There are many instances where it is desired to activate or allow the activation of the release of an active agent or its precursor (s) whether as a single dose, a continuous dose or as a pulsile dose. Instances include microprocessor control active delivery of agents as might be used to release a medicament into a body cavity such as, for example, disclosed in PCT/NZ98/00011.

Many forms of such active delivery device (in addition to microprocessor or other logic means capable of empowering the release) utilise a reservoir or barrel having a membrane or piston that separates the formulation of the active agent or its precursor (s) from a gas generating arrangement, eg, a hydrogel and its electrodes.

SUMMARY OF THE INVENTION The present invention is directed to providing the timing mechanism for dispensing apparatus (preferably which lends itself to an easier manufacturing procedure (as will be described hereinafter in more detail)). It is an object of the present invention to provide such apparatus and related means, methods and procedures.

The present invention has found there can be an effective staggering of materials to be delivered from a device (once initiated by some act) which thereafter is to continue with its delivery regime without a need for further human input where there is reliance on the movement (preferably rectilinearly) of a member or element having a known movement profile or characteristic as the stagger timing mechanism.

In one aspect the invention is a dispensing apparatus capable of expressing material, whether the same or different, from at least two reservoirs, the apparatus being characterised in that actuation means for expressing material from an outlet of a first of said reservoirs (hereafter"primary reservoir") also directly or indirectly expresses or times the expression of material from the outlet (s) of at least one other said reservoir (hereafter"secondary reservoir (s)") but only after a predetermined

state of expression of the material from said primary reservoir has occurred.

Preferably said actuation means for expressing material from said primary reservoir includes a piston (hereafter"primary piston").

Preferably said at least one said secondary reservoir at least in part includes a piston capable of expressing its material via its outlet.

In one embodiment said actuation means includes a gas generation unit the gas of which is capable of moving said primary piston.

Preferably said gas generation unit is a resistance circuit actuable to generate gas from the battery providing the powering therefor.

Preferably said gas generation unit includes a hydrogel electrolysed at least in part by a battery powered resistance circuit. In this respect see WO 94/01165, US Patent 5,402,42 and US Patent 5,741,275.

Preferably a switching mechanism is provided to allow the initiation of actuation of said gas generation unit.

In other embodiments said actuation means includes at least one of the group consisting of a spring, an osmotically expanding material, a chemical reaction, compressed gas, evolved or generated gas (es) and a motor.

Preferably said apparatus is capable of being inserted into a body cavity.

Preferably deployable members for retention in a target body cavity are provided.

Preferably said apparatus is of a configuration for a target mammal with retention features for intra vaginal use. See, for example, US Patent 4,091,807, WO 99/07346, WO 95/13760, WO 98/33452 and WO 96/29025.

Preferably at least one of the materials to be expressed is a liquid or liquid formulation.

Preferably at least one of the materials to be expressed is in the form of a solid or a solids formulation.

Preferably at least one of said outlets is sealed, plugged or otherwise closed yet is openable under the forces to act thereon as the associated material is pressed for expression out of such outlet (s).

Preferably at least one of said secondary reservoirs has its material expressible

under the action of gas from said gas generation unit bypassing or ducting through said primary piston once the primary piston has moved a predetermined amount.

Preferably (at least) one of said secondary reservoirs has its material expressible under the action of said primary piston coming into contact with and driving a material expressing piston of a said secondary reservoir.

Preferably said primary piston carries a magnet capable of switch actuation for a circuit in turn, once actuated, to cause movement of means to express material from at least one said secondary reservoir.

Preferably said primary piston using a magnet/reed switch interaction can cause, using at least one of the group defined in claim 8, an expression of the material from at least one said secondary reservoir.

In another aspect the invention is as previously defined substantially as herein described with reference to any example thereof and/or any of the accompanying drawings.

In another aspect the invention is a dispensing apparatus comprising or including an assembly defining partitioned chambers where the partitioning member can be moved by gas pressure increase (s) in one chamber to reduce the volume of the other chamber, a battery powered circuit actuable to generate gas within or for said one chamber, at least one assembly defining at least one material containing reservoir with an outlet (sealed, plugged or otherwise optionally closed) it or each capable of being reduced in volume by a piston, wherein at least one said piston of a said material containing reservoir is moved to express the associated material only once, under the action of said gas generation, said partitioning member has moved a predetermined amount.

