WO2010146358A2

WO2010146358A2 - Auto-injector

Info

Publication number: WO2010146358A2
Application number: PCT/GB2010/001182
Authority: WO
Inventors: Martin Mcloughlin
Original assignee: Ucb Pharma S.A.
Priority date: 2009-06-19
Filing date: 2010-06-17
Publication date: 2010-12-23
Also published as: WO2010146358A3; GB0910681D0

Abstract

There is provided an auto - injector (1) for a syringe (10) that is suitable for use in the injected delivery of drug to a patient. The auto - inj ector (1) comprises a housing (20) defining a housing cavity and a needle delivery aperture (25), the housing cavity arranged for receipt of a syringe (10). The syringe is movable within the housing cavity from a rest position, in which the needle tip (15) thereof is within the housing to a use position, in which the needle tip protrudes from the needle delivery aperture. The auto - inj ector further comprises a drive transfer element (70) for transferring axial drive; and a first coupling for coupling said drive transfer element to said syringe barrel (12) of the syringe (10). The drive transfer element (70) communicates with said plunger (18) of the syringe for transferring axial drive thereto. The first coupling is a friction clutch coupling arranged for decoupling by declutching thereof when the syringe moves to the use position.

Description

Auto-injector

The present invention relates to an auto-injector device for receipt of a syringe that is suitable for use in the injected delivery of a drug formulation to a patient.

It is well-known to use syringes for the delivery of injectable liquid drug formulation to a patient. Syringes rely on puncturing of the patient's skin by a hollow needle through which the injectable liquid drug (e.g. in solution or suspension form) is delivered to the muscle or tissue of the patient. Typically, syringes comprise a barrel for containing a volume of the liquid drug; a hollow needle defining a needle tip for dispensing of the liquid; and a plunger that is axially movable within the barrel.

It is also well-known to provide auto-injectors for use with syringes. Such auto- injectors typically comprise a body for housing the syringe and an actuating mechanism, which is triggered in use, to allow for automatic delivery of the liquid drug formulation from the syringe. Actuating mechanisms typically comprise a source of drive (e.g. a strong spring) for drivable movement of a drive transfer element (e.g. a plunger rod) that transfers drive to the plunger for axial movement thereof within the syringe barrel. Such movement of the plunger results in the plunged driving of the liquid drug from the syringe barrel to the hollow needle for dispensing to the patient via the needle tip thereof.

For safety and hygiene reasons, it is desirable that the hollow needle does not protrude from the housing of the auto-injector other than when expelling the liquid drug formulation during an injection procedure. Thus, auto -injectors have been developed in which, the housing is arranged such that a needle receiving part allows for the needle of the syringe to be axially moveable therein from a first (i.e. rest) position in which the hollow needle is shrouded by the needle receiving part to a second (i.e. use or ready to inject) position in which at least the tip of the needle protrudes from that needle receiving part of the housing. Applicant has realized that it is desirable that (1) this needle un -shrouding movement is readily enabled, but also (2) that such un -shrouding movement does not result in any premature delivery of the liquid drug. Thus, one ideal mode of operation would comprise a triggering of the actuating mechanism, which first acts to transfer force to move the syringe from the 'rest' to the 'use' (needle-protruding) position, and which only then acts to transfer force to the plunger for expelling of liquid drug contents from the syringe barrel.

In solution, Applicant has now devised an auto -injector, in which a drive transfer element (e.g. plunger rod) reversibly couples to the syringe barrel. Initially, the coupling is in place and drive movement applied to the plunger rod results in drivable movement of the syringe from the 'rest' to the 'use' position. That coupling then decouples such that further drive movement applied to the plunger rod results in drivable movement of the plunger within the syringe barrel, ultimately to the 'fully plunged' position when most, preferably all of the liquid drug contents of the syringe barrel have been drivably expelled therefrom.

In a detailed aspect of the solution, the coupling between drive transfer element and syringe barrel is achieved by means of a friction clutch relationship between these parts. In one aspect, the drive transfer element comprises a two (or multi-) part plunger rod assembly that interacts with the syringe barrel to provide the necessary friction clutch type relationship.

It is also desirable for the auto-injector to be provided with a syringe needle tip shroud advance mechanism. This acts to advance a needle tip shroud over the needle tip following completion of the injection procedure, thereby shrouding off at least the used needle tip. Applicant has realized that operation of such a syringe needle tip shroud advance mechanism may be in embodiments enabled if the source of drive (e.g. drive spring) couples to the needle tip shroud once the 'fully plunged' position has been reached. Applicant has also realized that such operation may be better enabled if in addition, the drive transfer element (e.g. plunger rod) decouples from the source of drive (e.g. drive spring) at that 'fully plunged' position such that further axial movement thereof is unhindered by any action of the drive source. The needle shroud advance mechanism may thus be advanced to shroud the needle tip of the syringe unhindered by any interaction with the now freely movable drive transfer element (e.g. plunger rod).

According to one aspect of the present invention there is provided an auto- injector comprising

a housing defining a housing cavity and a needle delivery aperture, said housing cavity arranged for receipt of a syringe comprising

a barrel for containing a volume of a liquid drug formulation;

a hollow needle at a front end of said barrel, said hollow needle defining a needle tip for dispensing of said liquid drug formulation; and

a plunger that is axially movable within the barrel,

wherein said syringe is movable from a rest position, in which the needle tip is within the housing cavity to a use position, in which the needle tip protrudes from said needle delivery aperture, the auto-injector further comprising

a drive transfer element for transferring axial drive; and a first coupling for coupling said drive transfer element to said syringe barrel of the syringe;

wherein the drive transfer element communicates with said plunger of the syringe, and wherein said first coupling is a friction clutch coupling arranged for decoupling by declutching thereof when the syringe moves to the use position.

Thus, in the initial rest position, the first coupling couples the drive transfer element to both the syringe barrel and the plunger. Application of axial drive force to the drive transfer element therefore results in movement of the syringe as a whole, but preferably not of the plunger relative to the syringe barrel. It may be appreciated that this preferred initial absence of relative plunger movement is favoured if the frictional forces to be overcome in moving the syringe barrel within the housing are arranged to be much less than for moving the plunger within the syringe barrel. This is typically so since the plunger is often a natural or synthetic rubber element, which frictionally interacts with the side wall of the syringe barrel.

Once the syringe is in the use position (i.e. needle protruding) the first coupling decouples (e.g. demounts) such that no coupling then exists between the drive transfer element and the syringe barrel. All further axial drive force applied to the drive transfer element, therefore results in plunging axial movement of the plunger within the syringe barrel, which acts to drive the liquid drug formulation contents of the syringe barrel into the hollow needle for injected delivery from the needle tip.

These and other embodiments of the present invention are set forth in the later description, which describes for illustrative purposes only various embodiments thereof. There is provided an auto-injector device that is arranged for use with a syringe that contains a liquid drug formulation. The syringe is arranged to be suitable for use in the injected delivery of the liquid drug formulation to a patient.

The auto-injector comprises a housing that defines a housing cavity (e.g. chamber form) that is arranged for receipt of the syringe and is therefore typically sized and shaped for this purpose. The housing may be arranged as a single part or a multi-part (e.g. two part) housing assembly.

