WO1999026853A1

WO1999026853A1 - Delayed release device

Info

Publication number: WO1999026853A1
Application number: PCT/GB1998/003325
Authority: WO
Inventors: Stephen Donald Mcfarlane; Mark Hegarty
Original assignee: R.P. Scherer Corporation
Priority date: 1997-11-20
Filing date: 1998-11-05
Publication date: 1999-06-03
Also published as: GB9724450D0; AU1041399A

Abstract

A delayed release device for delivering a liquid (usually aqueous liquid) after a predetermined time delay comprises a container (2) for containing the liquid and an outlet (3) controlled by a valve (5) for delivering the liquid. The valve includes a swellable hydrogel member (8) which swells in contact with the liquid and is ejected after said predetermined time so as to release the liquid. An openable member, such as a tap (80-88), may be arranged upstream of the valve to control access of the liquid to the swellable member.

Description

DELAYED RELEASE DEVICE

The present invention relates to a delayed release device for delivering a liquid after a predetermined time delay. In particular, the device may be used for delivering a chemical, bio-chemical or biological reagent into a reaction vessel according to a predetermined time schedule.

There have been previous proposals to deliver to a patient a solid medicament from within a capsule after a predetermined delay. Typically, such devices are intended to be swallowed and acted upon by the aqueous environment within the stomach or intestine. Typical of such devices are those disclosed in patent specifications W092\13521 and WO94\23705.

British Patent Application GB 2 241 485 discloses an oral dosage capsule which has an orifice closed by a water soluble or water dispersable plug. The time to release the active agent within the capsule depends on the rate of solubilisation or dispersion of the plug. British Patent publication GB 2 230 441 discloses a capsule formed in two parts and containing a water-swellable material and an active agent. Part of the capsule wall is water permeable so that when the capsule is in an aqueous environment, water permeates into the capsule and swelling of the material inside causes the capsule parts to separate, thereby releasing the active agent. Patent specification GB 2 230 442 discloses a capsule which contains an active material, the capsule being closed by means of a plug formed of a hydrogel material. When placed in a aqueous environment, such as within the stomach or intestine, the plug swells and ejects itself from the mouth of the capsule after predetermined time period. This allows the active material within to be released. The capsule is generally constructed to avoid the permeation of any significant quantities of water into the interior of the capsule prior to the ejection of the plug.

These prior proposals all relate to a delayed release device which contains an active material inside the device and which is acted upon by an aqueous environment present outside the device. Our published patent specification WO95\10262 is a device for the controlled delivery of liquids. The liquid is encapsulated within a water-soluble material which is in turn contained within a capsule body closed by a hydrogel plug. Once again, the plug is acted upon by an aqueous environment outside the device.

It is an object of the present invention to provide in a simple manner a delayed release device for delivering a liquid after a predetermined delay.

According to the present invention there is provided a delayed release device for delivering a liquid after a predetermined delay, which comprises: a container for containing a liquid and having an outlet for delivering the liquid: valve means connected to the outlet of the container, the valve means including a swellable valve member which swells in contact with said liquid to allow passage of the liquid through the valve means after said predetermined delay.

Thus, the present invention differs from prior proposals in that the valve means including the swellable valve member is acted upon by liquid contained within the container itself. The invention also provides a corresponding method of delivering a liquid.

The container can be an open container having an open top or other inlet for introducing liquid into the container. Alternatively, the container can be a closable container which may be closed once the liquid has been introduced. For example, the container may be a bag (for example formed of a shaped plastics material, such as polyethylene) a bottle or a drum, depending on the volume of liquid to be delivered. Typically, the container contains from 1 to 1000 mis of liquid.

The liquid itself may be any liquid capable of bringing about swelling of the swellable valve member when in contact therewith. The water swellable material may be any suitable liquid-swellable polymer known in the art, such as polyhydroxyethylmethyl methacrylates, polyurethanes etc. The preferred water-swellable material is a polyurethane hydrogel such as disclosed in patent specification WO90\09168 (equivalent to GB 2 230 442) . In addition to being water-swellable, these polyurethane materials are also swellable under the action of alcohols (such as methanol, ethanol, isopropanol etc) , ketones such as acetone and chlorinated solvents such as chloroform. Thus, in addition to being suitable for delivering aqueous liquids, swellable valve members formed of such polyurethanes may also deliver liquids of the above- mentioned types.

