NZ522681A - Rapidly-disintegrating tablets for animals - Google Patents

Abstract

A tablet for orally administering at least one agent to an animal or human subject, said tablet comprising said at least one agent dispersed within a matrix comprising particles of a natural, fibrous cellulose material, and characterized in that the tablet disintegrates in about 15 seconds or less when placed in still water at room temperature.

Description

52*681 WO 01/89575 PCT/AU01/00596 I RAPIDLY-DISINTEGRATING TABLETS FOR ANIMALS Field of the Invention: The present invention relates to orally-administered preparations for 5 veterinary and/or human therapeutic purposes. More particularly, the invention provides a tablet formulation which rapidly disintegrates in the mouth/oesophagus of an animal/human into a pallatable and readily swallowed mass.

Background to the Invention: Oral administration of veterinary preparations such as tablets, pastes and solubilised/suspended "drenching" formulations to livestock and other animals (e.g. companion animals), is often difficult and time consuming and can also result in the loss, by rejection, of all or a portion of the active 15 ingredient thereby leading to possible sub-therapeutic dosing (which can, in the case of agents such as antibiotics and anthelmintics, lead to the development of resistance in the target organism). For example, with tableted formulations, which animals must be forced to swallow, losses of the active ingredient are frequently caused through animals "spitting out" all or part of 20 the tablet placed in their mouth/oesophagus. In addition, it is not uncommon for animals to regurgitate and expel orally-administered veterinary preparations before they are fully dispersed in the rumen or stomach/intestine where they are absorbed. With "drench" formulations, further difficulties may be experienced through separation or "stratification" of components 25 either in the container, dosing apparatus or in the rumen which can cause inaccuracies in dosing. Further, chemical interaction or degradation (e.g. hydrolysis) of components of "drenching" formulations can result in the production of potentially toxic by-products. Moreover, inherent instability or lack of appropriate liquid excipients for some single or multiple active 30 ingredients have hitherto precluded use in liquid drench formulations. Also, drenching with liquid formulations demands considerable veterinarian/operator compliance with provision of clean, functioning delivery ("drench") apparatus, formulation preparation and correct dosage rate/volume selection.

The present invention provides a novel tablet formulation which appears to be less objectionable to animals than previous tablet formulations WO 01/89575 PCT/AU01/00596 2 and thereby offers a much increased likelihood that all or, at least, the vast majority of the tablet composition will be swallowed and retained by an animal. The tablet therefore offers advantages in terms of more successful and accurate dosing of animals while avoiding the abovementioned stability 5 and compliance problems of solubilised/suspended formulations.

Summary of the Invention: Thus, in a first aspect, the present invention provides a tablet for orally administering at least one agent to an animal or human subject, said tablet 10 comprising said at least one agent dispersed within a matrix comprising particles of a natural, fibrous cellulose material, and characterised in that the tablet disintegrates in about 15 seconds or less when placed in still water at room temperature.

In a second aspect, the present invention provides a method for orally 15 administering an animal or human subject with at least one agent, said method comprising delivering a tablet according to the first aspect into the mouth or oesophagus of said animal or human subject.

Detailed disclosure of the Invention: As mentioned above, tablets according to the present invention are characterised in that they disintegrate, when placed in still water at room temperature (i.e. about 22°C), in about 15 seconds or less, more preferably about 10 seconds or less, and most preferably about 5 seconds or less. Such disintegration times may be readily measured with the unaided eye by 25 placing a tablet into a container with, preferably, sufficient water to cover the tablet. Commencement of disintegration is observed as a rapid swelling of the tablet. When there is no further swelling of the tablet apparent to the unaided eye, the tablet is to be regarded as completely disintegrated. In some cases, the disintegrated tablet will appear as a "pile" of material at the bottom 30 of the container. In other cases, the disintegrated tablet will retain some shape related to the original tablet shape (e.g. a disc-shaped tablet may swell and disintegrate into a bar or "sausage" shape - the tablet may swell up to 5-10 times or more in the longitudinal axis), however slight agitation of the water (e.g. by gentle swirling) will reveal that the disintegrated tablet is very 35 unstable and, accordingly, a tablet which has swelled into a shape related to its original shape is also to be regarded as completely disintegrated.

WO 01/89575 PCT/AU01/00596 3 Preferred tablets according to the present invention rapidly disintegrate after being placed in the mouths/oesophaguses of animals (e.g. in less than 5 seconds, but preferably, in less than 3 seconds and, more preferably, in less than 2 seconds) into a pallatable and readily swallowed mass. While not 5 wishing to be bound by theory, it is believed that the particulate nature of the fibrous cellulose material of the disintegrated mass has a "feel" in the mouth/oesophagus which is more akin to that of normal foods or digesta rather than the somewhat "foreign" feel provided by a solid tablet, and is therefore more conducive to being swallowed. As the disintegrated mass is 10 formed so quickly after the tablet is placed in the mouth/oesophagus, "spitting out" of the tablet or its components by animals such as sheep may be largely avoided.

The tablet of the present invention is primarily intended for veterinary use (particularly for livestock and companion animal usage), but is also 15 expected to be suitable for human use. By the inclusion of suitable flavourings and/or colours, and/or agents which alter the "feel" of the tablet in the mouth, tablets according to the present invention may be readily prepared for use with children and elderly adults who frequently have difficulty in swallowing medicines in traditional tablet, caplet or capsule forms. 20 The at least one agent may be selected from biologically active agent(s) or essentially inert agents such as dyestuffs (e.g. rhodamine B).

Biologically active agent(s) may be selected from agents of veterinary or human therapeutic significance, such as antibiotics, anthelmintics, antiviral agents, antigens (i.e. for vaccination purposes), vitamins and hormones (e.g. 25 steroids and growth hormone). Especially preferred are anthelmintic agents (e.g. macrocylic lactone anthelmintic agents) for treatment of parasitic infestations, particularly in sheep. Suitable rumen-protected anthelmintics for use in tablets of the present invention have been described in International patent publication No. WO 94/27598, the entire disclosure of 30 which is to be regarded as incorporated herein by reference. The present invention makes the use of such rumen-protected anthelmintics (and other rumen-protected biologically active agents) commercially feasible, since drench formulations including such rumen-protected anthelmintics have previously proved to be unstable.

WO 01/89575 PCT/AU01/00596 4 The at least one agent may comprise 0.01-50 wt% of the tablet. Preferably, the at least one agent comprises 5-45 wt%, more preferably 35-45 wt%, of the tablet.

