NZ554633A

NZ554633A - Delivery devices and their uses

Info

Publication number: NZ554633A
Application number: NZ554633A
Authority: NZ
Inventors: Kevin George Green; Gary Robert Harrison; Barry William Axon; Brian Robert Duncan; Mitch Venning; David Chandler
Original assignee: Argenta Mfg Ltd
Priority date: 2004-09-09
Filing date: 2004-09-09
Publication date: 2008-11-28

Abstract

An intraruminal device capable of releasing at least two active ingredients is disclosed. The device includes an elongate body impervious to rumen fluids, where the body defines a barrel having a first outlet, a column of matrices in the barrel having one or more active ingredients, a compression arrangement within the body, and a release arrangement. The column of matrices within the barrel is biased so as to present each matrix to the first outlet. A release arrangement for an active ingredient is provided at or adjacent the end of the body distal to the first outlet.

Description

<div class="application article clearfix" id="description"> 55 4 6 3 3 NEW ZEALAND PATENTS ACT, 1953 Divided out of Application No: 535258 Date: 9 September 2004 / 9 September 2005 COMPLETE SPECIFICATION DELIVERY DEVICES AND THEIR USES We, NUFARM LIMITED, an Australian company with its registered office at 103-105 Pipe Road, Laverton North, Victoria, Australia, having a place of business at 2 Sterling Ave, Manurewa, Auckland, New Zealand, do 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 - -2- The present invention relates to the provision of additional delivery options for intraluminal controlled release devices and their related uses and methodologies. There are many instances where it is desirable to provide specific delivery sequences of active ingredients or other substances from intraluminal controlled-release devices in response to biological fluid contact and according to expected or desired timing regimen. This need has previously been addressed in "Controlled Release Veterinary Drug Delivery: Biological and Pharmaceutical Considerations" edited by Rathbone and Gurney (Elsevier 2000) where Chapter 3, a paper entitled "Intraruminal Controlled Release Boluses" by John R Cardinal discusses various methodologies that have been devised to provide long-term delivery of drugs. That Chapter discusses passively erodable matrix systems of various kinds, (including those of Laby, which included spring driven gel-forming tablets, stacked within a device ("Laby device") retained in the rumen by density or variable geometry). Control of release from the capsule through the surface area of the substance-releasing matrix exposed to the action of the rumen contents was described - see US Patents 3844285, 4251506, 4671789, and 4687480). Also disclosed in the aforementioned Chapter 3 are reservoir systems (active or passive release), passive release protected (but dispersed active ingredient) matrix systems, and osmotic systems. More recently Lowe et al (W003/033031 Eli Lilly and Company/Elanco) has disclosed a system related to the Laby capsules whereby a spring biases a piston against a barrel-contained stack of (various format) tablets capable of being exposed serially to ruminal fluids during the period of intraruminal payout. Eli Lilly WO 03/033031 (PCT/AU02/01426), the full content of which is hereby included by way of reference (including in respect of dosage, matrix and active agent formulations), discloses a controlled dosage release element adapted to be inserted into and retained in the rumen of a ruminant animal. The element comprises: a) one or more discrete and predetermined amounts of at least a first formulation comprising at least a first active agent, the formulation being adapted to dissolve in rumen fluids at a rate such that dissolution of each of the one or more amounts of first formulation provides a short or pulsed episode of release of the first active agent into the rumen; and b) one or more predetermined amounts of at least a second formulation adapted to dissolve at a controlled rate in rumen fluids. The one or more amounts of first formulation are provided at one or more predetermined locations within the element relative to said one or more amounts of second v A 1 k AUb 20U8 1 formulation for one or more delayed releases of at least the first active agent into the rumen at predetermined times before, during, after, or any combination thereof, of a predetermined extended time period defined by said second formulation. Varied, time spaced, pulsed, etc delivery of anthelmintics from controlled-release devices, including intra-ruminal capsules have also been disclosed in US patent 5,110,597 of Alza Corporation. This patent describes the release from the capsules of either the same or different active agents (actives) or drugs, sequentially or simultaneously, such that a desired release profile is achieved. Discrete longitudinally aligned units of drug or active are dispensed through an orifice using pressure from an osmotically activated driving component. Various shaped units of drug are aligned (interspersed as desired with inactive 'spacer' elements) such that the desired release/delivery profile is attained. Effective development of similar capabilities to the above, including the Laby design of capsule has been reviewed by Anderson N, Vet Parasitol 1985; 18:59-66. The improved bolus-type device described herein preferably relates to density or variable geometry retainable boluses for dosage to ruminants. Whilst preferably primarily intended for provision of controlled continuous or a controlled varying (e.g. intermittent) release of an active ingredient or ingredients (for example a pesticidal composition such as an anthelmintic, or an antibiotic, a bloat control agent, a digestion-resistant antigen, a vitamin, a trace mineral, etc), the boluses are optionally also particularly suited to applications where control of capsule operation is achieved automatically or remotely by electronic means, or optionally to boluses for which recording and identification functions (electronically controlled or not) are an important part of the function of the bolus. The term "active ingredient" or "actives' as herein used includes within its ambit any substance providing a beneficial effect on a particular animal whether in the actual circumstances of the animal or some possible future challenge to or deficiencies of the animal. It additionally desirable however to limit the number of devices that must be dosed to particular animals in order to achieve the animal management requirements. Removal of the devices at abattoirs may be an issue, as may be animal welfare issues (real or potential) relating to dosing injuries, reliability and/or tissue damage such as abrasion of the surfaces of the rumen or reticulum. A number of novel options for better use of the space within or adjacent to traditional intraruminal boluses are therefore presented herein, such that as few devices as possible are able to service the needs of the animal or those responsible for the animal's health, production, welfare or for veterinary or legislatory regulation. ;J^t0'erty ^ i, AUb zuua The invention described herein is, inter alia, suitable for further expanding the capabilities and/or application of the Laby-type capsules, as well as other types of intraruminal devices. Development of intraruminal capsules able to deliver actives according to predetermined profiles has been driven by the need to overcome pharmacological problems associated with continuous delivery of drugs, immunological agents and nutritional components. Continuous delivery of pharmaceuticals to recipient patients (human or non human) has been found to be possibly rendered ineffective or problematic because of the development of tolerance to the administered drug. Unfavourable immune responses may also be a problem. In the case of continuous delivery of antibiotics and/or anthelmintics, development of resistance by the target pathogen is a probable outcome. Delivery of an anthelmintic agents to sheep and cattle through continuous release of single anthelmintic agents from intra-ruminal capsules is an established means of attaining high productivity animals in both Australia and New Zealand. Although these capsules have provided effective worm control for many years, emergence of anthelmintic resistance is of concern. An example is the previously potent macrocyclic lactone group of anthelmintics of importance at least to the sheep industry. To suppress the development of resistant worm populations during the