WO1995013760A1

WO1995013760A1 - Gas driven controlled release device

Info

Publication number: WO1995013760A1
Application number: PCT/AU1994/000701
Authority: WO
Inventors: Peter Costigan; Keith James Ellis; Ralph Henry Laby; Bruno Kautzner; Warren Goodwin Chandler
Original assignee: Commonwealth Scientific And Industrial Research Organisation
Priority date: 1993-11-15
Filing date: 1994-11-15
Publication date: 1995-05-26

Abstract

A controlled release device adapted to contain a material and to release it over an extended period of time, includes a hollow body (11) adapted to contain the material, and egress means (14) in the body adapted to allow egress of the material. Means for urging the material towards the egress means for egress therefrom includes an expandable chamber (22) in the body separated from the environment external to the body by gas permeable partition means (16, 116, 119'). The gas permeable partition means is arranged to be differentially permeable for selected gases in the chamber and the external environment, whereby the gas pressure in the chamber increases above and is maintained above a level sufficient to produce a driving force for sustaining egress of the material over the extended period of time.

Description

GAS DRIVEN CONTROLLED RELEASE DEVICE

Field of the Invention

This invention relates to controlled release devices adapted to contain material, eg a solid liquid or paste material, and to release it over an extended period of time. Such devices are used, for example in pharmaceutical and veterinary applications, and the materials may comprise or contain therapeutic or prophylactic drugs, nutrients or dietary supplements, or other biologically active substances.

A well established application of such devices is for intra-ruminal administration of various agents to ruminants. The present application primarily discusses improved devices for these applications, but it is emphasised that the concepts of the invention are adaptable not only to ruminant husbandry and medication but also in the general field of animal and human medicine. Moreover, the device of the present invention may be employed as a controlled release device for use in the general environment or in industrial processes.

Background Art

The present applicant's prior Australian patents 520409 and 558009, and their respective United States counterparts, patents 4251506 and 4623330, disclose controlled release devices of a type in which a solid therapeutic composition retained in a generally hollow tubular body is urged towards a restricted exit opening by a spring-loaded plunger within the tubular body. These devices also carry variable geometry fittings to allow the devices to be administered in one configuration per os into the rumen of a ruminant, whereupon a second configuration minimises the possibility of regurgitation from the rumen. In the case of patent 520409, the plunger is relatively loosely movable under the action ®f a helical compression spring. With the device disclosed in patent 558009, a gas-tight plunger and a gas-permeable membrane are used to augment spring control of the release rate of the material from the device. Gas is allowed to permeate from the external environment into the tubular body behind the plunger and thereby can limit the rate at which the plunger can move under the influence of the helical spring.

Although these prior devices provide excellent reproducability and linearity of output and required lifetime, they are of relatively complex construction. They also suffer from the disadvantage of a metallic spring that can be of substantial length in its free state and can therefore be injurious to animals and damaging to rendering machinery at abattoirs.

United States patent 5198222 to Scully et al describes a time-release bolus containing a breakable plastic capsule or bag containing a fluorocarbon gas under pressure. Immediately prior to insertion of the bolus per os, the tubular body is squeezed to rupture this plastic capsule, which action releases gases into a sealed internal chamber. These gases exert pressure on a further inner container whose contents are thereby urged, over a period of time, through an exit orifice. The duration of this period is not specified but is thought by the present applicant to be likely to be relatively short, in view of the diminishing pressure of the internal chamber as it expands with release of the contents.

Disclosure of the Invention

It is an object of the present invention to provide an improved controlled release device which contains neither metal spring components nor fractured capsules, but is effective to contain any material and release it over an extended period of time.

The invention, at least in one aspect, essentially entails the concept of providing for differential permeability of one or more selected gases contained within a controlled release device relative to one or more gases of its external environment when in situ, whereby to provide a sustained gas pressure drive for controlled release of contained material over an extended period of time. It was realised by the present inventors that, with some configurations of device according to the aforementioned patent 558009, when installed in a rumen, carbon dioxide diffused into the device so rapidly compared to the efflux of oxygen and nitrogen outwardly, that there was a short-term increase in the total gas pressure behind the spring-loaded plunger before the movement of the plunger brought about the volume increase and accompanying pressure limitations. In essence, it has been appreciated that an improved device could be developed in which differential gas permeation could be selectively utilised to produce a driving force for sustaining egress of the material from the device over the delivery life of the device, thereby allowing the spring to be dispensed with.