The syringe that is received within the housing cavity comprises a syringe barrel for holding a volume of the liquid drug formulation; a hollow needle at a front end of the barrel, the hollow needle defining a needle tip for dispensing of said liquid drug formulation; and a plunger (e.g. in the form of a rubber stopper) that is axially movable within the syringe barrel. The plunger is movable axially within the barrel so as to enable the liquid drug formulation to be expelled from the barrel and thence through the hollow needle via the dispensing tip for injection into the patient. The syringe barrel is typically, comprised of glass but may also be comprised of a relatively hard plastic polymer such as hardened polyethylene, polycarbonate or cyclic olefin polymers.

In embodiments, the plunger is comprised of a natural or synthetic polymer friction material, which frictionally interacts with the side wall of the syringe barrel. Suitable plunger materials include natural or synthetic rubbers or elastomeric materials.

In more detail, the syringe barrel is selected such as to define a barrel chamber for containing a suitable volume of the liquid drug formulation. In embodiments, that suitable volume is selected to correspond to a single dose of the drug formulation to be delivered to the patient. In other words, delivery of that single dose involves expelling all of the liquid drug formulation contents of the barrel chamber through the hollow needle for injection into the patient.

The hollow needle defines a needle bore, which is most typically of circular cross-section and of selected bore diameter. It may be appreciated that in embodiments, the bore diameter may affect the force required to expel the liquid drug formulation through the needle and also the velocity at which the liquid drug formulation is expelled.

The selected needle bore may also, in embodiments affect the degree of patient discomfort during injection. Smaller bore diameters, typically provide more patient comfort, whereas larger bore diameters enable more rapid / lower force delivery of the liquid through the needle. A compromise is therefore needed in selecting needle bore to provide acceptable patient comfort and liquid delivery through the needle characteristics.

Examples of typical needles that are suitable for use therein include 12.5mm ("half inch") long thin wall needles of grade 23G, 25G or 27G. These have a needle bore of from about 0.2 to 0.4mm such as from 0.25 to 0.35mm. Other examples include both regular and thin wall needles used in conventional syringes including those with bevels such as 3 and 5 bevels.

The housing and any inner housing sub assembly of the auto -injector is shaped to define a housing cavity within which the syringe is receivable, and a needle delivery aperture. The housing cavity is typically cylindrical in form, thereby matching the typically cylindrical outer profile of a syringe. The housing cavity may be further shaped with any manner of grooves, indentations or other shaping or surface details to define a 'lock and key' relationship between the housing and any inner housing sub assembly thereof and the syringe. Colour guides, arrows and any other surface markings may also be employed. Typically, the housing and /or any inner housing sub assembly thereof is provided with a barrel receiving part for receiving the barrel of the syringe; a plunger receiving part for receiving the plunger of the syringe; and a needle receiving part for receiving the hollow needle of the syringe.

In embodiments, the plunger receiving part of the housing and /or any inner housing sub assembly thereof allows the plunger within the syringe barrel to be received thereby and for the plunger to be movable (e.g. axially) therein from a first position to a second position, in which it is moved somewhat into the barrel. During use the plunger is in embodiments, movable to a fully plunged position in which most, preferably all of the liquid drug formulation contents of the barrel have been expelled.

The needle receiving part of the auto-injector housing and /or any inner housing sub assembly thereof includes a needle delivery aperture through which the hollow needle may protrude from the housing, for example during expelling of the liquid drug formulation through the hollow needle and its needle tip for delivery to the patient.

The syringe is movable within the housing cavity from a rest position, in which the needle tip is within the housing to a use position, in which the needle tip protrudes from the needle delivery aperture.

In more detail, it is desirable for safety and hygiene reasons that the needle does not protrude from (i.e. outwith) the housing other than when expelling the liquid drug formulation during an injection procedure. Thus, the housing and /or any inner housing sub assembly thereof and housing cavity defined thereby is generally arranged such that the needle receiving part thereof allows for the needle of the syringe to be axially moveable therein from a first (i.e. rest) position in which the needle is wholly housed (or shrouded) by the needle receiving part to a second (i.e. use) position in which at least the tip of the needle protrudes from that needle receiving part of the housing. In certain embodiments, the housing includes biasing means (e.g. a spring) arranged such that the needle is normally biased towards the first (i.e. rest) position, wherein such biasing means are overcome during the actuation of the syringe (e.g. by an actuating mechanism) to allow for movement of the needle to the second (i.e. use) position.

In terms of function, the auto-injector is arranged to allow for actuation (i.e. firing) of the syringe. The auto-injector thus, also includes a drive transfer element for transferring axial drive to the syringe. Preferably, that drive transfer element takes the form of a plunger rod, but other suitable forms are also envisaged. In embodiments, the source of axial drive is automatically applied with the latter being most preferred. Thus, in embodiments the auto-injector includes an actuating mechanism.

In preferred embodiments, the auto-injector includes an energy store for storing energy that can then be released to provide the axial drive to the syringe via the drive transfer element. In embodiments, the auto-injector includes a second coupling (e.g. in the form of a shuttle element) for coupling the energy store to the drive transfer element. In embodiments, the energy store comprises a mechanical energy store such as a spring (e.g. a compression or torsion spring). In other aspects, the energy store may be provided by a container of compressed liquid or gas propellant that on release provides a source of jet energy propulsion.

In embodiments, the energy store is able to exert an axial drive force of up to 6ON on the syringe. Where the energy store is a compression spring the force exerted typically varies over the actuation profile such as from a range of 60 to 4ON at the start of actuation to from 40 to 2ON at the end of the actuation profile. Where the energy store is a compressed liquid or gas propellant a more constant force is typically exerted over the actuation profile.

In preferred embodiments, release of axial drive force (e.g. actuation of the actuating mechanism) is responsive to a trigger (e.g. a user-actuable trigger). In embodiments, the trigger comprises a button, switch or lever arrangement. In other embodiments, a press actuation mechanism that is actuable in response to pressing of the housing of the device against the skin is also envisaged.

The auto-injector includes a first coupling for coupling the drive transfer element to the syringe barrel of the syringe. In embodiments, the drive transfer element is a plunger rod.

The first coupling is a reversible (e.g. demountable) coupling arranged for decoupling (e.g. demounting) when the syringe moves to the use position. In embodiments, the first coupling is at a forward position of the drive transfer element. Thus during a use operation, the first coupling is initially in place and axial drive force applied to the drive transfer element (e.g. plunger rod) results in drivable movement of the syringe from the rest to the use position. That first coupling then decouples such that further axial drive force applied to the drive transfer element (e.g. plunger rod) results in drivable movement of the plunger within the syringe barrel, ultimately to a fully plunged position when most, preferably all of the liquid drug formulation contents of the syringe barrel have been drivably expelled therefrom.

The drive transfer element communicates with (e.g. contacts or abuts) the plunger of the syringe for transferring drive thereto. In embodiments, an end portion of the drive transfer element directly communicates with (e.g. contacts or abuts) the plunger. In other embodiments, an end portion of the drive transfer element indirectly communicates with (e.g. contacts or abuts) the plunger such as via a washer or other intermediate element.