The natural, fibrous cellulose material may be any natural, non-toxic 5 cellulose plant material or mixtures containing such plant material. Such plant material is generally in the form of fibres of crystalline cellulose embedded in a matrix of amorphous hemicellulose and lignin, although other compounds may also be present. On a dry weight basis, the cellulose and hemicellulose typically comprises 40 - 70 wt% of the matrix and lignin 5-25 10 wt% of the matrix. Again, while not wishing to be bound by theory, it is believed that the fibrous nature of the plant material facilitates the rapid disintegration of tablets according to the invention by providing pores and capillarity for ingress of water/saliva. Further, the presence of other natural components such as lignins is believed to assist production of tablets 15 according to the invention by methods which use only low compression forces. It is, however, to be understood that plant materials suitable for tablets according to the invention may be treated to remove lignins by, for example, methods routinely employed in the paper industry.

Suitable natural, fibrous cellulose materials include wood, cane 20 (especially sugar cane), seeds (especially cereal seeds such as wheat, oats and barley), legumes, grasses (especially lucerne) and mixtures thereof. In order to provide the food-like "feel" described above, it has been found that the natural, fibrous cellulose materials are required to be in a particle form (but, preferably, not a fine powder form), more preferably, a relatively coarse 25 particle form wherein the particles have em average dimension of 0.5 to 2 mm (i.e. they will be retained by a 10-14 mesh screen but will readily pass through larger screens). Presently, the most preferred natural, fibrous cellulose material is a mixture of two types of wood particles (e.g. meranti and pine shavings sieved through a 1.7 mm screen), but particulated pine 30 needles and ground sheep feed nuts are also suitable. 1 mm particles of oats, dried lucerne or a mixture thereof are also suitable and may offer some advantages in terms of increased quality control in supply and tablet production.

As indicated above, tablets according to the invention may be produced 35 by methods involving low compression forces. Preferably, the tablets are produced using standard tableting machines and compression forces applied WO 01/89575 PCT/AU01/00596 to achieve a "soft" tablet form having sufficient physical robustness to retain shape and integrity for packaging, storage and transport. The ability to produce tablets according to the invention with low compression forces provides an advantage in that it allows production of tableted formulations 5 with certain biologically active agents which show compromised absorption and bioavailability (e.g. microorganisms and coated or micro-encapsulated materials) when subjected to pressure or shear forces typical of production methods for highly compressed tablets.

Tablets according to the invention may be produced in any of the 10 common tablet shapes, for example, disc-like or pellet shapes, spheroids, ovoids, and caplet shapes. The present applicants have found that disc-like or pellet shaped tablets with a diameter ranging from about 7-15 mm and thickness of about 2.5 - 7 mm (weight range approx. 10 - 800 mg) are particularly suitable for rapid disintegration. However, most preferred are 15 disc-like tablets with a diameter of about 8 mm and thickness of about 3 mm (weight approx. 150 mg).

Tablets according to the present invention may be readily delivered into the mouth/oesophagus of an animal or human subject by hand. They may, however, be delivered by more automated procedures. For example, 20 tablets according to the present invention may be conveniently provided in long strips of bubble or blister-pack type packaging (i.e. with one or more tablets per blister), so that a strip containing large numbers of tablets (e.g. 50 to 250 or more) can be rolled into a cartridge or magazine which might be fitted into a dosing gun. Such a gun preferably includes a ratchet or similar 25 mechanism to continuously feed the strip to a dispensing mechanism which punches tablets from their respective blisters to a dispensing tube adapted for easy placement in an animal's mouth/oesophagus. Similarly, tablets according to the present invention may be conveniently provided in a substantially tubular container, wherein the tablets are arranged in a "stack" 30 formation and dispensed through a dosing gun or, alternatively, by providing the container with a plunger.

Thus, in a further aspect, the present invention provides a package containing a plurality of tablets according to the present invention, wherein said package is in the form of a strip and comprises, along the length of the 35 strip, a plurality of receptacles each containing one or more of said tablets.

WO 01/89575 PCT/AU01/00596 6 Preferably, the strip package is adapted such that pressure applied to a receptacle by, for example, a human finger/thumb or a simple punch mechanism, results in the contained tablet(s) being discharged from that receptacle. Preferably, the tablet(s), when discharged from the package, are 5 substantially intact.

Preferably, the package is formed from a laminate of a foil strip and a strip of durable but deformable plastic (e.g. cellophane, polycarbonate or polypropionate) defining receptacles or "blisters". The receptacles may be substantially equally spaced along the length of the package strip. Preferably, 10 the receptacles are water impermeable.

In a still further aspect, the present invention provides a package containing a plurality of tablets according to the present invention, wherein said package is in the form of a substantially tubular container defining a lumen containing said tablets.

The substantially tubular container package may include a plunger at a distal end of said container and, at the proximal end, said container may be adapted such that movement of the plunger towards the proximal end permits controlled dispensing of one or more tablets from said container.

The substantially tubular container package may otherwise be adapted 20 for attachment to a dosing gun such that one or more tablets may be controllably fed into the breech of the dosing gun for dispensing. The tablets may be fed into the breech of the dosing gun through gravity or by providing the substantially tubular container package with a spring mechanism such as those typical of gun magazines.

In a yet still further aspect, the present invention provides a kit comprising a dosing gun and a package of tablets according to the present ivention, wherein said dosing gun and package cooperate to permit dispensing of said tablets.

In a preferred embodiment of the invention, a tablet according to the 30 invention is provided which comprises; (i) 5-45 wt% of a biologically active agent, (ii) 30 - 95 wt% of a natural, fibrous cellulose material in particle form, and (iii) 0-25 wt% of at least one binding material.

More preferably, the tablet comprises 30 - 45 wt% of at least one biologically active agent, 45 - 65 wt% of a natural, fibrous cellulose material in particle form, and 5-10 wt% of at least one binding material. However, biologically active agents such as hormones and antigens may be used at amounts as little as 0.01 -1 wt%.

The binding material(s) may be selected from any of the binders 5 commonly used in the production of tablets for veterinary and/or human therapeutic purposes (e.g. lactose, icing sugar, synthetic celluloses, polyethylene oxides and others). Especially preferred by the applicants are lactose and F160 (a synthetic sucrose ester; Croda).

Tablets according to the invention may further comprise other 10 excipients such as disintegrant materials (e.g. gelling materials such as Aquasorb (ICI) and Separan AP30 (Dow Chemicals)), wetting agents (e.g. sodium lauryl sulphate at about 2-5 wt%) and builders/fillers. They may also comprise flavourings and/or colours, and/or agents which alter the viscosity, grannlarity, or "feel" of the tablets.

In a further preferred embodiment, a tablet according to the invention is provided which comprises: (i) 30 - 45 wt% of an anthelmintic agent, (ii) 45 - 65 wt% of a natural, fibrous cellulose material in particle form, and (iii) 0-25 wt% of at least one binding material.

In a still further preferred embodiment, a tablet according to the invention is provided which comprises: (i) 30 - 45 wt% of a dyestuff, (ii) 45 - 65 wt% of a natural, fibrous cellulose material in particle 25 form, and (iii) 0-25 wt% of at least one binding material.