Preferably said partitioned chambers have a piston as its partitioning member.

Preferably said one chamber of said partitioned chamber to reduce in volume has an outlet (sealed or otherwise) and contains a material expressible out of said chamber as said volume is reduced.

In another aspect the invention is a dispensing apparatus comprising or including an assembly defining partitioned chambers where the partitioning member can be moved to reduce the volume of the other chamber, at least one assembly defining at least one material containing reservoir with an outlet (sealed, plugged or otherwise optionally closed) it or each capable of being reduced in volume by a piston, wherein at least one said piston of a said material containing reservoir is moved to express the associated material only once said partitioning member has moved a predetermined amount.

Preferably said partitioning member is movable by mans of at least one of the group consisting of a spring, an osmotically expanding material, a chemical reaction, compressed gas, evolved or generated gas (es) and a motor.

Preferably a said piston of a said material containing reservoir is movable by means of at least one of the group consisting of a spring, an osmotically expanding material, a chemical reaction, compressed gas, evolved or generated gas (es) and a motor.

Preferably said partitioned chambers have a piston as its partitioning member.

Preferably said one chamber of said partitioned chamber to reduce in volume has an outlet (sealed or otherwise) and contains a material expressible out of said chamber as said volume is reduced.

In another aspect the invention is a multiple material dispensing apparatus having a primary reservoir containing a first material expressible via an outlet under the action of a primary piston, and at least one secondary reservoir itself containing a material to be dispensed via an outlet under the action of a secondary piston, wherein said secondary piston is actuable directly by said primary piston after an at least partial expression of the material of the primary reservoir.

In still another aspect the invention is a dispensing apparatus capable of expressing materials, whether the same or different, from at least two reservoirs, the

apparatus being characterised in that a piston (hereafter"primary piston") in use will express or cause the expression at least some material from a reservoir and that piston, directly or indirectly, activates or causes the expression of at least some material from at least one other reservoir, the relative timing of the at least partial emptying of the reservoirs between or amongst the reservoirs being predetermined but nonetheless being dependent on said piston and its travel.

In still another aspect the invention is a dispensing apparatus capable of expressing material, whether the same or different, from at least two reservoirs in a delayed manner, the apparatus being characterised in that a member capable in use of moving or being set to move, can, upon predetermined movement occurring to provide the delay or delays, directly or indirectly express or time the expression of material from the outlet (s) of said at least two reservoirs.

Preferably each said reservoir includes a piston.

Preferably the apparatus is also apparatus of any one of claims 1 to 29.

Preferably said member in use capable of moving, moves under the influence of at least one of the group consisting of a spring, an osmotically expanding material, a chemical reaction, compressed gas, evolved or generated gas (es) and a motor.

Preferably in use said delays are staggered.

Preferably said member capable in use of moving or being set to move is a piston capable of expressing material from its own reservoir.

Preferably said apparatus is in the form of a bolus or intra vaginal device, eg; for use as a bolus.

In another embodiment said apparatus is adapted for release of active ingredients into an environment.

In another aspect the invention consists in a dispensing apparatus capable of expressing materials, whether the same or different, from at least two reservoirs, the apparatus being characterised in that a piston in use that can be initiated to move or which, in its in use site, can move, will express or cause the expression of at least some material from a reservoir and that primary piston also, directly or indirectly, activates or causes the expression of at least some material from at least one other reservoir.

Preferably the expression of at least some material from at least one other reservoir is under the action of a piston in turn moved, initiated to move or allowed to move by the state of movement of the primary piston.

In another aspect the invention consists in a dispensing apparatus capable of expressing materials, whether the same or different, from at least two reservoirs, the apparatus being characterised in that a piston movable under the action of a generated gas in use will express or cause the expression at least some material from a reservoir and that primary piston also, directly or indirectly, activates or causes the expression of at least some material from at least one other reservoir.

In another aspect the invention consists in a device for intraruminal, intra vaginal, or the like body cavity use capable of expressing materials, whether the same or different, from at least two reservoirs, wherein the apparatus is characterised in that a piston in use will express at least some material from a reservoir and that piston directly or indirectly, activates or causes the expression of at least some material from at least one other reservoir.