pay-out term of an intra-ruminal anthelmintic capsule, additional oral drenches of different chemical class or activity spectrum may be given. Whilst this may be effective in maintaining a low infection status in the treated animals, it defeats the labour-saving benefits of capsule treatment. Of particular relevance to preferred forms of the current invention is a desire for an initial dose (commonly called a 'priming dose') of anthelmintic to animals that are subsequently to be continuously dosed by intraruminal bolus with another anthelmintic. The priming dose serves the purpose of killing the gut-resident (generally mature) worm population. These worms commonly have a greater tolerance to anthelmintic than that dose provided by continuous-dose anthelmintic boluses. Immature worms that are ingested during the payout period of continuous-dose bolus are much more likely to be effectively controlled. The ideal situation is therefore to kill the gut-resident worms with a priming dose at the commencement of the continuous dosing period, with the latter dosing serving to prevent or suppress re-establishment of a new worm population. The priming dosing is commonly given as a different anthelmintic class or combination treatment to that subsequently released from the intraruminal -dp^ice- The efficacy spectrum of the priming dose can be targeted to have high efficacy against those worm species most likely to have resistance to the anthelmintic(s) subsequently delivered by the device. Following provision of a priming dose, intraruminal bolus may deliver continuously a single anthelmintic or a pulsed delivery system as described in the review of Anderson Either way (i.e. for example a single anthelmintic or a pulsed delivery system), the long-term payout kinetics in the current invention would normally be achieved using delivery mechanisms similar to those previously described by Laby in PCT/AU81/00082 and US 4,687,480. These devices consists of (plastic) barrels containing formulation(s) that are dispensed serially to the ruminal contents. The barrel's bodies (unitary or fabricated) must either have sufficient density to ensure residence at the base of the rumen (from where regurgitation is unlikely), or be of the "variable-geometry" type. The former bolus devices are commonly referred to as "weighted" capsules or boluses. Variable-geometry boluses on the other hand, may have a similar barrel structure, but (typically) one end of the barrel is fitted with a pair of retractable 'wings' at one end. The wings are compressed against the body of the barrel during dosing, but once released in the rumen, the wings spring to a position approximately perpendicular to the barrel, effectively preventing regurgitation of the device. Within the barrel of either device is a stack of tablets or a solid core of matrix containing the active(s). This material is held against a release orifice, usually located at the end of the barrel opposite the wings. The active-containing formulation is compressed against the release orifice by a plunger and spring, typically located within the 'wing' end of the capsule. The spring and plunger provide sufficient pressure to hold one end of the formulation core against the release orifice, such that ingress of liquid from the rumen contents is minimal. Release of drug or active into the rumen contents is normally facilitated by progressive erosion or dissolution of the core formulation following action of moisture from the rumen contents on to the surface of the most advanced region of the formulation stack i.e. that region of the formulation that is closest to and/or abuts the orifice. Our experience has shown that an ineffective seal between the capsule body and the terminal face of the most advanced face of the formulation will allow other surfaces of the tablet stack or core to swell, adversely affecting, or stopping reliable payout of the 1985. medication. New Zealand Patent Specification 197543 describes a formulation based on a gel forming agent (viz. sucrose fatty acid ester). In this case, formation of a gel at the moisture: tablet interface following ingress of moisture from the rumen, through the release orifice created a self-limiting process for the release process. Extrusion of active in the form of a gel (into the rumen contents) was proposed to be largely determined by both gel-created restriction on further ingress of moisture and the restriction of movement of the gel past the orifice and into the rumen. For practical purposes, the diameter, and to a lesser extent, thickness of the orifice determined the release rate of active from such a device. Importantly, the release of active was claimed to be largely independent of the spring pressure applied to the tablets. If spring pressure determined the payout rate, release of active from the device would slow as the tablet stack shortened during payout. The possibility of using complex or multi-hole orifices to provide more desirable characteristics to the cavitation profile (the front of the moisture ingress into the active-containing core) was proposed by Laby and also later by Lowe. A major practical issue related to dump-dosing of therapeutic agent at the start of the capsule pay-out period (such as priming dose(s) of anthelmintic) was not however recognised in the earlier patent specifications by CSIRO or Eli Lilly. This practical issue is that the use of rapidly dissolving formulations may break the moisture seal otherwise provided by spring loading the gel-producing tablets against the orifice plate. As mentioned previously, breaking of this moisture seal enables ingress of water around the outside of the gel-producing tablets, resulting in swelling of tablets along the stack. The result of this ingress of water is development of a strong likelihood of the tablets swelling and jamming in the barrel. In this case release kinetics will become unpredictable and payout may slow or completely stop. We have found the provision of additional medications with preferred release profiles different from those practically enabled by the internal tablet stack or column matrix is a great advantage in terms of flexibility in the useful deployment of intraruminal devices. However technical difficulties related to ease and safety of dosing and robustness of the commercial product needed to be overcome. In an aspect the invention is an intraruminal device capable of releasing at least two active ingredients, the device comprising or including an elongate body or body assembly ("body") substantially impervious to rumen fluids the body defining a barrel having an end outlet at a firstend("first outlet"), a column of matrices in the barrel, at least some of the matrices having one or more active ingredient(s), a compression arrangement within the body adapted to bias the column in the barrel to serially present each matrix to said first outlet, a release arrangement for at least one active ingredient at or adjacent that end of the body distal to said first outlet, and at least one variable geometry device dependent from said body or body assembly to assist rumen retention; wherein the device contains at least two active ingredients. Preferably said release arrangement is from adjacent said variable geometry device(s). Optionally said column of matrices has one active ingredient in at least several of the matrices (eg, ionophore or anthelmintic). Optionally said column of matrices has at least a second active ingredient in at least several of the matrices (eg, ionophore and/or anthelmintic). Preferably or optionally said release arrangement is to dump at least one active ingredient into the rumen upon or soon after insertion. Preferably or optionally an active ingredient, or that active ingredient, of said release arrangement is different from any active ingredient of said matrices. Optionally an active ingredient, or that active ingredient, of said release arrangement is the same as the, or an, active ingredient of said matrices. Preferably there can be a pulsed release of at least one active ingredient from said first outlet. Otherwise it can be unpatterned or continuous. Preferably said compression arrangement involves a spring or spring and plunger. Preferably said release arrangement is from an outlet ("second outlet") at said distal end of said barrel. Preferably or optionally said release arrangement is from a matrix or reservoir connected to that end of the body distal to said first outlet. -8- Optionally said release arrangement can release at least two active