Tablets according to the present invention may be produced by standard methods well known in the art. For high speed production methods such as those wherein large dry volumes of tablet components are shaken 30 into die cavities for compression, in order to avoid non-uniform distribution of the at least one agent in a tablet batch (i.e. as may result from settling of "heavy" agent particles from the natural, fibrous cellulose material), it may be preferred to spray the at least one agent onto all or a portion of the particles of the natural, fibrous cellulose material prior to compression. This may be 35 achieved, for example, by forming a solution or suspension of the at least one agent and spraying the solution or suspension onto all or a portion (e.g. 10%) WO 01/89575 PCT/AU01/00596 8 of the particles of the natural, fibrous cellulose material with a suitable spraying apparatus (e.g. a fluid-bed spray dryer).

As mentioned above, tablets according to the invention may comprise a dystuff such as rhodamine B. Such tablets may be useful in methods of 5 assessing wool growth in wool-growing animals and, additionally, in methods for monitoring feeding of livestock.

Thus, in another aspect of the present invention, there is provided a method of measuring wool growth in a wool growing animal, said method comprising; (i) administering said animal with a first tablet according to the present invention comprising a wool fibre-staining dyestuff as the at least one agent, such that a first band of dyestuff may be subsequently detected in the wool fibres of said animal, (ii) after a predetermined period, administering to said animal a 15 second tablet according to the present invention comprising a wool fibre- staining dyestuff as the at least one agent, such that a second band of dyestuff may be subsequently detected in the wool fibres of said animal, and wherein the dyestuff of said second tablet may be the same or different to said dyestuff of the first tablet, and 20 (iii) thereafter obtaining a wool fibre sample from said animal and measuring the distance between said first and second bands of dyestuff in said wool fibre sample.

The distance between the first and second bands of dyestuff in said wool fibre sample indicates the wool growth dining the administration of the 25 first and second tablets. Typically, the said predetermined period will be 7 -42 days, but any period which results in distinct bands of dyestuff in the wool fibres may be suitable. Preferably, the said predetermined period will be about 28 days. The wool fibre sample may be obtained from the animal within about 7-21 days after administration of the second tablet, although 30 shorter and longer periods may also be suitable. Depending upon the particular dyestuff(s) used, the one or both of the bands may need to be visualised using a UV light source.

In an alternative, the wool growing animal may only be administered with a first tablet according to the present invention comprising a wool fibre-35 staining dyestuff as the at least one agent, and wool growth may be assessed by measuring the width of the band produced in the wool fibres of that WO 01/89575 PCT/AUO1/O0596 9 animal. That is, the width of the band will correspond to the time that it takes the animal to clear the dyestuff from its circulation after administration, and will therefore indicate the wool growth during that time.

In yet another aspect, the present invention provides a method of 5 monitoring feeding of a livestock animal, said method comprising providing feed to said animal which includes at least one tablet according to the present invention comprising a dyestuff as the at least one agent, and after a period whereby it would be normally expected that said animal would have fed on the provided feed, determining the presence or absence of said dyestuff in a 10 suitable sample from said animal.

Such a method allows monitoring of feeding of livestock animals from feed provided in feed bins or the like. The feed may be readily blended with a dyestuff-comprising tablets according to the present invention in an amount whereby a feeding animal is likely to consume one or more of said tablets. 15 The suitable sample is preferably selected from urine and/or droppings.

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other 20 element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base 25 or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

In order that the present invention may be more clearly understood, preferred forms will be described in the following example.

Brief description of the accompanying figures: Figure 1 provides a graph showing the systemic concentration of ivermectin in sheep over 100 hours following administration of 0.2 mg/kg ivermectin formulated as either a tablet according to the present invention or 35 as an oral drench (i.e. IVOMEC), Example 1: Tablets comprising rumen-protected abamectin MATERIALS AND METHODS Because this formulation was conducive to administration of a rumen 5 protected matrix, containing abamectin (ABA) as the therapeutic component, this material was used as the candidate active in the tableted formulation. Preparation of rumen-protected drug matrix Rumen protection of an orally administered biologically active agent is designed to prevent association with particulate digesta material in the rumen 10 but to provide for degradation and bioavailability as it passes through the abomasum and small intestine of the sheep. Such a "carrier" technology has been developed by the present applicants and is described in International patent publication No. WO 94/27598.

For preparation of rumen-protected ABA for tableting, pure ABA was 15 evenly dispersed in vegetable oil (sunflower or soybean oil) at a w/w ratio of 1 part ABA to 1 part oil. The ABA-oil mixture was then emulsified with a solution of 16.5% w/v casein adjusted to pHlO in distilled water. The w/w ratio of ABA:oil:casein was 1:1:1, and the microparticle product therefore had a 33% loading of ABA. The emulsions were then dried using standard freeze 20 drying or fluid bed drying procedures after which the dry matrix was comminuted in a small grinder to particles of 0.5 - 1.0 mm diameter.

Three levels of lipid and protein "protection" for ABA formulations, (low: 10 -15%), medium (40 - 45%) and high (75 - 80%) were prepared by cross-linking or denaturing the protein surface of the microparticle by 25 exposure to formaldehyde. The fine particles were placed in a sealed chamber and exposed to formaldehyde (36%) vapour for 10 days, the degree of protection (medium or high) depending on the concentration of formaldehyde used. As a comparison of the effect of formaldehyde protection, one sample of ABA matrix was not exposed to formaldehyde. As 30 an alternative procedure, the high level protection matrix could be prepared by adding the appropriate quantity of formaldehyde at the oil-protein emulsifying stage to form a gelatinous matrix. This material was then dried and comminuted as described above.

In vitro determination of the degree of rumen-protection 35 A donor sheep was surgically fitted with a cannula in the reticulo- rumen and fed a daily ration of 75 Og equal parts lucerne :wheaten chaff.

WO 01/89575 PCT/AU01/00596 11 Water was provided ad libitum. Rumen digesta was freshly obtained and the fluid was separated from particulate material by centrifugation (12000xg for 20 mins). Triplicate lOOmg samples of the matrix under test were added to 10ml of rumen fluid and incubated in darkness with gentle mixing at 38°C for 5 24 hours. Thereafter, the degree of matrix degradation was determined by the extent of hydrogenation of the lipid component and proteolysis of the protein.

For lipid protection, the lipids from 0 and 24 hour incubations were extracted and quantified by GLC. The ratio 0hr/24hr was expressed as a percentage.

To determine levels of protein protection, the incubated matrix was steam distilled and the quantity of ammonia present determined by titration. The level of protein protection (ammonia content) was determined by comparison with protein standards and "blank" rumen fluid, expressed as a percentage.

The levels of lipid and protein protection was designated as low (10 - %), medium (40 - 45%) and high (75 - 90%).

