NZ552291A

NZ552291A - Benzimidazole anthelmintic tablet formulation

Info

Publication number: NZ552291A
Application number: NZ55229106A
Authority: NZ
Inventors: Alawi Fadil Al; Karthigeyan Nanjan; Wayne Frederick Leech; Man Yik Li; Steve Li
Original assignee: Bomac Research Ltd
Priority date: 2006-12-21
Filing date: 2006-12-21
Publication date: 2009-04-30

Abstract

Disclosed is a tablet formulated for administration to an animal characterised in that the tablet includes at least one substituted or unsubstituted benzimidazole compound and characterised in that the benzimidazole compound has anthelmintic activity and is present in the tablet as micronised particles. The preferred benzimidazole compound or compounds are selected from: albendazole, ricobendazole, fenbendazole, oxfenbendazole, parbendazole, triclabendazole and combinations, analogues and derivatives thereof.

Description

<div class="application article clearfix" id="description"> 552291 *10055001497* PATENTS FORM NO. 5 Fee No. 4: $250.00 PATENTS ACT 1953 COMPLETE SPECIFICATION After Provisional No: 552291 Dated: 21 December 2006 4 \ Office of N.Z. 15 NOV 2007 RECEIVED! TABLET FORMULATION We, Bomac Research Limited, a New Zealand company having its registered office at Wiri Station Road, Manukau, 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: 1 James & Wells Ref: 44238/ 29 552291 TABLET FORMULATION STATEMENT OF CORRESPONDING APPLICATIONS This application is based on the Provisional specification filed in relation to New 5 Zealand Patent Application Number 552291, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The invention relates to a tablet formulation. More specifically, the invention 10 relates to a tablet formulation containing at least one benzimidazole compound with anthelmintic activity for use in treatment of an animal. BACKGROUND ART Anthelmintic chemical compounds are widely known agents that are destructive to 15 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 parasitic activity and chemical properties. A difficulty in formulating such compounds is that many are extremely insoluble in 20 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 may be required resulting in situations where one 2 James & Wells Ref: 44238 / 29 552291 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. 5 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. 10 In the present invention, an aim is to provide a tablet formulation containing at least one benzimidazole compound that has a useful bioavailability in treatment of animal pest infestations. A problem found in the prior art with existing anthelmintic compounds including benzimidazole anthelmintics, is the need to deliver the compound as an oral 15 suspension due to the poor solubility of this type of compound in aqueous environments. One preferred 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 patient due to inadequate absorption or precipitate formation. 20 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 continuous release of albendazole at levels 25 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 - 3 James & Wells Ref: 44238 / 29 552291 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 parasites to become resistant to the albendazole. Further reinforcing the resistance problem is 5 that, when this product is given to adult ewes, drug resistant parasites may 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, fast release products are more flexible as 10 the time period between delivery and slaughter may be significantly shorter. It should be appreciated that providing a tablet formulated to include at least one benzimidazole compound is a challenge particularly where the agents 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 15 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. Achieving a highly stable formulation is desirable as well as meeting other formulation requirements such as efficacy on delivery, avoidance of side effects 20 and so on. It should therefore be appreciated that it would be desirable to have a formulation that addresses these factors and enhances stability over that already known. It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice. 25 All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any 4 James & Wells Ref: 44238 / 29 552291 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 referred to herein, this reference does not 5 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 with either an exclusive or an inclusive meaning. For the purpose of this specification, and unless otherwise noted, the term 'comprise' shall have an 10 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. Further aspects and advantages of the present invention will become apparent 15 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 tablet formulated for administration to an animal including at least one substituted or 20 unsubstituted benzimidazole compound. 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 tube or other delivery device. 25 Preferably, at least one of the benzimidazole compounds used in the tablet may be 5 James & Wells Ref: 44238 / 29 552291 10 15 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 solubility and/or poor dispersion may result in corresponding poor oral absorption, which may lead to poor pharmacokinetics. These factors may contribute to the compound 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 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 the results obtained using an equivalent single active oral drench. Preferably, an 'aqueous environment' may be extracellular fluid. Preferably, the substituted or unsubstituted benzimidazole compound includes the structure: where n = 1 or 2; where Ri which may be the same or different at each occurrence = H, CI, -SC3H7, —SOC3H7, —SCeHs, —SOCgHs, —C4H9, or --OC6H3CI2; and, where R2 = -NHCOzCH3 or -SCH3. Preferably, the substituted or unsubstituted benzimidazole compound may be nh! H 6 James & Wells Ref: 44238 / 29 552291 selected from: albendazole, ricobendazole, fenbendazole, oxfenbendazole, parbendazole, triclabendazole and combinations, analogues and derivatives thereof. Most preferably, the benzimidazole compound is albendazole. Preferably, the substituted or unsubstituted benzimidazole compound or 5 