ingredients. Examples include one or more ionophore and/or one or more anthelmintic. Preferably said at least one variable geometry device comprises at least a pair of resilient wings, each extending outwardly from the end of the body, or adjacent the end of the body, distal to said first outlet. Preferably said wings for insertion can be held against said body. Preferably the outlets are opposed ends of the barrel. Preferably the active ingredients are any one or more anthelmintic(s) and/or one or more anthelmintic(s) with at least one ionophore. In another aspect the invention is an intraruminal device having provision in and on a body, or both in and on a body, of the device for (i) continuous or sequential release of at least one active agent, and (ii) a primary or dump release of at least one active agent. Preferably the release of (i) is from discrete units of formulation or formulations sequentially presented to an outlet. Preferably the release of (ii) is from a single delivery unit or formulations. The device may be of a variable geometry retention type or a density retention type. Preferably the release of (i) is of at least one anthelmintic (i.e. for preventing establishment of new worm populations in the gut). Preferably the primary or dump release is of at least one anthelmintic (i.e. to kill the already gut-resident worms), or to provide a medication (e.g. the micronutrient selenium) that may require a different dosage profile to that provided by the first sequential or continuous release matrix. Preferably the release of (i) relies on a column of matrices, at least some containing an active agent, biased in, or as if in, a barrel to an outlet of the body exposable to ruminal fluids so that the matrices are sequentially exposable to said outlet or, in use, the fluids, or both. Optionally a spring acting directly or indirectly on the furtherest matrix from said outlet provides said bias of said column of matrices. Optionally each of the releases (i) and (ii) is via a different outlet in the body of the device. -9- Preferably the release of (ii) is from a pocket in the body of the device. Optionally the release of (ii) is of at least an anthelmintically effective primer dose with respect to gut residents of at least one anthelmintic from each of the groups (a) macrocyclic lactones ("MLs"), (b) levamisole and (c) benzimidazoles and the release of (i) is of at least an anthelmintically effective amount with respect to population re-establishment of at least one anthelmintic from at least one of the groups (a), (b) and (c). Preferably the weight relativity (a):(b):(c) content in the release of (ii) is about 0.04:1.5:1. In another aspect the invention is an intraruminal device having a body with first and second outlets, at least a first active ingredient within said body and to be accessible to rumen fluid via at least substantially only said first outlet, and at least a second active ingredient at least substantially accessible only to rumen fluid via said second outlet. Preferably a barrel holds a column of matrices at least some of which matrices includes said first active ingredient(s). Preferably a compression device within the body is adapted to bias the column in said barrel to said first outlet. Preferably said at least second active ingredient is subject to a compression device. Optionally said first outlet opens into a pocket of the body of the device, the pocket having as its opening said second outlet. Optionally said second outlet is from a pocket of a body of the device and said first outlet is from the body of the device but not into said pocket. Optionally the release of (ii) is of at least an anthelmintically effective primer dose with respect to gut residents of at least one anthelmintic from each of the groups (a) macrocyclic lactones ("MLs"), (b) levamisole and (c) benzimidazoles and the release of (i) is of at least an anthelmintically effective amount with respect to population re-establishment of at least one anthelmintic from at least one of the groups (a), (b) and (c). Preferably the weight relativity (a):(b):(c) content in the release of (ii) is about 0.04:1.5:1. In another aspect the invention is a pulse, sequential or continuous release intraruminal device having at least a separate release to that of any pulsed, sequential or continuous release, thereby having capability of a priming dose release or dump dose release of an active agent. In another aspect the invention is an intraruminal device comprising orM 1 4 AUb 2008 vCY - 10- (I) a body substantially impervious to rumen fluid, the body including a barrel, at least two outlets or points of exposure of matrices to rumen fluid, a column of matrices in the barrel, at least some of which matrices includes a first active ingredient, (II) a compression arrangement within the body adapted to bias the column in the barrel to said first outlet, and (III) an active ingredient in the body in a reservoir or matrix accessible to said second outlet. Preferably the active ingredient of (III) is of a plurality of anthelmintic agents. Preferably the second outlet is from a pocket of the body. Preferably the compression arrangement is a spring and the pocket at least in part within the spring. Preferably there is an active ingredient as (III) and the release of (III) is of at least an anthelmintically effective primer dose with respect to gut residents of at least one anthelmintic from each of the groups (a) macrocyclic lactones ("MLs"), (b) levamisole and (c) benzimidazoles and the release of (II) is of at least an anthelmintically effective amount with respect to population re-establishment of at least one anthelmintic from at least one of the groups (a), (b) and (c). Preferably the weight relativity (a):(b):(c) content in the release of (i) is about 0.04:1.5:1. One aspect of the invention consists of an intraruminal device comprising or including any device as previously defined plus an additional capability being one or both of (i) via a separate release to that of any pulsed release, the capability of a priming dose release or dump dose release of an active agent, and/or (ii) a control and/or communication system capable of any one of (a) release control, (b) reporting inputted and/or sensed data to a remote receiver and/or (c) downloading information inputted and/or sensed thereby. Preferably the device is an intraruminal device and preferably at least one active agent for release pulsatile and/or priming dose wise is an anthelmintic. Preferably the form of the device is of a Laby kind and preferably a primary release dose is located prior to administration within the spring of such a device. In a further aspect the present invention consists in a Laby type device adapted for pulsatile release of an active agent or active agents yet having a sepaj^Hx^BJJSTt^Dn in a void -11 - space thereof (preferably to a separate outlet to that of the pulsatile release) for release of a dump or priming load or loads of the same and/or a different active agent. In another aspect, the present invention consists in an intraruminal device comprising or including: • a body substantially impervious to rumen fluid, the body including a barrel, first and second outlets, and a column of matrices in the barrel, at least some of which matrices includes a first active ingredient, • a compression arrangement within the body adapted to bias the column in the barrel to said first outlet, and • an active ingredient in the body in a reservoir or matrix accessible to said second outlet (for which a compression device may or may not be required to facilitate a desired release profile). In still a further aspect the present invention consists in the use of a device of any of the kinds herein defined and/or herein described with reference to the accompanying drawings. In yet a further aspect the present invention consists in a method of treating a ruminant which involves an intraruminal administration of a device of any of the kinds in accordance with the present invention so as to release a primary and/or dump dose in association with (whether serially or otherwise), a pulsatile release of the same and/or at least one different active agent. We have found as a space option, and of particular importance, the void space within the spring coils of the types of devices described in the Laby and Elanco patents described above. This provides one convenient space for 'dump-dose' formulation(s) and an outlet orifice may be conveniently spaced in the vicinity of the attachment point of