In accordance with a first aspect of the invention, therefore, there is provided a controlled release device adapted to contain a material and to release it over an extended period of time. The device includes a hollow body adapted to contain the material, and egress means in the body adapted to allow egress of the material. Means for urging the material towards the egress means for egress therefrom includes an expandable chamber in the body separated from the environment external to the body by gas-permeable partition means. This gas-permeable partition means is arranged to be differentially permeable for selected gases in the chamber and the extemal environment, whereby the gas pressure in the chamber increases above and is maintained above a level sufficient to produce a driving force for sustaining egress of said material over the extended period of time.

In one embodiment, the gas permeable partition means may comprise a wall segment of the body, for example a membrane. The membrane is preferably a polymer selected from the group comprising polyethylene, polypropylene, polyester, polyvinylidene chloride and poly(dimethylsiloxane), and is advantageously a metallised laminate of such a polymer. A low-polarity polymer may be preferred in some cases.

The urging means may alternatively or further include flexible sheet means about the chamber and expandable by the gas pressure as the material is released from the body over the extended period of time. In one arrangement, this flexible sheet means may be associated with a wall segment or membrane forming the gas permeable partition means. In another arrangement, the flexible sheet means may enclose the chamber and comprise the gas permeable partition means. In this case, there may be a separate opening through the body or the body may simply be of a material permeable in a non- differential or less differential manner with respect to the selected gases.

The urging means may include slidable plunger means which may be in contact with the material and may, for example separate the aforementioned chamber from a space adapted to contain the material. Depending upon the embodiment, this plunger means may be in gas-tight slidable engagement with an internal wall of the body.

In some cases, it may be desirable to provide for an additional pressure charge within the chamber. For example, the chamber may further contain a substance adapted to generate a vapour within the chamber, at least when the device is in situ, to provide an additional partial gas pressure in the chamber and thereby to provide the potential for further inward gas permeation from the environment. This vapour preferably has a vapour pressure less than one atmosphere at the temperature of the extemal environment within which the device is to be sited in use and may be selected from a suitable volatile substance. Possible such substances include methanol and other alcohols, acetonitrile, ammonia, acetic acid, a subliming substance such as iodine, or a carrier liquid or solid material (eg cyclodextrins) in which a gas can be dissolved or otherwise retained under some circumstances but which would be released in the environment of application.

Alternatively or additionally, the device may comprise pressure setting means operable to increase the gas pressure in the chamber prior to administration of the device and thereby to provide the potential for further inward gas permeation from the environment. This pressure setting means may comprise structure carried by the body and adjustable to compress the chamber and thereby reduce its volume and increase its contained gas pressure. Alternatively, there may be means to introduce a gas into the chamber to increase the gas pressure therein above that outside the body. A still further alternative comprises port means to draw in gas as the chamber is cooled, which port means is then sealable so that the gas pressure increases significantly at the in situ temperature.

Preferably, the controlled release device further includes means to vary the geometry of the device between a first configuration permitting administration or dosing of the device to an operating location and a second configuration adapted to facilitate retention of the device at the location.

In its first aspect, the invention also provides a method of delivering a composition to a ruminant over an extended period of time comprising: administering per os a controlled release device containing said composition to the rumen of the ruminant, allowing one or more of the gases in the rumen to permeate into a chamber of the device whereby gas pressure in said chamber in increased above and maintained above a level sufficient to produce a driving force for sustaining egress of said composition into the rumen over said extended period of time.

In a second aspect, the invention provides a controlled release device adapted to contain a material, eg a solid, liquid or paste material, and to release it over an extended period of time, the device comprising: a hollow body adapted to contain the material; egress means in the body adapted to allow egress of the material; and means for urging the material towards the egress means for egress therefrom, the means including an expandable chamber in the body; and a substance in the chamber adapted to at least partially vaporise within the chamber, at least when the device is in situ, to thereby increase and maintain the gas pressure in the chamber above a level sufficient to provide a driving force for sustaining egress of the material over said extended period of time.

In a third aspect of the invention, there is provided a controlled release device adapted to contain a material, eg a solid, liquid or paste material, and to release it over an extended period of time, the device comprising: a hollow body adapted to contain the material; egress means in the body adapted to allow egress of the material; and means for urging the material towards the egress means for egress therefrom, such means including an expandable chamber in the body; and means adaptable, prior to administration of the device, to increase the gas pressure in the chamber above that outside the body and to thereby provide a driving force for sustaining egress of the material over the extended period of time.