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. In a preferred embodiment, the tablet includes sufficient benzimidazole compound or compounds to provide the animal with a dose of the compound or compounds 10 equivalent to that which would be obtained from an oral drench containing the same benzimidazole compound or compounds 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 15 albendazole per kg of animal body weight where the animal is a sheep. In an alternative embodiment, albendazole is included at a rate of approximately 7.5 mg albendazole per kg of animal body weight where the animal is a bovine species. It should be appreciated that the above doses are sufficient to kill or at least reduce 20 parasite infestation including both larvae and adult parasites. In one particular embodiment of the present invention, the amount of active ingredient per 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 25 which would be obtained from an oral drench containing albendazole such as the 7 James & Wells Ref: 44238 / 29 552291 product Valbazen™. It should be appreciated that the dosage of albendazole may be varied depending on the amount of albendazole desired to 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 5 animals. Preferably, the benzimidazole compound or compounds are formulated to be rapidly released on oral administration. Preferably, the benzimidazole compound or compounds or its active metabolites are formulated so that the compound or compounds remain present in the 10 bloodstream of the animal for at least 12 hours. Preferably, the benzimidazole 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. It is understood by the applicant that the compound or its active metabolites has left the blood stream after a time period of no more than 15 4 days. Preferably, the benzimidazole raw material is a dry micronised particulate powder. The inventors have found that this is a further key characteristic. Without a micronised particle structure, the desired degree of oral bioavailability is difficult to achieve. 20 In addition to increasing the oral bioavailability, the inventors have found that the resulting tablet formulation remains stable with minimal loss in active stability during storage. For the 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°C or 25 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 8 James & Wells Ref: 44238 / 29 552291 tablet during storage or at the time of administration. Other agents are also envisaged as being added to the formulation including other 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 5 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 source of cobalt, copper, iodine, selenium and zinc. In a further embodiment additional inert compositions are added to the tablet 10 including: binders, fillers, bulking agents, carriers, disintegration agents, glidants, lubricants, and combinations thereof. In preferred embodiments, the tablet disintegrates within approximately 15 minutes when placed in water at 37 °C. According to a further aspect of the present invention there is provided a tablet 15 formulated for administration to an animal characterised in that the tablet includes albendazole wherein the raw material albendazole is in micronised particle form. Preferably, the tablet as described above contains at least approximately 3.75mg albendazole. According to a further aspect of the present invention there is provided a method of 20 treating non-human animals for parasite infestation by administration of a tablet composition containing at least one substituted or unsubstituted benzimidazole compound substantially as described above. According to a further aspect of the present invention there is provided the use of a tablet composition containing at least one substituted or unsubstituted 9 James & Wells Ref: 44238 / 29 552291 benzimidazole substantially as described above in the treatment of a parasite infestation in non-human animals. Preferably, in the above method and use, the raw material benzimidazole compound or compounds are micronised. 5 Preferably, the non-human animal is a ruminant animal. In specific embodiments envisaged by the inventors, the animals are of ovine or bovine species although it is anticipated that any animal susceptible to parasite infestation treatable using an anthelmintic composition may be treated. Preferably, the parasites treated include endoparasites. 10 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. 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 15 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 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. Commercially sold drenches 20 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 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. 25 Applicator devices such as a pill popper or gas actuated applicator may also be included. In a further embodiment, the applicator may be replaced by an 1 q James & Wells Ref: 44238 / 29 552291 administration/swallowing-enhancing coating such as a dough in which the tablet is encased and which masks the tablet from the animal. As should be appreciated by those skilled in the art, a key advantage from the formulation is that a benzimidazole compound may be presented in a tablet form 5 and provide equivalent levels of oral bioavailability as a comparative oral drench. It should further be appreciated by those skilled in the art that producing a formulation of this nature is particularly challenging. Besides the challenge of formulating the active ingredients into a tablet, common active agents often require different pH ranges in order to remain stable. The present invention addresses 10 these pH challenges by not needing to rely on pH alterations to achieve the desired oral bioavailability and stability. 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 15 animals (typically 500 doses). The cost of these treatments 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 20 that have passed their expiry date. 