The first coupling is a friction clutch coupling arranged for decoupling by declutching thereof when the syringe moves to the use position. By 'friction clutch coupling' it is meant a coupling that is frictional in nature and capable of adopting both a 'clutched' (i.e. coupled) state corresponding to high frictional interaction and a 'declutched' (i.e. uncoupled) state corresponding to low frictional interaction.

In embodiments, the drive transfer element is arranged to transfer axial drive to the syringe barrel via the plunger of the syringe and the friction clutch coupling acts to vary the frictional contact between the plunger of the syringe and the syringe barrel. Thus, the frictional contact is variable from (i) a high frictional contact state corresponding to coupling (i.e. clutched) interaction therebetween to (ii) a low frictional contact state corresponding to decoupling (i.e. declutched) interaction therebetween.

In embodiments, the friction clutch coupling comprises an element (or means) for distorting (e.g. compressing) the shape of the syringe plunger, thereby affecting its degree of frictional contact with the interior walls of the syringe barrel.

In embodiments, the drive transfer element comprises a syringe plunger rod, which interacts with the plunger of the syringe, and the means for distorting (e.g. compressing) the shape of the syringe plunger is provided to the syringe plunger rod such as by means of a movable plunger rod sleeve thereof. Thus, distortion of the plunger (and hence, variance of the frictional coupling/clutching state) is by movement of the plunger rod sleeve relative to the plunger rod. In such aspects, the syringe plunger is selected to have in embodiments, a distortable (e.g. compressible) nature, for example comprising a natural or synthetic rubber polymer material

In embodiments, movement of the plunger rod sleeve relative to the plunger rod to thereby change the frictional coupling/clutching state is responsive to movement of a shuttle element, the axial movement of which, in turn is responsive to the axial drive force provided by the source of axial drive. Thus, the axial drive acts on both the plunger rod and the driven shuttle.

In embodiments, the shuttle has an axially symmetric form such as cylindrical form, wherein the plunger rod and sleeve therefor are suitably received axially within the cylindrical form. Guides (e.g. a central aperture of an end wall) may be provided to the shuttle to assist that axial receipt.

In embodiments, the shuttle is provided with one or more followers (e.g. pegs or notches) arranged for track-follower receipt by one or more tracks (e.g. grooves or slots) of the plunger rod sleeve, thereby coupling the movement of the plunger rod sleeve to that of the driven shuttle.

In embodiments, in a first actuation step the track -follower relationship is arranged such that on initial driven movement of the shuttle (and plunger rod) forward axial drive force is transferred to the plunger rod sleeve. In embodiments, initial movement of the plunger rod is damped (e.g. through use of a source of damping between plunger rod and inner housing sleeve. In embodiments, the source of damping comprises an O -ring that locates between plunger rod and a boss provided to the rear end of the inner housing sleeve. Opposing forces are thus, set up between freely moving plunger rod sleeve and damped moving plunger rod, which centre at the plunger causing distortion thereof and set up a "friction clutch' type interaction thereat. In embodiments, at a further actuation step the source of damping is overcome, removed or becomes exhausted such that the opposing frictional forces between plunger rod and plunger rod sleeve reduce or cease and the 'friction clutch¹ is therefore effectively de-clutched. At this point, the plunger rod however, continues to receive axial drive and is thus, propelled forward with the plunger rod sleeve to drive the plunger into the syringe barrel to eject the contents thereof.

In embodiments, in a still further actuation step the track -follower relationship is arranged such that on subsequent driven movement of the shuttle (and plunger rod with sleeve) the driven shuttle and plunger rod with sleeve become decoupled such that forward axial drive force is no longer transferred to the plunger rod and sleeve. This corresponds to the fully plunged (or 'end of injection stroke') position of the device.

The track-follower relationship between driven shuttle and plunger rod with sleeve is in embodiments, set up to provide the decoupling therebetween by means of a discontinuity (e.g. sharp curve in the track) which allows the follower of the driven shuttle to decouple from the track of the plunger rod sleeve.

In embodiments, the driven shuttle also couples to the inner housing sleeve such as by means of a second track -follower relationship. Thus, the shuttle is provided with one or more second followers (e.g. pegs or notches) arranged for track-follower receipt by one or more tracks (e.g. grooves or slots) of the inner wall of the inner housing sleeve. In embodiments, the second track -follower relationship is arranged such that at point corresponding to the fully plunged position a discontinuity (e.g. curve) is provided, which causes the shuttle to rotate. It will be appreciated that this rotation of the shuttle will also affect its track-follower relationship with the plunger rod sleeve such as to cause a corresponding discontinuity therein. In embodiments, the rotation of the shuttle enables its decoupling from the plunger rod and sleeve by fundamentally changing the relationship between the follower thereof and the track of the plunger rod sleeve. Once so-decoupled the shuttle will continue to be subject to any remaining axial drive, but the plunger rod and sleeve is no longer subject to that axial drive.

Variations of the track-follower relationships described above are also envisaged including those in which the track-follower parts are substituted (e.g. track on shuttle, followers on plunger rod sleeve and/or inner housing sleeve). Further examples of track-follower relationships are described in Applicant's co-pending PCT patent publication no. WO2009/081132, the contents of which are incorporated herein by reference.

In embodiments, it is desirable for the auto-injector to allow for the needle of the syringe to be shrouded by a needle shroud element after use . Thus, in particular it is desirable to be able to provide a means of shrouding the needle of the syringe that is moved or otherwise brought into operation after completion the injection procedure. Such means in embodiments comprises a movable shroud element that is adapted to be movable to a shrouding configuration at the end of the injection procedure. Where the axial drive is provided by an energy store that couples to the drive transfer element by means of a second coupling (e.g. provided by reversible coupling of the drive shuttle to the plunger rod and sleeve as described above) it has been appreciated that such movement of a needle shroud element ('needle shroud means') may be enabled if the movable needle shroud element couples (e.g. via a third coupling) to the source of axial drive, wherein said coupling is a reversible coupling arranged to be coupled when the plunger moves to a fully plunged position within the syringe barrel. Thus, at this fully plunged position, axial drive becomes transferable to the movable shroud element to move it into a shrouding position.

In another aspect, it is desirable for the auto -injector to allow for the needle of the syringe to be retracted into the housing after use. Thus, it is desirable to be able to retract the needle back into the needle receiving part of the housing after the injection procedure, that is to say to retract the needle from the second (i.e. use) position to a retracted position that may in embodiments, correspond to the first (i.e. rest) position or in other embodiments, correspond to a third position, which in embodiments is further away from the needle delivery aperture. Where the axial drive is provided by an energy store that couples to the drive transfer element by means of a second coupling it has been appreciated that such syringe retraction is better enabled if the drive transfer element (e.g. plunger rod) reversibly couples to the energy store.

