WO2012153148A1

WO2012153148A1 - Injector

Info

Publication number: WO2012153148A1
Application number: PCT/GB2012/051058
Authority: WO
Inventors: Stephen Terence Dunne
Original assignee: New Injection Systems Ltd
Priority date: 2011-05-11
Filing date: 2012-05-11
Publication date: 2012-11-15
Also published as: GB201208320D0; GB2490807A

Abstract

An injector for delivering a liquid medicament comprises a collapsible container for containing the liquid medicament and a normally-closed valve coupled to the collapsible container for retaining the liquid medicament within the collapsible chamber. An injection means, for example a needle, is couplable to the normally-closed valve. Liquid contained within the collapsible container is pressurised such that it is delivered when the normally-closed valve is opened. The collapsible container is located within an inner retaining means, which is itself located within a rigid outer container. The collapsible container does not contact an inner wall of the rigid outer container.

Description

INJECTOR

The invention relates to an injector for delivering a liquid, for example for delivering a liquid medicament to a human or animal patient.

Background

Pre-filled syringes and auto-injectors are devices that are well known in the prior art for the delivery of liquids, often for the delivery of a liquid medicament to a patient. Both pre-filled syringes and auto-injectors tend to be constructed from a cylindrical barrel for containing the liquid with a plunger and needle to effect delivery of the liquid. The liquid is stored in the barrel and sealed at one end by the plunger and at the other by a cap. Sometimes such devices include a staked needle (i.e. a permanently fixed needle) which will have a cap over the needle to seal the device. The plunger is either depressed by the user to expel the liquid drug via the needle, or, in the case of auto-injectors, the plunger is depressed by an energy source which is often a compression spring.

These conventional devices suffer from many drawbacks including stability problems arising from the interaction of the medicament with the materials forming the device, such as the barrel glass, the plastic elastomeric plunger, the metallic needle, the adhesive used to stake the needle, and any necessary lubricants. The filling of these conventional devices is also problematic. The placement of a plunger during filling makes it difficult to fill many known devices bubble free and without risk of contamination. Movement of a plunger during storage due to expansion and contraction of air bubbles within the filled device may result in

contamination of the drug.

Additionally the liquid medicament is sealed within the barrel by a moving plunger. It is, therefore, difficult to completely seal the medicament and keep it sterile while also allowing the plunger to be capable of movement.

Furthermore, the barrel is often made of brittle glass which is breakable both in use and during production and filling.

In most devices the liquid is in contact with the needle during storage. This can lead to problems such as blockages due to drug crystallization within the needle and medicament instability due to the interaction of the drug with the metals in the needle.

The filling procedures for conventional pre-filled syringes need to be complex to ensure sterility at all times.

It is an aim of the invention to provide a better injector.

Summary of Invention

The invention provides an injector as defined in the appended independent claims, to which reference should now be made. Preferred and/or advantageous features of the invention are defined in various dependent sub-claims.

Thus, the invention may provide an injector for delivering a liquid, preferably in which the liquid is a liquid medicament. The injector comprises a collapsible container for containing the liquid, a normally-closed valve coupled to the collapsible container for retaining the liquid within the collapsible container, an injection means coupled to or couplable to the normally-closed valve for delivering the liquid from the collapsible container, and pressurising means for pressurising the liquid contained within the collapsible container, such that the liquid is delivered by the injection means when the normally-closed valve is opened. That is, the liquid is retained under pressure such that the liquid is delivered from, or expelled from, the collapsible chamber through the normally-closed valve when the valve is opened. The delivery of the liquid is stopped when the normally-closed valve is closed again.

Preferably, the collapsible container and the pressurising means are housed within a rigid outer container or canister that is coupled or fastened to the normally-closed valve. Particularly preferably, the collapsible container is defined by or located by an inner retaining means such that it does not contact an inner wall of the rigid outer container.

As used herein, a normally-closed valve is a valve in which the normal, unactuated position is closed. For example, the valve may comprise a biasing means that biases the valve towards a closed position. Actuation of the valve is required to open the valve. An aerosol valve is an example of a normally-closed valve.

As used herein, the term collapsible container refers to any container having an internal portion that may increase or reduce in volume. Walls of a collapsible container may be defined by a resilient material, such as a rubber. Walls of a collapsible container may be corrugated, for example as in a bellows. An internal portion of a collapsible container may be a space defined by a barrel and a piston, the piston sliding within the barrel to increase or decrease the volume of the container.

As used herein, the term pressurising means refers to any physical or mechanical means for applying a pressure to liquid contents of the collapsible chamber such that liquid is expelled from the collapsible chamber when the normally-closed valve is opened.

A rigid outer container is coupled to the normally-closed valve, preferably irremovably coupled or fastened to the normally-closed valve, and may be sealed from the external environment. The collapsible container is located within the rigid outer container. The rigid outer container may be in the form of a rigid frame.

An inner retaining means may be any physical structure that acts to retain the collapsible container within the rigid outer container. The inner retaining means may act to seal the collapsible container from the external environment.

Preferably, at least one of the rigid outer container and the inner retaining means acts to seal the collapsible chamber from the external environment.

The collapsible chamber may be defined, at least in part, by the inner retaining means, for example in embodiments in which the collapsible container comprises a piston.

Some liquids are susceptible to contamination or degradation on contact with air, or air and water vapour. For example, many medical solutions degrade on prolonged contact with oxygen and some liquid drugs are susceptible to water vapour. If such solutions are to be stored for a period of time the systems need to meet barrier requirements for product susceptibility to oxygen and water vapour. The inner retaining means may improve the storage of liquids within the device by separating or spacing the collapsible chamber from inner walls of the rigid outer chamber, thereby reducing gas/vapour transfer.

The rigid outer container and the inner retaining means may be formed from different materials. For example, the rigid outer container may be formed from a metal or a glass, while the inner retaining means may be formed from a plastic. If the rigid outer container provides a good seal against atmospheric gases the inner retaining means need not be made of an expensive barrier plastic such as cyclic olefin copolymer (COC) or cyclic olefin polymer (COP) and may, instead, be formed from a relatively cheap material such as polyethylene (PE) or polypropylene (PP).

It may be advantageous for the inner retaining means to be in the form of an inner chamber formed from a rigid material. For example, such an inner chamber may take the form of a rigid barrel, sheath, or cylinder located inside the rigid outer container. The inner chamber retains the collapsible container. The collapsible container may, in part, be defined by an inner chamber as described above. For example, the collapsible chamber may be defined by a plunger and inner walls of the inner chamber. Alternatively, the inner chamber may act to retain a collapsible bag or bellows.

