic activity. A problem found in the prior art with existing anthelmintic compounds including benzimidazole anthelmintics, is the need to deliver the compound as an oral suspension due 40 to the poor solubility of this type of compound in aqueous environments. One preferred WO 2008/075984 PCT/NZ2007/000383 method of administration is by injection however, as the solubility of the anthelmintic is often poor, drugs delivered by injection are not always readily absorbed and often may cause pain to the animal or human absorption or precipitate formation. 5 The macrocyclic lactone family of anthelmintic compounds, which family includes abamectin and ivermectin, present a different challenge again with such compounds being lipophilic and largely insoluble in aqueous environments. It should be appreciated that providing a tablet formulated to include one or more 10 anthelmintic agents is a challenge particularly where the agents are lipophilic, require specific conditions in which to dissolve or may lose viability when stored over time. Another problem specific to tablets is ensuring that the tablet dissolves on administration and releases the active agents in a form that is bioavailable and does not simply pass through the animal without achieving the desired therapeutic effect. 15 One attempt to address the above problem is an albendazole capsule for the treatment of gastrointestinal parasites in adult sheep and lambs (marketed in New Zealand as EXTENDER@ 100). This product is formulated to provide a slow release of albendazole to 'control' parasites over a time period of 100 days. A disadvantage of this product is the 20 continuous release of albendazole at levels below that required to kill adult parasites. The drug levels are designed to the kill incoming larvae, which require a lower dose rate for control than adult parasites - in effect the product's main use may be as a prevention method and not to address infestation once it occurs. Besides not addressing adult parasites, use of the product may lead to drug resistance where the low dose allows adult 25 parasites to become resistant to the ivermectin. Further reinforcing the resistance problem is that, when this product is given to adult ewes, drug resistant parasites may often also be transferred to progeny from the ewes prolonging resistance across different generations. A further problem with the above slow release capsule is that the time period between delivery and slaughter must be sufficiently long to ensure all agent has been released. By contrast, 30 fast release products are more flexible as the time period between delivery and slaughter may be significantly shorter. -Another product is a slow release capsule containing ivermectin (marketed in New Zealand as IVOMEC@ MaximiserTM CR). It gives a slow release of ivermectin over 100 days with 35 ivermectin levels dropping below that required to kill adult parasites for a substantial amount of that time. It consequently suffers from the disadvantages previously described. It should be appreciated that it is desirable to have a formulation: 0 for delivery of parasiticidal compounds including lipophilic agents, 40 e which stabilises these agents so that they may be stored over time with minimal physical or chemical degradation, and 2 WO 2008/075984 PCT/NZ2007/000383 . delivers a consistent dose of the agents on administration to an animal. It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice. 5 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 are 10 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. It is acknowledged that the term 'comprise' may, under varying jurisdictions, be attributed 15 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 20 process. Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only. 25 DISCLOSURE OF INVENTION For the purposes of this specification, the term 'tablet' refers to the formulation being administered orally and in a consistency able to be administered as a granular material, discrete tablet or capsule, or alternatively expelled by device such as a 'pill popper', stomach 30 tube or other delivery device. According to one aspect of the present invention there is provided a tablet formulated for administration to an animal characterised in that the tablet includes: (a) at least one macrocyclic lactone compound having anthelmintic activity and; 35 (b) at least one levamisole compound with anthelmintic activity; and, wherein the macrocyclic lactone compound or compounds are dissolved in at least one organic solvent. As should be appreciated, macrocyclic lactone compounds used in the tablet are generally 40 characterised by being lipophilic and having poor solubility and/or poor dispersion characteristics in an aqueous environment. It is understood by the inventors that this poor 3 WO 2008/075984 PCT/NZ2007/000383 solubility and/or poor dispersion results in corresponding poor oral absorption, which may lead to poor pharmacokinetics. These factors may contribute to the macrocyclic lactone compound(s) having poor oral bioavailability. If such a compound is administered absent of a suitably formulated delivery system, the compound may either not be absorbed or be only 5 poorly absorbed within an aqueous environment such as the blood stream. Preferably a compound may display 'poor oral bioavailability' if, when orally delivered to an animal on its own (i.e. absent of a suitably formulated delivery system), it achieves less than approximately 20% absorption of the compound into the blood stream when compared with 10 the results obtained using an equivalent single active oral drench. Preferably, an 'aqueous environment' may be extracellular fluid. Preferably, the macrocyclic Iactone compound or compounds may be selected from: 15 abamectin, ivermectin, moxidectin, eprinomectin, doramectin and combinations thereof. More preferably, the macrocyclic lactone compound is abamectin or ivermectin. Preferably, the macrocyclic lactone compound or compounds and levamisole compound or compounds included in the tablet are at a dose sufficient to: prevent growth of parasites; 20 reduce parasite numbers; kill parasites; kill incoming parasite larvae; lower the number of surviving incoming parasite larvae; kill or reduce the number of hypobiotic state parasites; and combinations thereof. In a preferred embodiment, the tablet includes sufficient macrocyclic lactone and levamisole 25 compound or compounds to provide the animal with a dose of the compound or compounds equivalent to that which would be obtained from an oral drench containing the same compound or compounds In one embodiment where abamectin is present, the abamectin is included at a rate of at 30 least approximately 0.2mg to 0.6 mg of abamectin or ivermectin per kg of animal body weight. More preferably, the rate is approximately 0.2 mg/kg. Most preferably the rate is approximately 0.4mg/kg. It should be appreciated that this dose is sufficient to kill or at least reduce parasite infestation including both larvae and adult parasites. 35 In one embodiment of the present invention, the amount of active ingredient per tablet for a cattle formulation is 64mg abamectin per tablet dosed to an animal weighing approximately 160kg. It is the inventor's experience that this level of abamectin provides a blood level of abamectin to the animal equivalent to that which would be obtained from an oral drench containing abamectin such as the product GenesisTM. It should be appreciated that the 40 dosage of abamectin may be varied depending on the amount of abamectin desired to be administered and that levels of abamectin above or below 64mg may be used without 4 WO 2008/075984 PCT/NZ2007/000383 departing from the scope of the invention. Similarly, the dose may be varied for different animals. Preferably, the levamisole compound is levamisole hydrochloride (HCI). In a preferred 5 embodiment, the levamisole is levamisole HCI included at a rate of approximately 5 to 9 mg levamisole per kg of animal body weight, more preferably, approximately 7.5 mg levamisole per kg of animal body weight. It should be appreciated that it is unexpected to be able to produce a single dose tablet that includes both a macrocyclic lactone compound or compounds co-administered with a levamisole compound or compounds and maintain 10 efficacy and stability. This is because each agent has very different solubilities and simply mixing the two compounds-would not obviously result in a stable and efficacious formulation. In addition, tablets have different pharma-kinetics to solutions such as drenches so combinations in the art which use drenches and pour-on formulations are not suitable guidance when developing a tablet. 