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 25 accompanying drawings in which: 11 James & Wells Ref: 44238 / 29 552291 Figure 1 shows a graph of albendazole sulfoxide blood levels measured post administration based on two formulations labelled Reformulation 1 and Reformulation 2; Figure 2 shows a graph of albendazole sulfoxide blood levels measured post 5 administration based on a third formulation labelled Reformulation 3 and a Reference albendazole oral drench product; Figure 3 shows a graph of albendazole sulfoxide blood levels measured post administration based on Reformulation 2 and a Reference albendazole oral drench product; 10 Figure 4 shows a graph of albendazole sulfoxide blood levels measured post administration based on an active only capsule with no carriers or surrounding formulation; and, Figure 5 shows a graph of albendazole sulfoxide blood levels measured post administration of a fourth formulation (Reformulation 4) compared to 15 a Reference albendazole oral drench. BEST MODES FOR CARRYING OUT THE INVENTION Examples are now provided showing various embodiments of the present invention. 20 EXAMPLE 1 In a first trial, the inventors developed tablet formulations containing albendazole and the bioavailability of these formulations was tested. 12 James & Wells Ref: 44238 / 29 552291 Formulations Three formulations were tested containing: • Reformulation 1 includes: Table' : Reformulation 1 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: 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 13 James & Wells Ref: 44238 / 29 552291 • Reformulation 3 includes: Table 3: Reformulation 3 Composition Component Quantity per tablet [%] Quantity per tablet (mg) Abamectin 1.28 12.0 Monopropylene glycol 6.52 58.0 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 5 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 which Reformulation 2 was compared with the Reference products. Animal Selection 10 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 3.75 mg/kg albendazole. Prior to administration of the invention or Reference formulation, all animals were dosed to their individual liveweight with Scanda™ (Batch 52888, expiry April 2006) 15 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. 14 James & Wells Ref: 44238 / 29 552291 Dosing All sheep were administered with a dose sufficient for a 60kg animal. Reference Products Reference product used was a single albendazole oral drench being Valbazen™ 5 (Batch 800211, Expiry 06/2007). It should be appreciated that this Reference product provides a high bar in terms of bioavailability to be reached by the present invention. Therefore, providing a tablet formulation with comparable levels of bioavailability would be an advantage. It should be noted that lower levels of bioavailability may still be of commercial value 10 given the advantages a tablet offers as noted previously. Sampling times Blood samples (4ml per sample) were taken from the tested animals at time intervals of 6 hours (h), 12h, and 24h post administration. Blood was collected from the jugular vein via venipuncture, directly into heparinised 15 vacutainer tubes and refrigerated at 4°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 -18°C in separate freezers before laboratory analysis. Results 20 Treatment Session 1 Albendazole 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 15 James & Wells Ref: 44238 / 29 552291 (Figure 1). The plasma concentrations peaked at 4.6|jg/ml and 5.1pg/ml for Reformulation 1 and Reformulation 2. The Tmax for both formulations occurred 15h post administration. Treatment Session 2 5 Albendazole The albendazole plasma profiles observed for Reformulation 3 and the Reference products are shown (Figure 2). The Cmax observed for the Reformulation 3 and Reference treatment groups were 0.54|jg/ml and 2.2|jg/ml respectively. For both formulations Tmax was 15h after administration. Reformulation 3 showed some release and absorption of albendazole but not the extent desired to be comparable to Reference oral drench product Valbazen™. Treatment Session 3 After comparing the Reformulation 2 results from Treatment Session 1 with the Reference results from Treatment Session 2, it was decided to compare Reformulation 2 with the Reference products in the 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. Albendazole The albendazole plasma profiles observed for Reformulation 2 and the Reference 20 product is shown (Figure 3). The Cmax observed for the Reformulation 2 and Reference treatment groups were 0.64|jg/ml and 0.92|jg/ml respectively. The Tmax for both formulations occurred 15h post administration, and the error bars (showing standard deviations) demonstrate the variation between individuals to be considerable and may largely explain the difference observed in the plasma profile 16 James & Wells Ref: 44238 / 29 10 15 552291 of two formulations. Therefore it may be concluded that Reformulation 2 compared well against the Reference product Valbazen™. EXAMPLE 2 5 Given the results in Example 1, a further trial was completed to determine the influence of the formulation on the degree of absorption of albendazole compound. This was completed by ascertaining baseline levels of drug bioavailability when animals are dosed with raw albendazole active (no excipients). Experimental Design 10 Five sheep weighing 59.0kg to 63.5kg (mean = 61.2kg) were all dosed with one albendazole treatment, which contained a dose sufficient for a 60kg animal at the standard dose rates of 3.75mg/kg albendazole. The dose for albendazole was contained within a gelatine capsule. Experimental Animals 15 Prior to administration of the invention or Reference formulation, all animals were dosed to their individual liveweight with Scanda™ (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. 20 Dosing Regime Gelatine capsules containing an albendazole anthelmintic drug (two capsules per sheep) were used. All animals were dosed orally (with the assistance of a "pill popper", which was followed immediately by approx 60ml of tap water. The capsules were dark green in colour. 17 James & Wells Ref: 44238 / 29 552291 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 5 time. Sampling times were 6h, 15h, and 24h post administration. The blood was collected from the jugular vein via venipuncture, directly into heparinised vacutainer tubes and refrigerated at 4°C until processing. It was then centrifuged at 2500 rpm for 10 minutes before the plasma was collected, and 10 divided into test (2ml/analyte) and reserve (2ml), samples and frozen. Test and reserve samples were maintained at -18°C in separate freezers before laboratory analysis. Results Albendazole 15 The data found indicates that Tmax for albendazole sulfoxide occurred between the 6h and 15h sampling times (Figure 4). However, Cmax was approximately 50% of that generally considered necessary for full therapeutic efficacy. 