Metals, such as aluminium or steel, have advantageous properties for use in the formation of a rigid outer container. Such materials are relatively rigid, provide a good barrier to oxygen and are also tough. One potential problem with the use of metals as the rigid outer container is the situation where a visual inspection of the contents of the container is desired or required.

Windows may be added, but these then tend to allow air to enter the container (or require expensive sealing). One solution provided by the present invention is for the collapsible container to be defined by or located within an inner chamber that is sealed from the outer chamber. In this way the rigidity and toughness of the metal can be utilised for the rigid outer container. The inner container should then provide an oxygen barrier if the contents of the collapsible container are to be stored.

An alternative is for holes to be defined through walls of a rigid metal outer container to act as windows for viewing of the contents of the container. These holes or windows may then be sealed by a suitable removable seal to prevent passage of atmospheric gasses. Such a seal may then be removed immediately prior to use of the injector. A suitable removable seal may be formed, for example, by a barrier foil that is sealed over the hole in the rigid outer container but can be ripped off by a user. A removable seal may be coupled by adhesive, crimping or welding techniques.

A further alternative is to use an outer container formed from glass. Glass is a fragile material, however, and it is preferred that the pressurising means, such as a spring, does not act directly on the outer container. This can be achieved in a number of ways, for example the use of a collapsible chamber having an integral spring, or the use of an inner chamber that locates the spring in separation from the outer chamber.

The liquid is preferably a liquid medicament, for example a drug solution or suspension, or a mixture of more than one solution or suspension, for treatment of a disease or condition of a human or animal. It is envisaged, however, that the liquid may not be a medicament, but may be some other injectable liquid. For example, it is known to inject various polymer solutions such as hydrogels into the human or animal body.

It is envisaged that the injection means will preferably be a needle for injection of the liquid, for example a hollow needle such as a hypodermic needle for piercing the skin of a human or animal patient and injecting the liquid into the human or animal body. The injection means may, thus, be a hypodermic needle or some other piercing element such as a micro-needle or a nozzle. The injection means may be an array of needles for piercing the skin. Suitable hypodermic needles may have any standard gauge, for example any needle between G20 and G30. Needles suitable for use with the injector may be micro-needles under 2 mm long, for example, under 1 mm long, or between 0.1 mm and 1 mm long. The injection means may, alternatively, be a needleless injection element such as are known in the prior art for injecting a liquid into the human or animal body.

The injector may be used to inject the liquid into any part of the human or animal body. The injector may be used to provide intramuscular, subcutaneous, intradermal, or intravenous injections. The device may be used for injecting into other locations, for example for delivering liquid medicaments or other substances into a body's organs or bones.

In preferred embodiments of an injector, the collapsible container and the pressuring means are both housed within a rigid outer container or canister, the rigid outer container or canister forming a component element of the injector. Preferably, the normally-closed valve is connected to the rigid container. In preferred embodiments, the collapsible container and the normally-closed valve are fastened to the rigid outer container such that, after assembly, these elements constitute a single component part of an injector. The injector may be filled through the normally-closed valve. A needle may also be fastened to the normally-closed valve.

The rigid outer container may be formed from any suitable material, for example a rigid plastic or metal or glass. Particularly preferred materials may include polyethylene, polypropylene, PET, COC (cyclic olefin copolymer), COP (cyclic olefin polymer), and Ethylene vinyl alcohol.

The rigid outer container may be hermetically sealed, such that the contents of the rigid outer container are shielded from the external environment. Alternatively, the rigid outer container may be a frame or cage that acts to locate the collapsible container and the pressurising means. It is particularly advantageous if the rigid container is formed from a transparent material, such as a transparent polymer or glass, such that the contents can be viewed and monitored.

The rigid outer container may comprise a vent to allow displaced air within the rigid outer container to escape during filling of the collapsible container. Advantageously, the vent may be a closable vent so that the internal contents of the container may be re-sealed after venting. If the rigid outer container is not entirely made of a transparent material, it may be advantageous that the rigid outer container includes an observation window for allowing inspection of the rigid container's contents. Such a window may be formed from a transparent material such as glass or plastic, or may simply be a hole in walls of the rigid container where the rigid container is not sealed. Advantageously, the widow may be formed as a lens, or incorporating a lens, to facilitate inspection of the liquid contents of the collapsible container. As stated above, a window defined through the rigid outer container may be covered and/or sealed by a removable cover such as a foil until needed for use.

The liquid being delivered by the injector may be a liquid that is adversely affected by interaction with oxygen. For example, many liquid medicaments react adversely with oxygen and, therefore, have a limited shelf life. Thus, it may be advantageous that the rigid outer container can be fully sealed from the external environment. In this way, a liquid medicament contained within the collapsible container is less likely to be exposed to the external environment and may have a longer shelf life. Thus, it is preferred that the rigid outer container is fully sealed or, where the container has a vent, that the vent may be plugged. It may be particularly

advantageous that the rigid outer container may be hermetically sealed, preferably with an inert gas atmosphere surrounding the collapsible container. For example, air within the rigid outer container may be purged by an inert gas that has a low solubility in the liquid medicament, for example nitrogen. An inert gas atmosphere within the rigid outer container may be developed during manufacture of the injector. For example, air may be replaced by nitrogen, or any other suitable gas, during valve placement or valve crimping procedures. This may be effected using known under the cup filling procedures. Alternatively, a vacuum may be created during crimping so that, when the collapsible container has been filled with liquid, the atmospheric pressure surrounding the container is close to atmospheric pressure.

Preferably, the collapsible container is a separate sealed container that may expand or collapse to vary the volume within the container. A particularly preferred configuration of the collapsible container is in the form of a bellows. A bellows container has pleated or corrugated sides that allow the container to expand or contract. The collapsible bag or bellows may be made of any material suitable for containing the liquid. For example, where the liquid is a medicament the bag or bellows is preferably any suitable material approved for pharmaceutical use. The bag or bellows may be laminated in order to provide specified material properties. For example, an internal surface of the bag or bellows may be formed from a material having a low reactivity with the liquid, whereas an outer layer or outer layers of the bag may be formed from a material having low liquid transfer properties or low gas transfer properties. The bag may

advantageously be formed from or comprise a substantially inert polymeric material such as polyethylene or polypropylene.

It may be particularly advantageous if the collapsible bag or bellows is formed from a transparent material. This allows the contents of the bag or bellows to be inspected visually.

It is preferred that the collapsible container is a bellows that is directly coupled to the normally- closed valve. This configuration allows the bellows to be filled directly through the normally- closed valve, thereby expanding the bellows, and the liquid will be retained within the bellows when the normally-closed valve is closed.