the wings at the apex of variable geometry devices. If additional space is required to encompass the additional dose, the body of the capsule can be extended (within the limits of safe dosing). Depending on the payload requirement of the continuous release component, the compartment of the barrel containing the formulation and driving component may also be able to be truncated and the component added at either end of the principal formulation, again, within the constraints of dose volume requirement and ease and safety of dosing. The outlet or outlets may be fitted with a rumen-erodable seal, cap, tape, encapsulation or the equivalent. /W J? 1 4 AUB 20 - 12- Generally the second outlet formulation will be 'dump-dosed' or release its active content(s) in a substantially different (fast or slow) profile to that provided by the principal controlled-release formulation. The invention is particularly suited to delivery of rapidly released priming doses, which if delivered through incorporation in the tablet stack, would facilitate undesirable ingress of water and loss of reliability in the controlled release. Alternatively the second mentioned matrix may include a different active to any active in one or some or all of the matrix or column of matrices first mentioned, possibly one that is unstable or incompatible when included with components active or excipient contained within the tablet stack. Alternatively the void space allocated within the re-designed body of the capsule may be allocated to a mechanism able to provide individual identification of the treated animal, more preferably with the capacity to provide (directly or indirectly) a record of the treatment in terms of dose type and/or timing, or that can facilitate the control of dose and or timing. Such void space can therefor be used for recording/identification or mechanisation of the device. Preferably the device is substantially tubular save for the ends and/or any deployable retention feature or features, and there is an outlet or exposure to rumen environment at each end. Most preferably the redesigned device will retain the ease of application and safety characteristics of the unmodified "Laby capsule" device. Appropriate modifications to the body of the intraruminal capsules are illustrated in the following diagrammatic representations. As used herein the term "and/or" means "and" or "or". As used herein the term "s" following a noun means the pleural or singular form of that noun as might be appropriate and not necessarily dependent on the Syntax in which it is present as to which is meant. As used herein the term "episode" includes a preferred release duration of a single matrix or tablet. As used herein the term "pulse" includes that release from a single matrix or tablet which is spaced in time from another such pulse i.e. is episodic or sequential with each episode dependent on a single matrix but such episodes are spaced by at least one intervening matrix of another kind. - 13 - Use of the terms "episode", "sequence" and/or "pulse" does not rule out some hybrid arrangement in a core sequence e.g. can have some pulse releasing matrices as well as contiguous like matrices, each containing one or more biologically active components. The term "dump-dose" includes the release of either formulated or unformulated active from a designated isolated portion of the capsule into the rumen contents. Dump-dosed actives are designed to commences release from the capsule within one hour of dosing, with dosing being essentially completed within 12 hours. A typical example of a dump dose would be a priming dose of anthelmintic as outlined earlier or an alternative "narrow spectrum" anthelmintic such as praziquantal, which may be desirable for the purpose of rapidly removing tape worm infections from treated lambs. As used herein the term "opening" in respect of a single opening or at least one opening optionally (and preferably) includes a passageway past (unless otherwise specified) a retention shoulder, projections or the like that may halt the advance of a core sequence or the like of matrices towards some extended outlet arrangement of the barrel. It can also include plural "openings". In the case of intraruminal boluses fitted with electronic measuring or recording devices, the above opening may simply be used for assembly purposes. As used herein the term "outlet" or its plural refers to a single or a multiple outlet or opening in each case. For the purpose of such an outlet the opening need not necessarily be one with a retention shoulder, projections or the like. Certainly that is not the case in some options for the primary or dump dose release. Preferred forms of the present invention will now be described with reference to the accompanying drawings in which Figure 1. An (optionally) capped compartment moulded into the void space within the coils of a traditional intraruminal capsule of the type described in US Patent 4,687,480. Figure 2. A capsule body of the above format following completion of payout. Payout may be facilitated by the use (for example) of liquid, low viscosity, or effervescent formulations and release may be facilitated by the fitting of additional holes or grooves to permit easier penetration of moisture and better dissolution of optional solid (erodable or gel-forming) matrices. Figure 3. An exploded view of the same capsule format, but in this case a solid insert is exemplified. This solid component could be a selenium pellet, designed to erode from within the moulded space, or to fall or be extruded from the void and fall to the base of - 14- the rumen where release (erosion) of its contents can occur completely independently of the capsule body and its remaining contents. Figure 4. The parent capsule in this case has an additional space within the original controlled release format to allow the use of a higher payload (for example, a high potency macrocyclic lactone anthelmintic may have been included in the primary matrix). The additional space within the capsule has therefore been used for a separate additional delivery mechanism. A divider between the two matrices was not considered to be necessary in this case and a common driving mechanism (in this case a spring) was also satisfactory. If a divider is used within the capsule body for this format, filling of the capsule is facilitated by the use of a separate press or screw-fit orifice plate / wing fitting (as shown in the diagram). Figure 5. In this case the additional void was considered to be best provided on the end of the capsule opposite the wings. Figures 6 and 7. Loaded and exploded views respectively of the capsule illustrated in Figure 5. This provision of the void in this position is commonly suitable for priming or released solid dose forms, but would obviously be unsuited for fixed components such as electronic controls without provision for access of rumen fluid to, and release of formulation from, the original orifice. Figures 8A to 8D show different dump dose body pocket forms. It should be appreciated that preferred forms of the present invention for the sake of simplicity disclose a priming or dump dose of some kind with some suitable active agent which can be the same or different from any active agent or the active agent that might be included in (preferably) a barrel contained stack of matrices for sequential advancement to the outlet therefor. Persons skilled in the art will appreciate how the various void spaces can be utilised for the ancillary purposes herein disclosed in ways herein disclosed. It is preferred that any release via a second outlet, i.e. that for a primary dose is not such as to allow the ingress of fluids likely to detract from the pulsatile and/or sustained release of the active agent(s) of the barrel contained stack in its preferred form. Any appropriate partitioning whether by way of a moulded or fabricated partition or a surround for the priming dose material (i.e. a reservoir) can be provided for that purpose. The above illustrations of the invention show that selected reallocations of the space available within the overall (safely dosed) shape of a traditionally designed, barrel-shaped intraruminal device can surprisingly achieve a multiplicity of advanced and desirable additional applications. - 15- Medications within the additional cavity or cavities associated with the capsule body may be in the form of liquid, gel/paste (semi solid) or solid. The included material may be a press fit, retained by adhesive or by a restraining device that