In one embodiment of the third aspect of the invention, said means to increase the gas pressure comprises structure carried by said body and adjustable to compress said chamber and thereby reduce its volume and increase its contained gas pressure.

Alternatively, in another embodiment, said means to increase the gas pressure comprises means to introduce a gas into said chamber from outside said body to increase the gas pressure therein above that outside the body.

A still further alternative for the pressure increasing means comprises port means to draw in gas as the chamber is cooled, which port means is then sealable so that the gas pressure increases significantly at the in situ temperature.

Brief Description of the Drawings

The invention will be further described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1 is a diagrammatic axial cross-sectional view of a controlled release device in accordance with a first embodiment of the invention, suitable for administering therapeutic and other agents in the rumen of a ruminant;

Figure 2 is a similar view of a modified form of the device illustrated in Figure 1 and additionally containing a volatile substance;

Figure 3 is a similar view of a further embodiment of the invention which also incorporates an arrangement for pre-loading the gas pressure chamber, the device being shown in its transport and storage condition prior to administration;

Figure 4 is a view corresponding to Figure 3 but depicting the device in its loaded condition ready for administration; Figures 5 and 6 are views similar to Figures 3 and 4 respectively of a still further embodiment of the invention; and

Figures 7 to 10 depict the results of various experiments utilising devices of the form depicted in Figures 5 and 6.

Description of Preferred Embodiments

The controlled release device 10 depicted in Figure 1 is an experimental device for use in rumen fϊstulated cattle. The device 10 includes a hollow body formed from a disposable polypropylene hypodermic syringe barrel 11 which has the usual flange 12 at its open end 13 and a nozzle 14 at the other end. Nozzle 14 serves as restricted egress means which allows egress of therapeutic material 9 housed within barrel 11 adjacent nozzle 14. The therapeutic material is depicted in this case as a packed powder, paste, or the like and would typically consist of an active constituent in a rratrix chosen to facilitate subsequent delivery of the active constituent from the barrel.

Means 20 is provided for urging material 9 towards nozzle 14 for egress therefrom. This means 20 includes an expandable chamber 22 defined by a suitable substantially impermeable flexible sheet means such as metallised laminate film 19 and separated from the extemal environment by a gas- permeable partition provided by a diaphragm or membrane 16. Membrane 16 is clamped to flange 12 by means of a pair of clamping rings 17,18 to provide a gas-tight seal around the flange 12 and membrane 16. Rings 17,18 are held together by any suitable means, for example screws (not shown). Film 19 is in the shape of an open bag and is sealed at the mouth of the bag to the inner rim of barrel 11 adjacent flange 12 by an internal sealing ring 24.

Membrane 16 is selected to be differentially permeable with respect to the principal gases of the extemal environment and in chamber 22 so that the gas pressure in the chamber increases above and is maintained above a level sufficient to produce a driving force for sustaining egress of therapeutic material 9 from outlet 14 over the extended period of time for which the device 10 is expected to release its contents. For the application in mind, for administration to the rumen of cattle, membrane 16 is selected to be more permeable with respect to carbon dioxide and/or methane, the principal gases of the rumen, than oxygen and/or nitrogen, the principal components of the air with which chamber 22 is initially charged. Suitable membrane materials, especially for an aqueous environment, are the polymers such as polyethylene, polypropylene, poly(dimethyl siloxane), polyester and polyvinylidene chloride.

Ruminal fluids enter the outlet nozzle 14 and contact the therapeutic material 9, acting on the matrix and causing it to slowly change its physical characteristics. For example, the composition may progressively soften and be urged through the outlet and be wiped clear. The driving force applied by the pressurised chamber 22 retains the composition in contact with the restricted outlet, thereby preventing rumen-derived solids from entering the device and tending to act as a barrier to excessive degradation. In this way, the device provides an approximately uniform rate of delivery of the therapeutic material.