Thus, in embodiments, the drive transfer element communicates with the energy store via a second coupling, wherein the second coupling is a reversible coupling arranged for decoupling when the plunger moves to a fully plunged position within the syringe barrel (e.g. provided by reversible coupling of the drive shuttle to the plunger rod and sleeve as described above). Thus, the second coupling is a reversible (e.g. demountable) coupling arranged for decoupling (e.g. demounting) when the plunger of the syringe moves to a fully plunged position. Ideally in use, once decoupled from the energy store (i .e. source of axial drive force) the drive transfer element is free to move such that reverse axial movement thereof is unhindered. A needle retract mechanism may then be arranged (e.g. responsive to a light return spring) to retract the syringe needle back into the housing unhindered by any interaction with the now free to move drive transfer element. Or alternatively, a needle shroud mechanism may be arranged to be activated at this point. In embodiments, the auto-injector housing is provided with a removable cap that fits over and thereby, acts such as to close off, the needle delivery aperture. It may therefore, be appreciated that when in the capped position, the removable cap acts such as to prevent ingress of contaminants into the needle receiving part of the housing.

In embodiments, the auto-injector further comprises a needle cover defining a needle sheath arranged in a rest configuration for sealing of the needle tip.

In embodiments, the needle sheath is comprised of a (e.g. resiliency) compressible material such as a natural or synthetic rubber material. In the rest configuration, the needle tip sticks into (e.g. is spiked or staked into) the needle sheath such that sealing of the needle tip is achieved. Usually, at least the first 3 to 4mm of the needle tip end is so sheathed. It will be appreciated that for clinical reasons, the sealing of the needle tip is preferably such as to prevent passage of contaminant, bacterial or otherwise, through the needle tip and thus into the needle bore and syringe barrel chamber. Sterile sealing is preferred.

In embodiments, the needle cover is provided with a needle sheath cover for covering the needle sheath thereof. In embodiments, the needle sheath cover is provided with one or more gripping elements (e.g. hooks) arranged for gripping of the needle sheath. In embodiments, the needle sheath is provided with one or more features arranged for receipt of the one or more gripping elements such as one or more indents, grooves or cavities.

In embodiments, the needle cover is provided to (e.g. fixed to or integral with) a removable cap for the housing. Thus, in embodiments, the needle cover projects within the cap such that when the removable cap is in the capped position the needle sheath cover and needle sheath therewithin projects towards the needle tip of the syringe. In such embodiments, when in the capped position, the needle tip is sheathed by the needle sheath, and when the cap is removed the needle sheath cover and needle sheath within are also removed such as to thereby, unsheathe the needle tip. In embodiments, the removable cap defines an essentially closed cylindrical cap chamber, optionally tapering, and the needle sheath cover is provided along the axis of that cylindrical chamber.

In embodiments, the housing is provided with one or more (e.g. resiliently) flexible elements that extend (e.g. protrude) into the housing cavity. In embodiments, the one or more (e.g. resiliently) flexible elements are provided as one or more separate parts that attach or fix to an inner wall of the housing or are otherwise in embodiments held within the housing. In other embodiments, the one or more (e.g. resiliently) flexible elements are provided integrally with the housing (e.g. formed as an integral moulding therewith). The one or more flexible elements are typically provided to the needle receiving part of the auto- injector housing

The one or more (e.g. resiliently) flexible elements are desirably arranged to perform two separate functions.

Generally, in the rest configuration the needle sheath locates to seal off the needle tip, the one or more (e.g. resiliently) flexible elements contact the needle cover to restrict (e.g. prevent) movement thereof. Thus, movement of the needle cover is restricted by the action of the (e.g. resiliently) flexible elements, which in embodiments engage with the needle cover to hold it, and thereby restrict movement thereof. Such restriction of movement assists in maintaining the integrity of the seal relationship between the needle tip and the needle sheath.

In the use configuration, the needle cover is generally removed from the needle tip such as to unseal that tip. In this use configuration, the one or more (e.g. resiliently) flexible elements flex into the housing cavity to provide a barrier surface. This barrier surface acts such as to obstruct the exit of the syringe barrel from the housing cavity. Such obstructing function is particularly important in the instance of fracture (i.e. breakage) of the syringe, which is generally comprised of glass material. In this instance, the barrier surface acts such as to obstruct the exit of fractured parts (e.g. glass shards) of the syringe from the housing cavity. The patient is thereby, protected from coming into contact with such fractured parts, and thus potential injury in the event of such a syringe fracture event occurring.

In embodiments, the one or more (e.g. resiliently) flexible elements comprise a ring comprised of a (e.g. resiliently) flexible material such as a plastic polymer (e.g. an elastomer) or natural or synthetic rubber material. That ring (e.g. an O- ring) is generally provided to an inner wall of the (cylindrical) housing such that the outer ring circumference thereof attaches to the inner wall of the housing. In the rest configuration, the inner ring circumference thereof contacts the needle cover (e.g. the needle sheath or a needle sheath cover provided thereto) and is somewhat compressed inwards as a result of that contact, the effect of which is to restrict movement of the needle cover. In the use config uration, the needle cover is removed, and in the absence of compressive contact with the needle cover, the ring expands outwards into the housing cavity to provide a barrier surface, which acts such as to obstruct the exit of the syringe barrel from the housing cavity. Preferably, the diameter of the uncompressed inner ring circumference of the ring is less than that of the syringe barrel such that when the ring is in its uncompressed state the syringe barrel may not pass through the ring.

In embodiments, each of the one or more (e.g. resiliently) flexible elements comprises a flexible finger element comprised of a (e.g. resiliently) flexible material such as a plastic polymer. Each finger element is generally provided to an inner wall of the (cylindrical) housing such that the finger base thereof attaches to the inner wall of the housing. Typically, an arrangement (e.g. circular arrangement) of flexible finger elements is employed such as from three to eight finger elements. In the rest configuration, the finger tip of each finger element contacts the needle cover (e.g. the needle sheath or a needle sheath cover provided thereto) and is somewhat flexed inwards as a result of that contact, the effect of which is to restrict movement of the needle cover. In the use configuration, the needle cover is removed, and in the absence of the compressive contact with the needle cover, the flexible finger element(s) flex into the housing cavity to provide a barrier surface, which acts such as to obstruct the exit of the syringe barrel from the housing cavity. Where the flexible finger elements are provided as a circular arrangement, it is preferable that the diameter of the inner circumferential aperture defined by the extremes of the finger tips thereof is less than that of the syringe barrel such that when the finger elements of that circular arrangement flex outwards the syringe barrel may not pass through the inner circumferential aperture defined thereby.

For ease of assembly, Applicant has realized that it is advantageous if the one or more (e.g. resiliently) flexible elements are arranged such that when the needle cover is inserted into the housing for sheathing of the needle tip, part thereof interacts with the one or more (e.g. resiliently) flexible elements such that these flex (or compress) towards the inner wall of the housing. On completion of that insertion step (i.e. in the rest configuration) the one or more (e.g. resiliently) flexible elements are thus, in a somewhat tensed state, which better acts such as to impact on thus, restrict movement of the needle cover. Conversely, on removal of the needle cover during a use operation the one or more (e.g. resiliently) flexible elements flex (or compress) away from the inner wall of the housing, and thus further into the housing cavity. Representative auto-injectors that may be modified in accord with the present invention include those described in United States Patent No.s US-A-4,553,962; US-A-4,378,015; US-A-5,304,128 and PCT Patent Application No.s WO99/22790 (Elan Corporation); WO00/09186 (Mediject Corporation); and WO2005/070.481 and WO2007/083.115 (The Medical House PLC) and Applicant's co-pending PCT patent applications nos. WO2009/081133, WO2009/081103, WO2009/081132, WO2009/081130 and WO2010/007395 , the contents of all of which are incorporated herein by reference.