Tableting machines and tablet manufacture Tablets were produced using either of a single 7mm diameter cavity press (constructed in the CSIRO Armidale, NSW workshop) with a hand 20 operated screw-thread pushing a compression plunger, and a motor-driven Manesty F3 tablet machine modified to permit slow hand filling of the cavity and single compression strokes when required, Cavities and punches are interchangeable to allow production of tablets with diameters up to approx. 20 mm, the positioning of the bottom punch dictating the cavity depth (and 25 hence weight and thickness of the tablet produced) and the top punch positioning dictating the compression pressure applied to the tablet.

The required components for each formulation were weighed out separately and mixed by gentle shaking in an air-filled plastic bag. The cavity of the tabletting machine was then filled with the mixture either by hand (i.e. 30 using a spatula to fill to the top of the die) or automatically with a filling shoe which clears the top of the die. Low compression force was then applied to achieve a tablet form.

Tablet stability and disintegration Tablet stability is usually described in terms of "hardness". Due to the 35 softness of tablets according to the invention, conventional measures for stability was unsuitable. Accordingly, a simple "drop test" was adopted WO 01/89575 PCT/AU01/00596 12 involving dropping tablets from a height of 1.5m onto a hard surface such that the tablets landed edge-on. Tablets fracturing with loss of more than about 3% were considered to be failures. Because of the known propensity for compressed mixtures to undergo some change over time after the 5 compression force is released, the drop test was repeated after storage for extended periods.

A simple model for disintegration after oral administration by an animal was used which involved measuring the time taken for the tablet to visibly swell and become diffuse or disintegrate when placed into a container 10 of water at room temperature without any turbulence or agitation. Initial studies with citrate/bicarbonate preparations showed that "fizzer" (COz generation) technology was unsuitable because of the long (minutes) disintegration times. Exploratory formulations using soft compression of fine wood chips or shavings produced the desired disintegration times indicating 15 that plant materials were an appropriate tablet matrix.

In vivo evaluation of rumen-protected ABA formulations The behaviour of tablets including ABA as the biologically active agent was examined in sheep by determining the pharmacokinetic disposition of the active agent in the bloodstream and abomasal fluid. ABA was 20 administered in the "free" powder form of the rumen-protected matrix and as the commercial ABA formulation, Virbamec (Virbac Animal Health, Australia). The principal pharmacokinetic parameters Cmox (maximum concentration), Tmax (time of Cmax ) and AUC (area under the concentration-time curve) were determined and compared between treatments. 25 Specifically, 17 nine-month old Border Leicester wether sheep of good health (and having been treated with 0.2mg ivermectin (IVM)/kg (Ivomec, Australia) to remove any resident worms), were surgically fitted with a permanent sampling cannula in the pyloric region of the abomasum and were restrained in individual metabolism cages in an air-conditioned room. After recovery 30 from surgery they were accustomed to a daily ration of 600g equal parts lucerne: wheat chaff with water provided ad libitum.

Trial 1 (rumen-protected formulation v commercial formulation): Eight of the animals were divided randomly into 4 sub-groups of 2 animals with similar bodyweight distribution. The 4 sub-groups were orally administered 35 with ABA at a dose rate of 0.2mg/kg either as the commercial formulation, Virbamec (Virbac Animal Health) or rumen-protected ABA matrix WO 01/89575 PCT/AU01/00596 13 formulation with low, medium or high level of protection (see "Preparation of rumen-protected anthelmintic" below]. Virbamec was administered by intraruminal injection whereas the rumen-protected doses were dispensed into a gelatin capsule and administered per os using a balling gun. 5 Trial 2 Cfree" v tableted rumen-protected formulation): The remaining nine sheep were divided into 3 groups of 3 animals with similar bodyweight distribution and were orally administered with ABA at a dose rate of 0.2mg/kg either as the commercial formulation, Virbamec or rumen-protected ABA matrix formulation with medium-high level of protection either as "free" 10 matrix or as the rumen-protected matrix which had been compressed with cellulose (wood shavings) into a soft tablet according to the present invention. Virbamec was administered by intraruminal injection whereas the protected doses were dispensed into a gelatin capsule and administered per os using a balling gun.

Blood was sampled from the sheep by jugular venipuncture into heparinised evacuated tubes ("Vacutainer" tubes, Becton Dickinson, Australia) and abomasal digesta was collected directly from the sampling cannula at 1, 2, 4, 6, 9, 12, 16, 24, 30, 36, 48, 56, 72, 80, 96, 120, 144, 192 and 240 hours after dose administration. Plasma and abomasal fluid were 20 separated from blood and abomasal digesta by centrifugation at 200 rpm and 20000 rpm for 20 minutes respectively. Both analytical matrices were stored at - 11°C for subsequent analysis.

Determination of ABA concentration ABA and the internal standard, IVM, were determined in plasma and 25 abomasal fluid after pre-extraction and derivatisation following a method modified from that described by Nowakowski, M. A., Lynch, M. J., Smith, D. G., Logan, N..B., Mouzin, D. E,, Liukaszewitz, J., Ryan, N. I., Hunter, R. P. & Jones, R. M. (1995), Pharmacokinetics and bioequivalence of parenterally administered doramectin in cattle. Journal of Veterinary Pharmacology? and 30 Therapeutics, 18, 290-298. The derivatised samples were analysed by reverse phase HPLC using a Waters (Waters Associates, USA) 4jim Nova-Pak 3.9 x 150mm analytical steel column, eluted isocratically with a mobile phase of 50: 30: 20 (volume/volume) acetonitrile: tetrahydrofuran: water at a flow rate of 1.2ml/min using a Waters Model 510 solvent pump. The fluorescent 35 derivatives of ABA and IVM were detected after excitation at a wavelength of 360nm.and emission wavelength 470nm using a Waters Model 470 scanning WO 01/89575 PCT/AU01/00596 14 fluorescence detector. Waters "Milleimium-32" data handling software was used for all instrument control, data logging, peak integration and sample quantitation. The mean accuracy of estimation of ABA or IVM over the range of concentrations examined was 103.9 (7.8%, the %CV was highest at the 5 lowest standard (19.9(5.0% at the 3.125 ng/ml standard] but was <5.0%, with the precision of analysis <4% over the remaining standard range to 50ng/ml. The limit of quantitation was 0.25ng/ml.

RESULTS AND DISCUSSION 10 Tablet stability and disintegration Tablet stability and disintegration tests are provided in Table 1. For the drop test results, "P" indicates a pass, and "F" indicates failure; at the time of production (compression], the punch settings were chosen to ensure the minimum compression commensurate with passing the drop test within the 15 first few minutes after manufacture. Density refers to mass per unit volume (gm/cc). All tablets passed the drop test immediately after production in accord with the manufacturing set-up of the machine for each formulation. Tablets including binding materials such as lactose and F160 also generally passed the drop test after 20 hours and 3 weeks (F160 only] post production. 20 It is considered that the diminishing hardness of some tablet formulations after production would not necessarily preclude their commercial use, particularly if they were to be packaged into blister-type packs as described above.