In another aspect the invention is an intra vaginal device having (i) a progesterone containing material in a primary reservoir, and (ii) oestradiol or an oestradiol containing material in a secondary reservoir, where, in use, a member which moves in a predetermined way provides a delay in the release of (ii) with respect to (i).

Preferably said device has four reservoirs to release in sequence, reliant on said member's movement (a) a progesterone containing material, (b) oestradiol benzoate, (c) cloprostenol sodium, and (d) oestradiol 17P.

Preferably said device is also a device as previously defined.

In one embodiment said device is a bolus for use in a ruminant having in separate reservoirs a trace metal (eg; zinc) and an anthelmintic (eg; ivermectin) which is also a device as previously defined.

In another aspect the invention is, in a plural reservoir (solids and/or liquid)

material dispensing apparatus, the use of a directly or indirectly (eg; through gas generation) driven member capable after initiation of progressive movement having predetermined travel characteristics as the initiator and/or force providing member for time staggered expression of material from the reservoirs.

In another aspect the invention is the use of a member initiable to move (directly or indirectly under battery power) in a predetermined progressive manner to act as the timing element in the expression from material from different reservoirs in at least a staggered manner.

Preferably, in acting as the timing element said member applies directly or indirectly force to an expression piston of at least one reservoir.

Preferably said member is itself an expression piston of a material containing reservoir.

In another aspect the invention is a method of, at least in part, serially or sequentially expressing materials from a delivery device, said method comprising actuating a battery powered device to move an element thereof in a substantially known manner to thereby, with delay of such travel, to act, staggered with respect to time, upon a material expression component of each material containing reservoir to thereby express such material via an outlet.

In still another aspect the invention is a method of stagger expressing materials from a delivery device, said method comprising setting, actuating or initiating the device to move an element thereof, firstly, to commence (directly or indirectly) materially expression from a first reservoir of the device, and secondly, after the element has traveled a predetermined distance and as it continues to travel, to commence (directly or indirectly) material expression from another material containing reservoir.

In another aspect the invention is a method of patterning the delivery of plural materials into a body cavity of an animal which comprises or includes the steps of introducing into a said cavity a device containing said plural materials, discharging at least one of said plural materials from a reservoir under the action of a plunger which reduces the volume of a reservoir available therefor

sometime after the initiation of the device, and, by (direct or indirect) interaction with said plunger subsequently discharging at least one other material of the device from that material's reservoir within the device.

In one embodiment said device is an intra vaginal device.

In one embodiment said plunger is moved under the action of a gas generation unit.

Preferably said action with said plunger is by abutment with a piston to discharge said at least one other material.

Preferably said interaction with said plunger involves a bypass for a gas but moves said plunger to then in turn act directly upon a piston for discharging said at least one other material.

Preferably said interaction is indirect and involves magnetic switching.

Preferably said device is a bolus or an intra vaginal device and includes means of variable geometry deployable from an insertion condition to a retention condition.

Preferably said method is performed using, as said device, apparatus as previously defined.

In another aspect the present invention consists in a dispensing apparatus capable of expressing materials, whether the same or different, from at least two reservoirs, the apparatus being characterised in that a piston in use will express or cause the expression at least some material from a reservoir and that piston, directly or indirectly, activates or causes the expression of at least some material from at least one other reservoir, the relative timing of the at least partial emptying of the reservoirs between or amongst the reservoirs being predetermined but nonetheless being dependent on said piston and its travel.

Preferably the expressions are linked timewise to the travel of the piston.

Preferably the apparatus is for use as a bolus or as an intra vaginal device.

Other uses could be for timed release of actives into any environment, eg; fishtanks, lubricants into bearings, etc.

Preferably the expressions are linked timewise to the travel of the piston.

Preferments in respect of the dispensing apparatus or the bolus of the present

invention will now be described.

Preferably said apparatus is of a kind where the piston of said first reservoir advances without rotation. In other forms it may rotate.

Preferably the advancement of the piston of the first reservoir is under the action of a gas and/or an activated electrical circuit.