In embodiments, the auto-injector is provided with child-resistant features to prevent undesirable actuation of the actuating mechanism by a young child.

In embodiments, the auto-injector is provided with a visual indicator that is arranged to provide the user with a visual indication of the temperature state of the auto-injector, and particularly of the syringe and its contents (i.e. the liquid drug formulation), which at least allows the user to differentiate between a 'too cold to use' state and a 'sufficiently warm to use' state. Such visual indicators are described in Applicant's co-pending PCT patent application no. WO2008/146,021, which claims priority from UK patent application no. 0710433.4 filed on 31 ^st May 2007, the contents of both of which are incorporated herein by reference.

In embodiments, the syringe of the auto-injector herein contains a liquid drug formulation, which is designed for refrigerated rest (e.g. at from 2-8°C) and for injected delivery at room temperature (e.g. at or about 18-30°C). In embodiments, the viscosity of the liquid drug formulation is less than 120 mPa.s (120 centipoise), preferably less than 100 mPa.s (100 centipoise) at a delivery temperature of 20⁰C. Applicant has appreciated that the concept of using a ring comprised of a (e.g. resiliently) flexible material such as a plastic polymer or natural or synthetic rubber material as a barrier surface is more generally applicable.

Thus, the auto-injector may comprise a needle cover defining a needle sheath arranged in a rest configuration for sealing of said needle tip; and a flexible ring element, wherein in a use configuration said ring provides a barrier surface for obstructing exit of the syringe barrel therefrom, with the proviso that the ring is not provided to the housing.

Unlike previously described embodiments, the ring is typically not provided (e.g. directly) to the housing. That is to say, the ring does not fix or attach to the housing or is not provided as an integral part thereof. The ring is comprised of a (e.g. resiliently) flexible material such as a plastic polymer or natural or synthetic rubber material, and is embodiments of O -ring form.

In embodiments, the ring is provided to the auto-injector such that in the rest configuration, the ring contacts the needle cover to restrict movement thereof, and wherein in a use configuration the needle cover is removed from the needle tip such that the ring extends into the housing cavity to provide a barrier surface for obstructing exit of the syringe barrel therefrom.

In embodiments, the needle barrel is provided with a barrel sleeve that is arranged to fit over part or all of the length of the needle barrel, and the ring is provided to that sleeve (e.g. by attaching or fixing thereto or as an integral part thereof). In these embodiments, the ring (e.g. an O -ring) is generally provided to an inner wall of the (cylindrical) barrel sleeve such that the outer ring circumference thereof attaches to the inner wall of the barrel sleeve. The barrel sleeve may also extend out beyond the syringe barrel to wholly or partly enclose a length of the end -shoulder of the syringe barrel and of the hollow needle that extends from (the end-shoulder) of the syringe barrel.

In embodiments, the ring is provided to a forward part of the barrel sleeve (e.g. corresponding to a part that extends out beyond the syringe barrel). In embodiments thereof, in the rest configuration, the inner ring circumference contacts the needle cover (e.g. the needle sheath or a needle sheath cover provided thereto) and is somewhat compressed inwards as a result of that contact, the effect of which is to restrict movement of the needle cover. In the use configuration, the needle cover is removed, and in the absence of compressive contact with the needle cover, the ring expands outwards into the housing cavity to provide a barrier surface, which acts such as to obstruct the exit of the syringe barrel from the barrel sleeve, and preferably hence also from the housing cavity. Preferably, the ring provides the only such barrier surface and the barrel sleeve is not provided with any other barrier surface-providing elements such as flexible fingers or flanges. Preferably, the diameter of the uncompressed inner ring circumference of the ring is less than that of the syringe barrel such that when the ring is in its uncompressed state the syringe barrel may not pass through the ring.

According to another aspect of the present invention there is provided an auto- injector comprising

a barrel for containing a volume of a liquid drug formulation;

a hollow needle at a front end of said barrel, said hollow needle defining a needle tip for dispensing of said liquid drug formulation; and a plunger that is axially movable within the barrel,

a source of axial drive;

a drive transfer element for transferring said axial drive;

a movable needle shroud element;

a first coupling for coupling said drive transfer element to said syringe barrel of the syringe, wherein said first coupling is a reversible coupling arranged for decoupling when the syringe moves to the use position;

a second coupling for coupling the drive transfer element to the plunger of the syringe; and

a third coupling for coupling the movable shroud element to the source of axial drive, wherein said third coupling is a reversible coupling arranged for coupling when the plunger moves to a fully plunged position within the syringe barrel.

In embodiments, the second coupling is a reversible coupling arranged for decoupling when the plunger moves to a fully plunged position within the syringe barrel.

In embodiments, any or all of the first, second and third couplings are comprised within a common coupling element. In embodiments, the first coupling is a friction clutch coupling arranged for decoupling by declutching thereof when the syringe moves to the use position.

According to a further aspect of the present invention there is provided a kit of parts comprising an auto-injector as described above; and a syringe containing a liquid drug formulation.

According to a further aspect of the present invention there is provided a kit of parts comprising an auto-injector as described above; and packaging therefor; and optionally a syringe containing a liquid drug formulation.

Suitable packaging typically comprises a container for the auto-injector and syringe. In embodiments, the packaging comprises a compartment for the auto- injector pre-loaded with the syringe. In embodiments, the packaging comprises a separate compartment for a 'kit' of the auto -injector and the syringe.

The invention will now be described further with reference to the accompanying drawings in which:

Figure 1 is a perspective view of an auto-injector herein in the 'at rest' position with removable cap thereof in docked receipt by the outer housing thereof;

Figure 2 is a sectional cut-away view in perspective of the auto-injector of Figure 1 also in the 'at rest¹ position;

Figure 3 is a perspective view of the auto-injector of Figure 1 in the 'at rest' position with removable cap thereof now removed from the outer housing thereof; Figure 4 is a sectional cut-away view in perspective of the removable cap of the auto-injector of Figure 1;

Figure 5 is a perspective view of the cage-like needle cover gripping part of the removable cap of Figure 4;

Figures 6a and 6b show perspective views of the auto-injector of Figure 1 with outer housing removed and showing an inner housing assembly of front cylinder and rear inner housing sleeve as shown in the 'at rest' and 'end of use' positions respectively;

Figure 7 is a perspective view of the front cylinder of the inner housing assembly of Figures 6a and 6b;

Figure 8 is a perspective view of the rear inner housing sleeve of the inner housing assembly of Figures 6a and 6b;

Figure 9 is a sectional cut-away view in perspective of the rear inner housing sleeve of Figure 8 shown rotated by about 120° from the configuration of Figure 8;

Figure 10 is a perspective view of the syringe barrel sleeve ('syringe carriage') of the auto-injector of Figures 1 and 2;

Figure 11a is a sectional view and Figure 11b a perspective view of the plunger rod assembly of the auto-injector of Figures 1 and 2;