It is possible for the container to hold a powder or other solid form which becomes dissolved once the liquid is introduced into the container, the container being resealed if necessary. Equally the container could hold an initial charge of a non-swelling liquid to which a swelling liquid is added. The valve means is generally in the form of a conduit, usually a tube of annular cross-section, which is closed by means of a swellable plug. Generally, the conduit has an inner end in connection with the outlet of the container and an outer end through which the liquid is delivered. The plug may be inserted in either the inner end or the outer end of the conduit. In use, the swellable plug swells once it has been brought into contact with liquid and after a predetermined time the plug becomes ejected from the conduit, thereby opening the conduit to the flow of liquid therethrough. Generally, the container is oriented to be above the valve means in use, so that the liquid is delivered by gravity through the valve means once opened. In this case, if the swellable plug is located in the outer end of the conduit, after ejection the plug will fall away from the conduit leaving the conduit free for passage of liquid. However, when the swellable plug is located in the inner end of the conduit adjacent the outlet of the container, ejection of the plug will be in an upwardly direction into the container itself. To avoid the possibility that the ejected plug may remain seated over the inner end of the conduit and thus impede the flow of liquid even in the ejected state, it is preferred that the inner end of the conduit be of a non-planar nature, for example, scalloped, undulating, or provided with a series of cut-aways of various cross-sections so that even if the ejected plug remains over the inner end of the conduit, a flow path for liquid into the conduit from the container exists.

In use, swelling of the swellable valve member is initiated once the valve member comes into contact with the liquid. In a simple form of the device, this occurs once liquid is introduced into the container. However, introducing liquid into the container and simultaneously initiating the predetermined delay time can be inconvenient. In a preferred embodiment, a openable member is disposed between the outlet of the container and the valve means so as to protect the swellable member from contact with the liquid until the desired time. The openable member may be a tap or similar valve member, but in a preferred embodiment is a breakable seal which may be broken so as to initiate the predetermined delay time. The breakable seal may be a glass tube or a membrane contained within a flexible housing, such that flexing the housing causes the glass or membrane to break and allow liquid to pass through and into contact with the swellable valve member. In another embodiment, the breakable seal is in the form of a membrane which is punctured by a needle, provision being made to allow relative movement between the needle and the membrane in use.

In another embodiment, the openable member is in the form of a hollow plunger sealingly slideable within a sleeve. The inner end of the plunger is closed but one or more aperture (s) are provided around a curved portion thereof. The arrangement is such that when the plunger is retracted into the sleeve, the apertur (s) are closed by the sleeve. In the open position, the inner end of the plunger protrudes beyond the sleeve to expose the aperture(s), so that liquid-flow communication is established between the container and the interior of the plunger. In a further embodiment, the openable member also comprises a sleeve and slideable plunger. However, a cover is provided on the inner end of the sleeve to protect the hydrogel plug, which cover is disengaged by movement of the plunger along the sleeve. In a yet further embodiment, the openable member is in the form of a rotary valve mechanism having an inner member with an oblique conduit in communication with a conduit in a second member rotateably mounted relative thereto, whereby rotation of the two members brings the conduits in and out of communication with one another.

Embodiments of the present invention will now be described by way of example only with reference to the drawings wherein.

Figure 1 is a schematic elevation of a delayed release device according to a first embodiment, wherein a swellable plug is arranged to eject outside the device;

Figure 2 is a device according to a second embodiment, wherein a swellable plug is arranged to eject into the container;

Figure 3 is an enlarged schematic view of the inner end of the valve means of the second embodiment after ejection of the plug and showing the scalloped end of the valve conduit;

Figure 4 is an enlarged view of a valve conduit for use in the first embodiment according to Figure 1 ;

Figure 5 is an enlarged schematic view of a valve conduit for use in the second embodiment of Figure 2; Figure 6 is an enlarged schematic view of one form of openable member for initiating a predetermined time delay;

Figure 7 is an enlarged schematic view including a second form of openable member having a plunger action;

Figure 8 is an enlarged schematic view including a third form of openable member including a buoyant cover; and

Figure 9 is an enlarged schematic view including a fourth form of openable member having a rotary valve action .