is integral or temporarily attached to the body of the device. Adhesives or tapes that are affected by moisture after delivery may also be used to affect release of the enclosed active at an appropriate time. Alternatively traits provided by formulation of the active (gel formation, effervescence, changes in the physical size, shape or other characteristic) may be used to affect the desired release. Actives may also be 'trickle - released' over periods equal to or beyond the entire pay-out period of the tablet stack. An example of this could be release of the micro-nutrient selenium, whereby the active could be in the presented in the forms of relatively inert, solid or scintered metal(s) or alloy(s). Slow disintegration or corrosion may then occur over a much longer period than the payout of other actives from the body of the capsule. In yet another formats of invention, the additional terminal cavity of the type(s) described above may be used to release its content(s) entirely at some stage after delivery, such that these content(s) reside by density retention in the rumen, releasing independently from the contents of the remainder of the capsule (e.g. the additional component may be in the format of a weighted bolus that falls or is coerced from the capsule body and releases substantially from within the liquid material contained within the lower portions of the rumen). The terminal facilities for appending secondary formulation components to the capsule body may be moulded such that the desired release profile is reliably attained (for example through the fitting of an appropriate cap to the orifice or by provision of channels or additional holes to facilitate or control release or merely by provision of "clips" to hold externally delivered tablets of rapidly released formulation. One optional embodiment of the present invention will now be described with reference to an intraruminal capsule capable of being retained in the rumen by density and size factors or by a variable geometry (such as described previously in respect of some of the prior art forms). The embodiment, as just one of many preferred embodiments of the present invention, is based upon individual disc shaped tablets, each with a cylindrical edge and each aligned axially with respect to each other on the axis of a barrel of the delivery device, such that they are sequentially presentable to the outlet region, as originally proposed by Laby. Within the additional void, in this case encompassed within a hollow moulded within the <foto5ertTJ^ -16- space normally encompassed by the compressed spring is a priming dose of the water-soluble anthelmintic, levamisole. The preferred arrangement is as depicted in Figure 1. We have also found advantage from the provision of a capacity for delivery of minerals or other veterinary or nutritional agents that are preferably delivered with a different profile to that for which delivery from the tablet stack is suited. Further advantages can arise from the capacity to add electronic controls (e.g. of using geometry or integrity) or monitoring/identification provisions, or simply the addition of a weight, such that a hybrid (variable geometry/gravity) retained intraruminal device is achieved. The embodiment of Figure 1 shows the body 1 having wings 2 at one end that deploy to the condition as shown so as to retain the overall device in the rumen. Positioned within the barrel portion 1A of the body 1 is the stack of tablets or matrices 5 urged towards an outlet at 6, (i.e. at one axial end) under the action of a spring 3 acting through a member 4 or a matrix 4. Disposed within the spring 3 is a reservoir 8 or a matrix for an additional entity, dump or primary dosage or alternative release component to exit via an outlet (not shown) under the cap 7. Thus in the embodiment of Figure 1 the outlets are at opposed ends of the barrel but that outlet under the cap 7 preferably does not allow the ingress of rumen fluids to the tablet or matrices stack 5 whether by sealing about the outlet or the reliant upon the seal properties (if any) of the member 4 about the outlet under the cap 7. Figure 2 shows the device of Figure 1 following payout. Figure 3 is the exploded view of the same format as shown in Figures 1 and 2. Figure 4 shows a divided stack of matrices. Figure 4 shows a spring 13 acting via sealing plugs or members 14 and 15 upon tablet or matrices stack 9 and 10 respectively so as to urge each tablet or matrix of a stack serially towards its respective outlet 11 and 12. Optional capping can be provided. Figure 5, 6 and 7 show additional views with a priming or released solid dose form 16 to be carried into the rumen of a target species ruminant on the outside (optionally covered initially) in the sleeve member 17 which attaches to the barrel 18, members 17 and 18 together forming the body and being adapted to retain against the internal outlet of sleeve 18, the foremost tablet or matrix 19 of the stack 20 which is urged towards the outlet 18 under the action of an optional seal member 21 on which the spring 22 bears. Figures 8A through D show respectively a variable geometry type device shown in stylised form. /W *A sf -A # v\ - 17- In the form as shown in Figure 8A through 8D there is an outlet 23 in each case although, in the embodiments as shown in Figures 8C and 8D, a dump dose formulation unit 24 is held in a pocket over the outlet 23 by either a retaining annulus or some return thereby effectively to define a pocket from which the dump dose is released preferably prior to release of the column held actives. Those embodiments as shown in Figures 8A through 8C has a dump dose 25 from the spring and preferred winged end of the device, the outlet accordingly being at 26. In the case of the device of Figure 8 A the pocket is in part within the biasing spring of the column whilst in the embodiment of Figures 8B and 8C the pocket is shown outside of the spring. Preferably such variants do not allow ruminal fluid to the spring via the pocket as Other forms are possible. In the arrangement of Figure 8C the dump release matrix 24 and 25 can be identical but need not be so. Indeed the matrix 24 need not be both for the same purpose as matrix 25, i.e. there could be a growth promotant and an anthelmintic. The embodiments shown are just some of the many forms of embodiment possible reliant upon the present invention. The capsules (wings, if any, included) are preferably made from one or more parts moulded in a plastics material (e.g. polypropylene) and fabricated together by adhesive and/or welding. We preferably use tablets as a column in a traditional 'barrel' body. We additionally use tablets or encapsulated formulations (liquids, granules, crystals, powders) [preferably within the 'nose cone' (wing end) or for external to the orifice plate]. Our device preferably will have at least two discharge points and not just a 'discharge' end and a 'closed' end of the capsule or device. The release spikes from WO 03/033031 seem to be clearly related to particular types of tablet within the barrel. Our additional discharges from the capsule may be of any speed and are largely independant of the tablet stack in the barrel. The additional discharge options from the devices of the present invention may therefore be in the form of an initial pulse of required duration (e.g. a primer dose of anthelmintic), or may be continuous throughout or beyond that from the tablet stack within the barrel or the additional entities may be retained for provision of density improved retention, animal identification or electronic recording and transponding of rumen functional 8C or 8D. -18- parameters. Protective coatings or inactive layers of controlled release formulation may facilitate payout at any selected timing, or provide water on gas-proof sealing. Tablets or boluses attached to either end of our device may be weighted. These units may also be designed to be released from the capsule once it is resident in the rumen (e.g. may be retained by a water soluble adhesive). If designed to have a specific gravity greater than 2, these tablets or boluses may be expected to reside in the liquid fraction of the rumen contents at the base of the rumen or within the reticulum. An example of this option would be the addition of a releasable selenium pellet to one or both of the pockets of the device (e.g. as in Figure 8C). This design option effectively provides two payout points for medication within the rumen, with the weighted device in the lower portions of the