Figure 12 is a perspective cut away view of the inner plunger rod of the plunger rod assembly of Figures 11a and 11b; Figures 13a to 3d respectively show perspective; sectional cut-away in perspective; side; and end-on views of the follower shuttle part of the auto- injector of Figures 1 and 2;

Figures 14a to 14f show sectional cut-away views in perspective of the auto- injector of Figure 1 during sequential use steps thereof;

Figure 15 shows in a sectional cut-away view in perspective the plunger drive sub assembly of the auto-injector of Figures 1 and 2 shown in the 'at rest' position, which sub assembly comprises the rear inner housing sleeve of

Figures 8 and 9; the plunger drive sub assembly of Figures 11a and 11b; and a plunger rod follower (with drive spring hidden for clarity of view);

Figure 16 shows in a sectional cut-away view in perspective detail of the relationship between the rear end of the plunger sub assembly and th e plunger rod follower of the plunger drive sub assembly of Figure 15;

Figure 17 shows in a sectional cut-away view in perspective detail of the relationship between the front end of the plunger sub assembly and the rear inner housing sleeve of the plunger drive sub assembly of Figure 15;

Figures 18a to 18d show sectional cut-away views in perspective of the plunger drive sub assembly of Figure 15 during sequential use steps thereof on actuation of the auto-injector of Figures 1 and 2, wherein all these figures are shown with the drive spring hidden for clarity of view;

Figure 19 is a perspective view of a modified syringe barrel sleeve ('syringe carriage') for use with a modified version of the auto-injector of Figures 1 and 2; Figure 20 shows a perspective view of a modified version of the auto-injector of Figure 1 with outer housing removed and showing a modified inner housing assembly of front cylinder and rear inner housing sleeve as shown in the 'end of use' position;

Figure 21 is a perspective view of the modified front cylinder of the modified inner housing assembly of Figure 20;

Figure 22 is a cross-sectional view of a detail of a modified auto -injector incorporating the modified syringe barrel sleeve of Figure 19 and modified inner housing assembly of Figure 20, as shown in the 'end of use' position;

Figure 23 is a perspective view of a modified inner plunger rod suitable for use with the plunger rod assembly of Figures 11a and 11b;

Figure 24 is a perspective view of a detail of the modified inner plunger rod of Figure 23;

Figures 25a to 25e show sectional views of a modified auto-injector incorporating the inner plunger rod part of Figures 23 and 24 during sequential use steps thereof;

Referring now to the drawings, Figures 1 and 2 show a first auto-injector device 1 herein that is arranged for use with a syringe 10 that contains a liquid drug formulation 5. The auto-injector device 1 comprises a generally cylindrical form outer housing 20 that is arranged for receipt of the syringe 10 a nd is sized and shaped for this purpose. Release trigger 48 may be seen to protrude from the rear of the outer housing 20. The device 1 is provided with a removable cap 60 that is shown in the capped position. Figure 3 shows the auto-injector device 1 with the cap 60 removed, which cap 60 is shown separately and in more detail in Figure 4.

The syringe 10 comprises a barrel 12 for holding the liquid drug formulation 5; a hollow needle 14 at one end of the barrel 12; and a syringe plunger 18 in the form of a rubber stopper 18 that is arranged for axial movement (e.g. in response to plunging motion of plunger rod assembly 70) within the barrel 12 such as to enable the liquid drug formulation 5 to be expelled through the hollow needle 14. The hollow needle 14 defines a needle bore, which is of circular cross-section (e.g. 23G, 25G or 27G bore diameter) and a needle tip 15.

The outer housing 20 of the auto-injector device 1 is arranged to receive an inner housing assembly (shown at Figure 6) comprising front cylinder 30 (shown in more detail at Figure 7) and rear inner housing sleeve 40 (shown in more detail at Figures 8 and 9), which in combination define an inner housing cavity within which the syringe 10 and its syringe barrel sleeve are received. In more detail, the inner housing assembly of the auto-injector defines a needle receiving cavity 22, barrel receiving cavity 23 and plunger receiving cavity 24. The needle receiving cavity 22 is provided with a needle delivery aperture 25 through which in use, the hollow needle 14 of the syringe 10 may protrude from the inner housing assembly. It may be seen that the inner wall 26 of needle receiving cavity 22 of the front cylinder 30 steps inwardly to define a needle delivery aperture 25 of reduced diameter compared to the diameter of the needle receiving cavity 22.

Referring now in particular to Figures 2 to 4, the removable cap 60 may be appreciated to function such as to close off, the needle delivery aperture 25 (i.e. as shown at Figure 1). Projecting into the cap 60 interior, from the top inner surface 61 thereof, there is provided a cage-like needle sheath gripper 62 (shown in detail at Figure 5) that at its forward end projects away from the top inner surface 61 of the cap 60 and towards its rear end defines h ooks 64 arranged for gripped receipt of the needle sheath 17. In the 'at rest' position of Figure 2, the needle sheath 17, which typically comprises a natural or synthetic rubber, may be seen to sheathe the needle tip 15 of hollow needle 14 to provide a hygienic seal thereat. In turn, the hooks 64 of the needle sheath gripper 62 act such as to grip the outer part of the needle sheath 17, thereby maintaining the sheath 17 in close proximity with the needle 14 and its sheathed tip 15 when the cap 60 is in the capped position. The needle sheath 17 is also provided with a sheath shell (e.g. of polypropylene), one purpose of which is to add rigidity and to reduce the tendency of the needle sheath 17 to flex away from the axis defined by the needle 14, and /or a polypropylene end ring, which comprises an integral moulded part of needle sheath shell and which assists in maintaining rigidity of the rear end portion thereof. Other needle sheath 17 and needle sheath gripper 62 arrangements are disclosed in Applicant's co-pending PCT publication no. WO2009/081103 the entire contents of which are incorporated herein by reference.

It may also be seen that the needle receiving cavity part 22 of the front cylinder 30 is provided close to the stepped inner wall 26 thereof with a flexible element in the form of an O-ring 80 comprised of a plastic polymer or natural or synthetic rubber material. An outer ring circumference of that O -ring 80 attaches to the inner wall of the front cylinder 30. In the 'at rest' configuration of Figures 2 and 14a, the inner ring circumference 82 thereof contacts the rigid central boss 63 of the cap needle sheath gripper 62 and is somewhat compressed (i.e. tensed) as a result of that contact. The rigid central boss 63 also acts such as to direct t he hooks 64 of the gripper 62 into the needle sheath 17 to thereby restrict movement of the needle sheath 17. Other suitable cap arrangements are disclosed in Applicant's co-pending PCT publication no. WO2010/007395, the entire contents of which are incorporated herein by reference. In the 'ready for use' configuration of Figure 14b, the cap 60 and gripped needle sheath 17 are removed to open up the needle delivery aperture 25. In the absence of compressive contact with the needle sheath gripper 62 and needle sheath 17, the O-ring 80 expands outwards into the needle receiving cavity 22 to provide a barrier surface 83 at its syringe-facing wall. The barrier surface 83 may thus, act such as to obstruct the exit of the syringe barrel 12 from the front cylinder 30. This barrier function is assisted by the fact that the diameter of the uncompressed inner ring circumference 82 of the O-ring 80 is less than the diameter of the syringe barrel 12 such that the syringe barrel 12 is unable to pass through the uncompressed O-ring 80. In the event of fracture of the syringe 10, the O-ring 80 thus, acts to obstruct passage of any syringe 10 fragments through the needle delivery aperture 25, and thereby protects the patient from harm.