Preferably the material of at least the first reservoir is a fluid. Preferably that fluid is a liquid. Preferably the liquid is or contains an active ingredient (whether solid or not). In other forms the material may be a gas or a mixture of a gas and liquid. Any such liquids may include a solids content and/or itself is a mixture of multiple liquids. In some instances the material to be expressed from a reservoir can be a solid or almost a solid, eg loose powders, a gel, a capsule, or the like.

In some forms of the present invention at least one and preferably each of the reservoirs is provided with a closed outlet capable of being opened under the direct or indirect action on the contents of the associated reservoir, eg, as would be the case with, for example, a waxed or frangible seal.

Preferably said apparatus has the piston thereof movable under the action of a gas which is generated upon the device being switch activated, eg, at the time of insertion.

In some forms of the present invention the gas may be generated from a hydrogel or the like using an electrolysis dependent gas generation circuit capable of being activated. In still other forms preferably said gas is generated directly from the energisation of a circuit including a gas generation battery.

In some forms of the present invention the first reservoir may in turn discharge its content onto a down stream reservoir, eg utilising as a piston therebetween a seal between the materials for the purpose of discharging first material from the second reservoir.

In still other arrangements there is a direct discharge through a rupturable or dischargeable seal of the material of the first chamber and a sequential movement of the piston towards at least one other reservoir until such time as there is interaction therewith as a result of the pistons movement. Such interaction may be direct contact or penetration. For example, a needle type arrangement could penetrate the

piston of the first reservoir to thus allow the action of a gas that moves the first piston directly onto a piston or like member of such a second reservoir. In the same or different apparatus such interaction might mean there might equally be some extension of the piston into the reservoir of another material to itself act as a separate delayed action thereof.

In still other interactions the piston may time (eg by magnetic interaction) some energisation of a release circuit forming part of a release arrangement of another reservoir.

BRIEF DESCRIPTION OF THE DRAWINGS The invention consists in the foregoing and also envisages constructions of which the following gives examples.

In the accompanying drawings Figure 1 shows a hybrid apparatus in accordance with the present invention where there can be an actuation of the device and some control of a discharge sequence of materials from different reservoirs in a pre-determined manner, Figures 2A to 2D shows a sequence of materials expression using a device substantially similar to that of Figure 1 with both a piston/needle and piston/piston interaction for the delayed deliveries, Figures 3A to 3B in a similar manner to that of Figures 2A to 2D shows an expression sequence again with a device similar to that of Figure 1 but this time with a primary piston interacting directly on a piston of at least two of the secondary reservoirs with stagger timing as to delivery therefrom, Figure 4 shows the rate of vehicle delivery for a device of a kind as shown in Figure 1 in a simplified form, Figure 5 shows the effect of the needle and piston (diamond) or piston only (square) on delivery rate at 38°C of vehicle from an infusion reservoir of a device possessing the bolus reservoir option as depicted in the embodiments shown in Figures 2A to 2D, Figure 6 shows the effect of short secondary piston (circle) or long secondary piston (square) upon flow rate at 38°C of vehicle from the infusion reservoir of a device possessing piston/piston interaction options as shown in options of Figures

2A to 2D and more particularly 3A to 3D, Figure 7 shows a plot to show the effect of the static resistance of the piston and seals of a primary bolus reservoir and the subsequent influence thereof on time lag between initiation of hydrogen production of a gas cell and release of a primary bolus reservoir dosage unit and vehicle from the infusion reservoir, Figure 7 showing the release of fluorescence from a primary bolus reservoir with a high static pressure piston, Figure 8 is a similar plot to that of Figure 7 but in respect of a low static pressure piston, Figure 9 shows the use of an interaction with the piston to time subsequent discharges, Figures 10A through 10D show a device having (shown diagrammatically and not in an assembly) a sequence of three secondary reservoirs capable of being activated by passage past, for example, a read switch of a magnet that moves as the moveable element or member, and Figure 11 shows a most preferred form of the present invention having materials discharged from the primary reservoir under the action of a primary piston (moved by gas being generated after initiation), the primary piston subsequently, by abutment on piston extensions of two secondary reservoirs, leading to the staggered discharge from the secondary reservoirs.

While the preferred propulsion mechanism for the main piston is a gas generating or hydrogel cell, other mechanisms may be used.