rumen and/or reticulum - with the winged device paying out within the 'raft' of moist material within the mid to upper portions of the rumen. Alternatively the pocket provisions may be used to weight the capsule, such that retention within the rumen is improved. This may be particularly important where the pocket(s) or barrel is or are used to contain 'whole of life' animal identification devices or other electronic sensors or controls. This option may include controls that affect wing integrity - such that the capsule retention is terminated (e.g. before slaughter). The electronic sensors contained within one or either of the pockets and/or the body of the capsule may also be used to monitor rumen function with the aim of optimising production or avoiding metabolic abnormalities. In our device we have the use of fast dissolving tablets within the tablet stack leads to lateral as well as longitudinal swelling of the dissolving tablet or during gel formation. Lateral swelling commonly leads to jamming of tablets against the wall of the barrel - with consequent stopping or loss of accurate in the pay-out kinetics of the capsule. Our preferred devices release one or more of anthelmintics (preferably of several families); growth promotants or rumen modifiers - for the improvement or optimisation of energy production, growth or milk production, or for the reduction in greenhouse gas emissions or the prevention of bloat (for example, using ionophores, such as monensin or lasolocid); micronutrients, such as selenium, cobalt, zinc, iodine, copper, vitamins, such as biotin to prevent lameness disorders, or vitamin D to modify calcium metabolism, V> 1 h AU6 2008 -19- appropriate antibacterials/antivirals as may required to treat enteric diseases (such as Lawsonia, Campylobacter, Yersinia, Salmonella, Cryptosporia, or enteric viruses), microbial additives such as probiotics or nematophagous microbes for the control of nematodes in faeces such as Duddingtonia flagrans, ectoparasiticides that may be absorbed in the gut and act systemically such as the macrocyclic lactones, or insect growth regulators or the like, that may control ectoparasites in the breech region of the animals or in the faeces, electronic controls, measuring devices, senders/transponders identification units. Preferred dosage elements will provide a substantially continuous release of the second and/or first active agent over a period of 70 to 150 days with one or more short or pulsed episodes of release of the first active agent during this period. Preferred vessels for containing the at least first and second formulations are controlled release capsules (CRCs) which are inserted into the rumen of the livestock. Example of suitable capsules may be found in Australian Patent No. 650113, (filed on 1 April 1992 and assigned to Eli Lilly and Company), Australian Patent No. 672520 (filed on 1 April 1992 and assigned to Eli Lilly and Company), US Patent No. 5277912 (filed on 6 April 1992 and assigned to Eli Lilly and Company) and US Patent No. 5562915 (filed on 7 December 1993 and assigned to Eli Lilly and Company). Intraruminal capsule may be designed to be retained in the rumen of a ruminant animal for extended periods of time, for example periods of months to whole of life, and may be administered to cattle, sheep or any other ruminant. The capsule may be adapted to suit any sized ruminant species. The present invention further provides a method for delivering at least a first active agent to the rumen of a ruminant animal in a controlled manner at one or more predetermined times after administration to said animal of a composition containing said active agent, said method comprising administering to said animal a controlled dosage release element according to the invention. -20- The invention also provides a method for the treatment, prophylaxis or both of a diseased or infested state in a ruminant animal, comprising administering to said ruminant an element according to the invention, whereby an effective amount of an agent active against said disease/infested state is released into the rumen of the animal at one or more delayed time periods. As used herein the term "treatment, prophylaxis or both", refers to any and all uses which remedy and/or prevent a diseased or infested state or symptoms, or otherwise prevent, hinder, retard, and/or reverse the progression of disease/infestation or other undesirable symptoms in any way whatsoever. "Infestation" and corresponding derived terms relate to infestation by endo- and/or ecto-parasites pathogens or commensal organisms such as nematophagous fungi. The invention further provides a method for altering the physiological status of a ruminant animal, comprising administering to said ruminant an element according to the invention, whereby an effective amount of an agent active in the control of the physiology of a ruminant is released into the rumen of the animal at one or more delayed time periods. As used herein the term "altering the physiological status", refers to, for example: control of the timing of physiological events, such as oestrus through, for example, administration of sex hormones or analogs; or alteration of the normal physiology of an animal, such as growth rates through, for example, administration of agents which enhance the food conversion efficiency of an animal. An "effective amount", as referred to herein, includes a non-toxic therapeutic/prophylactic amount of an active agent to provide the desired effect. The "effective amount" will vary from subject to subject depending on one or more of a number of factors amongst, for example, the particular agent being administered, the type and/or severity of a condition being treated, the species being treated, the weight, age and general condition of the subject and the mode of administration. For any given case, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine experimentation. Also, extensive literature is available for many known active agents through, for example, manufacturers' catalogues, the internet, scientific journals and patent literature, including effective amounts for administration to target animals. Typically, "effective amount" refers to an amount of active agent sufficient to result in one or more or the following: recession/reduction in the extent of a disease/infestation; inhibition of disease/infestation growth or progression; cessation of disease/infestation growth -21 - or progression; prevention of disease/infestation; relief of disease/infestation imposed discomfort; and prolongation of life of the animal having the disease. Further, "effective amount" refers to an amount of active agent sufficient to result in one or more or the following: suppression of a physiological event such as oestrus; activation of a physiological event such as oestrus; a detectable alteration in the metabolism of an animal such as detectable increase in growth rate and/or food conversion efficiency, or a detectable alteration in throughput in at least one metabolic pathway. Active agents which may be used in the dosage elements of the invention include any active agent which is suitable for oral administration to a ruminant animal. Preferred are those which are desirably administrable directly into the rumen. Active agents preferred for delayed release may be selected from orally active hormones, antibiotics, repartitioning agents, anthelmintics, ectoparasiticides, minerals, and vitamins. Examples of hormones suitable for formulations according to the present invention include orally active hormones or hormone-like substances such as anabolic steroids and progesterone and oestrogen analogs. Preferred examples of anthelmintics are macrocyclic lactones including avermectins and milbermycines, benzimidazoles, imidazothiazoles, niclosamide, piperazine, pyrantel pamoate, phenothiazine, praziquantal, paraherquamide nicotine sulphate suitable organophosphates, such as pyraclophos or napthalophos. Especially preferred anthelmintics are benzimidazoles, imidazothiazoles, and macrocyclic lactones. Examples of suitable thiazoles include teramisole, levamisole or active derivatives thereof. Typically, macrocyclic lactones are selected from the group consisting of ivermectin (22,23-dihydroavermectin Bi described in EP295117), abamectin, avermectin Aia, avermectin Aib, avermectin Aza, avermectin A2b, avermectin Bia, avermectin Bib, avermectin B2a, and avermectin B2. Also typically, the macrocyclic lactone of the first aspect of the invention can include moxidectin, doramectin, eprinomectin and milbemycins. Examples of an ectoparasiticide are organophosphates and carbamates, macrocyclic lactones, including avermectins and milbemycins as described above, closanteL fipronil, imidaclorprid, fluazuron, cyromazine, triflumuron or diflubenzuron. 