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 20 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. 18 James & Wells Ref: 44238 / 29 552291 Conclusions The results from this study (when compared to Reference product) suggest that the inclusion of excipients in albendazole formulations improves the bioavailability. In the absence of excipients, plasma levels obtained for albendazole were reduced 5 (compared to reference product), but comparable to previous test formulations tested. The results show that tablet formulations (containing excipients) are an important factor in achieving drug bioavailability. 10 EXAMPLE 3 A fresh formulation (Reformulation 4) was tested based on prior trials including those identified above in Example 1. The formulation included: 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 15 The above ingredients were used to manufacture Reformulation 4. 19 James & Wells Ref: 44238 1 29 552291 The finished product is a tablet that breaks down within approximately 15 minutes in 37°C water. During storage, the tablet remains stable and active agent levels remain stable. In this example, the animals used were cattle with other characteristics of the study 5 remaining the same as that of Example 1 except that the formulation was also altered as noted above. Results Albendazole Reformulation 4 was altered by using approximately double the amount of 10 albendazole in order to ensure that the amount of albendazole provided was comparable to that normally used for cattle. As seen in Figure 5, Reformulation 4 resulted in the albendazole profile also becoming almost equivalent with that observed for the Reference oral drench formulation Valbazen™. 15 EXAMPLE 4 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 20 • Disintegration time • Average weight • Weight variation 20 James & Wells Ref: 44238 / 29 552291 • Concentration of abamectin • Hardness Subsequent to initial tests, a first trial was commenced with 12 tablets placed into an environment held at a constant temperature of 30°C and 60% relative humidity. 5 A second trial was also commenced with 12 tablets placed into an environment held at a constant temperature if 40°C and 75% relative humidity. 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. 10 The first trial was conducted over 18 months and the second trial over 6 months. 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'. 15 Table 5: Storage Stability for a Temperature of 30°C and Relative Humidity of 60% Test Specification/ Standard Initial 3 Months 6 Months 9 Months 12 Months 18 Months Visual Description An off-white, round, flat tablet: bevelled edge. May have score-line on one side. Complies Complies Complies Complies Complies Complies Disintegration Time in Water Less than 15 minutes Complies Complies Complies Complies Complies Complies Average tablet weight (mq/tablet) 795.2-920.8 mg/tablet Complies Complies Complies Complies Complies Complies Weight Variation Tablets were individually weighed. Of the total tablets, no more than two Complies Complies Complies Complies Complies Complies 21 James & Wells Ref: 44238 / 29 552291 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 10.8-13.20 mg/tablet by HPLC 12.9 12.7 11.9 11.9 12.0 12.0 Levamisole HCL content ±10% w/w basis or 412.2-503.80 mq/tablet bv HPLC 489 492 — 495 486 465 Albendazole content 205.2- 250.80 ma/tablet by HPLC 235 247 246 248 244 243 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% Test Specification/ Standard Initial 1 Month 3 Months 6 Months Visual Description An off-white, round, flat tablet: bevelled edge. May have score-line on one side. Complies Complies Complies Complies Disintegration Time in water Less than 15 minutes Complies Complies Complies Complies Average tablet weight (mg/tablet) 795.2 - 920.8 mg/tablet Complies Complies Complies Complies Weight Variation Tablets were individually weighed. 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% Complies Complies Complies Complies Abamectin content ±10% w/w basis or 10.8-13.20 mg/tablet by HPLC 12.9 12.4 12.3 11.5 Levamisole HCL content ±10% w/w basis or 412.2-503.80 mg/tablet by HPLC 489 489 473 480 Albendazole content ±10% w/w basis or 205.2-250.80 mg/tablet by HPLC 235 235 238 243 Hardness > 5.0 Kg Complies Complies Complies Complies 22 James & Wells Ref: 44238 / 29 552291 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. 5 EXAMPLE 5 The tablet formulations described above were manufactured as described and packaged in a blister pack sealing the tablets into a package. Markings may be included on the packaging indicating the user when the tablets should be 10 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 package for sale jointly as a kit. Besides mechanical devices for administration such as a pill popper of gas 15 actuated applicator, there may be, in the place of an applicator, a dough composition which encases the pill and which masks the pill from 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 be supplied with or without an applicator. EXAMPLES CONCLUSION It should be appreciated from the above examples that developing a tablet for delivery of albendazole (and benzimidazoles generally) has presented many challenges. The inventors have achieved this, providing a formulation including 23 James & Wells Ref: 44238129 552291 albendazole that not only provides agent 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 administration such as oral drenches. An advantage of tablets is that they provide a fixed and known dose of agent and 5 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 example are only sold in large volumes (and at greater expense). Aspects of the present invention have been described by way of example only and 10 it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims. 24 James & Wells Ref: 44238 / 29 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 552291 WHAT WE CLAIM IS:

1. A tablet formulated for administration to an animal characterised in that the tablet includes at least one substituted or unsubstituted benzimidazole compound and characterised in that the benzimidazole compound has anthelmintic activity and is present in the tablet as micronised particles.

2. The tablet of claim 1 wherein the benzimidazole compound or compounds are characterised by having poor solubility and/or dispersion characteristics in an aqueous environment.

3. The tablet as claimed in claim 2 wherein the aqueous environment is extracellular fluid.

4. The tablet as claimed in any one of the above claims wherein the benzimidazole compound or compounds include the structure: where n = 1 or 2; where R-i which may be the same or different at each occurrence = H, CI, -SC3H7) —SOCsHy, —SCeHs, —SOCeHs, —C4H9, or —OC6H3CI2! and, where R2 = -NHC02CH3 or -SCH3.

5. The tablet as claimed in any one of the above claims wherein the benzimidazole compound or compounds are selected from: albendazole, ricobendazole, fenbendazole, oxfenbendazole, parbendazole, triciabendazole and combinations, analogues and derivatives thereof. 25 552291

6. The tablet as claimed in any one of the above claims wherein the benzimidazole compound is albendazole.

7. The tablet as claimed in any ore of the above claims wherein the 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.

8. The tablet as claimed in any one of claims 1 to 7 wherein the benzimidazole compound or compounds included in the tablet are at a dose sufficient 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.