For ease of assembly the flexible O-ring element 80 of the first auto-injector device 1 is arranged such that during a capping operation when needle sheath gripper 62 and gripped needle sheath 17 are inserted into the front cylinder 30 for sheathing of the needle tip 15, the central boss 63 of the cap 60 interacts with the flexible O-ring element 80 such that this flexes (or compresses) towards the inner wall of the front cylinder 30. On completion of that insertion step (i.e. in the rest configuration) the flexible O-ring element 80 is thus, in a somewhat tensed state. Conversely, on removal of the cap 60 and gripped needle sheath 17 during a use operation the flexible O-ring element 80 flexes (or compresses) away from the inner wall of the front cylinder 30 and thus further into the cavity defined thereby. Other O-ring barrier arrangements are disclosed in Applicant's co-pending PCT publication no. WO2009/081133, the entire contents of which are incorporated herein by reference.

Further details of the inner housing assembly may be seen by refe rence to Figures 6 to 9. Front cylinder 30 may be seen to be provided with forward radially spaced tabs 32; central radially spaced tabs 34; rear radially spaced tabs 36; and rear radially spaced notches 38. Rear inner housing sleeve 40 may be seen to be provided with radially spaced axial slots 42; central radially spaced latch arms 44 with inner facing latch ramps 45; and track arrangement comprising forward straight track 46, curved track 47 and rearward straight track 48.

As will be described in more detail hereinafter, in the 'at rest' position of Figure 6a (also corresponding to Figure 14a), ramps 45 of the radially spaced latch arms 44 of the rear inner housing sleeve latchingly engage in radially spaced notches 38 of the front cylinder. In addition, rear radially spaced notches 36 of the front cylinder are received within, and to the rearwards part of, the radially spaced axial slots 42 of the inner housing sleeve. In the 'end of use' position of Figure 6b (also corresponding to Figure 14f), ramps 45 of the radially spaced latch arms 44 of the rear inner housing sleeve have disengaged from the radially spaced notches 38 of the front cylinder. The outer cylinder 30 has then been displaced somewhat forwards relative to the rear inner housing sleeve 40. The rear radially spaced notches 36 of the front cylinder are still received within, but now rest against the forwards part of, the radially spaced axial slots 42 of the inner housing sleeve 40, thereby restricting absolute detachment of the forward ly-displaced front cylinder 30 from the inner housing sleeve 40.

As may be seen in Figure 9, rear housing sleeve 40 is further provided with boss 50 at the rear end thereof, which inner boss walls 51 define a cylindrical passage arranged for receipt of the rear end of the plunger rod assembly 70, as described in more detail hereinafter.

Figure 10 shows details of the barrel sleeve 35, which has front 39 and rear flanges 37 provided thereto. As may be seen in Figure 2, the barrel sleeve 35 is received within the front cylinder 30 at a position corresponding to the barrel receiving part 23 thereof. The barrel sleeve 30 is cylindrical and arranged for receipt of the syringe barrel 12, wherein an end circular barrel lip 13 of the syringe barrel 12 seats against the rear flange 37. In embodiments, the barrel lip 13 may be of truncated circular or other suitable form. As is described in more detail hereinafter, during actuation (e.g. see Figure 14d) the syringe barrel sleeve 35, syringe barrel 12 and needle 14 move axially forward such that the barrel sleeve 35 seats up against the O-ring 80 and the tip 15 of the needle 14 protrudes out through the delivery aperture 25 of the needle -receiving part 22 of the housing 20 to enable the liquid drug formulation 5 to be del ivered by injection to a patient.

The syringe barrel 12 is provided with a rubber plunger 18, which connects to the plunger rod assembly 70, which is now described in more detail by reference to Figures 11 to 13. It may be appreciated that in general terms, actuation of the syringe 10 occurs in response to plunging of the plunger rod assembly 70 against the rubber plunger 18, thereby plunging both of these parts 70, 18 into the barrel 12 of the syringe 10, which causes the liquid drug formulation 5 to be expelled through the tip 15 of the hollow needle 14.

As may be seen at Figures 11a and 11b, the plunger rod assembly 70 comprises an outer plunger rod 72, the forward conically tapering end 71 of which seats up against the syringe plunger 18; and an inner plunger rod 75 (shown at Figure 12). The outer plunger rod 72 is thus, essentially an outer cylinder within which the inner plunger rod 75 locates. The outer plunger rod 72 is provided with a track arrangement comprising first 73a and second 73b parallel, but displaced track sections separated by perpendicular link section 74. The track arrangement 73a, 73b, 74 is arranged for receipt of inner follower pegs 94 of follower shuttle 90, which will be described in more detail hereinafter. The forward end 76 of the inner plunger rod is threaded for receipt within the threaded inner cavity 19 of the syringe plunger 18. The mid -rift part of the inner plunger rod defines a relatively narrow waist 77 section to allow for receipt of the inner follower pegs 92 of the follower shuttle 90 by the track arrangement 73a, 73b, 74 of the outer plunger rod 72. The rear part of the inner plunger rod 75 is provided with a slot 78 for the receipt of release trigger 48 and an embedded O- ring 79 (typically housed within a groove).

Figures 23 and 24 show a slightly modified version 175 of the inner plunger rod 75 that comprises separable forward 165 and rear 167 inner rod parts. This modification provides a rotational degree of freedom so that the rear part 167 can be oriented and positioned with respect to the inner housing sleeve 40, plunger rod sleeve 72 and follower 94 of the drive shuttle 90 without the need to rotate the plunger 18 in the syringe 10. This is achieved with a simple snap fit between mating end parts 166, 168 of the respective parts 165, 167. Once enclosed (i.e. in situ) within the plunger rod sleeve the female mating parts 166 of the forward inner rod part 165 are confined and cannot slip off. The modified inner plunger rod 175 is further provided with an incomplete band of material 169 against which the inner follower pegs 94 of the follower can be braced to restrict the movement in use, and also to an extent during storage, of the outer plunger rod 72.

Figures 13a to 13d show details of the follower shuttle 90, which defines an essentially cylindrical form provided at its front with end wall 95 having central aperture 96 defined therein and arranged for receipt of the plunger rod assembly 70. The outer wall of the cylinder 90 is provided with a pair of outer follower pegs 92 locating diametrically opposite each other. The central aperture 96 is provided with a pair of inner follower pegs 94 also locating diametrically opposite each other.

Figures 15 and 16 show details of how the plunger rod assembly 70 and follower shuttle 90 are received within the inner housing sleeve 40 in the 'at rest' position of the device 1. For clarity, these Figures do not show drive spring 55 (e.g. as shown in Figure 2). It is also noted that due to the orientation of these views, the follower pegs 92, 94 of the follower shuttle 90 are not visible.