Where the injector comprises a rigid outer container, the collapsible container may be defined within the rigid outer container. For example, the collapsible container may be defined in part by internal walls of the rigid container and in part by a piston that is slideably arranged within the rigid container, such that the volume of the collapsible container varies depending on the position of the piston. As described above, the collapsible container may be defined in part by an inner chamber, within the rigid outer chamber, and in part by a piston slideably arranged within the inner chamber. In these arrangements the collapsible container is similar to that defined within a standard syringe. In this example, force from the pressurising means may act via the piston to pressurise the liquid contained within the collapsible container. Where the collapsible container is defined by internal walls of the rigid outer container (or an inner container located within the rigid outer container) and a piston, the normally-closed valve will be coupled to the collapsible container, such that the liquid may be delivered through the valve when the normally-closed valve is open. The piston in such a piston/cylinder arrangement may be made of plastic or any other suitable material with or without an elastomer seal.

The pressurising means applies a continuous pressure to the liquid once the collapsible container has been filled. Thus, the liquid is maintained under pressure during storage before use. Preferably, the pressurising means for pressurising the liquid contained within the collapsible container is a biasing element that exerts a force that acts upon the collapsible container, and thereby upon the liquid contained within the collapsible container. Preferably, the force acting to collapse the collapsible container is generated by a resilient means such as a spring, for example a compressed helical spring arranged to urge the collapsible container to collapse. Where the collapsible container is in the form of a collapsible bag or bellows, the pressurising means may advantageously comprise a spring that forms an integral part of the collapsible container. For example, walls of the collapsible container may be connected to or coupled to a spring that acts to collapse the collapsible container thereby minimising the internal volume of the collapsible container. On filling with the liquid, the spring will be extended and the volume of the collapsible container increased to accommodate the liquid. As the spring is constantly urging towards its un-extended state it pressurises the liquid medicament contained within the collapsible container. While the normally-closed valve is closed, the liquid remains within the collapsible container. When the normally-closed valve is opened, however, the pressure exerted by the integral spring urges the liquid out of the collapsible container through the normally-closed valve. An integral spring may provide the advantage that a force is not directly applied to the rigid outer container, which may make it safer to construct the rigid outer container from a fragile material such as glass.

The force that acts to collapse the collapsible container may be a force generated by a compressed gas or a liquefied gas. For example, the device may comprise a second collapsible container containing a gas that is compressed when the collapsible container is filled with liquid and exerts a force on the collapsible container. Alternatively, where the collapsible container is defined within walls of a rigid container, the force may be generated by a compressed gas acting on a plunger that pressurises the liquid within the collapsible container. It may be preferable that the injector comprises a rigid outer container within which the collapsible container and the pressurising means are housed. The pressurising means may then apply a force to the collapsible container and the rigid outer container simultaneously. As the rigid outer container is unable to move, the collapsible container is therefore urged into a collapsed state. Thus, the injector may comprise a rigid outer container housing a collapsible container coupled to a normally-closed valve that extends through a wall of the rigid outer container, the rigid outer container further comprising or housing a pressurising means that acts to urge the collapsible container away from an internal surface of the rigid outer container. The pressuring means may therefore be a resilient spring housed within the rigid outer container, such that it is compressed when the collapsible container is filled with liquid and acts to collapse the collapsible container when the normally-closed valve is opened. The pressurising means may, alternatively, comprise a compressed gas confined within a second collapsible container that when compressed generates a force that acts on the collapsible container to expel liquid from the collapsible container when the normally-closed valve is opened.

In an advantageous alternative configuration, the collapsible container may be defined by or housed within an inner retaining means, for example an inner cavity or chamber, and the pressurising means may bias the collapsible chamber with respect to this inner retaining means rather than with respect to the rigid outer chamber. As suggested for the configuration in which the pressurising means is an integral spring, this may provide the advantage that a force is not directly applied to the rigid outer container, which may make it safer to construct the rigid outer container from a fragile material such as glass.

Advantageously, the pressurising means may comprise a piston or ram that is urged into contact with the collapsible container. The piston or ram may be urged by the force of a biasing means such as a helical spring, or other form of spring, or may be forced into contact with the collapsible container by means of a compressed gas or a liquefied gas. Advantageously, the piston or ram may be shaped to reduce or eliminate dead volume in the collapsible container when it is collapsed. For example, the piston or ram may comprise a shaped front portion for contacting the collapsible container, and this shaped front portion may be any suitable shape, for example a substantially conical shape. The shaped piston or ram may force the collapsible container into a shaped portion of the injector, for example a shaped portion of the rigid outer container, or a shaped entranceway to the normally-closed valve, such that the majority of the contents of the collapsible chamber may be expelled through the normally-closed valve.

The normally-closed valve is an openable valve that may be opened to deliver the liquid or to allow the collapsible container to be filled with the liquid, but is normally closed to retain the liquid in a sealed condition within the collapsible container. The normally-closed valve is capable of being actuated, i.e. of being opened and closed, to regulate the flow of liquid from the collapsible container. Preferably the normally-closed valve is a continuous flow valve or an aerosol valve. The aerosol valve may be a conventional type male aerosol valve or a female aerosol valve, although any normally-closed valve may be used. A conventional aerosol valve with an axial movement opening may be used, or alternatively a toggle action aerosol valve may be used, in which the valve is opened by tilting the valve stem.

Particularly preferably, the normally-closed valve comprises a spring that acts to urge the valve into its closed position. Preferably this spring is a non-metallic spring, for example a plastic spring. An aerosol valve having such a plastic spring is described, for example in

US 4,471 ,893. By using a normally-closed valve comprising a non-metallic spring, the liquid contents of the collapsible container do not contact any metallic surface when the injector is in storage. The stability of the drug within the injector may thus be improved during storage, and safe storage times may be longer than they would otherwise be. It is particularly preferred that the normally-closed valve has a minimised dead space to maximise the percentage of the liquid contents of the collapsible container that may be delivered.

It may be advantageous that the normally-closed valve comprises a solid elastomeric spring. Such a spring may take the form of a solid portion (for example a solid cylinder) of an elastomeric material, such as a rubber, or may be a hollow elastomeric material. The elastomeric spring is deformed when the normally-closed valve is opened, but the resilience of the elastomeric material urges the normally-closed valve towards its closed position.

An elastomeric material may provide a number of advantages. The volume taken up by such a spring may help minimise dead-volume within the valve. Dead-volume defines a volume that cannot be delivered. In the case of a helical spring, dead-volume may be relatively high as the liquid within the injector flows between the spring's coils. An elastomeric spring would only allow the liquid to flow around the outside of the spring and would minimise dead-volume. Minimising dead volume may be important when the injector is used to deliver expensive medicaments.