In general, the rates of permeation are determined by the characteristics and dimensions of the gas-permeable partition and the permeability coefficients of the gases. The reported permeability coefficients for the gases in question at 39°C (a typical interior rumen temperature) across a polypropylene membrane are approximately in the ratio 1:4:2:16 in the order nitrogen:oxygen:methane:carbon dioxide. These are for an ideal system but are thought to indicate the general relative relationship for the device in a real rumen environment. Under working conditions, the increasing volume as the material is dispensed serves to enhance the relative differences between the permeabilities of the gases entering the chamber and permeating out of the chamber. Initially, in situ, it will be seen that there is a net inward flow of gases, especially in view of the high permeation rate of carbon dioxide, and the total gas pressure rises in chamber 22 to a peak (when the volume rate of gas permeation into the chamber equals that out of the chamber) and then slowly declines as the partial pressure of the slowest gas, nitrogen, declines as it approaches the partial pressure of nitrogen in the rumen, and as the available gas volume in chamber 22 expands with delivery of therapeutic material from outlet 14. Provided the chamber maintains a reservoir of other gases, carbon dioxide and/or methane continue to permeate in as the chamber expands and pressure drops, thus helping to sustain a driving pressure for an extended period of time.

The time that the gas pressure remains at or above "operational pressure" ie a pressure within chamber 22 exceeding the intra-rumen pressure acting at outlet nozzle 14, is determined by the permeability characteristics of the membrane, by the volume of gas in chamber 22, and by the rate of increase in the initial volume and composition of chamber 22 caused by the dissolution and disappearance of the material at the outlet nozzle 14. It will thus be appreciated that the slow permeation of the gases exercises a control over the delivery of the therapeutic material, and that the rate and duration of this control is also determined by selection of the above-mentioned parameters. Selection of the parameters in turn depends on the particular application and on the nature of the particular material to be dispensed. In the latter case, for example, the nature of the material will influence the driving force required.

It will be further understood that- the device 10 may be used in other applications by appropriate selection of the permeability characteristics of the membrane 16, the volume and composition of the gas within chamber 22, the rates of volume and pressure change in volume 22, and the composition of the external environmental gas.

For rumen application, device 10 is desirably fitted with means to vary its geometry between a first configuration permitting administration of the device to the rumen, and a second configuration adapted to facilitate retention of the device in the rumen, ie to reduce the risk of regurgitation. Suitable such means are disclosed in the aforementioned Australian patents 520409 and 558009, or in Australian patent application 47162/85, or in US patent 3844285.

In embodiment of Figure 1, flexible film 19 is ideally made of a gas impermeable film, for example a suitable metallised polymer or proprietary laminate with one or more impermeable layers. As illustrated, film 19 is in the form of an unfolding soft bag. With this arrangement, the bag does not need to slide along the inner wall of barrel 11 thereby causing frictional drag, which might otherwise impair movement of the bag since the degree of contact of the bag with the inside wall of barrel 11 would depend on the internal vapour pressure. Alternatively, the film 19 may be provided in the form of a stretchable material, provided the permeability does not significantly alter as it stretches, or of a folded rigid rib bag. This construction offers the advantage that the bag may be made of laminated plastics which will be of heavier wall thickness and thereby reduce the gradual permeation of drive gas from within chamber 22.

For some applications, in order to ensure initial egress of composition at outlet nozzle 14, or generally to facilitate the long-term performance of the pressurised gas drive configuration, it may be desirable to pre-load gas pressure in chamber 22. Typically, there will be some increase in this pressure when the device is administered to a rumen which would usually be at a temperature above the air temperature on the day. This may be a sufficient starting pressure for some applications. One way of providing a pre-load where it is desirable is to initially include in chamber 22' a small volume of a volatile substance and Figure 2 shows a modification 10' of the embodiment of Figure 1 in which just such a substance is depicted at 30. The device of Figure 2 is shown prior to charging with a therapeutic material.

A suitable volatile substance is methyl alcohol (CH₃OH). This substance provides an additional vapour pressure within chamber 22'. Like the other principal gases in the system already discussed, methyl alcohol vapour permeates through membrane 16' as has been demonstrated by its gradual loss from an experimental device. Appropriate choice of volatile substance 30 and membrane 16' would allow for optimum selectivity and result in a lower rate of loss of the vapour and thereby enhance the medium to long-term pressure within chamber 22' arising from the inward permeation of, eg carbon dioxide and methane, and thus the lifetime of the device. The small volume of volatile substance within chamber 22 serves to maintain a partial pressure gradient for the extemal gases downward into chamber 22'. That is, because the vapour pressure of the volatile substance 30' remains constant at constant temperature, the partial pressure will also remain constant despite the steady increase in volume, thus reducing the partial pressures of the other gas components within the chamber. Hence, a partial pressure gradient downward into the chamber is established for extemal gases while volatile substance remains in the chamber. While these conditions apply, the total pressure in chamber 22' exerts positive drive to the therapeutic material 9'.