The disintegration test was a simple model for the disintegration 25 behaviour of the tablets upon placement in an animal's mouth/oesophagus. It is, however, considered that in in vivo application, abrasion and movement by the tongue and mouth of an animal and the effect of higher temperature will result in significantly more rapid disintegration times then those recorded using this test. Thus, it is considered that tablet formulations which 30 achieve a disintegration time with the water test of 15 seconds or less will disintegrate in an animal's mouth sufficiently rapidly so as to reduce the likelihood of the animal spitting out the delivered tablet. Indeed, it is considered that tablet formulations which achieve a disintegration time with the water test of 5 seconds or less are likely to disintegrate in an animal's 35 mouth within about 2 to 3 seconds or less thereby providing the animal with substantially no opportunity to spit out the tablet before it disintegrates into a pallatable and readily swallowed mass. Visual tests conducted with sheep using tablet formulations prepared from wood chip or shavings have indicated this to be the case.

Many of the tablet formulations detailed in Table 1 showed 5 disintegration times in the water test of 20 - 100 seconds, which is likely to be too long to avoid spitting out of the tablet when delivered to an animal. However, tablet formulations comprising the biologically active agent ("drug") and wood chips/shavings or 1 mm oat alone (i.e. without the inclusion of a binding material or gelling agent) showed suitable disintegration times of 15 10 seconds or less. Further studies of these wood chips/shavings formulations has shown that, when stored under normal atmospheric conditions (i.e. humidity and temperature), they retained their physical characteristics passing the "drop test" for at least 6 months after manufacture. These tablets also retained their required disintegration rate of 15 seconds or less and it 15 was clearly observed that the application of any additional force (i.e. agitation) significantly speeded up the disintegration. 00 Table 1: --4 Base Material wt% Drug* wt% Binding material wt% Ratio of Base Material to Binding Material Gelling Agent droptest droptest top punch Ave. weight Ave. thick density disintegration time Disintegration time after 1 month storage 1mm 1mm oat lucerne lactose F160 Aquasorb Separan 20hrs 3 weeks mm 8 mm S.G. sees sees 67 33 F P 22.5 0.48 2.5 1.247 -15 ■15-30 57 33 .7 F F 21 0.56 3 1.212 -20 47 33 2.35 F F 0.61 3.3 1.200 -20 27 33 40 0.675 F F 0.72 J 3.9 1.199 -30 67 33 F F 22.5 0.43 2.7 1.034 -35 57 33 .7 P • P 21 0.43 2.9 1.075 -60 -150 47 33 2.35 P P 0.6 3.7 1.053 -60 -90 27 33 40 0.675 P P 0.75 4.2 1.159 -80 60-100 57 33 .7 P P 21 0.58 3.2 1.177 -40 300+ 47 33 2.35 P P 0.61 3.4 1.165 60-100 400+ 27 33 40 0.675 P P 0.75 4.1 1.188 -45 120+ 57 33 .7 P F 21 0.51 3.2 1.035 -30 47 33 2.35 F F 0.59 3.9 0.982 -40 27 33 40 0.675 P F 0.72 3.9 1.199 -15 On *0 o H > o 0 01 Table 1 continued Base Drug* Binding Ratio of Base Gelling Agent droptest droptest top Ave.

Ave. density disinte Disintegration Material wt% material Material to punch weight thick gration time after 1 wt% wt% Binding Material time month storage 1mm 1mm lactose F160 Aquasorb Separan 20hrs 3 weeks mm g mm S.G. sees sees oat lucerne 53 33 9 .7 P P 21 0.6 3.3 1.18 -45 P 22.5 0.58 3.1 1.21 60-90 180+ 48.5 33 8.5 .7 F F 21 0.57 3.2 1.16 -45 P P 22.5 0.62 3.2 1.26 60-90 60-200 53 33 9 .7 P F 21 0.57 3.1 1.19 60-90 P P 22.5 0.52 2.9 1.16 >100 '60-300 48.5 33 8.5 ,7 P F 21 0.58 3.3 1.14 >100 P P 22.5 0.6 3.2 1.22 >100 100+ 53 33 9 .7 F F 21 0.52 3.2 1.06 -30 F 22.5 0.48 2.8 1.11 -45 48.5 33 8.5 .7 F F 21 0.52 3.2 1.06 -45 P F 22.5 0.55 3 1.19 -45 53 33 9 .7 F F 21 0.48 3.1 1.01 60-90 P F 22.5 0.52 2.9 1.16 60-90 48.5 33 6.5 .7 F F 21 0.52 3.2 1.06 >100 P P 22.5 0.56 3 1.21 >100 53 9 .7 F F 21 0.54 3.2 1.10 60-90 P P 22.5 0.51 3 1.10 60-90 -60 48.5 8.5 .7 F F 21 0.53 3.3 1.04 60-90 P F 22.5 0.56 3.2 1.14 60-90 53 9 .7 P F 21 0.56 3.3 1.10 60-90 60 P P 22.5 0.53 2.9 1.19 60-90 48.5 8.5 .7 F F 21 0.52 3.3 1.02 >100 P P 22.5 0.55 3.1 1.15 >100 90 Table 1 continued Base Drug* Binding Ratio of Base Gelling Agent droptest droptest top Ave.

Ave. den disinte Disintegration Material wt% materia Material to punch Weight thick sity gration time after 1 wt% wt% Binding Material time month storage 1mm 1mm lactose F160 Aquasorb Separan 20hrs 3 weeks mm g mm S.G. sees sees oat lucerne Manesty mechanical press 14mm diameter mixed sawdust -10096 0 0 0 0 0 P - 22-25 0.2-0.3 2-3 0.6 3 - mixed sawdust-100% (double fill) 0 0 0 0 0 P -40 0.4-0.5g 4-5 0.6 3 lucerne chaff-100% (multiple compression) 0 0 0 0 0 P 23 0.5 4 0.7 5 red wood chip-100% 0 0 0 0 0 P 23 ground sheep pellets [single compression) 0 0 0 0 0 i F 23 ground sheep pel lets (multiple compression) 0 0 0 0 0 P 23 ground sheep pellets (single compression) 0 0 0 0 0 P 28 ground sheep nuts-66% ABZ (33%) 0 0 0 0 P 1.5 ground sheep nuts-66% cyclo-dextrin (33%) ground sheep nuts-6096 cyclo-dextrin (33%) 1094PVP P variable variable 3 o Table 1 continued 2 Base Drug* Binding material Ratio of Base Gelling Agent droptest droptest top Ave.