The first embodiment shown in Figure 1 comprises a container 2 which is open at the top and has an outlet 3 at the lower end thereof connected to a conduit 4 of a valve member 5 by means of an elastomeric O-ring 6. The conduit 4 of the valve means is closed by means of a swellable hydrogel plug 8.

The container 2 is formed by heat sealing sheets of thermoplastic polymer, such as polyethylene or polypropylene into a funnel-shaped container 2 having an open top 10 and a lower outlet 3.

The valve means 5 comprises a conduit 4 in the form of a plastics tube, e.g. of polypropylene, having an inner end 12 and an outer end 14. The outlet of container 2 is slipped over the inner end 12 of the polypropylene tube 4 and secured in place by means of the O-ring 6. Figure 4 shows in more detail a practical conduit construction which will be described later. A cylindrical hydrogel plug formed of a polyurethane of the composition described in patent specification WO95\10262 is inserted into the outer end 14 of the conduit (in its unswollen state) so to form a liquid-tight seal. The plug may be inserted flush with the outer end 14 or may be recessed inside the outer end or may protrude outside the outer end. Figure 4 shows a detailed practical construction of the conduit 4 and includes a flange 16 which acts as stop when the funnel-shaped container 2 is attached thereto by means of the O-ring 6. The outer end 14 includes a frusto- conical portion 18 which provides a tapered lead-in when the hydrogel plug 8 is inserted into the end of the conduit 4.

Operation of the first embodiment is described in Example 1.

Figures 2, 3 and 5 illustrate a second embodiment wherein the plug 8 ejects into the inside of the container 2. The construction is analogous to the first embodiment except as noted below. The plug 8 is inserted into the inner end 12 of the conduit 4 so as to eject inwardly into the bag 2. Figures 3 and 5 show that the inner end of the conduit 4 is provided with a scallop-shaped recess 20. This ensures that once the plug has been ejected, even if the plug sits over the end of the inner end 12 of the conduit due to gravity, it cannot prevent flow of liquid through the valve means since the recess 20 provides a flow path for the liquid.

Figure 6 shows an openable member 30 comprising a flexible outer tube 32 sealingly engaging a breakable glass tube 34 sealed at a lower end. The flexible tube 32 is formed of a plastics material such as polyethylene or polypropylene and has an upper end 36 to which the outlet of the container may be connected in the manner described above and a lower end 38 which is a push fit over the inner end 12 of conduit 4. The upper end 36 is a sealing fit over an upper end 40 of glass tube 34 which has a tapered central portion 42 and a sealed lower end 44. A scratch 46 across the glass tube facilitates breaking of the glass tube by flexing the plastics tube 32. The glass tube then breaks along the scratch 46 and the lower end 44 freely falls away allowing liquid to flow downwardly through the glass tube and into contact with the swellable plug in the valve means.

Figures 7, 8 and 9 are further embodiments including various forms of openable member analogous to the two embodiments described above (the container being omitted for clarity) . Specifically, the second form of openable member shown in Figure 7 is analogous to the first embodiment shown in Figure 1. The third form of openable member shown in Figure 8 is analogous to the second embodiment shown in Figure 2 but an adaptation thereof to insert the hydrogel plug at the outer end can be used analogous to the first embodiment shown in Figure 1. Figure 9 is a fourth form of openable member having a rotary valve action which is analogous to both the first and second embodiments above.

The devices may be moulded or machined from plastics materials having some inherent resiliency, such as polyethylene, polypropylene or nylon.