Preferably, the volatile substance has a vapour pressure of less than one atmosphere at the temperature of the environment within which the device is to be used. Furthermore, the volatile substance should have no adverse effects on the gas permeable partition, ie membrane 16' in this case, and film material. The permeation loss through the membrane of the volatile substance should be low in order to minimise its loss over time from the device. Thus, choice of a volatile substance which in its liquid state has a polarity contrasting with that of the membrane and device materials is particularly desirable. For example, common low polarity plastics such as polyethylene, and polypropylene will retain highly volatile liquids such as methanol (methyl alcohol) or acetonitrile preferentially. Methanol and the other volatile alcohols are the preferred liquids when low-polarity components are used in the device 10'.

The rumen gases permeating into chamber 22' cause a dilution of the vapour generated by substance 30 and therefore more of the volatile substance must vaporise so as to maintain the partial vapour pressure of the substance constant. The device falls into two operational groups depending on the state of the therapeutic material 9' (ie the payload) it may contain:-

(a) A fluid payload system where the device works at an isobaric equilibrium, that is, the pressure inside the chamber 22' of the device is equal to the rumen pressure, and therefore any increase in volume of the chamber results in the expulsion of an equal volume of material 9' from the device. Furthermore, the partial pressure difference between the rumen and chamber 22' remains approximately constant, which means that the rate of permeation of rumen gas is approximately constant and the rate of release of material 9' from the device will approach a zero order release rate.

For proper operation this device preferably includes a non-return valve at outlet 14' so as to eliminate the effect of minor fluctuations in rumen gas pressure. Applying Boyle's law it can be shown that permeation of 1 ml of rumen gas into a chamber, the initial gas volume of which is 10 ml, and which contains a volatile substance with a vapour pressure of 1/2 atmosphere at the rumen temperature (which is a constant 39°C) results in a 2 ml increase in the gas volume of the chamber. Similarly, if the volatile substance had a vapour pressure of 3/4 atmosph. (at 39°C) , the increase in the gas volume of the chamber would be 4 ml.

(b) A solid (or "matrix") payload system in which the pressure increases and where the release rate is a function of the dissolution mechanisms occurring at the matrix/rumen interface at outlet nozzle 14', and the drive forces derived from gas pressure. In this system there is a pressure increase resulting from the net inward permeation of rumen gases plus the partial pressure of the volatile substance. This will result in, relative to a device without a volatile substance :-

(i) a higher drive force on the matrix;

(ii) the achievement of a proportionally less variable total gas pressure because as the rumen gases permeating into chamber 22' approach equilibrium , ie by approaching the same partial pressure inside chamber 22' as in the rumen, the force acting on the matrix will be the sum of the partial pressures of the volatile substance, the rumen gases and the residual atmospheric gases and this will then be the maximum total pressure. Consequently the minimum pressure will then result when the atmospheric gases have permeated out, and the total pressure will then be the sum of the partial pressures of rumen gas and the volatile substance, and the net driving force will be the partial pressure of the volatile substance; (iii) me drive pressure always remaining at above rumen pressure under normal operating conditions, thereby eliminating the need to use driving springs.

Figures 3 and 4 illustrate a further embodiment 110 of the invention which differs from the earlier described embodiments in a number of respects. In this case, there is again a tubular barrel 111. The therapeutic material is provided in the form of tablets 109a and is delivered through a restricted forward outlet nozzle 114. However, there is no distinctive membrane and no flexible bag defining a drive chamber. Instead, the rear end of barrel 111 is closed by an end wall I l ia and the chamber 122 comprises a rear portion of the interior of the barrel completed by a lubricated, gas-tight and gas impermeable rubber plunger 119 formed of similar elastomeric material to the septa used in evacuated blood collection tubes and of similar construction to a disposable syringe plunger. The plunger is made gas-tight by deforming it for insertion into the barrel. In this embodiment, moreover, the gas-permeable partition means 116 is provided by appropriate choice of the material of barrel 111, to achieve the required differential permeation characteristics together with the necessary rigidity, eg a solid plastics such as polypropylene, polyethylene, or polyvinylchloride. Alternatively, the barrel can be coated internally with an appropriate material, eg a metallised polymer such as a metallised polyester or a coating of polyvinylidene chloride (saran), to produce the required differential permeation characteristics.