Ave. density disinte Disintegration Material wt% wt% Material to punch weight thick gration time after 1 wt% Binding Material time month storage 1mm 1mm lactose Fieo Aquasorb Separan 20hrs 3 weeks mm g mm S.G. sees sees oat lucerne Manesty mechanical press 9mm diameter powdered chipboard 0 0 0 0 0 P - 39 0.2 4 0.84 pine 0 0 0 0 0 P - 39 0.11 4 0.2 3-5 - meranti (ccarsel 0 0 0 0 0 P 39 0.15 ' 4 0.59 3-5 meranti (fine) P 39 0.14 4 0.55 3-5 meranti (fine) (1 1/2 fflll 0 0 0 0 0 P P 39 '0.2 4 0.78 3-5 meranti/pine (50/50) 0 0 0 0 0 P 39 0.128 3 0.67 85% meranti/15% pine 0 0 0 0 P 39 0.259 4 1.14 3-5 85% meranti/15% pine 33 0 0 0 0 P 39 0.19 3 1 85% meranti/15% pine 33 0 0 0 0 P 0.13 3 0.68 3 85% meranti/15% pine 33 0 0 0 0 P 36.5 0.168 3.5 0.75 3 ground sheep nuts - 60% FBZ (40%) 0 0 F 0.875 n H £ o o o <0 0\ Table 1 continued Base Material wt% Drug* wt% Binding material wt% Ratio of Base Material to Binding Materia] Gelling Agent droptest droptest top punch Ave. weight Ave. thick density disintegration time Disintegratio n time after 1 month storage 1mm 1mm oat lucerne lactose F160 Aquasorb Separan 20hrs 3 weeks mm g mm S.G. sees sees Hand Press - 7mm dia pine shavings-100% 0 P 21 0.92 -20 1.04-1.39 2-3 pine shavings-82% 18 P 0.38 6 2.42 3 ground sheep nuts 0 0 0 P 0.43 6 1.62 4-5 ground sheep nuts-84% 16 0 0 P 0.41 1.86 4-5 ground sheep nuts-60% 40 0 0 P 26 0.15 3 ground sheep nuts-75% FBZ 25 0 0 P 22 1.2 2-3 ground sheep nuts 0 0 0 P 1.3 0.984 ground sheep nuts-80% 0 0 P *p-ABA (protected ABA) unless stated. ABZ = albendazole FBZ = fenbendazole WO 01/89575 PCT/AU01/00596 21 La vivo evaluation of rumen-protected ABA formulations Tried 1: The disposition of ABA in plasma and abomasal fluid is shown in Tables 2 and 3 respectively. Compared to administration of conventional 5 ABA, the protected formulations displayed higher Cmny and AUC of ABA in both plasma and abomasal fluid. In plasma there were no differences between the three levels of protection whereas in abomasal fluid the "low" level appeared to show higher mean Cmax but this was largely attributed to one high value. From these results a "medium" level of protection was then used 10 for subsequent tableting and efficacy studies.

Tried 2\ The disposition of ABA in plasma and abomasal fluid is also shown in Tables 2 and 3 respectively. Compared to administration of conventional ABA formulation, the protected formulations either as the free matrix or in the form of "soft" cellulose tablets prepared from wood chip or 15 shavings displayed higher Cmax and AUC of ABA in both plasma and abomasal fluid. In plasma and abomasal fluid the tablet preparation provided higher Cmox and AUC of ABA compared to the free matrix. 22 Table 2: Kinetic behaviour of Abamectin in PLASMA following administration as conventional (Intra ruminal) administration of a commercial formulation and as oral administration as protected (targetted) 5 matrix in a free form or as tabletted as described above. Abamectin administered at 0.2mg/kg.

Route of Administration Disposition of ABAMECTIN in PLASMA Cmax (ng/ml) Tmax (hr) AUC (ngh/ml) Trial 1 Single Intraruminal injection (n=2) Mean-(range) .1.151 (1.50-1.51) 23 127.3 (118.8-135.8) , Oral protected ABA "Low" protection (n=2) 4.27 (3.65-4.89) 24 410.9 (371.3-450.4) Oral protected ABA "Medium" protection (n=2) 3.84 (3.48-4.19) 26 300.6 (240.3-360.8) Oral protected ABA "High" protection [n=2] 4.49 (3.29-5.05) 28 408.2 (400.8-415.5) Trial 2 Single Intraruminal injection (n=3) 2.47 ± 0.78 32 301.2 ± 101.1 Oral protected ABA "Mixed level" protection (n=3) 4.59 ± 1.15 27 508.7 ± 219.6 Oral protected ABA "Medium" protection Tablet form (n=3) 11.26 ± 3.33 36 1364.8 ± 483.5 23 Table 3: Kinetic behaviour of Abamectin in ABOMASAL FLUID following administration as conventional (Intra ruminal) administration of a commercial formulation and as oral administration as protected (targetted) 5 matrix in a free form or as tabletted as described above. Abamectin administered at 0.2mg/kg.

Route of administration Disposition of ABAMECTIN m ABOMASAL FLUID Cmax (ng/ml) Tmax (hr) AUC (ngh/ml) Trial 1 Single Intraruminal injection (n=2) Mean-(range) 1.33 (1.10-1.56) 18 48.4 (44.4-52.4) Oral protected ABA "Low" protection (n=2) 11.97 (4.59-19.35) 8 217.5 (141.5-293.4) Oral protected ABA "Medium" protection (n=2) 3.98 (3.66-4.29) 104.5 (90.6-118.4) Oral protected ABA "High" protection (n=2) .00 (3.93-6.05") 165.9 (10.3-231.4) Trial 2 Single Intraruminal injection (n=3) 1.08 ± 0.48 47.3 ± 20.0 Oral protected ABA "Mixed level" protection (n=3) 3.58 ± 0.54 16 129.1 ± 22.2 Oral protected ABA "Medium" protection. Tablet form (n-3) 6.13 ± 1.21 21 244.5 ± 65.4 24 Example 2: Tablets comprising ivermectin MATERIALS AND METHODS Forty sheep (28-32kg bodyweight) were maintained on pas toe. Water 5 was freely available. They were weighed and randomly divided into two groups of 20 sheep such that each group had members that had a similar range of body weight. Each sheep was orally administered with ivermectin at a common dose which was set to a 60 kg animal. That is, at the commercially recommend 0.2mg/kg dose rate, each sheep received 12 mg ivermectin. 10 Tablets according to the present invention comprising 12 mg ivermectin with meranti/pine (85%: 15%) particles were prepared by mixing the weighed components by gentle shaking in an air-filled plastic bag and subsequently forming tablets in a tableting machine with low compression. The formed tablets had a total weight of 150 mg.

Group 1 were given the ivermectin in the tablet form.