15 Preferably, the tablet rapidly releases the macrocyclic lactone and levamisole compounds on oral administration. Preferably, the macrocyclic lactone and levamisole compound or compounds remain 20 present in the bloodstream of the animal for at least 24 hours. Preferably, the macrocyclic lactone and levamisole compound or compounds are formulated so that the compound or compounds dissipate from the bloodstream of the animal in a similar manner as an oral drench containing each compounds individually. It is understood 25 by the applicant that the compound has left the blood stream after a time period of no more than two weeks. Preferably, the tablet includes at least one additional compound with anthelmintic activity. In preferred embodiments, the additional anthelmintic compound or compounds have a 30 different spectrum of anthelmintic activity than the macrocyclic lactone or levamisole compounds used. Alternatively, the additional anthelmintic targets parasites which have resistance to macrocyclic lactone compounds. In one embodiment, the additional compound with anthelmintic activity is a substituted or 35 unsubstituted benzimidazole compound with anthelmintic activity. Preferably, the substituted or unsubstituted benzimidazole compound has the structure: N >4
)_R
2 N nR 1 H 5 WO 2008/075984 PCT/NZ2007/000383 where n = 1 or 2; where R 1 which may be the same or different at each occurrence = H, Cl, -SC 3
H
7 , SOC 3
H
7 , -SCH 5 , -SOC 6
H
5 , -C 4
H
9 , or -OCH 3 Cl 2 ; and, where R 2 = -NHCO 2
CH
3 or -SCH 3 . 5 Preferably, the substituted or unsubstituted benzimidazole compound may be selected from: albendazole, ricobendazole, fenbendazole, oxfenbendazole, parbendazole, triclabendazole and combinations, analogues and derivatives thereof. Most preferably, the benzimidazole compound is albendazole. 10 Preferably, the substituted or unsubstituted benzimidazole compound or compounds included in the tablet are at a dose sufficient to: prevent growth of parasites; reduce parasite numbers; kill parasites; kill incoming parasite larvae; lower the amount of incoming parasite larvae; and combinations thereof. 15 In a preferred embodiment, the tablet includes sufficient benzimidazole compound or compounds to provide the animal with a dose of the compound or compounds equivalent to that which would be obtained from an oral drench containing the same benzimidazole compound or compounds 20 Preferably, where albendazole is present, the albendazole is included at a rate of at least 1 mg albendazole per kg of animal body weight. In one embodiment, albendazole is included at a rate of approximately 3.7 mg albendazole per kg of animal body weight where the animal is a sheep. In an alternative embodiment, albendazole is included at a rate of 25 approximately 7.5 mg albendazole per kg of animal body weight where the animal is a bovine. It should be appreciated that this dose is sufficient to kill or at least reduce parasite infestation including both larvae and adult parasites. In one particular embodiment of the present invention, the amount of active ingredient per 30 tablet for a cattle formulation is 1200mg albendazole per tablet dosed to an animal weighing approximately 160kg. It is the inventor's experience that this level of albendazole provides an oral bioavailability equivalent to that which would be obtained from an oral drench containing albendazole such as the product ValbazenTM. It should be appreciated that the dosage of albendazole may be varied depending on the amount of albendazole desired to 35 be administered and that levels of albendazole above or below 1200mg may be used without departing from the scope of the invention. Similarly, the dose may be varied for different animals. Preferably, the tablet is formulated to also rapidly release the benzimidazole compound or 40 compounds on oral administration. 6 WO 2008/075984 PCT/NZ2007/000383 Preferably, the benzimidazole compound or compounds or their active metabolites remain present in the bloodstream of the animal for at least 12 hours. Preferably, the benzimidazole compound or compounds are formulated so that the 5 compound or compounds or its active metabolites dissipate from the bloodstream of the animal in a similar manner as an oral drench. It is understood by the applicant that the compound has left the blood stream after a time period of no more than two weeks. Preferably, the benzimidazole raw material is formulated into the tablet as a dry micronised 10 particulate powder. The inventors have found that this is a further key characteristic. Without a micronised particle structure, the desired degree of bioavailability of the benzimidazole compound or compounds in the tablet is difficult to achieve. According to a further aspect of the present invention there is provided a tablet formulated 15 for administration to an animal including: (a) at least one macrocyclic lactone compound or compounds with anthelmintic activity; (b) at least one levamisole compound; (c) at least one substituted or unsubstituted benzimidazole compound with anthelmintic activity; and, 20 wherein the macrocyclic lactone compound or compounds are dissolved in at least one organic solvent. Preferably, the macrocyclic lactone compound or compounds are also subsequently mixed with at least one second organic solvent (termed a 'co-solvent' for the purposes of this 25 specification). Preferably, the solvent or solvents and co-solvent or co-solvents are different compounds. Preferably, the first organic solvent or solvents may be selected from: an alcohol, a glycol, 30 an ether, a pyrrolidone compound with two or more carbon atoms, and combinations thereof. More preferably, the solvent or solvents may include: ethyl alcohol, benzyl alcohol, phenethyl alcohol, ethyl benzyl alcohol and other aromatic monohydric alcohols; glycols, glycol ethers, glycol ether acetates, C 1 to C 8 alkyl pyrrolidones, and combinations thereof. In a preferred embodiment, the solvent is benzyl alcohol which is preferred as it not only 35 dissolves the macrocyclic lactone compound, but also, acting with the co-solvent, stabilises the compound increasing the overall stability of the product. Preferably, the co-solvent or co-solvents are alcohol or ether compounds with three or more carbon atoms. More preferably, the co-solvent or co-solvents include: diol alcohols or 40 ethers including glycols, aromatic monohydric alcohols, glycol ethers, glycol ether acetates, and combinations thereof. In a preferred embodiment, the co-solvent is a propylene glycol 7 WO 2008/075984 PCT/NZ2007/000383 compound such as monopropylene glycol which is preferred as it not only mixes with the macrocyclic lactone compound and solvent but also stabilises the compound increasing stability and provides emulsifying properties. It is understood that the emulsifying properties assist in preventing crystallisation / precipitation of the macrocyclic lactone compound on 5 release in the gut although other factors may also account for the increased bioavailability effect and this description should not be seen as limiting. A further advantage of the organic solvents and co-solvents chosen are that they provide improved bioavailability by the solvents giving a transmucosal effect whereby the solvents 10 and co-solvents assist in transfer. of the agent or agents from the gut and into the animal bloodstream. Without use of the above solvents and co-solvents, the macrocyclic lactone compound or compounds would pass through the animal on administration with no or only sparing 15 absorption. By dissolution and mixing with solvents and co-solvents, the macrocyclic lactone anthelmintic compound(s) are made absorbable and can be mixed with levamisole and other anthelmintic agents without risk of reducing efficacy or tablet