The configuration for pre-charging chamber 122 before administration of the device is provided by forming outlet orifice 114 in a separable snap-on cap 150 which has a cylindrical rim 151 defining a socket with peripheral shallow ribs 152. These ribs are designed to snap over and behind a matching pair of ribs or shallow lug rings 153 on the outside of the open end of barrel 111. Device 110 is assembled with its tablets for transport by having the set of tablets 109a project beyond the barrel and retaining cap 150 on the last tablet with a plastic shrink-wrap 155 (Figure 3). Water soluble adhesive is placed on the outside surface of the plunger 120 and between each of the tablets 109a containing the active compound so that the plunger, tablets and cap 150 form an integral unit. Shrink-wrap 155 is provided to maintain the integrity of the assembly during shipping, handling and storage The gluing of the tablets into an integral core prevents or at least minimises permeation of gas between the tablets during storage.

At the time of dosing, cap 150 is snapped onto the end of the barrel to achieve the configuration shown in Figure 4. This is done either by pushing the cap and barrel together manually or with the aid of a caulking type gun or with the actual dosing gun so that dosing cannot be formed without assembly and pressure pre-loading. The shrink- wrap 155 is then removed. The process of connecting cap 150 to the barrel 111 results in the plunger 122 moving down the barrel, reducing the volume of chamber 122 and increasing the air pressure in the chamber by an amount determined by the initial positioning of plunger 119. The air in the chamber is therefore at an increased predetermined pressure surrounded by a relatively gas impermeable plunger and metallised polyester. The chamber 122 will now behave akin to chamber 22 in the embodiments of Figures 1 and 2.

Figures 3 and 4 include a schematic representation at 160 of geometry varying collapsible wings.

Figures 5 and 6 depict a still further embodiment 110' in which a compressible telescopically mounted cap 150' is provided at the rear end of the barrel rather than at the outlet end. In this case, chamber 122' is defined by a ribbed flexible bag 119' of a differentially gas-permeable material. This bag is wholly sealed closed and is disposed between the rear-most tablet and the head of cap 150' slidably disposed about barrel 111'. Cap 150' has an internal rib 152' at its mouth and is movable between an extended condition determined by an extemal rib 153' at the rear end of the barrel and an inward position (Figure 6) defined by a peripheral groove 157 on the barrel. By pushing the cap 150' in from one position to the other, chamber 122' is pressure pre- loaded just as with the previously described embodiment. Figure 5 shows the situation as the cap is half-way from its fully extended to its pre-load position.

The embodiment of Figure 5 and 6 also differs from the previous embodiments in that flexible bag 119' constitutes the gas-permeable partition means corresponding to the membrane 16 of the embodiments of Figures 1 and 2 and the rear part 116 of the barrel itself in the embodiment of Figures 3 and 4. To allow this to occur, the barrel and cap are formed in a material which is highly and non-differentially permeable, or less differentially permeable, with respect to the principal extemal and internal gases, at least to an extent sufficient to ensure that the bag controls the relative gas flows. Bag 119' should be formed from materials generally similar to the gas permeable partitions of the other embodiments, but having regard to the requirement for both strength and flexibility. The pressure required within the chamber initially will depend on the desired rate and duration of material pay-out. The pressure must also remain sufficiently positive to overcome the frictional resistance of the walls on the plunger. This should amount to no more than a maximum of 20mm of Hg. The maximum pressure required in the chamber for any current commercial active would not exceed two atmospheres. This pressure is easily achievable by finger compression of the plunger and would not place excessive strain on existing hardware.

A pressure pre-load can also be produced within the gas bag or chamber by the incorporation of a silicon mbber septum into the closed end of the barrel and in the bag. A gas cylinder incorporated into the device used to administer the CRD to animals could inject a predetermined amount of gas through the septum.

Similarly by the incorporation of a tap into the gas bag or chamber a small pressure pre-load could be produced within the drive bag by opening the tap, cooling the device in a refrigerator or freezer, causing additional air to be drawn in, and closing the tap. On administration the increase in temperature to rumen temperature would produce a significant pressure increase (Pj/T, = P₂ T₂).