In order to minimise degradation of a liquid stored within an injector it is desirable to minimise the number of different materials that the liquid comes into contact with. Where a valve is crimped onto a rigid container, an elastomeric gasket is normally used to effect a seal.

Advantageously, an elastomeric spring in a normally-opened valve may be made from the same material as the gasket.

The material used to form an elastomeric spring and/or a resilient gasket may be any elastomeric material, for example a rubber such as natural rubber, butyl rubber, or silicone. Laminated components may also be used. For example, elastomeric materials coated with coatings such as fluoropolymers may be used. Such coated elastomeric materials may provide the advantage that the interaction of extractable or leachable components of the elastomer with the dispensable product is minimised or prevented. In some embodiments, an injector may comprise a rigid outer container, a normally-closed valve and a collapsible container coupled to the normally closed valve. Pressurising means act on liquid contents of the collapsible container such that these contents can be expelled from the collapsible container when the normally-closed valve is opened. The normally-closed valve comprises an elastomeric spring as described above. In some embodiments the injector may further comprise an inner retaining means as described above, or any other preferred or advantageous features as described above.

It may be advantageous that the normally-closed valve comprises an external spring, i.e. a spring that is not located in an internal portion of the valve where it may come into contact with the liquid contents of the collapsible container. Such an external spring may be located over a stem of the valve and may be retained by a shoulder such that the stem is biased to close the valve under the action of the spring.

An external spring may advantageously reduce the number of components of the valve, and the therefore of the injector, that come into contact with the liquid. An external spring may also allow the dead volume within the valve to be reduced. This results as there is no need to

accommodate a spring, and space for the spring to work, within the valve.

In some embodiments, an injector may comprise a rigid outer container, a normally-closed valve and a collapsible container coupled to the normally closed valve. Pressurising means act on liquid contents of the collapsible container such that these contents can be expelled from the collapsible container when the normally-closed valve is opened. The normally-closed valve comprises an external spring as described above. In some embodiments the injector may further comprise an inner retaining means as described above, or any other preferred or advantageous features as described above.

The injector may comprise a manually operated switch for opening the normally-closed valve. For example, the injector may comprise a button or toggle or switch that a user can actuate once the injector is in a predetermined position for injection. The manually operated switch opens the normally-closed valve, thereby allowing the contents of the collapsible container to be delivered or dispensed.

Preferably, the injector comprises an actuator for opening the normally-closed valve

automatically when a predetermined condition is met. For example, the injector may comprise an actuator that opens the normally-closed valve when the injector is pressed against a patient's skin.

Conventional auto-injectors deliver their full dose of drug solution after the delivery has been actuated. The use of a normally-closed valve to control delivery of the liquid in injectors according to the invention allows the delivery of the drug to be stopped by closing the valve during delivery, should this be required. This may be particularly advantageous in embodiments of the injector that are manually-actuated. This may allow an injection to be halted if a problem occurs, or allow a break in the injection cycle. This flexibility is currently only provided by standard manual injections.

An injector according to an embodiment of the invention may comprise a collapsible container containing a liquid, a normally-closed valve, a rigid container, means of pressurising the contents of the collapsible bag, and means of piercing skin to enable injection of the liquid. Holes may be defined through the rigid container and these holes may be closed by removable seals as described above. For example, the seals may be peelable foil seals that act to seal the contents of the rigid container until it is used. Preferred or advantageous features of the injector may be the same as those described above.

In a preferred configuration, the injector may comprise a needle injection means for delivering the liquid into the body of a patient, and the normally-closed valve is arranged to actuate when the needle has been inserted a predetermined distance into the patient. This predetermined distance will depend upon the type of drug or medicament that is being delivered to the patient, and the tissue type that the delivery is required to be made into. For example, the injector may be configured to automatically open the normally-closed valve when the needle reaches a predetermined depth into the patient's body.

The switch or actuator for opening the normally-closed valve may include means for gaining a mechanical advantage, such as a lever. This arrangement may be advantageous where the force keeping the normally-closed valve closed is a high one.

It is particularly preferred that the injection means comprises a protective sleeve or shield. This is of greatest advantage where the injector means is a needle, and the protective sleeve or shield thereby provides a safety mechanism to help prevent inadvertent needle stick by the user of the injector. A protective sleeve or shield may also help maintain sterility of the injection means during storage. A passive needle shield is described by US 2009/0227956 or

US 5,092,851 . A manually activated needle shield may be used, for example, of the type described in US 4,738,663 or US 4,944,397.

It is preferred that the injection means is coupled to the injector during storage, so that a user of the injector has a minimal number of preparation steps to go through before the injector is ready to use. It is possible, however, that the injection means will be supplied separately from the rest of the injector components and will need to be coupled to the normally-closed valve by an operator prior to use.

A particularly advantageous property of the injector is that, as the liquid within the collapsible container is under constant pressure, any leak of liquid from the collapsible container will result in the collapsible container moving. For example, if a collapsible bellows is used, any leak will result in the partial collapse of the bellows as the bellows are under a constant pressure. If the injector has a configuration such that the bellows can be viewed during use, then any collapse of the bellows prior to use can be noted. Thus, it is preferred that the injector comprises a level indicator that shows a user when liquid has escaped from the collapsible container. A level indicator or level indicator marks on the injector may also be useful in order to determine the extent to which the liquid has been delivered from the injector during use.

A further advantage of the injector is that the pressurised system makes it harder for foreign matter or material to contaminate the liquid contents.

In a particularly preferred embodiment, an injector for delivering a liquid medicament comprises a collapsible bellows for containing the liquid medicament, an aerosol valve coupled to the collapsible bellows for retaining the liquid medicament within the collapsible bellows, a hypodermic needle coupled to the aerosol valve for delivering the liquid medicament from the collapsible bellows, a rigid outer container housing the collapsible bellows and coupled to the normally-closed valve, such that the collapsible bellows are housed within the rigid outer container and the normally-closed valve allows communication with the collapsible bellows through the walls of the rigid container, and a spring housed within the rigid container acting to urge the collapsible bellows to a collapsed state, thereby pressuring liquid medicament contained within the collapsible bellows such that the liquid medicament is delivered through the hypodermic needle when the aerosol valve is opened. Preferably the collapsible bellows are retained within an inner retaining means, for example an inner cavity or cylinder, located within the rigid outer container.

Particularly preferably, such an injector comprises a piston or ram disposed between the spring and the collapsible bellows, in which the spring urges the piston or ram into contact with the collapsible bellows, thereby pressuring the liquid medicament. Such a piston or ram may act to guide the force applied by the spring and stabilise the engagement between the spring and the collapsible container.