stability. Preferably, the tablet as described above includes the above components in a ratio within 20 the range of approximately I part macrocyclic lactone to 0.8-1.2 parts organic solvent to 3.2 3.6 parts organic co-solvent. In one embodiment of the present invention, the amount of active ingredient per tablet for a cattle formulation is 64mg abamectin, 1200mg levamisole HCI and 1200mg albendazole per 25 tablet dosed to an animal weight of approximately 160kg. It is the inventor's experience that these levels of agent provide sufficient bioavailability to the animal on administration equivalent to that which would be obtained from single agent oral drenches. It should be appreciated that the dosage of each agent may be varied depending on the amount of agent desired to be administered and that levels of agent above or below the example provided 30 may be used without departing from the scope of the invention. Similarly, the dose may be varied for different animals. In addition to increasing oral bioavailability, the inventors have found that the resulting tablet formulation remains stable with minimal loss in active stability during storage. For the 35 purposes of this specification, the term 'stable' refers to at least 6 months (preferably 18 months) chemical stability (e.g. within ±10% w/w active agent of the stated composition) of active agent when stored at 40 0 C or below and at a high humidity (relative humidity of less than 75%) and of a reasonable physical stability such that no physical alteration is observed in the tablet during storage or at the time of administration. 40 Other agents are also envisaged as being added to the formulation including other 8 WO 2008/075984 PCT/NZ2007/000383 anthelmintic agents as well as other-non-anthelmintic agents. For example, in farming applications, other nutrients such as trace minerals may be added to the formulation to allow the animal to be dosed for parasites but also to enhance the animal's nutrition. In one embodiment mineral supplementation may be included in the formulation to provide a 5 source of cobalt, copper, iodine, selenium and zinc. In a further embodiment additional inert compositions are added to the tablet including: binders, fillers, bulking agents, carriers, disintegration agents, glidants, lubricants, and combinations thereof. 10 In preferred embodiments, the tablet disintegrates within approximately 15 minutes when placed in water at 370C. Preferably, the tablet is administered orally to an animal. 15 According to a further aspect of the present invention there is provided a method of treating animals for parasite infestation by administration of a tablet containing at least one macrocyclic lactone compound and at least one levamisole compound substantially as described above. 20 According to a further aspect of the present invention there is provided the use of a tablet composition containing at least one macrocyclic lactone compound and at least one levamisole compound with anthelmintic activity substantially as described above in the treatment of a parasite infestation in animals. 25 Preferably, the animal is non-human animal. More preferably, the animal is a ruminant animal. In specific embodiments envisaged by the inventors, the animals are ovine or bovine species although it is anticipated that any animal susceptible to parasite infestation treatable using an anthelmintic composition may be treated. 30 Preferably, the parasites treated include endoparasites. According to a further aspect of the present invention there is provided a kit containing a pill administration device and a package of tablets substantially as described above. 35 It should be appreciated that the tablet may be sold commercially in bulk or in smaller kits. Smaller kits containing a package of tablets have the advantage over existing drenches and pour on formulations in that large amounts of formulation need not be purchased. It should be noted that, due to the stability of the tablets of the present invention, the packaging need 40 not provide specific stabilising properties but rather is likely to be best used to assist in administration such as by use of labelling to identify sequence or dose information. 9 WO 2008/075984 PCT/NZ2007/000383 Commercially sold drenches and pour on formulations are typically sold in containers including 500 or more doses which is excessive for the small lifestyle farmer or other purchasers. The convenience of a package also lends itself well to smaller dosing runs with 5 little mess and fuss required. In one embodiment the package may be sold with a disposable tablet applicator in order to further simplify the process for the user. Applicator devices such as a pill popper or gas actuated applicator may also be included. In a further embodiment, there may be, in the place of an applicator, a dough in which the tablet is encased and which masks the tablet from the animal. 10 Tablets may be supplied with or without an applicator. .lt should be appreciated by those skilled in the art that producing a formulation of this nature is particularly challenging. Besides the lipophilic versus hydrophilic nature of such 15 combinations, the different agents may require very different pH ranges in order to remain stable. The present invention addresses these pH challenges by not needing to rely on pH alterations to achieve the desired oral bioavailability and stability. A further advantage of the formulation is that, as multiple agents are included, product 20 effectiveness is increased (several classes of parasite may be targeted in one dose) and. has labour savings in terms of not having to dose two or more times with different products. A yet further advantage of the present invention is that tablets may be advantageous in small farm applications. At present drenches and topical pour-on solutions are packaged in large containers for use in dosing large numbers of animals (typically 500 doses). The cost 25 of these containers is considerable. In contrast, the present invention may be sold as a package containing any number of doses which, for a small farm of lifestyle block would be preferable than purchasing a large container at significant cost. Purchase of a small number of tablets would also remove the need to dump unused drenches or pour-on solutions that have passed their expiry date. 30 BRIEF DESCRIPTION OF DRAWINGS Further aspects of the present invention will become apparent from the ensuing description which is given by way of example only and with reference to the accompanying drawings in 35 which: Figure I shows a graph of levamisole blood levels measured post administration based on two formulations labelled Reformulation 1 and Reformulation 2; Figure 2 shows a graph of abamectin blood levels measured post administration based on two formulations labelled Reformulation 1 and Reformulation 2; 40 Figure 3 shows a graph of albendazole sulfoxide blood levels measured post administration based on two formulations labelled Reformulation I and 10 WO 2008/075984 PCT/NZ2007/000383 Reformulation 2; Figure 4 shows a graph of levamisole blood levels measured post administration based on a third formulation labelled Reformulation 3 and a Reference levamisole oral drench product; 5 Figure 5 shows a graph of abamectin blood levels measured post administration based on a third formulation labelled Reformulation 3 and a Reference abamectin oral drench product; Figure 6 shows a graph of albendazole sulfoxide blood levels measured post administration based on a third formulation labelled Reformulation 3 and a 10 Reference albendazole oral drench product; Figure 7 shows a graph of levamisole blood levels measured post administration based on Reformulation 2 and a Reference levamisole oral drench product; Figure 8 shows a graph of abamectin blood levels measured post administration based on Reformulation 2 and a Reference abamectin oral drench product; 15 Figure 9 shows a graph of albendazole sulfoxide blood levels measured post administration based on Reformulation 2 and a Reference albendazole oral drench product; Figure 10' shows a graph of levamisole blood levels measured post administration based on an active only capsule with no carriers or surrounding formulation; 20 Figure 11 shows a graph of albendazole sulfoxide blood levels measured post administration based on an active only capsule with no carriers or surrounding formulation; Figure 12 shows a graph of abamectin blood levels measured post administration of a fourth formulation (Reformulation 4) compared to a Reference abamectin 25 oral drench; Figure 13 shows a graph of albendazole sulfoxide blood levels measured post administration of a fourth formulation (Reformulation 4) compared to a Reference albendazole oral drench; and, Figure 14 shows a graph of levamisole blood levels measured post administration of a 30 fourth formulation (Reformulation 4) compared to a Reference levamisole oral drench. BEST MODES FOR CARRYING OUT THE INVENTION 35 Examples are now provided showing various embodiments of the present invention. EXAMPLE 1 In a first trial, the inventors developed tablet formulations containing abamectin, albendazole and levamisole HCI and the bioavailability of these formulations was tested. 