Other mechanisms that may be employed to drive the main piston (or secondary pistons, especially following activations by a main piston via a magnet and reed switch) include; -a spring, -an osmotically expanding material, e. g. gelatin, -chemical reaction, e. g. acid/base reaction resulting in the liberation of C02, -compressed gas, e. g. a hydrocarbon, and -a motor, e. g. a"watch"or turning screw.

Figure 1 shows a main barrel or reservoir having an outlet the upper end adjacent to smaller reservoirs. Preferably the formulations are protected within the barrel and smaller reservoirs by rupturible seals 1. A main piston 2 acts to dispense the contents from a main reservoir 3 as a result of an increase in pressure from a gas cell 4 that is activated by a switch 5. The contents of the main reservoir act upon the primary piston 6 of a primary reservoir 7 to dispense the primary reservoir contents after the rupture of the primary reservoir seal. The primary piston may also act directly upon the rod and piston 8 to dispense the contents of a terminal reservoir 9.

The primary piston may also be pierced by a needle 10 thereby enabling gas to by- pass the main piston and act upon a piston 11. Also present on the device are means by way of retention arms 12 for locating the device in a body cavity such as a vagina.

One configuration of the Figure 1 option is better presented in Figures 2A to 2D. As the infusion piston commences its migration towards the infusion reservoir orifice a dosage unit (e. g. tablet) located within the orifice (primary bolus reservoir) is expelled. Towards the end of the infusion pistons migration it acts upon a secondary piston whilst simultaneously being pierced by a needle. This action has two results; (1) a dosage unit in the secondary bolus reservoir is expelled, and (2) hydrogen from the gas cell is able to bypass the infusion piston in order to act upon the piston of the tertiary bolus reservoir and, once sufficient pressure has been reached, expel the contents of said reservoir.

A different configuration is presented in Figures 3A to 3D. As the infusion piston commences its migration towards the infusion reservoir orifice a dosage unit (e. g. tablet) located within the orifice (primary bolus reservoir) is expelled. Towards the end of the infusion pistons migration it acts upon a secondary piston and thereby a dosage unit in the secondary bolus reservoir is expelled. Following this action the infusion piston commences action upon a tertiary piston and thereby a dosage unit in the tertiary bolus reservoir is expelled.

Figure 4 shows the rate of vehicle delivery from a device similar to that represented in Figure 1 with the exception that the needle 10 and piston 11 are

absent.

The action of the infusion piston coming into contact with a secondary piston reduces the flow of vehicle from the infusion reservoir (Figure 5). However no additional reduction in flow of vehicle from the infusion reservoir is observed as a result of the action of the infusion piston coming into contact with the needle as present in bolus reservoir mechanism of Figures 2A to 2D (see Figure 5).

In Figure 5 the arrow represents the time point at which the infusion piston comes into contact with the secondary piston and/or needle. The vehicle was aqueous 2% HPMC held at 38°C. The interaction between the needle and piston as shown by the diamonds and the interaction between the piston with a piston is shown with the squares.

The action of the infusion piston coming into contact with a secondary piston reduces the flow of vehicle from the infusion reservoir (Figure 6). However selection of long (i. e. projecting further into the infusion reservoir) or short pistons for the secondary bolus reservoir piston and altering the external resistor allows for control of the flow rate from the infusion reservoir (Figure 6).

In Figure 6 the vehicle is aqueous 4% HPMC at 38°C and the circles depict the effect of a short piston whilst the square depict the effect of a long piston. The piston options are those depicted as piston to piston interactions in Figures 2A to 2D and 3A to 3D.

The static resistance of the piston and seals of the primary bolus reservoir influences the time lag between initiation of hydrogen production by the gas cell and release of the primary bolus reservoir dosage unit and vehicle from the infusion reservoir (see Figure 7 and 8 and Table 1).

Table 1. Effect of high static pressure (2 points of contact between piston and reservoir walls) and low static pressure (1 point of contact between piston and reservoir walls) upon the lag between initiating hydrogen production by the gas cell and release of a dosage unit from the primary bolus reservoir.

ReplicateHiqh friction Lowfriction 1 655-660 mins 125 mins 2 Did not release 410 mins Choice of appropriate rod lengths for the bolus chamber delivery mechanism and static pressure of the pistons within each individual reservoir would enable the selection of any desired delivery rate and profile.