Group 2 were given ivermectin as the commercial oral drench "IVOMEC" (Merial, Australia).

Blood samples were taken from all sheep at 24, 48, 70, 96 hours after treatment. The concentration of ivermectin in the blood was then 20 determined. The aim was to ensure that at each bleeding time, the mean concentration of drug was the same in both treatment groups. That is, the tablet provided similar behaviours of ivermectin in the blood as the commercial drench formulation. Twenty sheep per group were used to obtain a reasonable range of response.

Also, three animals from each group were also bled at 3, 6, 10, 12, 28, 44 and 52 hours, and the concentration of ivermectin determined to see if the profile of ivermectin was similar in the two groups.

RESULTS AND DISCUSSION 30 Table 4 shows the mean ± standard deviation concentration for ivermectin (ng/ml) at each of the 4 time points for the two treatments. From this, the concentration of ivermectin appears greater in the tablet group compared to the IVOMEC drench, but this is not statistically significant. Nevertheless, the tablet performed as well, if not better, than the commercial 35 drench.

WO 01/89575 PCT/AU01/00596 Table 4: Treatment Mean weight (kg] 24h 48h 70h 96h tablet 28.9 8.76±4.22 4.22±2.31 2.31±1.42 1.28±0.81 IVOMEC 29.0 7.70±2.66 3.92+1.44 2.12+0.93 1.08+0.64 Figure 1 shows the profile of ivermectin concentration after 5 administration with the tablet and drench formulation. While there is not statistically significant difference (only 3 animals per group were analysed) the tablet formulation appeared to have a better response than IVOMEC.

From previous studies, it has been found that ivermectin from a soluble drench strongly associates with particulate digesta in the rumen which 10 reduces its availability for absorption. Bioavailability is only about 30%.

With the tablet formulation, the ivermectin is present as a solid form which is likely to reduce to the extent of association with particulate digesta and allow more of the drug to be available for absorption. Hence, there appears a more rapid, and to a greater extent, appearance of ivermectin in the bloodstream, 15 after administration of ivermectin in the tablet formulation compared with IVOMEC drench. Thereafter, from the higher maximum concentration, the ivermectin is eliminated following the conventional "first order" process.

Also, it would appear that at any given concentration (say, at 6 ng/ml), the duration that ivermectin is present in the bloodstream is longer than with the 20 drench. Because these drugs largely rely on duration of contact for efficacy, the tablet formulation may provide better efficacy.

Example 3: Tablets comprising rhndamine Gross wool growth can be measured by the mass harvested at shearing 25 each year, but there is frequently a need to measure growth over shorter periods of time and without the need for a complete harvest. Dye-banding has long been recognised as a way to achieve this.

A liquid-based, (but water insoluble), dye placed on the skin surface will mark the adjacent fibres, and will "grow out" as the fibre lengthens. 30 Provided that the dye is placed carefully and not allowed to spread, any subsequent application at a later time will produce another discrete band further along the fibre. Measurement of the distance between the bands allows an estimate to be made of the growth rate. While the process of dye- WO 01/89575 PCT/AU01/00596 26 banding appears to be simple it is not well suited to on-farm use, since it actually requires considerable expertise to avoid unwanted spreading of the band, is time-consuming, and can result in (colour) contamination of the wool.

UV fluorescent dyes have been suggested as alternatives. Furthermore, a dye which can be absorbed quickly from the GI tract and then be incorporated into the fibre would provide a relatively simple and reliable process. Rhodamine B has been demonstrated as a suitable candidate for oral drenching, but in solution is a highly intense red colour which stains 10 everything including the operator, the sheep's mouth, and anything else it inadvertently contacts. The process by which it is absorbed from the gut and transferred to the skin results only in the UV fluorescent band, and no red colouration of the skin or fibres.

Rhodamine B provided in the form of a tablet according to the present 15 invention provides a convenient alternative to oral drenching.

MATERIALS AND METHODS A matrix mix of 85 wt% meranti/15 wt% pine was used to produce tablets containing 40 wt% rhodamine B (Manesty). The mean tablet weight 20 was 131.4mg, with each containing 49.8mg of dye. (target = 50 mg) Ten sheep were each treated 3 times at intervals of about 28 days, with either an aqueous mixture or tablets containing rhodamine B. Some animals received only the oral drench, others a different treatment at the individual time intervals (see Table 5).

A staple was harvested from each animal 14 days after the last treatment, and about 30 fibres from each staple were examined for the presence of bands using a fluorescent microscope. The available magnification provided for clear measurement of the length of each band, but it did not allow for measurement of the between band intervals within a 30 single field of view of the microscope.

The mean value for each band on a staple was calculated, and those values were then used to compute means and standard deviations for the various bands related to the two treatments. 27 RESULTS AND DISCUSSION All tablets passed the "drop test", and had disintegration times in room temperature water of about 5 seconds Bands on cleaned wool staple were visible (under UV irradiation) for 5 both drench and tablet doses. The staples could have been cut to measure wool growth between the bands for both forms of administration. All bands were clearly visible on individual fibres when viewed under the microscope, however those obtained from the drench exhibited a "hot" spot near the centre of the band, whereas the tablet-related bands appeared more intense at 10 the onset, tailing off over time.

Treatment allocations and results are presented in Table 5. The measured band widths listed below refer to the start and end of each band of fluorescence. The meanwidth and staple S.D. (standard deviation) represent the mean of about 30 fibres from the same staple. The mean and S.D. in the 15 right hand columns refer to the mean for each animal over the duration of the trial (3 dosings). 28 Table 5: Sheep Tablet=l Band Meanwidth staple S.D.

No.

Drench=0 mean S.D. 437 1 3 739 79 437 1 2 755 74 437 1 1 689 74 728 34 482 0 3 718 70 482 1 2 690 73 , 482 1 1 688 61 699 17 489 0 3 777 69 489 1 2 655 34 489 1 1 670 47 701 67 498 0 3 773 53 498 1 2 725 68 498 1 1 677 50 725 48 503 0 3 823 59 503 1 2 785 66 503 1 1 728 61 779 48 532 0 3 701 80 532 0 2 678 66 532 0 1 624 66 668 39 557 0 3 790 74 557 0 2 723 64 557 0 1 699 69 737 47 567 0 3 715 62 567 0 2 666 61 567 0 1 628 48 670 44 605 0 3 701 68 605 0 2 640 54 605 0 1 617 86 652 44 615 0 3 691 62 615 0 2 643 52 615 0 1 548 34 628 73 WO 01/89575 PCT/AU01/00596 29 Delivering tablets to the animals was simple and significantly cleaner than drench administration as the dye did not become dissolved until after the animal had swallowed. The tablets offer advantages over drenching in 5 terms of reduced storage space and transport costs.

All bandwidths are between about 550 and 800|im. There were clearly individual animal differences, but the widths coincide with expected growth rates of 300 to 600|j.m per day, and an effective residence time in the body of between 1 and 2 days.