40 Formulations Three formulations were tested: 11 WO 2008/075984 PCT/NZ2007/000383 Reformulation I includes abamectin, levamisole HCI, and albendazole. Abamectin is dissolved in one solvent (monopropylene glycol) and includes: Table 1: Reformulation I Composition Component Quantity per tablet [%] Quantity per tablet (mg) Abamectin 1.35 12.0 Monopropylene glycol 12.13 108.0 Levamisole hydrochloride 51.45 457.9 Albendazole 25.63 228.1 Polyvinyl pyrrolidone 0.26 2.35 Corn starch 3.24 28.86 Sodium starch glycolate 3.95 35.19 Aerosil 200 0.88 7.82 Magnesium stearate 1.10 9.78 Total: 100% 890 mg 5 * Reformulation 2 includes abamectin, levamisole HCI, and albendazole. Abamectin is dissolved in two solvents (benzyl alcohol and monopropyleie glycol) and includes: Table 2: Reformulation 2 Composition Component Quantity per tablet [%] Quantity per tablet (mg) Abamectin 1.43 12.0 Monopropylene glycol 5.14 43.0 Benzyl alcohol 1.43 12.0 Levamisole hydrochloride 54.71 457.9 Albendazole 27.25 228.1 Polyvinyl pyrrolidone 0.28 2.35 Corn starch 3.45 28.86 Sodium starch glycolate 4.20 35.19 Aerosil 200 0.93 7.82 Magnesium stearate 1.17 9.78 Total: 100% 837 mg 10 * Reformulation 3 includes abamectin, levamisole HCI, and albendazole. Abamectin is dissolved in one solvent (monopropylene glycol) and a surfactant (sodium lauryl sulphate) and includes: Table 3: Reformulation 3 Composition Component Quantity per tablet [%] Quantity per tablet (mg) Abamectin 1.35 12.0 Monopropylene glycol 6.52 58.0 12 WO 2008/075984 PCT/NZ2007/000383 Sodium Lauryl Sulphate 5.62 50.0 Levamisole hydrochloride 51.45 457.9 Albendazole 25.63 228.1 Polyvinyl pyrrolidone 0.26 2.35 Corn starch 3.24 28.86 Sodium starch glycolate 3.95 35.19 Aerosil 200 0.88 7.82 Magnesium stearate 1.10 9.78 Total: 100% 890 mg Reformulation 1 and Reformulation 2 were investigated during the first treatment session. In the second treatment session, Reformulation 3 and the Reference products (see below) were compared. The animals were then re-randomised for the third sampling session, in 5 which Reformulation 2 was compared with the Reference products. Animal Selection Twelve sheep weighing 62.5 kg to 78 kg (mean = 68.6 kg) were all dosed to individual liveweight with one anthelmintic treatment, at the standard dose rates of 0.2 mg/kg, 3.75 10 mg/kg and 7.5 mg/kg for abamectin, albendazole and levamisole HCI respectively. Prior to administration of the invention or Reference formulation, all animals were dosed to their individual liveweight with ScandaTM (Batch 52888, expiry April 2006) at least 14 days prior to each treatment session, and tested free of strongylid nematodes (via faecal egg count) prior to the commencement of each treatment session. 15 Dosing All sheep were administered with a dose sufficient for a 60kg animal. Reference Products 20 Reference products used were single anthelmintic drenches being ValbazenTM (albendazole) (Batch 800211, Expiry 06/2007), GenesisTM Oral Drench (abamectin) (Batch 2204, Expiry 02/2009), and NilvermTM (levamisole) (Batch 52827, Expiry 04/2008). It should be appreciated that such reference products provide a high bar in terms of 25 bioavailability to be reached by the present invention. It is the inventor's experience that other liquid based multiple anthelmintic products accept a lower bioavailability of one or more of the agents in order to be able to combine multiple agents together. Therefore providing a multiple tablet formulation where comparable levels of bioavailability are achieved as single reference products would be an advantage. It should be noted that lower 30 levels of bioavailability may still be of commercial value given advantages offered by tablets and commercial activity of existing marketed multiple agent products with lower levels. 13 WO 2008/075984 PCT/NZ2007/000383 Sampling times Blood samples (4ml per sample) were taken from the tested animals at time intervals (by active) as follows: 5 0 Abamectin: 6 hours (h), 12h, 24h. * Albendazole: 6h, 15h, 24h e Levamisole: 15 min, 30 min, 2h, 6h Blood was collected from the jugular vein via venipuncture, directly into heparinised vacutainer tubes and refrigerated at 4 0 C until processing. It was then centrifuged at 2500 10 rpm for 10 minutes before the plasma was collected, and divided into test (2ml/analyte) and reserve (2ml), samples and frozen. Test and reserve samples were maintained at -. 180C in separate freezers before laboratory analysis. Results 15 Treatment Session 1 Levamisole The plasma profile for levamisole is shown in Figure 1. There appears to be a delayed absorption of the levamisole in this formulation, as the Tmax shown here is much later than 20 expected. It is likely that the true Cmax occurred between the 0.5h and 6h sampling time, and the 6h sampling actually reflected the plasma concentration decreasing. The results found were otherwise as expected. Abamectin 25 Blood plasma levels for abamectin peaked at 4.7ng/ml and 8.5ng/ml for Reformulation 1 and Reformulation 2 respectively (Figure 2). The Tmax occurred 24h and 12h for the two formulations, indicating the absorption of abamectin from Reformulation I was also delayed. Albendazole 30 Parent albendazole was not detected in any of the samples at any time. The plasma profile obtained for albendazole sulfoxide (the active metabolite) is shown (Figure 3). The plasma concentrations peaked at 4.6pg/ml and 5.1pg/ml for Reformulation I and Reformulation 2. The Tmax for both formulations occurred 15h post administration. 35 Treatment Session 2 Levamisole The levamisole plasma profiles obtained for Reformulation 3 and the Reference treatment groups are shown (Figure 4). The Cmax for levamisole was 0.78pg/ml and 0.52pg/ml for Reformulation 3 and the Reference groups respectively. 14 WO 2008/075984 PCT/NZ2007/000383 This showed that the degree of absorption of levamisole from Reformulation 3 was comparable to the Reference NilvermTM oral drench. Abamectin 5 The abamectin plasma profiles observed for Reformulation 3 and the Reference products are shown (Figure 5). The Cmax observed for the Reformulation 3 and Reference treatment groups were 1.5ng/ml and 10.2ng/ml respectively. In this case, abamectin absorbed from Reformulation 3 was not comparable to levels observed from the Reference oral drench GenesisTM. 10 Albendazole The albendazole plasma profiles observed for Reformulation 3 and the Reference products are shown (Figure 6). The Cmax observed for the Reformulation 3 and Reference treatment groups were 0.54pg/ml and 2.2pg/ml respectively. For both formulations Tmax was 15h after 15 administration. Reformulation 3 showed some release and absorption of albendazole but not to the extent desired to be comparable to Reference oral drench product ValbazenTM. Treatment Session 3 20 After comparing the Reformulation 2 results from Treatment Session I with the Reference results from Treatment Session 2, it was decided to compare Reformulation 2 with the Reference products in a third Treatment Session (Treatment Session 3). This was done as a side by side trial to re-confirm the results observed in Treatment Sessions 1 and 2. 