In an alternative aspect, an injector may comprise a liquid medicament retained within a collapsible container by a normally-closed valve, and a needle for injecting the liquid

medicament coupled to the normally-closed valve, in which a force is arranged to act on the collapsible container, such that the liquid medicament is delivered through the needle when the normally-closed valve is opened.

Preferably, at least an inner surface of the collapsible container is formed from a polymer, and the normally-closed valve is formed from a polymer, such that the liquid medicament does not come into contact with any metallic component while retained within the collapsible container. Advantageously, the liquid medicament does not contact the needle until the normally-closed valve is opened to deliver the liquid medicament. Preferably, the injector is an injector according to any injector described above, in which the dead volume of the collapsible container and the normally-closed valve are low enough to ensure that more than 85% of the liquid medicament contained within the collapsible container can be delivered. Many medicaments and drugs are expensive and it is desirable to reduce waste as much as possible. Particularly preferably, the injector is configured such that more than 90% or more than 95%, and particularly preferably, more than 97% of the liquid medicament contained within the collapsible container may be delivered.

Advantageously, the injector may be a hand-held injector. A healthcare professional may, therefore, be able to carry a number of injectors each pre-loaded with a liquid medicament that are substantially ready for employment in delivering the liquid medicament. The injector may have improved sterility and stability of drug contents and may allow a dose of drug to be delivered simply and effectively.

Particularly preferably, the injector according to any embodiment described above is filled with the liquid medicament. The liquid medicament may comprise a constituent classified within any one of the following categories of pharmaceuticals or biopharmaceuticals; Alphal -Adrenergic Antagonists, Analgesic Agents, Anaesthetics, Angiotensin Antagonists, Anti-Inflammatory Agents, Antianxiety Agents, Antiarrhythmics, Anticholinergics, Anticoagulants, Anticonvulsants, Antidiarrheal Agents, Antihistamines, Antineoplastics and Antimetabolites, Antineoplastics and Antimetabolites, Antiplasticity Agents, Antiulcer Agents, Beta-Adrenergic Antagonists,

Bisphosphonates, Bronchodilators, Cardiac Inotropes, Cardiovascular Agents, Central Acting Alpha2-stimulants, Contrast Agents, Converting Enzyme Inhibitors, Dermatologies, Diuretics, Drugs for Erectile Dysfunction, Drugs of Abuse, Endothelin Antegonists, Hormonal Agents and Cytokines, Hypoglycaemic Agents, Hypouricemic Agents and Drugs Used For Gout,

Immunosuppressants, Lipid Lowering Agents, Miscellaneous, Morphines and other painkillers, Psychotherapeutic Agents, Renin Inhibitors, Serotonergic Antagonist, Steroids,

Sympathomimetics, Thyroid and Antithyroid Agents, and Vasodilators, Vasopeptidase Inhibitors, Salines, Insulins, Blood factors, Thrombolytic agents, Hormones, Haematopoietic growth factors, Interferons, Interleukin -based products, Vaccines, Monoclonal antibodies, Tumour necrosis factors, Therapeutic enzymes, Antibody-drug conjugates, Biosimilars, Erythropoietin, Immunoglobulin, Blood and Blood components, Allergenics, Somatic cells, Gene therapy, Tissues, and Recombinant therapeutic proteins. The liquid may be any other medicament existing or in development capable of being injected into animals or humans.

An injector as described above may further comprise an external casing or housing. The casing or housing may itself comprise features such as needle shields or actuating buttons that assist in operation of the injector. The casing or housing may also be shaped to assist a user, for example the casing or housing may be economically shaped.

Injections for different medicaments may require different volumes of drug to be delivered. If using conventional autoinjectors a separate autoinjector is required for each pre-filled syringe size. Advantageously, an injector as described above may be used to deliver a wide range of liquid volumes. The liquid contents are pressurised by the pressurising means whether the collapsible container is filled to capacity, only half filled, or filled to a low percentage of capacity. By varying the fill volumes, a single size of injector may be used to deliver a wide range of liquid volumes.

Conventional syringes and autoinjectors tend to be unsuited to the delivery of viscous drug solutions. The pressure required to deliver a viscous solution through an injection means such as a needle may be high and there is a risk that a syringe may break under such high pressures. The use of an injector as described above, preferably an injector in which the collapsible container is a collapsible bag or bellows, may overcome problems associated with delivery of viscous drugs. Where the collapsible container is filled with a viscous liquid, the pressurising means, for example a spring, may apply a high pressure to the viscous liquid to enable it to be delivered. The high pressure does not need to act on a delicate glass syringe and, thus, the injector may be more suitable for delivery of viscous liquids.

The invention may provide a method of injecting a liquid, the liquid being retained under pressure within a collapsible container of an injector by a normally-closed valve, the method comprising the steps of positioning the injector to deliver the liquid to a predetermined position, and opening the normally-closed valve, such that the liquid is injected. Preferably, the liquid is a liquid medicament, and the injector is positioned to deliver the liquid medicament into a patient by injection.

Once in position, for example, once a needle of the injector has been inserted into a patient's vein or elsewhere within a patient's body, the normally-closed valve may be opened manually by actuating a switch. This configuration allows a user to deliver the liquid contents of the injector only when he or she is satisfied that the injector is correctly positioned.

Where an injection is made using a conventional auto-injector, the liquid tends to be maintained at atmospheric pressure during storage before use. On activation, a plunger applies a pressure to the liquid to effect injection. The sudden application of pressure causes an initial pressure spike that may cause discomfort to a patient. The pressure spike may also be extreme enough to cause breakage of a syringe. Furthermore, where a plunger is depressed, stiction between the plunger and the syringe barrel may cause a fluctuating pressure profile during injection. The use of an injector or method of injection as described above may considerably alleviate these problems. As the liquid is maintained under pressure, there is no pressure spike when the injector is actuated. Furthermore, embodiments that use a collapsible bellows or similar collapsible bag will not suffer from the effects of stiction during delivery. The method may comprise the step of the normally-closed valve being opened automatically when the injector is correctly positioned for delivery. For example, the injector may comprise a needle, and the normally-closed valve may be actuated when the needle has been inserted into the patient to a predetermined depth. Thus, the injector may comprise an actuator that is set to automatically open the normally-closed valve when the injector has been positioned in a predetermined position.

Preferably, the injector used in the method of injecting a liquid is an injector having any feature or combination of features described above.