A simple demonstration of the performance of the device according to the invention is depicted in Figure 7, which shows the change in plunger position with time for in vivo delivery of chromic oxide capsules to the rumen of cattle utilising a device similar to that of Figures 5 and 6. The membrane bag used was a laminated bilayer of metallised polyester and the gas drive chamber initially occupied about 45% of the intemal volume of the device. Each bag was pre-loaded to 1.45 atmospheres. There is reasonably good linearity with some loss of linearity with most experiments at the upper end of the trial period of 28 days. The result is nevertheless clearly better than that observed in a corresponding experiment with spring-driven devices.

Figure 8 compares change in total pressure with time for a device of the type depicted in Figures 5 and 6, for bag materials of different construction, when placed in a similar carbon dioxide atmosphere with a similar bag chamber atmosphere of air plus a major component of chlorodifluoromethane [CHC1F₂] from a volatile deposit. These curves demonstrate the different driving pressure profile achievable according to the choice of gas permeable partition.

Figure 9 is a similar curve but for different mixes of gases in the drive gas chamber. The bag is of laminated metallised polyester, the bottom curve case in Figure 8. Again the curves demonstrate how different pressure profiles are available according to the choice of gas mixture and vapour pre-load in the pressure drive chamber.

Figure 10 compares plunger travel with time for two devices of the type shown in Figures 5 and 6 (A,B) with two devices which are similar save that they have a conventional spring drive rather than a gas pressure drive (C,D). The former exhibits a high level of sustained linearity.

Solid s, pastes and liquids can all be delivered utilising devices in accordance with the invention. When the device is used with liquids it may be desirable to include a non¬ return or one-way valve at the liquid egress port. For a solid or paste, the egress opening may be designed for either direct expulsion of the material therefrom or for holding the material for dissolution.

It will be understood that where reference is made herein to differential permeability for selected gases, the actual permeability of these gases may be zero, ie the gas-permeable partition means in question may be totally impermeable, for example to air or one of its components, or substantially so. Such a partition material would be of optimum shelf-life prior to dosing.

The invention is highly versatile in adaptability to different applications. For example, a long-term tablet composition with a high payload of active material may require a relatively high pre-load and a relatively high sustained gas pressure, and therefore a high differential permeability. On the other hand, a matrix for an organism (eg worm larvae) may necessarily be a low viscosity aqueous solution, a syrup or a paste, necessitating a relatively small pre-load and a sustained relatively small operating pressure, and a relatively low differential permeability. Either situation can be readily catered for by appropriate choice of the adjustable parameters including gas-permeable material, volume and pressure of the drive chamber, and pre-loading technique.

By appropriate choice of variables, it is believed possible to achieve devices which reliably deliver their contents of an extended period of time from a few days to more than 100 days.

Claims

CLAIMS:-

1. A controlled release device adapted to contain a material and to release it over an extended period of time, the device comprising: a hollow body adapted to contain said material; egress means in said body adapted to allow egress of the material; and means for urging the material towards said egress means for egress therefrom, said means including an expandable chamber in said body separated from the environment extemal to the body by gas permeable partition means; wherein said gas permeable partition means is arranged to be differentially permeable for selected gases in said chamber and said extemal environment, whereby the gas pressure in said chamber increases above and is maintained above a level sufficient to produce a driving force for sustaining egress of said material over said extended period of time.

2. A controlled release device according to claim 1 wherein said gas permeable partition means comprises a wall segment of said body.

3. A controlled release device according to claim 1 or 2 wherein said gas permeable partition means comprises a membrane.

4. A controlled release device according to claim 3 wherein the membrane is a polymer selected from the group comprising polyethylene, polypropylene, polyester, polyvinylidene chloride, and poly(dimethyl siloxane), preferably a metallised laminate of such a polymer.

5. A controlled release device according to any preceding claim wherein said urging means further includes flexible sheet means about said chamber and expandable by said gas pressure as said material is released from said body over said extended period of time.

6. A controlled release device according to claim 5 wherein said flexible sheet means comprises a gas impermeable film.

7. A controlled release device according to claim 1 wherein said gas permeable partition means comprises flexible sheet means enclosing said chamber and expandable by said gas pressure as said material is released from said body over said extended period of time also comprises said gas permeable partition means.

8. A controlled release device according to claim 7 wherein said flexible sheet means is a metallised polyester, polyvinylidene chloride, polyethylene or polypropylene film.

9. A controlled release device according to any preceding claim wherein said urging means further includes slidable plunger means in contact with said material when the device contains the material.

10. A controlled release device according to claim 9 wherein said plunger means is in gas-tight slidable engagement with an intemal wall of said body.