25 Levamisole The levamisole plasma profiles observed for Reformulation 2 and the Reference products are shown (Figure 7). The Cmax observed for Reformulation 2 and Reference treatment groups were 0.74pg/ml and 0.66pg/ml respectively. The Tmax for both formulations occurred 2h post administration, and the error bars calculated (showing standard deviations) 30 demonstrate the variation between individuals to be greater than that resulting from the different formulations. Therefore, Reformulation 2 compared well against the levamisole reference oral drench product NilvermTM. Abamectin 35 The abamectin plasma profiles observed for Reformulation 2 and the Reference products are shown (Figure 8).' The Cmax observed for the Reformulation 2 and Reference treatment groups were 5.8ng/ml and 11.3ng/ml respectively. The Tmax for both formulations occurred 12h post administration. Whilst some effect was achieved using Reformulation 2, the bioavailability of abamectin from Reformulation 2 approximates to half that of the Reference 40 product GenesisTM. 15 WO 2008/075984 PCT/NZ2007/000383 Albendazole The albendazole plasma profiles observed for Reformulation 2 and the Reference product is shown (Figure 9). The Cma, observed for the Reformulation 2 and Reference treatment 5 groups were 0.64pg/ml and 0.92pg/ml respectively. The Tma for both formulations occurred 15h post administration, and the error bars calculated (showing standard deviations) demonstrate the variation between individuals to be considerable and may largely explain the difference observed in the plasma profile of two formulations. Therefore it may be concluded that Reformulation 2 compared well against the Reference product Valbazen TM. 10 EXAMPLE 2 Given the results in Example 1, a further trial was completed to determine the influence of the formulation on the degree of absorption of each anthelmintic compound. This was completed by ascertaining baseline levels of drug bioavailability when animals are dosed 15 with raw actives (no excipients), Experimental Design Five sheep weighing 59.0kg to 63.5kg (mean = 61.2kg) were all dosed with one anthelmintic treatment, which contained a dose sufficient for a 60kg animal at the standard dose rates of 20 0.2mg/kg, 3.75mg/kg and 7.5mg/kg for abamectin, albendazole and levamisole HCI respectively. The dose for each active was contained within a separate gelatine capsule. Experimental Animals Prior to administration of the invention or Reference formulation, all animals were dosed to 25 their.individual liveweight with ScandaTM (Batch 52888, expiry April 2006) at least 14 days prior to each treatment session, and tested free of strongylid nematodes (via faecal egg count) prior to the commencement of each treatment session. Dosing Regime 30 Gelatine capsules containing a single anthelmintic drug (one capsule per sheep per drug for levamisole and abamectin, two capsules per sheep for albendazole) were used. The capsules were dark green in colour, to prevent the light sensitive abamectin from being prematurely exposed to light. 35 Sampling times All animals were blood sampled seven times. Four millilitres of whole blood were collected from each sheep, for each active at each sampling time, and an additional 4ml reserve sample was collected from each sheep at each sampling time. 40 Sampling times (by active) were as follows: 16 WO 2008/075984 PCT/NZ2007/000383 * Abamectin: 6h, 12h, 24h. * Albendazole: 6h, 15h, 24h * Levamisole: 15 min, 30 min, 2h, 6h 5 The blood was collected from the jugular vein via venipuncture, directly into heparinised vacutainer tubes and refrigerated at 4 0 C until processing. It was then centrifuged at 2500 rpm for 10 minutes before the plasma was collected, and divided into test (2ml/analyte) and reserve (2ml), samples and frozen. Test and reserve samples were maintained at -1 8'C in separate freezers before laboratory analysis. 10 Results Abamectin Blood plasma levels for abamectin peaked just above the detection threshold indicating that abamectin was not absorbed. 15 The minimal levels of abamectin absorbed are not surprising considering that this drug is lipophilic and usually formulated as a solution. Therefore, it is expected to require. excipients to facilitate bioavailability of this drug. Levamisole 20 The plasma profile for levamisole is shown in Figure 10. The Tmax shown here is later than predicted by publications, but consistent with previous studies by the inventor's. It is envisaged that this is because the drugs were all administered in a gelatine capsule, and this would have taken several minutes to break down, which may have delayed the release of the levamisole to the rumen. The Cmax was approximately 50% of that generally 25 considered necessary for full therapeutic efficacy. The plasma profile for levamisole was similar to that observed in previous studies, suggesting that formulations do not cause delayed absorption of the drug as previously thought. Rather, this delay may be due to the active passing through the mucosal layer between the gut and bloodstream. 30 Albendazole This data indicates that Tmax for albendazole sulfoxide occurred between the 6h and 15h sampling times (Figure 11). However, Cmax was approximately 50% of that generally considered necessary for full therapeutic efficacy. 35 The low bioavailability of albendazole was surprising,'as this drug is usually formulated as a suspension, with the majority of excipients being included as aids keeping the drug in suspension and not necessarily to assist in bioavailability. The formulation in tablet usage appears to have an effect on albendazole bioavailability. 40 Conclusions 17 WO 2008/075984 PCT/NZ2007/000383 The results from this study (when compared to Reference products) suggest that the inclusion of excipients in anthelmintic formulations improves the bioavailability of each of the three drugs discussed here. In the absence of excipients, plasma levels obtained for albendazole and levamisole were reduced (compared to reference products), but 5 comparable to previous test formulations tested. Plasma concentrations of abamectin were lower than those obtained previously for example that shown in Example 1. 10 The results show that tablet formulations (containing excipients) are an important factor in achieving drug bioavailability. EXAMPLE 3 A fresh formulation (Reformulation 4) was tested based on prior trials including those 15 identified above in Examples 1. The formulation included abamectin, albendazole and levamisole. The abamectin was dissolved and mixed with two organic solvents during manufacturing (benzyl alcohol and monopropylene glycol). More specifically, the formulation was as follows (formulated for 20 cattle weighing 160kg): Table 4: Reformulation 4 Composition Component Quantity per tablet [%] Quantity per tablet (mg) Abamectin 2.12 68.0 Monopropylene glycol 7.17 230.0 Benzyl alcohol 1.99 64.0 Levamisole hydrochloride 37.38 1200.0 Albendazole 37.38 1200.0 Polyvinyl pyrrolidone 0.39 12.55 Corn starch 4.80 154.07 Sodium starch glycolate 5.84 187.4 Aerosil 200 1.30 41.76 Magnesium stearate 1.63 52.22 Total: 100% 3210 Mg In this example, the animals used were cattle with other characteristics of the study remaining the same as in Example I except that the formulation was altered as noted 25 above. Results Abamectin 18 WO 2008/075984 PCT/NZ2007/000383 Abamectin is lipophilic and requires formulation in order for the abamectin to be absorbed. The formulation was altered to increase this absorption by dissolving and mixing the abamectin with solvents. In addition, the dosage of abamectin was approximately doubled in order to achieve a comparable result to the Reference product. Increasing the dose for 5 abamectin is standard practice when designing cattle formulations as sheep have a greater absorption, distribution, metabolism and excretion (ADME) profile than cattle. As can be seen in Figure 12, Reformulation 4 resulted in the abamectin profile becoming almost equivalent with that observed from the Reference oral drench formulation GenesisTM. 10 Albendazole For albendazole, the amount of albendazole used was approximately doubled in order to ensure that the amount of albendazole provided was comparable to that used normally for cattle. 