The invention may further provide a method of manufacturing an injector for delivering a liquid, for example a liquid medicament, the method of manufacturing comprising the steps of coupling a normally-closed valve to a collapsible container, opening the normally closed valve, filling the collapsible container with the liquid through the normally-closed valve causing the collapsible container to expand and deflect a pressuring means, closing the normally-closed valve to retain the liquid within the collapsible container, the liquid being pressurised due to a force exerted on the collapsible container by the pressuring means, and coupling the normally-closed valve to an injection means for delivering the liquid from the collapsible container.

Many conventional auto-injectors have a staked needle. The liquid drug is, therefore, in contact with the needle during storage. By filling an injector through a normally-closed valve and then attaching a needle downstream to the normally-closed valve, the needle is maintained in a dry condition during storage before use and cannot, therefore, react with the liquid medicament during storage. Furthermore, as the needle can be a "dry needle", i.e. a needle that is not in contact with the liquid drug, there is no need for a needle cap or shield for closing the needle tip. Any such cap may blunt the needle, and the removal of the cap requires a further user step. Additionally, standard needle caps or shields are held tightly to the needle to reduce

evaporation and may prove difficult to remove, particularly for older patients.

The liquid is preferably a liquid medicament.

Advantageously, the method may further comprise the step of applying a vacuum to the collapsible container through the normally-closed valve in order to remove air trapped within the collapsible container and the normally closed valve prior to filling. The removal of air may help prevent oxidation of the liquid or the undesirable solution of gases from the air into the liquid.

Preferably, the normally-closed valve is flushed with a sterilising fluid, for example ethanol, prior to coupling with the injection means.

The injector is preferably an injector having any feature or combination of features described above.

The injector may comprise a rigid container, and the method may further comprise the step of removing the air from the rigid container or flushing the rigid container with an inert gas such as nitrogen. The inert gas may be sealed within the rigid container with the collapsible container and the pressurising means. A vacuum may be applied to the rigid container by known "under the cup" vacuuming techniques or the rigid container may be evacuated via a vent defined through the walls of the rigid container.

The rigid container may contain a vent for allowing gas within the rigid container to be expelled during filling of the collapsible container. The method may further comprise the step of sealing the vent after filling in order to retain sterility and/or minimise contact between the air and the collapsible container.

Injectors according to preferred embodiments contain only a small number of component parts relative to many conventional auto-injectors. The low number of component parts and technical simplicity of preferred embodiments allows the cost per unit to be reduced relative to conventional auto-injectors.

Specific Embodiments of the Invention

The invention will now be described with reference to the figures in which;

Figures 1 and 2 are schematic illustrations of an injector according to an embodiment of the invention,

Figures 3 and 4 are schematic illustrations of an injector according to an embodiment of the invention,

Figure 5 is a schematic illustration of an injector according to an embodiment of the invention,

Figures 6 and 7 are schematic illustrations of an injector according to an embodiment of the invention,

Figures 8 and 9 are schematic illustrations of an injector according to an embodiment of the invention,

Figures 10, 1 1 , 12, and 13 are schematic illustrations showing cross-sections of embodiments of normally-closed valves suitable as component parts of an injector according to one or more emodiments of the invention, and

Figures 14 and 15 are schematic illustrations of an injector according to an embodiment of the invention.

Figures 1 and 2 schematically illustrate the components and operation of an injector according to an embodiment of the invention. A rigid container or rigid outer container 1 houses a collapsible bellows 2 containing a liquid drug 10 and a spring 3 for pressurising or compressing the liquid drug 10. A normally-closed valve 4 connects the liquid drug 10 contained within the collapsible bellows to a valve actuator 8 and a needle 6 for delivering the drug. An inner retaining means 101 is located within the rigid outer container 1 . The inner retaining means 101 is in the form of a rigid cylinder of transparent polyethylene affixed within the rigid container 1 . The cylinder could be any other suitable material, such as any other transparent rigid polymer. In this embodiment of an injector the cylinder locates a collapsible bellows 2 containing a liquid medicament 10.

Figure 1 shows the injector before use. The collapsible bellows 2 are filled with the liquid drug 10 and the collapsible bellows compresses the spring 3 against an internal wall 1 a of the rigid container 1 . In its compressed condition, the spring 3 exerts a force against both the internal wall of the rigid container 1 a and the collapsible bellows 2, thereby pressurising the liquid drug 10 contained within the bellows. A cap 9 keeps the needle free from contamination prior to use. The cap 9 may be fixed to the device with a tamper evident feature.

When the injector is used, the needle 6 pierces the skin and enters the body to a predetermined depth depending on the target location. When the actuator 8 touches the skin and is pressed against it, the actuator 8 moves towards the rigid container (in the direction shown by arrow 5) thereby opening the normally-closed valve 4 and allowing the liquid drug 10 contained within the bellows 2 to flow through needle 6 under the pressure generated by spring 3.

In Figure 2 the device is shown after use with the spring 3 extended and the bellows 2 collapsed, the liquid drug contents 10 having been expelled.

Alternatively the actuator may be pressed by a separate mechanical linkage attached to a finger button. Such an arrangement may be spring loaded to aid activation.

The collapsible bellows 2 may be made of any suitable plastic such as Polyethylene, ABS, Polycarbonate, Polypropylene, PPO, PET or any other plastic suitable for blow moulding and compatible with the liquid drug being stored in the bellows. The rigid container 1 may be transparent and made from for example PET plastic or other transparent material.

Methods of filling an injector comprising a normally-closed valve are disclosed in WO

201 1/1 17592, the contents and teaching of which are hereby incorporated by reference.

Figures 3 and 4 illustrate an embodiment of an injector in which the collapsible container is formed from a piston and cylinder arrangement rather than a collapsible bellows. Components of the injector that are common to the various embodiments of injectors described above have been given the same reference numerals. A rigid container 1 is cylindrical in shape and defined a cylindrical internal cavity. An inner retaining means 101 is located within the rigid outer container 1 . The inner retaining means 101 is in the form of a rigid cylinder of transparent polyethylene affixed within the rigid container 1 . The cylinder could be any other suitable material, such as any other transparent rigid polymer. In this embodiment of an injector the cylinder locates a piston 21 with a seal 22 that contacts an internal wall 105 of the cylinder. The piston 21 and the internal walls 105 of the inner retaining means (rigid cylinder 101 ) define a collapsible chamber for containing a liquid drug 10.

Before use, the piston 21 rests against a seal 23, which may be a flexible seal or a spring loaded seal, to minimise drug evaporation and gas interchange. A spring 3 urges against the piston 21 and an end wall 1 a of the rigid container, compressing the liquid contents 10 of the collapsible container and expelling them via a needle 6. The piston 21 may be associated with more than one seal 22. The piston is preferably made of a plastic or elastomer, and in some cases a separate seal 22 may not be needed.