Figure 7 shows a second form of openable member having a plunger action, which comprises a sleeve 50 having a flange 16 for attachment to the lower outlet of the funnel- shaped container. A plunger 52 is slideably received within the sleeve, and is closed at an inner end 54 and open at an outer end 56 to receive a hydrogel plug 8. The openable member is shown in its open position. The sleeve includes a flange member 51 and the plunger comprises a flange member 53 to assist squeezing the together. The plunger 52 includes integrally moulded sealing rings 58, 60 which are engageable with grooves 62, 64 provided on the inside of sleeve 50. Alternatively, separate 0-rings seated in grooves could be used. These sealing rings serve to seal the plunger to the sleeve in both the open and closed positions of the openable member and also serve as click-stops. The hollow plunger 52 includes a series of circular apertures 66 around the inner end thereof which, in the open position of the openable member (as shown in Figure 7) allow liquid to flow from the bag into the interior of the plunger and into contact with the plug 8. The hydrogel plug 8 is inserted into the outer end of the hollow plunger 52, which is provided with a frustro-conical portion 18 as before to assist insertion of the plug during manufacture. Operation is as follows. In the closed position of the openable member, the plunger 52 is retracted so that the sealing rings 58, 60 sealingly engage the grooves 62, 64 in the sleeve, thereby preventing egress of liquid from the container. In order to initiate the time delayed release of liquid from the container, the plunger 52 is pushed into the sleeve so that inner end 54 projects beyond the sleeve and exposes the circular apertures 66, until sealing ring 60 engages in groove 62 on the sleeve. This opens apertures 66 and allows flow of liquid from the container into the inside of the hollow plunger 52 and into contact with the inner surface of the hydrogel plug. Swelling of the plug takes place as before leading to a timed release.

Figure 8 shows a third form of openable member which includes a removable cover. The openable member comprises a sleeve 70 having a flange 16 for connection with the container as before, and a hollow plunger 72 slideably received therein. The inner end of the sleeve is sealed by means of a cover 74 in engagement with a groove 76 in an inner end of the sleeve. The cover is buoyant so that after removal it floats to the top of the liquid and does not obstruct liquid flow through the openable member. The plunger 72 is hollow and open at both ends. A hydrogel plug 8 is fitted in an inner end thereof. The inner end is provided with a scalloped edge 77 to prevent the ejected plug from obstructing the flow of liquid as above. Sealing ring 78 is received in a corresponding groove on the plunger and sealingly engages a corresponding groove 79 on the inside of the sleeve. The sleeve includes a flange member 71, and the plunger includes a flange member 73 which assist relative movement of the sleeve and plunger using fingers. Operation is as follows. In the closed position shown in Figure 8, the cover seals the openable member against egress of liquid from the container. To initiate the timed delay, the plunger is pushed into the sleeve so that the hydrogel plug presses against the cover and causes the cover to be ejected. The cover has a dome-shaped interior surface, so that it tips away from the openable member and is buoyant so that it floats to the surface of the liquid. At the end of the travel of the plunger, the sealing ring engages in groove 76. The hydrogel plug is now exposed to the liquid in the bag and the timed release process is initiated.

In an alternative construction, the hydrogel plug is located in an extension of the outer end of the plunger (in the manner of Figure 7) , so as to provide a construction wherein the plug ejects outwardly of the container.

Figure 9 shows a fourth form of openable member having a rotary valve action. The openable member comprises an inner member 80 for connection to the container and having an obliquely angled inner bore 82. A central member 84 having an off-centre bore 86 communicates with the bore 82 in the open position of the openable member and is not in communication in the closed position. The central member 84 is a snap fit into a lower member 88 which includes an outlet conduit 90 into which a hydrogel plug 8 may be fitted (either at the inner or outer end thereof) . As shown, the plug is fitted in the inner end of the conduit 90, which is provided with a scalloped edge 92. The openable member is formed of a plastics material having some inherent resiliency which allows the parts to be snap-fitted into one another. Thus, the inner member 80 includes a semi circular section ridge 94 which engages a corresponding groove 96 in the centre member 84. The inner member is rotatable relative to the central member 84 and the lower end of oblique conduit 82 is surrounded by an 0 ring 98 which seals the end of the conduit. The hydrogel plug is fitted into position as shown and then the central member 84 is sealingly snapped into place. Operation is as follows. Figure 9 shows the openable member in the open position. In its closed position, the inner and central members are rotated 180° relative to one another so that the oblique conduit 82 is not in communication with the conduit 86 so that there is no flow of liquid from the container. Relative rotation through 180° brings the two conduits into communication and allows the lower member to become filled with liquid from the container, which comes into contact with the swellable plug 8 and initiates the timed release of the plug by swelling thereof.