11. A controlled release device according to claim 9 or 10 wherein said plunger means separates said chamber from a space adapted to contain said material.

12. A controlled release device according to any preceding claim wherein said chamber further contains a substance adapted to generate a vapour within said chamber, at least when the device is in situ, to provide an additional partial gas pressure in said chamber, and thereby to provide the potential for further inward gas permeation from the environment.

13. A controlled release device according to claim 12 wherein said vapour has a vapour pressure less than one atmosphere at the temperature of the extemal environment within which the device is to be sited in use.

14. A controlled release device according to claim 12 or 13 wherein substance has a polarity which contrasts with that of the gas permeable partition means.

15. A controlled release device according to claim 12, 13 or 14 wherein said substance is selected from the group comprising methanol and other alcohols, acetonitrile, ammonia, acetic acid, a subliming substance, and carrier liquid or solid materials in which a releasable gas is dissolved or otherwise retained.

16. A controlled release device according to any preceding claim further comprising pressure setting means operable to increase the gas pressure in said chamber prior to administration of the device and thereby to provide the potential for further inward gas permeation from the environment.

17. A controlled release device according to claim 16 wherein said pressure setting means comprises structure carried by said body and adjustable to compress said chamber and thereby reduce its volume and increase its contained gas pressure.

18. A controlled release device according to claim 17 wherein said structure is adjustable to reposition said material in said body and thereby to compress said chamber.

19. A controlled release device according to any one of claims 1 to 15 further including means to introduce a gas into said chamber to increase the gas pressure therein above that outside the body.

20. A controlled release device according to any one of claims 1 to 15 further including means to increase the gas pressure in the chamber comprising port means to draw in gas as the chamber is cooled, which port means is then sealable so that the gas pressure increases significantly at the in situ temperature.

21. A controlled release device according to any preceding claim for use in the rumen of ruminants wherein said gas permeable section is differentially permeable by strongly favouring permeation of carbon dioxide and/or methane over nitrogen and/or oxygen, said chamber initially containing primarily air.

22. A controlled release device according to claim 21 and any one of claims 12 to 15 wherein said gas permeable section further strongly favours permeation of carbon dioxide and/or methane over the vapour generated by said substance.

23. A controlled release device according to any preceding claim further including means to vary the geometry of the device between a first configuration permitting administration of the device to an operating location, and a second configuration adapted to facilitate retention of the device at the location.

24. A controlled release device according to any preceding claim further including a removable impermeable cover for said gas permeable section to prevent premature excessive loss of gas or vapour from said chamber.

25. A controlled release device adapted to contain a material and to release it over an extended period of time, the device comprising: a hollow body adapted to contain said material; egress means in said body adapted to allow egress of the material; and means for urging the material towards said egress means for egress therefrom, said means including an expandable chamber in said body; and a substance in said chamber adapted to at least partially vaporise within said chamber, at least when the device is in situ, to thereby increase and maintain the gas pressure in said chamber above a level sufficient to provide a driving force for sustaining egress of said material over said extended period of time.

26. A controlled release device adapted to contain a material and to release it over an extended period of time, the device comprising: a hollow body adapted to contain said material; egress means in said body adapted to allow egress of the material; and means for urging the material towards said egress means for egress therefrom, said means including an expandable chamber in said body; and means adaptable, prior to administration of the device, to increase the gas pressure in the chamber above that outside the body and to thereby provide a driving force for sustaining egress of the material over the extended period of time.

27. A controlled release device according to claim 26 wherein said means to increase the gas pressure comprises structure carried by said body and adjustable to compress said chamber and thereby reduce its volume and increase its contained gas pressure.

28. A controlled release device according to claim 26 wherein said means to increase the gas pressure comprises means to introduce a gas into said chamber from outside said body to increase the gas pressure therein above that outside the body.

29. A controlled release device according to claim 26 wherein said means to increase the gas pressure comprises port means to draw in gas as the chamber is cooled, which port means is then sealable so that the gas pressure increases significantly at the in situ temperature.

30. A method of delivering a composition to a ruminant over an extended period of time comprising: administering per os a controlled release device containing said composition to the rumen of the ruminant, allowing one or more of the gases in the rumen to permeate into a chamber of the device whereby gas pressure in said chamber in increased above and maintained above a level sufficient to produce a driving force for sustaining egress of said composition into the rumen over said extended period of time.