Figure 5 illustrates a normally-closed valve (of the type similar to that illustrated in figure 1 1 and described below), crimped onto a rigid outer container 201 formed from aluminium to form part of an injector. A suitable outer container may also be formed from other metals, for example from steel. An inner retaining cylinder 202 is also crimped onto the normally-closed valve. The inner cylinder 202 is formed from transparent polyethylene. A piston 210 is arranged to slide within the inner cylinder 202 to define a collapsible container 220 for containing a liquid medicament. The contents of the collapsible container 220 are maintained under pressure by the action of a spring 230 that urges the piston 210 into the inner cylinder 202 in reaction to an inner wall 201 a of the rigid container 201 . Viewing holes 240 are defined through portions of the wall of the rigid outer container 201. These holes act as viewing windows or inspection windows and allow a visual inspection of the inner chamber 202 and its contents. An air-tight seal to the rigid container 201 is provided by removable foil seals 250, which are sealingly adhered over the viewing holes 240. The removable foil seals can be removed immediately prior to use on the injector. A delivery means such as a hypodermic needle (not shown) can be coupled to the normally-closed valve for delivery of the contents of the collapsible container. Figures 6 and 7 illustrate an embodiment of an injector that is substantially similar to that described above in relation to figures 3 and 4. The injector has a rigid container 1 and an inner cylinder 101 within the rigid container. A piston 21 is slideable within the inner cylinder 101 to define a collapsible container containing a liquid medicament 10. The difference from the injector of figure 49 is that an internal opening of the inner cylinder 101 is closed by means of a locking ring or cap 201. The spring 3 (which acts against an inner surface of the rigid container in the example illustrated in figure 3) urges the piston 21 against this locking ring 201. Thus, the spring 3 does not directly urge against the rigid container 1 . As there is less force on the rigid container 1 , it is safer to make the rigid container from a fragile material such as glass.

Figures 8 and 9 illustrate an embodiment of an injector that is substantially similar to that illustrated in figure 6 and 7. The piston 21 is formed from two components. A front portion 21 a is formed from a plastic material such as PTFE or PE. This component may be made from any suitable plastic. A rear portion 21 b of the piston 21 is formed from a resilient material, such as an elastomeric spring material or a metallic spring arrangement. The front portion 21 a of the piston 21 forms an inner surface of the collapsible chamber and also forms a seal with an inner wall of the inner retaining means 1 a. The rear portion 21 b engages with the spring 3. Force from the spring urges the rear portion 21 b towards the normally-closed valve 4. This results in a lateral expansion of the material forming the rear portion 21 b, which helps form a secure seal between the front portion 21 a and inner walls of the inner retaining means 1 a. It is preferred that the rear portion is an elastomeric material such as a rubber.

Figure 10 illustrates a typical normally-closed valve which is suitable for use in an injector according to one or more embodiments or aspects of the invention. The valve is shown together with an attached bellows 54. Figure 25 illustrates a male aerosol valve. It has a body 53 with a spring 52 within. A stem 57 has stem orifice 59 sealingly mounted against an inner gasket 55. A bellows 54 is sealingly connected to the valve body 53. When the stem 57 is depressed into the valve body 53 (the direction of arrow 58) the valve opens by exposing the stem orifice 59 to the pressurised liquid contents which are inside the valve cavities 61 and 63.

After filling the bellows 54 with drug contents via the valve, the valve stem 57 passageway 62 and stem orifice 59 (or gasket and cup in the case of a female valve) are preferably flushed with a clean liquid such as ethanol or any other suitable liquid or any suitable gas or a gas and liquid mixture or separately by both to ensure sterility.

It is preferable that the dead volumes 61 , 62 and 63 in the valve are kept to a minimum. The bellows 54 and valve body 53 may be moulded as one part in any suitable plastic material.

Figure 1 1 illustrates a normally-closed valve in which the dead volume 61 is much reduced by eliminating the metal spring (spring 52 in figure 25). In Figure 1 1 the valve comprises a spring 65 that is formed as part of the plastic stem 57. This eliminates the extra material of a separate spring and may help in minimising any drug stability issues. The valve shown in Figure 26 can be manufactured from two materials. The stem 57 and spring 65, body 53 and bellows 54 can all be made from a single plastic. The only other material in contact with the drug solution is a gasket 55.

The normally-closed valve illustrated in Figure 1 1 includes a stem orifice 59 which is located above an inner gasket 55 when the valve is closed and the stem passageway 62 is shortened to end at the point that the stem orifice 59 enters the stem 57. This feature may assist the flushing and cleaning of the stem after filling. Figure 1 1 also illustrates a valve/bellows arrangement in which the bellows has concave bottom section 67. This configuration of the bellows may be of beneficial use in combination with other features of one or more aspects or embodiments of the invention. For example, this

configuration may help to minimise dead volume in the bellows when it is fully collapsed at the end of device use.

An injector as described herein may be used to inject any class of drug anywhere in the body of both humans and animals. Both conventional drugs (small molecule) and biopharmaceuticals may be used with the device. The injector may be filled with diluent for lyophilized drug reconstitution.

Figure 12 illustrates an embodiment of a normally-closed valve that may be a suitable component part of an injector according to an embodiment or aspect of the invention as disclosed herein. The valve consists of a valve stem 31 1 having an upper portion 31 13 and a lower portion 31 16. The valve stem 31 1 defines a valve passageway 31 12 and a stem inlet 31 14. The stem 31 1 is urged into a sealing engagement with a stem-sealing gasket 313 such that the stem inlet 31 14 is sealed from communication with any material to be dispensed. The lower portion 31 16 of the stem 31 1 is located within a valve housing 315 defining a cavity 390 and an inlet hole 400 for allowing passage of a material contained in a can or bag attached to the valve to pass into the cavity 390. The stem 31 1 is urged into the sealing engagement with the gasket 313 by means of a cylindrical butyl rubber spring 318 located within the cavity 390 of the housing 315.

The free space or dead space within the cavity 390 (i.e. the remaining space not taken up by the valve stem or the rubber spring 318) is typically less than a third or less than a quarter of the free space in an equivalent sized valve comprising a helical spring.

Actuation of the valve is illustrated in Figure 12. As the stem 31 1 is depressed the butyl rubber spring is deformed and the stem inlet 31 14 is brought into communication with the cavity 390. Thus, any dispensable material within the cavity may pass through the stem inlet and thereby out of the valve. On releasing the force depressing the valve stem 31 1 , the butyl rubber spring regains its original shape and, once more, urges the valve stem into sealing engagement with the stem-sealing gasket 313 to close the valve.