1 4 AUb 20 -22- A particularly preferred active agent for delayed release is ivermectin, and a single delayed release of ivermectin will typically provide between about 0.05 to 1 .Omg ivermectin per kg animal weight, more typically 0.1 to 0.5 mg ivermectin per kg animal weight, and more typically about 0.2 to about 0.3mg ivermectin per kg animal weight. For beef cattle, delayed release episodes of ivermectin are typically provided at intervals of about ten to thirty, preferably thirty days. For dairy cattle, a single delayed release episode would be preferred at, for example, ten days after administration of the dosage element to the animal, so as to overcome the long milk withholding period. Further pulses for dairy cattle may be possible, depending on the existence and threshold of a Maximum Residue Limit as stipulated by any given jurisdiction. Active agents preferred for controlled release into the rumen over extended time periods may be selected from ionophores such as polyether antibiotics or carboxylic ionophores. Preferably the ionophore is a polyether antibiotic. Examples of polyether antibiotics which can be employed include those produced by the Streptomyces genus or other microorganisms. They are characterised by comprising a multiplicity of cyclic ethers in their structures. Especially preferred representatives of the polyether antibiotics to be employed include ruminal propionate enhancers such as monensin, narasin, lasalocid and salinomycin. An especially preferred polyether for controlled release according to this invention is monensin, a compound widely used in the improvement of feed utilisation in ruminants (see U.S. Patent No. 3,839,557). Generally the amount of ionophore used in the formulation ranges from 0.5 to 60% w/w, preferably 0.5 to 50% w/w based on the total amount of formulation. Typically a monensin dosage will range from about 100 to about 500mg monensin per head of cattle per day, depending on the weight of the animal. Preferably about 150mg is released per day into the rumen of cattle of less than 200kg in weight, and about 300 to 500mg per day for cattle of over 200, and up to 500kg in weight. Generally 0.5 to 2.5, usually 0.5 to 1.5mg, preferably 0.75 to 1.5mg or 0.75 to lmg of monensin is delivered per kg animal weight per day for cattle. Selenium or selenium compounds including selenium salts may be used advantageously in an ionophore containing formulation as outlined in W003/033 oft /# \ 1 \ Abfi M -23- Generally the amount of selenium used in the formulation ranges from 0.0 i to 2w/w% based on the total amount of formulation, and typically the rate of release of selenium into the rumen will be 5 to lOmg per animal per day, or 10 to 20 (j,g/kg animal weight per day. Examples of repartitioning agents include P-agonists such as ractopamine or clenbuterol. The use of these substances for nutrient repartitioning in animals being described in, for example, US patents numbers 5,686,413 and 5,308,870. The formulation for use in the controlled release dosage elements of the invention will be prepared with any one of carriers known in the art which are suitable for veterinary purposes. Veterinary acceptable carriers or excipients for use in preparing the formulations include, for example, sodium citrate; dicalcium phosphate; binders and disintegrants such as agaragar, alginate, povidones including polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone (crospovidone), gelatine, sucrose esters, zein, starches such as potato starch or tapioca starch, modified starches such as starch glycollate salts, and other natural or modified carbohydrate polymers such as xanthan gum, gum tragacanth, guar or locust gums, carboxymethylcellulose (carmellose), methyl-, hyroxypropyl-, hydroxymethyl- or hydroxypropylmethyl- celluloses; other disintegrating agents, for example, carbonate or bicarbonate salts, when mixed with suitable organic acids such as citric or tartaric acids, or silicates such as aluminium magnesium silicate or bentonite; solution retarders, for example, paraffin, glycerol- or polyglycerol esters, waxes, including microcrystalline waxes; humectants, for example, glycerol; fillers and extenders, for example, sucrose, lactose, starch, glucose, mannitol or silicic acid, many of which may also act as binders and/or disintegrants; absorption accelerators, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol monostearate; absorbents, for example, kaolin, bentonite;lubricants, for example, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, talc, or calcium stearate; and enteric coatings dissolvable in rumen fluids, such as acrylic acid/methacrylic acid polymers/co-polymers, and hydoxymethyl-, hydroxypropyl- and hydroxypropylmethyl- celluloses. Examples of suitable carriers for disintegrating formulations for pulsed delayed release of an active agent may include, for example: effervescent biocompatible acid/bicarbonate combinations such as citric acid/sodium bicarbonate or tartaric acid/sodium bicarbonate mixtures; polyvinylpyrrolidones and/or crospovidones; alginates; starch gly collates; microcrystalline cellulose, alkyl ethers of celb&l&jrty as -24- carboxymethylcellulose and salts thereof, and alkylated or hydroxyalkylated celluloses such as high-viscosity grade methylcellulose; or silicates such as bentonite. Examples of suitable carriers for controlled release of an active agent include glycerol-or polyglycerol esters such as hexaglycerol ester, including glycerol or polyglycerol stearates, palmitates, laureates, or oleates, waxes, such as carnauba wax or microcrystalline waxes, sucrose esters, low to medium viscosity methylcellulose grades, starches, dextrins, zein, or combinations of one or more of the above. Formulations of different rates of dissolution may be prepared by careful selection of the carrier(s), and/or including varying amounts of binders with disintegrants, or by regulating the access of rumen fluids to the disintegrants/effervescent combinations by inclusion of, for example, waxes, including microcrystalline waxes, glycerol-or polyglycerol esters in the formulation, or vice-versa. Preparation of appropriate formulations of particular dissolution/disintegrating characteristics is within the skills of appropriately trained formulators, with knowledge of known carriers/excipients such as listed above, by no more than routine experimentation. If necessary, one or more of the formulations maybe provided with a coating, such as a sugar layer or a film dissolvable by rumen fluids, existing at least at boundaries between first and second formulations, so as to protect one formulation from the other, particularly if these are non-compatible such as may arise in the case of, for example, effervescent formulations. Materials, compositions and techniques for sugar or film coating are known to those skilled in the art. The formulations for use in the controlled release dosage elements of the invention may further contain one or more veterinary acceptable adjuvants, diluents, lubricants, or combinations thereof. Examples of veterinary acceptable adjuvants for inclusion in the formulations according to the invention are preserving, wetting, lubricating, emulsifying or dispensing agents. Some examples of these agents are lecithin, hexaglycerol distearate (HGDS), magnesium stearate, sucrose esters, polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, ethyl or n-propyl p-hydroxybenzoate. Examples of veterinary acceptable diluents are cottonseed oil, groundnut oil, castor oil, olive oil, sesame oil, corn germ oil, glycerol, glycerolformal, tetrahv^gg^I^iilcohol, fW -25 - polyethylene glycol, fatty acid esters of sorbitan, benzyl alcohol, propylene glycol, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzl benzoate, 1,3-butylene glycol, corn meal, rice hulls or soy meal, sugars such as lactose, dextrins, or starches. Generally the amount of vertinary carrier, diluent, excipient and/or adjuvant is 40 to 99w/w%, preferably 60 to 99wt% based on the total amount of formulation. Usually 95 to 99w/w% of veterinary carrier, diluent, excipient and/or adjuvant is used. The formulations may also comprise further additives such as a non-ionic surfactant such as alcohol ethoxylates or a silicone antifoam agent. </div>