A consistent increase in band width from period 1 to period 3 is undoubtedly associated with increased growth rates over time (i.e. a normal seasonal trend in Western Australia, where the trial was conducted, as pastures improve from winter to spring).

Overall there is little difference between the mean widths of bands 15 resulting from either a drench or a tablet (696 vs 702 um). However, there is more variation in the drench group (s.d. 69 vs. 45, ave.dev. 51 vs.36), a feature which again is probably attributable to the more uniform onset of a pulsed dose from the tablet and better accuracy of dosing (eg no spitting onto the ground, no oesophageal groove rumen bypass).

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to 25 be considered in all respects as illustrative and not restrictive.

Claims (35)

Claims:

1. A tablet for orally administering at least one agent to an animal or human subject, said tablet comprising said at least one agent dispersed within 5 a matrix comprising particles of a natural, fibrous cellulose material, and characterised in that the tablet disintegrates in about 15 seconds or less when placed in still water at room temperature.

2. A tablet according to claim 1, wherein disintegration of the tablet when 10 placed in still water at room temperature is complete in about 10 seconds or less.

3. A tablet according to claim 1, wherein disintegration of the tablet when placed in still water at room temperature is complete in about 5 seconds or 15 less.

4. A tablet according to any one of the preceding claims, wherein said agent(s) is/are selected from biologically active agents. 20

5. A tablet according to claim 4, wherein the agent(s) is/are selected from antibiotics, anthelmintics, antiviral agents, antigens, vitamins, hormones and microorganisms.

6. A tablet according to claim 5, wherein the agent(s) is/are selected from 25 rumen-protected anthelmintics.

7. A tablet according to claim 5 or 6, wherein the agent(s) is/are selected from the macrocyclic lactone class of anthelmintics. 30

8. A tablet according to claim 4 or 5 for human therapeutic use.

9. A tablet according to any one of claims 4-7 for veterinary use.

10. A tablet according to any one of claims 1-3, wherein said agent(s) is a 35 dyestuff. WO 01/89575 PCT/AU01/00596 31

11. A tablet according to any one of the preceding claims, wherein said natural, fibrous cellulose material is selected from wood, cane, seeds, legumes, grasses and mixtures thereof. 5

12. A tablet according to any one of the preceding claims, wherein the natural, fibrous cellulose material comprises particles having an average dimension of 0.5 to 2 mm.

13. A tablet according to claim 12, wherein the natural, fibrous cellulose 10 material is a mixture of meranti and pine wood particles.

14. A tablet according to claim 13, wherein the natural, fibrous cellulose material comprises about 85% meranti wood particles and about 15% pine wood particles. 15

15. A tablet according to any one of the preceding claims, wherein the agent(s) comprises 0.01 - 50 wt% of the tablet.

16. A tablet according to claim 15, wherein the agent(s) comprises 10-50 20 wt% of the tablet.

17. A tablet according to claim 15, wherein the agent(s) comprises 30-45 wt% of the tablet. 25

18. A tablet according to any one of the preceding claims, further comprising 0-25 wt% of at least one binding material.

19. A tablet according to any one of claims 1-17, further comprising 5-10 wt% of at least one binding material. 30

20. A tablet according to any one of the preceding claims, further comprising 0-5 wt% of at least one disintegrant and/or wetting material.

21. A tablet comprising: 35 (i) 5 - 45 wt% of a biologically active agent, 32 (ii) 30-95 wt% of a natural, fibrous cellulose material in particle form, and (iii) 0-25 wt% of at least one binding material.

22. A tablet according to claim 21, comprising: (i) 30-45 wt% of a biologically active agent, (ii) 45-65 wt% of a natural, fibrous cellulose material in particle form, and (iii) 5-10 wt% of at least one binding material.

23. A tablet comprising: (i) 30-45 wt% of an anthelmintic agent, (ii) 45-65 wt% of a natural, fibrous cellulose material in particle form, and (iii) 0-25 wt% of a binding agent.

24. A tablet according to claim 23, wherein said anthelmintic agent is selected from the macrocyclic lactone class of anthelmintic agents.

25. A tablet comprising: (i) 30-45 wt% of a dyestuff, (ii) 45-65 wt% of a natural, fibrous cellulose material in particle form, and (iii) 0-25 wt% of at least one binding material.

26. A method of orally administering at least one agent to a non-human animal subject, the method comprising delivering a tablet according to any one of the preceding claims into the mouth or oesophagus of said non-human animal.

27. Use of at least one agent dispersed within a matrix comprising particles of a natural, fibrous cellulose material in the preparation of a tablet which disintegrates in about 15 seconds or less when placed in still water at room temperature, for administration said at least one agent to an animal or human subj& INTELLECTUAL PROPERTY OFPfCE OF NZ 2 9 JUL 2004 received 33

28. A package containing a plurality of a tablet according to any one of claims 1-25, the package being in the form of a strip and comprising, along the length of the strip, a plurality of receptacles each consisting of one or more of said tablets.

29. A package containing a plurality of a tablet according to any one of claims 1 to 25, wherein said package is in the form of a substantially tubular container defining a lumen containing said tablets.

30. A method of measuring wool growth in a wool growing animal, said method comprising: (i) administering said animal with a first tablet according to claim 10 or 25, such that a first band of said dyestuff may be subsequently detected in the wool fibres of said animal, (ii) after a predetermined period, administering to said animal a second tablet according to claim 10 or 25, such that a second band of dyestuff may be subsequently detected in the wool fibres of said animal, and wherein the dyestuff of said second tablet may be the same or different to said dyestuff of the first tablet, and (iii) thereafter obtaining a wool fibre sample from said animal and measuring the distance between said first and second bands of dyestuff in said wool fibre sample.

31. The method of claim 30, wherein the said predetermined period is in the range of 7-42 days.

32. A method of measuring wool growth in a wool growing animal, said method comprising: (i) administering said animal with a first tablet according to claim 10 or 25, such that the band of said dyestuff may be subsequently detected in the wool fibres of said animal, (ii) measuring the clearance time of the dyestuff from the circulation of said animal, and 2 9 JUL 2004 34 (iii) obtaining a wool fibre sample from said animal and measuring the width of the band of dyestuff in said wool fibre sample.

33. A method of monitoring feeding of a livestock animal, said method comprising providing feed to said animal which includes at least one tablet according to claim 10 or 25 and after a period whereby it would normally be expected that said animal would have fed on the provided feed, determining the presence or absence of said dyestuff in a suitable sample from said animal.

34. The method of claim 33, wherein the suitable sample is urine or droppings.

35. A tablet according to claim 1, substantially as herein described with reference to the example. INTELLECTUAL PROPERTY OFRCE OF M.Z 29 JUL 200* received