In the embodiment shown in Figure 12 both the elastomeric spring 318 and the stem-sealing gasket 313 are formed from the same butyl rubber material.

Figure 13 illustrates an embodiment of a normally-closed valve that may be a suitable component part of an injector according to an embodiment or aspect of the invention as disclosed herein. The valve comprises an external spring 69 located around an external portion of a stem 62. The spring is located by means of a shoulder 68, which extends radially outwards from the stem. The force of the spring urges the shoulder 68 and stem 62 such that the valve is in a closed position. This embodiment of a normally-closed valve may be of particular benefit when used as a component of an injector according to one or more embodiments or aspects of the invention as described herein.

Figures 1 to 7 illustrate embodiments of an injector comprising an inner retaining means for the collapsible container. Aspects of the invention may provide, however, injectors that include normally closed valves of the type illustrated in figures 12 or 13 that do not comprise an inner retaining means. Figures 14 and 15 schematically illustrate the components and operation of such an injector according to an embodiment of the invention. A rigid container or rigid outer container 1 houses a collapsible bellows 2 containing a liquid drug 10 and a spring 3 for pressurising or compressing the liquid drug 10. A normally-closed valve 4 connects the liquid drug 10 contained within the collapsible bellows to a valve actuator 8 and a needle 6 for delivering the drug. The normally-closed valve comprises an internal elastomeric spring or an external spring (for example valves illustrated in figures 12 or 13) in order to reduce dead volume within the valve and to reduce contamination of any drug product. Operation of the injectors is as described above in relation to Figures 1 and 2.

Claims

1 . An injector for delivering a liquid medicament comprising,

a collapsible container for containing the liquid medicament,

a normally-closed valve coupled to the collapsible container for retaining the liquid medicament within the collapsible container,

an injection means couplable to the normally-closed valve for delivering the liquid medicament from the collapsible container, and

pressurising means for retaining the liquid medicament contained within the collapsible container under pressure such that the liquid medicament is delivered by the injection means when the normally-closed valve is opened,

in which the collapsible container and the pressurising means are housed within a rigid outer container, the collapsible container being located by an inner retaining means such that the collapsible container does not contact an inner wall of the rigid outer container.

2. An injector according to claim 1 in which the rigid outer container comprises a first material and the inner retaining means comprises a second material disposed within the rigid outer container between the collapsible container and the rigid outer container.

3. An injector according to claim 1 or 2 in which the inner retaining means comprises a rigid material, for example a rigid barrel, sheath, or cylinder, within which the collapsible chamber is defined or retained, preferably in which the inner retaining means is spaced from the inner wall of the rigid outer container.

4. An injector according to claim 3 in which the inner retaining means is formed from an rigid transparent polymer, for example polyethylene or polypropylene.

5. An injector according to any preceding claim in which the rigid outer container is formed from an oxygen barrier material.

6. An injector according to any preceding claim in which the rigid outer container is formed from a transparent polymer or glass.

7. An injector according to any of claims 1 to 5 in which the rigid outer container is formed from a metal, preferably in which the rigid outer container comprises windows to enable the contents of the rigid outer container to be viewed.

8. An injector according to claim 7 in which the windows are sealed by a transparent material, for example glass or a rigid transparent polymer, preferably in which the windows form a gas-tight seal.

9. An injector according to claim 7 in which windows defined through a wall of the rigid outer container are sealed by a removable covering, for example a removable foil covering that is capable of being removed prior to use to enable a user to view the contents of the rigid outer chamber during delivery of the medicament.

10. An injector according to any preceding claim in which the injection means is a hollow needle such as a hypodermic needle, or in which the injection means is a needleless injection element for injecting medicament into a human or animal body.

1 1 . An injector according to any preceding claim in which the rigid outer container includes a vent to allow displaced air within the rigid outer container to escape when the collapsible container is filled, preferably in which the vent is a closable vent.

12. An injector according to any preceding claim in which the inner retaining means is in the form of a barrel or cylinder located within the rigid outer container in which the collapsible container is defined by internal walls of the barrel or cylinder and a piston that is slidably arranged within the barrel or cylinder, the volume of the collapsible container varying depending on the position of the piston.

13. An injector according to any of claims 1 to 1 1 in which the collapsible container is a bellows coupled to the normally-closed valve.

14. An injector according to any preceding claim in which the pressurising means is a biasing element that exerts a force that acts on the collapsible container.

15. An injector according to claim 14 in which the force acting to collapse the collapsible container is generated by a spring, for example a compressed helical spring arranged to urge the collapsible container to collapse.

16. An injector according to claim 15 in which the pressurising means comprises a spring and is an integral part of the collapsible container.

17. An injector according to claim 14 in which the force that acts on the collapsible container is generated by a compressed gas or a liquefied gas.

18. An injector according to any of claims 14 to 17 in which the pressurising means comprises a piston or ram that is urged by the force into contact with the collapsible container.

19. An injector according to any preceding claim in which the inner retaining means comprises a location point for the pressurising means and the pressurising means is a biasing element that exerts a force acting on both the location point and the collapsible container.

20. An injector according to any preceding claim in which the pressurising means does not apply a direct force on an internal wall of the rigid outer container.

21 . An injector according to any preceding claim in which the pressurising means applies a force acting between an internal wall of the rigid outer container and the collapsible container.

22. An injector according to any preceding claim in which the normally-closed valve is a continuous flow valve or an aerosol valve.

23. An injector according to any preceding claim in which the normally-closed valve comprises a spring that acts to urge the valve to a closed position, in which the spring is a non- metallic spring, for example a plastic spring.

24. An injector according to claim 23 in which the non-metallic spring is formed from an elastomeric material, for example from a rubber material, so as to reduce the dead volume of the valve.

25. An injector according to any preceding claim in which the normally-closed valve comprises a spring that acts to urge the valve to a closed position, in which the spring is located on an external portion of the valve.

26. An injector according to any preceding claim comprising a manually operated switch for opening the normally-closed valve.

27. An injector according to any of claims 1 to 25 comprising an actuator for opening the normally-closed valve, in which the normally-closed valve is opened when the actuator is pressed against a patients skin.

28. An injector according to any of claims 1 to 25 in which the injection means is a needle and the normally-closed valve is arranged to open when the needle has been inserted a predetermined distance into the patient, the predetermined distance depending on the type of drug that is being delivered and the tissue that the delivery is required to be made into.

29. An injector according to any preceding claim in which the injector means is a needle and the injector comprises a protective sleeve or shield.

30. An injector according to any preceding claim when filled with the liquid medicament.