15 As can be seen in Figure 13, Reformulation 4 resulted in the albendazole profile also becoming almost equivalent with that observed for the Reference oral drench formulation Valbazen TM. Levamisole 20 Minimal changes were made to levamisole handling and amount in Reformulation 4 compared to Example I as the dose of levamisole was already comparable to the Reference product in earlier tests. As can be seen in Figure 14, Reformulation 4 resulted in the levamisole profile also 25 becoming almost equivalent with that observed for the Reference oral drench formulation NilvermTM. EXAMPLE 4 30 Two further trials were completed to test the storage stability of the tablets over time. The trials were conducted using Reformulation 2 described above. In the trials, a total of 24 tablets were initially tested for: " General visual description * Disintegration time 35 - Average weight * Weight variation * Concentration of abamectin " Hardness 40 Subsequent to initial tests, a first trial was commenced with 12 tablets placed into an 19 WO 2008/075984 PCT/NZ2007/000383 environment held at a constant temperature of 30*C and 60% relative humidity. A second trial was also commenced with 12 tablets placed into an environment held at a constant temperature if 40 0 C and 75% relative humidity. 5 The above temperatures and humidity's were chosen as being 'trying' conditions in which the tablets might be stored and represent worst case scenarios where deterioration might occur. The first trial was conducted over 18 months and the second trial over 6 months. 10 At time intervals noted in Tables 5 and 6 below, the tablets were tested using the same tests as that completed during the initial test and the results compared. Where there were no variations to initial results, the stored tablet was said to 'comply'. Table 5: Storage Stability for a Temperature of 30*C and 15 Relative Humidity of 60% Test Specification/ Initial 3 Months 6 9 12 18 Standard Months Months Months Months Visual An off-white, round, Complies Complies Complies Complies Complies Complies Description flat tablet: bevelled edge. May have score-line on one side. Disintegration Less than 15 Complies Complies Complies Complies Complies Complies Time in Water minutes Average tablet 795.2 - 920.8 Complies Complies Complies Complies Complies Complies weight mg/tablet (mg/tablet) Tablets were individually weighed. Of the total tablets, no more than two tablet weights may Weight Variation deviate from the Complies Complies Complies Complies Complies Complies average by more than ± 5%. No tablet should deviate from the average by more than 10% ±10% w/w basis or Abamectin 10.8-13.20 12.9 12.7 11.9 11.9 12.0 12.0 content mg/tablet by HPLC ±10% w/w basis or Levamisole 412.2- 503.80 489 492 -- 495 486 465 mg/tablet by HPLC Albendazole 205.2- 250.80 235 247 246 248 244 243 20 WO 2008/075984 PCT/NZ2007/000383 content mg/tablet by HPLC Hardness 5.0 Kg Complies Complies Complies Complies Complies Complies Table 6: Storage Stability for a Temperature of 40*C and Relative Humidity of 75% 6 Test Specification/ Standard Initial 1 Month 3 Months Months Visual Description An off-white, round, flat Complies Complies Complies Complies tablet: bevelled edge. May have score-line on one side. Disintegration Time in Less than 15 minutes Complies Complies Complies Complies water Average tablet weight 795.2 - 920.8 mg/tablet Complies Complies Complies Complies (mg/tablet) Weight Variation Tablets were individually Complies Complies Complies Complies weighted. Of the total tablets, no more than two tablet weights may deviate from the average by more than ± 5%. No tablet should deviate from the average by more than 10% Abamectin content ±10% w/w basis or 10.8- 12.9 12.4 12.3 11.5 13.20 mg/tablet by HPLC Levamisole HCL ±10% w/w basis or 412.2- 489 489 473 480 content 503.80 mg/tablet by HPLC Albendazole content ±10% w/w basis or 205.2- 235 235 238 243 250.80 mg/tablet by HPLC Hardness > 5.0 Kg Complies Complies Complies Complies 5 The above trials showed that the tablet product was remarkably stable and did not breakdown under trying conditions in terms of temperature and humidity over significant time periods. In particular, the tablet is water resistant and not hydroscopic or too hydroscopic to prevent disintegration when administered. 10 EXAMPLE 5 Further formulations are described below in Tables 7 and 8 showing other variations in the formulation make up including use of different anthelmintic compounds. 15 Table 7 - Tablets formulated with various macrocyclic lactones (For cattle weighing 160kg) 21 WO 2008/075984 PCT/NZ2007/000383 1 2 3 4 Component Quantity per Quantity per Quantity per Quantity per tablet (mg) tablet (mg) tablet (mg) tablet (mg) Ivermectin 68.0 - Doramectin - 68.0 Eprinomectin . - 68.0 Moxidectin - - - 68.0 Monopropylene 230.0 230.0 230.0 230.0 glycol Benzyl alcohol 64.0 64.0 64.0 64.0 Levamisole 1200.0 1200.0 1200.0 1200.0 hydrochloride Albendazole 1200.0 1200.0 1200.0 1200.0 Polyvinyl pyrrolidone 12.55 12.55 12.55 12.55 Corn starch 154.07 154.07 154.07 154.07 Sodium starch 187.4 187.4 187.4 187.4 glycolate Aerosil 200 41.76 41.76 41.76 41.76 Magnesium stearate 52.22 52.22 52.22 52.22 Total: 3210 Mg 3210 Mg 3210 Mg 3210 Mg Table 8 - Tablets formulated with oxfendazole (For cattle weighing 160kg) 5 6 Component Quantity per tablet (mg) Quantity per tablet (mg) Abamectin 68.0 Moxidectin - 68.0 Monopropylene 230.0 230.0 glycol Benzyl alcohol 64.0 64.0 Levamisole 1200.0 1200.0 hydrochloride Oxfendazole 800.0 800.0 Polyvinyl pyrrolidone 12.55 12.55 Corn starch 154.07 154.07 Sodium starch 187.4 187.4 glycolate Aerosil 200 41.76 41.76 Magnesium stearate 52.22 52.22 22 WO 2008/075984 PCT/NZ2007/000383 Total: 2810 Mg 2810 Mg EXAMPLE 6 The talblet formulations described above were manufactured as described and packaged in 5 a blister pack sealing the tablets into a package. Markings may be included on the packaging indicating the user when the tablets should be administered and any dosing instructions such as how to use an applicator device such as a pill popper device. The blister pack is attached to a pill applicator device or composition and placed into a 10 package for sale jointly as a kit. Besides mechanical devices for administration such as a pill popper or gas actuated applicator, the applicator may be replaced by an administration/swallowing-enhancing coating such as a dough composition which encases the pill and which masks the pill from 15 the animal. For convenience, a disposable applicator is preferred. As should be appreciated the kit may contain as little as one dose or many thousands of doses as may be required. 20 Tablets may also be sold in containers absent of a blister pack and again may be sold with or without an applicator. EXAMPLES CONCLUSION 25 It should be appreciated from the above examples that developing a tablet for delivery of two or more anthelmintic agents including abamectin and albendazole has presented many challenges. The inventors have achieved this providing a formulation including multiple actives that not only provides agents in a state able to be absorbed, but also in a state that may be absorbed at comparable levels to that achieved using other methods of 30 administration such as oral drenches. It should be appreciated that as ivermectin has similar lipophilic properties as abamectin, similar results may be achieved if ivermectin were used. In addition, similar results may also be expected for other benzimidazole compounds based on results found for 35 albendazole. An advantage of tablets is that they provide a fixed and known dose of agent and there is no need to dilute, measure out and use specialised equipment such as drench guns. In addition, tablets may.easily be sold in large or small numbers whereas oral drenches for 40 example are only sold in large volumes (and at greater expense). 23 WO 2008/075984 PCT/NZ2007/000383 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. 5 24
Claims (36)
1. A tablet formulated for administration to an animal characterised in that the tablet includes: (a) at least one macrocyclic lactone compound having anthelmintic activity and; (b) at least one levamisole compound having anthelmintic activity; and, wherein the macrocyclic lactone compound or compounds are dissolved in at least one organic solvent.