Figure 7 shows the release of fluorescence from the primary bolus reservoir with a high static pressure piston whilst Figure 8 shows the release of fluorescence from the primary reservoir with a low static pressure piston.

Figure 9 shows a main barrel or reservoir 1 in which a piston 2 containing a magnetic material 3 is enabled to migrate within the main barrel as a result of an increase in pressure from a gas cell 4. The magnet material is able to activate individual sensors 5 or sensor part or an array 6 which in turn control the action of a device (s) 7 and/or 8.

In vivo performance of multiple material dispensing option of Figures 3A to 3D An in vivo trial investigated the performance of bolus reservoir mechanism of Figure 3A to 3D. Devices were assembled as per Figures 3A to 3D, and inserted into the vagina of normal cattle for 9 days. It was visually confirmed upon removal of the devices that all chambers were activated and the dosage units therein delivered.

Description of multiple material dispensing option of Figures l0A to 10D The configuration of this option is presented in Figures I OA to 1 OD. As the infusion piston commences its migration towards the infusion reservoir orifice dosage units (e. g. tablet) located within bolus reservoir are expelled due to the action of a magnet within the infusion piston activating sequential reed switches thereby

initiating the electrolytic production of gasses.

In vitro performance of multiple material dispensing option of Figures 10A to 10D Three devices as per Figures I OA to lOD and Figure 9 were constructed.

Activation and expulsion of dosage units from all bolus reservoirs was visually confirmed.

In vivo performance of multiple material dispensing option of Figures 10A to 10D An in vivo trial investigated the performance of bolus reservoir mechanism of Figures 1 OA to 1 OD. Devices were inserted into the vagina of normal cattle for 9 days. It was visually confirmed upon removal of the devices that all chambers had been activated and the dosage units therein delivered.

Preferred multiple material dispensing option A preferred configuration is detailed in Figure 11 and Table 2. It consists of a cylinder that is divided by piston 13 in reservoir 14, containing the formulation, and part 15, containing the gas and the gas producing components. The action of piston 13 upon the formulation contained in reservoir 14 causes piston 16 to expel the contents of reservoir 17 following the rupture of a seal 18.

Following the expulsion of formulation piston 13 migrates towards the outlet of reservoir 17 thereby coming into contact with rod 19. Rod 19 acting under the influence of piston 13 drives piston 20 to expel the contents of reservoir 21 following the rupture of seal 22.

Following further expulsion of formulation piston 13 migrates further towards the outlet of reservoir 17 thereby coming into contact with rod 23. Rod 23 acting under the influence of piston 13 drives piston 24 to expel the contents of reservoir 25 following the rupture of seal 26.

Table 2. Physical parameters of design brief for electronically modulated intravaginal synchrony device.

Parameter Specification Gross physical dimensions Delivery component outer diameter (cm) 2.5 Delivery component length (cm) 13 retention mechanism width (cm) 15 Infusion reservoir (1) Volume (mi) 30 Delivery rate (ml/day) 3.33 Bolus reservoir one (5) rod protrusion into infusion reservoir (%) NA Volume (ml) 0.10 Bolus reservoir two (8) rod protrusion into infusion reservoir (%) 11 Volume (ml) 0.10 Bolus reservoir two (11) rod protrusion into infusion reservoir (%) 1 Volume (ml) 0.10 Example 1: RESERVOIR CONTENTS FOR INTRA VAGINAL PRODUCT Main reservoir contents: 15 mg/ml progesterone dissolved in ethanol thickened with 4% hydroypropyl methyl cellulose (P4) Secondary reservoir contents: Primary-a tablet, liquid or semi-solid dosage unit of 10 mg oestradiol benzoate (ODB) Secondary-a tablet, liquid or semi-solid dosage unit of 1000 mcg of cloprostenol sodium (PG) tertio-a tablet, liquid or semi-solid dosage unit of 7.2 mg oestradiol 17beta (E 17b) Example 2: CONTENTS OF INTRARUMINAL PRODUCT Main reservoir contents-Zinc oxide liquid or semi-solid formulation Secondary reservoir (s)-tablet, liquid or semi-solid Ivermectin 60 mg