9. The tablet as claimed in any one of claims 1 to 8 wherein the benzimidazole compound is albendazole included at a rate of at least 1 mg of albendazole per kg of animal body weight.

10. The tablet as claimed in any one of claims 1 to 8 wherein the benzimidazole compound is albendazole included at a rate of at least 3.7 mg of albendazole per kg of animal body weight wherein the animal is a sheep.

11. The tablet as claimed in any one of claims 1 to 8 wherein the benzimidazole compound is albendazole included at a rate of at least 7.5 mg of albendazole per kg of animal body weight wherein the animal is a bovine.

12. The tablet as claimed in any one of the above claims wherein the benzimidazole compound or compounds are formulated to be rapidly released on oral administration.

13. The tablet as claimed in any one of the above claims wherein the benzimidazole compound or compounds are formulated so that the compound or 26 552291 compounds or its active metabolites remain present in the bloodstream of the animal for at least 12 hours.

14. The tablet as claimed in any one of the above claims wherein the benzimidazole compound or compounds are formulated so that the compound or compounds or its active metabolites dissipate from the bloodstream within 4 days.

15. The tablet as claimed in any one of the above claims wherein the tablet remains 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%.

16. The tablet as claimed in claim 15 wherein the tablet remains stable for at least 18 months.

17. The tablet as claimed in claim 15 or claim 16 wherein the tablet is chemically stable whereby the active agent concentration remains at within 10% of initial levels and is physically stable such that no physical alteration is observed in the tablet during storage or at the time of administration.

18. 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.

19. The tablet as claimed in any one of the above claims wherein the tablet contains inert compositions selected from: binders; fillers; bulking agents; carriers; disintegration agents; glidants; lubricants; and combinations thereof.

20. A tablet formulated for administration to an animal characterised in that the tablet includes albendazole wherein the raw material albendazole is in micronised particle form. 27 552291

21. The tablet as claimed in claim 20 wherein the tablet contains at least 1 mg/kg albendazole.

22. A method of treating non-human animals for parasite infestation by administration of a tablet composition containing at least one substituted or unsubstituted benzimidazole compound as claimed in any one of the above claims.

23. The method as claimed in claim 22 wherein the raw material benzimidazole compound or compounds are micronised.

24. The method as claimed in claim 22 or claim 23 wherein the non-human animal is a ruminant animal.

25. The method as claimed in claim 24 wherein the non-human animal is of ovine of bovine species.

26. The method as claimed in any one of claims 22 to 25 wherein the parasites are endoparasites.

27. Use of at least one substituted or unsubstituted benzimidazole compound in the manufacture of a tablet as claimed in any one of claims 1 to 21 for the treatment of parasites in non-human animals.

28. The use as claimed in claim 27 wherein the raw material benzimidazole compound or compounds are micronised.

29. The use as claimed in claim 27 or claim 28 wherein the non-human animal is a ruminant animal.

30. The use as claimed in any one of claims 27 to 29 wherein the non-human animal is of ovine or bovine species. 28 552291

31. The use as claimed in any one of claims 27 to 30 wherein the parasites are endoparasites.

32. A tablet, substantially as hereinbefore described with reference to Example 1 and Reformulation 2 as well as Figure 3.

33. A tablet, substantially as hereinbefore described with reference to Example 3 and Reformulation 4 as well as Figure 4.

34. A method of treatment of a pest infestation in a non-human animal in need thereof substantially as hereinbefore described with reference to Example 1 and Reformulation 2 as well as Figure 3.

35. A method of treatment of a pest infestation in a non-human animal in need thereof substantially as hereinbefore described with reference to Example 3 and Reformulation 4 as well as Figure 4.

36. Use of at least one substituted or unsubstituted benzimidazole compound in the manufacture of a tablet for treatment of a parasite infestation in an animal substantially as hereinbefore described with reference to Example 1 and Reformulation 2 as well as Figure 3.

37. Use of at least one substituted or unsubstituted benzimidazole compound in the manufacture of a tablet for treatment of a parasite infestation in an animal substantially as hereinbefore described with reference to Example 3 and Reformulation 4 as well as Figure 4. BOMAC RESEARCH LIMITED JAMES & WELLS 29 </div>