2. The tablet as claimed in claim 1 wherein the macrocyclic lactone compound is selected from: abamectin, ivermectin, moxidectin, eprinomectin, doramectin and combinations thereof.
3. The tablet as claimed in claim I or claim 2 wherein the levamisole compound is levamisole HCl.
4. The tablet as claimed in any one of the above claims wherein the macrocyclic lactone and levamisole compound or compounds included in the tablet are at a dose sufficient to: prevent growth of parasites; reduce parasite numbers; kill parasites; kill incoming parasite larvae; lower the number of surviving incoming parasite larvae; kill or reduce the number of hypobiotic state parasites; and combinations thereof.
5. The tablet as claimed in any one of claims I to 3 wherein the macrocyclic lactone and levamisole compound or compounds included in the tablet are at a concentration sufficient to provide the animal with a dose of the compound or compounds to the animal equivalent to that which would be obtained from an oral drench containing the same compound or compounds.
6. The tablet as claimed in any one of the above claims wherein the macrocyclic lactone compound is abamectin or ivermectin included at a rate of 0.2mg to 0.6 mg of abamectin or ivermectin per kg of animal body weight.
7. The tablet as claimed in any one of claims 1 to 5 wherein the macrocyclic lactone compound is abamectin or ivermectin included at a rate of 0.4mg of abamectin per kg of animal body weight.
8. The tablet as claimed in any one of the above claims wherein the levamisole compound is included at a rate of approximately 5 to 9 mg levamisole per kg of animal body weight. WO 2008/075984 PCT/NZ2007/000383
9. The tablet as claimed in any one of the above claims wherein the macrocyclic lactone and levamisole compounds are rapidly released on oral administration.
10. The tablet as claimed in any one of the above claims wherein the macrocyclic lactone and levamisole compounds remain present in the bloodstream of the animal for at least 24 hours.
11. The tablet as claimed in any one of the above claims wherein the macrocyclic lactone and levamisole compounds dissipate from the bloodstream of the animal in a similar manner as an oral drench.
12. The tablet as claimed in any one of the above claims wherein the tablet also includes at least one substituted or unsubstituted benzimidazole compound with anthelmintic activity.
13. The tablet as claimed in claim 12 wherein the substituted or unsubstituted benzimidazole compound has the structure: N _R2 nR 1 H where n = 1 or 2; where R 1 which may be the same or different at each occurrence = H, Cl, SC 3 H 7 , -SOC 3 H 7 , -SC 6 H 5 , -SOC 6 H 5 , -C 4 H 9 , or -OCH 3 Cl 2 ; and, where R 2 = -NHCO 2 CH 3 or -SCH 3 .
14. The tablet as claimed in claim 12 or claim 13 wherein the substituted or unsubstituted benzimidazole compound is selected from: albendazole, ricobendazole, fenbendazole, oxfenbendazole, parbendazole, triclabendazole and combinations, analogues and derivatives thereof.
15. The tablet as claimed in any one of claims 12 to 14 wherein the benzimidazole raw material is a dry micronised particulate powder.
16. The tablet as claimed in any one of claims 12 to 15 wherein the benzimidazole compound is albendazole or oxfendazole included at a rate of at least I mg of albendazole or oxfendazole per kg of animal body weight.
17. A tablet formulated for administration to an animal including: WO 2008/075984 PCT/NZ2007/000383 (a) at least one macrocyclic lactone compound with anthelmintic activity; (b) at least one levamisole compound with anthelmintic activity; (c) at least one substituted or unsubstituted benzimidazole compound with anthelmintic activity; and, wherein the macrocyclic lactone compound or compounds are dissolved in at least one organic solvent.
18. The tablet as claimed in any one of the above claims wherein organic solvent or solvents are selected from: an alcohol, a glycol, an ether, a pyrrolidone compound with two or more carbon atoms, and combinations thereof.
19. The tablet as claimed in any one of the above claims wherein the organic solvent or solvents used are selected from: ethyl alcohol, benzyl alcohol, phenethyl alcohol, ethyl benzyl alcohol and other aromatic monohydric alcohols; glycols, glycol ethers, glycol ether acetates, C1 to C8 alkyl pyrrolidones, and combinations thereof.
20. The tablet as claimed in any one of the above claims wherein the organic solvent is benzyl alcohol.
21. The tablet as claimed in any one of the above claims wherein wherein the macrocyclic lactone compound or compounds are dissolved in at least one organic solvent and subsequently mixed with at least one co-solvent.
22. The tablet as claimed in claim 21 wherein solvent or solvents and co-solvent or co solvents are different compounds.
23. The tablet as claimed in claim 21 or claim 22 wherein the co-solvent or co-solvents are alcohol or ether compounds with three or more carbon atoms.
24. The tablet as claimed in any one of claims 21 to 23 wherein the co-solvent or co solvents used are selected from: diol alcohols including glycols, aromatic monohydric alcohols, glycol ethers, glycol ether acetates, and combinations thereof.