The practical use of the embodiments of Figures 1 and 2 will now be described in the following examples.

EXAMPLE 1 (OUTWARD PLUG EJECTION)

A funnel-shaped plastic bag 2 was formed by heat sealing sheets of polyethylene. The base of the conical section was formed into an outlet 3 in the form of a short cylindrical sleeve into which a short plain section of polypropylene tube 4 was inserted.

A rubber O-ring 6 was then rolled over the cylindrical sleeve to fix the tube in place. The contact pressure was such that a watertight seal was achieved.

A hydrogel polymer plug 8 (7 mm diameter, 4 mm long) was pushed into the outer end 14 of the tube, creating a watertight seal. The bag was then filled with a solution containing blue dye (malachite green) for test purposes, and the bag was suspended over a glass beaker. The glass beaker was filled with clear water until the external section of the valve means was submerged. Over a period of 4 hours the hydrogel plug gradually began to swell until it ejected from the tube allowing the blue dye to freely flow into the clear water, causing complete mixing within seconds. In this embodiment the hydrogel plug falls into the final mixed solution.

EXAMPLE 2 (INWARD PLUG EJECTION)

A polyethylene bag 2 was formed as in Example 1.

The polypropylene tube 4 was sculpted to produce a scalloped edge 20, and the hydrogel plug was inserted into this end. The tube was inserted into the sleeve, such that the hydrogel plug faced inside the bag, and sealed with an

O-ring.

The bag was suspended over an empty glass beaker.

Blue dye solution was added to the bag, causing the hydrogel plug to swell and eject within two hours, thus allowing the solution to flow freely into the empty beaker.

The scalloped edge was employed to ensure that even if a swollen plug ejects and sits on top of the tube 4 there is always an exit hole for liquid to flow through.

Other forms of the invention are possible. For example, the valve means could be provided with attachment means e.g. a screw thread or bayonet coupling, for attaching to a separate container just prior to use.

Claims

1. A delayed release device for delivering a liquid after a predetermined delay, which comprises: a container for containing a liquid and having an outlet for delivering the liquid; valve means connected to the outlet of the container, the valve means including a swellable valve member which swells in contact with said liquid to allow passage of the liquid through the valve means after said predetermined delay.

2. A device according to claim 1 wherein the valve means comprises a conduit which is closed by means of a swellable valve member in the form of a swellable plug, the conduit having an inner end connected to said container outlet and an outer end through which the liquid is delivered.

3. A device according to claim 2 wherein the swellable plug is inserted in the outer end of the conduit.

4. A device according to claim 2 wherein the swellable plug is inserted in the inner end of the conduit.

5. A device according to claim 4 wherein the inner end of the conduit is non-planar.

6. A device according to any preceding claim wherein the swellable valve member is formed of a swellable hydrogel.

7. A device according to any preceding claim which further comprises an openable member disposed between the container outlet and the valve means.

8. A device according to claim 7 wherein the openable member is a tap.

9. A device according to claim 7 wherein the openable member is a breakable seal.

10. A device according to claim 7 wherein the openable member comprises a sleeve and a hollow plunger sealingly slideable within the sleeve; an aperture provided at one end of the plunger which is opened for liquid flow by sliding of the plunger from a retracted closed position inside the sleeve to an open position wherein the aperture is exposed.

11. A device according to claim 7 wherein the openable member comprises a sleeve and a hollow plunger sealingly slideable within the sleeve; and further comprising a cover on an inner end of the sleeve, which cover is disengageable by sliding of the plunger along the sleeve.

12. A device according to claim 7 wherein the openable member is in the form of a rotary valve mechanism.