Claims

-26- WHAT WE CLAIM IS:

1. An intraruminal device capable of releasing at least two active ingredients, the device comprising or including an elongate body or body assembly ("body") substantially impervious to rumen fluids, the body defining a barrel having an end outlet at a first end("first outlet"), a column of matrices in the barrel, at least some of the matrices having one or more active ingredient(s), a compression arrangement within the body adapted to bias the column in the barrel to serially present each matrix to said first outlet, a release arrangement for at least one active ingredient at or adjacent that end of the body distal to said first outlet, and at least one variable geometry device dependent from said body or body assembly to assist rumen retention; wherein the device contains at least two active ingredients.

2. The device of claim 1 wherein said release arrangement is from adjacent said variable geometry device(s).

3. The device of claim 1 or 2 wherein said column of matrices has one active ingredient in at least several of the matrices.

4. The device of any one of the preceding claims wherein said column of matrices has at least a second active ingredient in at least several of the matrices (eg, ionophore and/or anthelmintic).

5. The device of any of the preceding claims wherein said release arrangement is to dump at least one active ingredient into the rumen upon or soon after insertion.

6. The device of any one of the preceding claims wherein an active ingredient, or that active ingredient, of said release arrangement is different from any active ingredient of said matrices.

7. The device of any one of the claim 1 to 5 wherein an active ingredient, or that active ingredient, of said release arrangement is the same as the, or an, active ingredient of said matrices.

8. The device of any one of the preceding claims to provide a pulsed release of at least one active ingredient from said first outlet.

9. The device of any one of the preceding claims wherein said compression arrangement involves a spring or spring and plunger.

10. The device of any one of the preceding claims wherein said release arrangement is -27- from an outlet ("second outlet") at said distal end of said barrel.

11. The device of any one of claims 1 to 9 wherein said release arrangement is from a matrix or reservoir connected to that end of the body distal to said first outlet.

12. The device of any one of the preceding claims wherein said release arrangement can release at least two active ingredients.

13. The device of any one of the preceding claims wherein said at least one variable geometry device comprises at least a pair of resilient wings, each extending outwardly from the end of the body, or adjacent the end of the body, distal to said first outlet.

14. The device of claim 13 wherein said wings for insertion can be held against said body.

15. The device of any one of the preceding claims having opposed end outlets of the barrel.

16. The device of any one of the preceding claims wherein the active ingredients are any one or more one or more anthelmintic(s) and/or one or more anthelmintic(s) with at least one ionophore. END OF CUIHIS