25. The tablet as claimed in any one of claims 21 to 24 wherein the co-solvent used is a propylene glycol compound.
26. The tablet as claimed in any one of claims 21 to 24 wherein the co-solvent used is monopropylene glycol.
27. The tablet as claimed in any one of the above claims wherein the tablet remains WO 2008/075984 PCT/NZ2007/000383 stable with a less than 10% w/w loss in active concentration during storage for at least 6 months at a temperature of less than 40*C and relative humidity of less than 75%.
28. The tablet as claimed in claim 27 wherein the tablet remains stable for at least 18 months.
29. The tablet as claimed in claim 27 or claim 28 wherein the tablet is chemically stable whereby the active agent concentration remains at within 10% of initial levels and is physical stable such that no physical alteration is observed in the tablet during storage or at the time of administration.
30. The tablet as claimed in any one of the above claims wherein the tablet contains mineral sources selected from: cobalt, copper, iodine, selenium, zinc and combinations thereof.
31. The tablet as claimed in any one of the above claims wherein the tablet contains inert excipients selected from: binders; fillers; bulking agents; carriers; disintegration agents; glidants; lubricants; and combinations thereof.
32. A method of treating animals for parasite infestation by administration of a tablet as claimed in any one of claims 1 to 31.
33. The method as claimed in claim 32 wherein the animal is a ruminant animal.
34. The method as claimed in claim 32 or claim 33 wherein the animal is of ovine or bovine species.
35. The method as claimed in any one of claims 32 to 34 wherein the parasites are endoparasites.
36. A kit containing a pill administration device or pill administration composition and one or more tablets as claimed in any one of claims I to 31.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2014201152A AU2014201152C1 (en) | 2006-12-21 | 2014-03-04 | Tablet Formulation |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ552293A NZ552293A (en) | 2006-12-21 | 2006-12-21 | Tablet formulation comprising a macrocyclic lactone and a levamisole compound having anthelmintic activity |
NZ552293 | 2006-12-21 | ||
PCT/NZ2007/000383 WO2008075984A2 (en) | 2006-12-21 | 2007-12-20 | Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2014201152A Division AU2014201152C1 (en) | 2006-12-21 | 2014-03-04 | Tablet Formulation |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2007334747A1 true AU2007334747A1 (en) | 2008-06-26 |
Family
ID=39536845
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2007334747A Abandoned AU2007334747A1 (en) | 2006-12-21 | 2007-12-20 | Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU2007334747A1 (en) |
NZ (1) | NZ552293A (en) |
WO (1) | WO2008075984A2 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2008360070B2 (en) * | 2008-07-29 | 2015-04-30 | Bomac Research Limited | Tablet manufacturing method |
TW201041509A (en) * | 2009-04-30 | 2010-12-01 | Dow Agrosciences Llc | Pesticide compositions exhibiting enhanced activity |
CA2839491A1 (en) | 2011-06-23 | 2012-12-27 | Bayer New Zealand Limited | Anti-parasitic composition comprising a macrocyclic lactone and levamisole and method of treatment of parasitic infestation |
NZ594610A (en) | 2011-08-16 | 2013-03-28 | Virbac New Zealand Ltd | Injectable Anthelmintic Formulations cotaining levamisole and one or more macrocyclic lactones for controlling internal parasites in ruminants |
CN110151910A (en) * | 2019-05-28 | 2019-08-23 | 石家庄九鼎动物药业有限公司 | A kind of antiparasite drugs for animals albendazole ivermectin piece and preparation method thereof |
CN111067875B (en) * | 2020-01-16 | 2021-11-30 | 兰州大学 | Albendazole liquid-solid compressed tablet and preparation method thereof |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE313952T1 (en) * | 1999-06-04 | 2006-01-15 | Nufarm Ltd | STABLE BIOCIDAL COMPOSITION |
CN1376466A (en) * | 2001-03-26 | 2002-10-30 | 王玉万 | Solution-type oral liquid or injection containing triclabendazole |
GB0111391D0 (en) * | 2001-05-10 | 2001-07-04 | Porter William L | Pulse release bolus |
CN1522706A (en) * | 2003-02-19 | 2004-08-25 | 王玉万 | Preparation of solid dispersoid containing large ring lactone parasite medicine |
CN1582925A (en) * | 2003-08-19 | 2005-02-23 | 王玉万 | Powder injection of benzimidazole hydrochloride, etc. for animals |
CN1698636A (en) * | 2004-05-17 | 2005-11-23 | 王玉万 | Mixing method of antiparasitic preparation for animals |
-
2006
- 2006-12-21 NZ NZ552293A patent/NZ552293A/en not_active Application Discontinuation
-
2007
- 2007-12-20 WO PCT/NZ2007/000383 patent/WO2008075984A2/en active Application Filing
- 2007-12-20 AU AU2007334747A patent/AU2007334747A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO2008075984A3 (en) | 2008-07-31 |
WO2008075984A2 (en) | 2008-06-26 |
NZ552293A (en) | 2009-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SG185794A1 (en) | Oral dosage forms of bendamustine and therapeutic use thereof | |
ES2435240T3 (en) | Solid pharmaceutical fixed dose compositions comprising irbesartan and amlodipine, their preparation and therapeutic application | |
AU2007334742B2 (en) | Tablet formulation | |
AU2007334747A1 (en) | Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents | |
PL220457B1 (en) | Solid drug for oral use | |
CA3171890A1 (en) | Compositions and therapeutic uses of cannabidiol | |
AU2008360070B2 (en) | Tablet manufacturing method | |
CA3191671A1 (en) | Palatable formulations | |
AU2014201152B2 (en) | Tablet Formulation | |
US11737986B1 (en) | Thyroid hormone oral dosage forms and methods of using the same | |
IL230074A (en) | Anti-parasitic composition comprising a macrocyclic lactone and levamisole and uses thereof | |
NZ552291A (en) | Benzimidazole anthelmintic tablet formulation | |
WO2008121107A1 (en) | Minocycline oral dosage forms for the treatment of acne | |
RU2248205C1 (en) | Medicinal agent as gelatin capsule | |
AU2015326572A1 (en) | A suspension | |
TR2024001686T2 (en) | SOLID PHARMACEUTICAL COMPOSITIONS CONTAINING IVERMECTIN AND RELATED AUXILIARIES | |
Kafedjiiski | Effect of binder type on physical and in vitro properties of high dose inosine acedoben dimepranol tablets | |
KR20240025534A (en) | Excellent tasting veterinary composition | |
WO2024043842A1 (en) | Pharmaceutical compositions comprising chenodeoxycholic acid (cdca) as active ingredient and other relevant excipients | |
PL234395B1 (en) | Pharmaceutical composition that contains furazidin and method for producing it |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted | ||
PC1 | Assignment before grant (sect. 113) |
Owner name: ELANCO NEW ZEALAND Free format text: FORMER APPLICANT(S): BAYER NEW ZEALAND LIMITED |