Thus, follower shuttle 90 is received within the rearwards section of the inner housing sleeve 40. The outer follower pegs 92 (not visible) thereof locate within the rear straight part 48 of the track section of the inner housing sleeve 40. The inner follower pegs 94 (also not visible) thereof locate within the first, rearward part 73a of the track section of the outer plunger rod 72. Rear end of the plunger rod assembly 70 is received within the cylindrical passage 51 defined by the boss 50 at rear end 49 of the rear housing sleeve 40. The slot 78 at the rear end of the inner plunger rod 75 protrudes from the boss 50 to allow for receipt of the release trigger 48 (not shown in Figure 15, but see Figure 2). Embedded O-ring 79 also at the rear part of the inner plunger rod 75 seats up against inner wall 51 of the boss 50 and frictionally engages therewith. Figure 17 shows in detail how the forward end 76 of the inner plunger rod is threaded for receipt within the threaded inner cavity 19 of the syringe plunger 18.

Referring now also to Figures 14a to 14f, the actuating mechanism of the auto- injector device 1 comprises a strong drive compression spring 55 that fits within follower shuttle 90 around the rear end of the plunger rod assembly 70 and boss 50 at end of the rear housing sleeve 40. The forward end of the spring 55 seats against the forward end wall 91 of the follower shuttle 90 and the rearward end of the spring 55 seats against rear end wall 49 of the inner sleeve housing 40. In the 'at rest' position of Figure 14a, the inner plunger rod 75 is firmly held by the trigger release 48, thereby preventing any forward movement of the plunger rod assembly 70 and follower shuttle 90 coupled thereto.

In an aspect of detail, it will be noted that although the inner plunger rod 75 is restrained firmly by the trigger release 48, the outer plunger rod 72 is unrestrained except for the indirect restraint on it through the rubber plunger 18 itself. This inevitably means that the spring 55 is always pushing and squeezing the rubber plunger 18, even prior to release of the trigger 48. This may help provide a tight seal and for a low strength spring 55 may well be advantageous. When the cap 60 is on, the detent tabs prevent the syringe advancing, however if the device 1 has a strong spring 55, after cap 60 removal there is a risk that the outer plunger rod 72 may push the plunger 18 out of threaded engagement with the inner plunger rod and thereby, start an uncontrolled premature injection. There are two ways in which this may be avoided. Firstly the rear end of the plunger rod assembly 70 can be modified so that the outer plunger rod 72 is also restrained by the trigger release 48. Alternatively, the inner plunger rod 75 can have the modified form 175 as shown at Figures 23 and 24, in which a band of material 169 is provided at a point that lies in use one mm or so in front of the inner follower pegs 94 which would prevent excessive movement of the outer plunger rod 72 with respect to the inner plunger rod 175. This band of material 169 is arranged to have a gap aligned with the outer plunger rod tracks 73a, 73b 74 for the inner follower pegs 94 to move through on the decouple stroke.

Further aspects of the first auto-injector device 1 herein may now be appreciated by reference to Figures 14a to 14f; and Figures 18a to 18d, which show key parts of the device assembly; and to the following description of a typical use operation. For clarity, only the parts of Figures 14b to 14f; and 18a to 18d most relevant to the use operation being described are labelled.

In a first stage of a typical use operation, the device 1 'at rest' (e.g. as shown in Figures 2 and 14a) is taken and the cap 60 is removed to uncover the needle delivery aperture 25 as shown at Figure 14b. Once uncapped, as shown at Figure 14c, in the absence of the needle sheath gripper 62 and needle sheath 17, the O-ring 80 expands into the needle receiving cavity 22 to provide a barrier surface 83 as previously described. Prior to and during cap 60 removal, the forward radially spaced tabs 32 of the inner cylinder 30 are sprung inwards and interact with the front flange 39 of the syringe barrel sleeve 35 to thereby prevent forward movement of the syringe 10 during cap removal, which may otherwise cause the plunger 18 to be dislodged from the syringe barrel 12 spilling its contents.

Referring now to Figures 14d and 18b, in a second use stage, the trigger 48 is released by decoupling from the rear notch 78 of the inner plunger rod 75. Under the action of the drive spring 55 the outer plunger rod 72 pushes against the plunger 18 in the syringe 10, but is resisted by the inner plunger rod 75, the motion forward of which is retarded by the friction of the embedded O-ring 79 in the boss 50 in the inner housing sleeve 40. This results in squeezing the plunger 18 as it experiences shear forces due to the inner plunger rod 75 via the threaded end 76, and the outer plunger rod 72 pressing against the rear surface thereof. The conical tapering 71 of the outer plunger rod 72 squeezes (i.e. distorts) the plunger 18 radially against the syringe barrel 12 and the resulting high friction 'clutching' between syringe barrel 12 and plunger 18 prevents relative movement of the two with the result that the entire syringe 10 with needle 14 and its contents are advanced forward to the 'ready to inject' position of Figure 14d, in which the needle tip 15 of the syringe protrudes from the needle delivery aperture 25. Since the plunger 18 is prevented moving forward within the syringe barrel 12, no fluid 5 is expelled during this syringe advancement step.

In the 'ready to inject' position, the end-shoulder 11 of the syringe 10 seats up against the syringe-facing wall 83 of the O-ring 80, thereby acting to somewhat compress (e.g. 'squash') the O-ring 80 which thus, tends to flex inwards e.g. to block/grip the syringe 10. In alternative embodiments, a forward end of the syringe barrel sleeve 35 seats up against the syringe-facing wall 83 of the O-ring 80 in this position, which again acts such as to somewhat compress (e.g. 'squash') the O-ring 80 which thus, tends to flex inwards e.g. to block/grip the syringe 10. The syringe barrel sleeve 35 may thus, be provided with shaped end-features (e.g. lip or flange form) that facilitate this seating up against the O - ring 80 and compression thereof.

In a third use stage, the embedded O-ring 79 of the inner plunger rod 75 emerges from the boss 50 of the inner-housing sleeve. As a result, the opposing forces on the plunger 18 are relaxed and the frictional force between the plunger 18 and syringe barrel 12 is reduced (i.e. 'friction un-clutching'), thus enabling the plunger 18 to slide down the syringe barrel 12, expelling the fluid contents thereof. As shown in Figures 14e and 18e, as the end of the injection stroke is reached, the follower shuttle 90 begins to rotate due to the outer follower pegs 92 entering the curved section 47 of the track arrangement of the inner housing sleeve 40. In turn, this causes the inner follower pegs 94 to rotate in their track 73a, 74 in the outer plunger rod 72, causing the follower shuttle 90 and outer- plunger rod 72 to decouple. As a result of this decoupling, the spring 55 can no longer exert drive force on the outer plunger rod 72. However, the spring 55 continues to exert drive force on the follower shuttle 90 which moves forward to engage with ramps 45 of radially spaced latch arms 44 of the rear inner housing sleeve. This results in unlatching of the latch arms 44 from the notches 38 of the front cylinder. Under the continuing influence of the spring 55, the follower 90 pushes the now unlatched front cylinder 30 forwards relative to the inner housing sleeve to the 'end of use' position of Figures 14f and 18d, in which the forward end 31 of the front cylinder 30 is advanced over the syringe 10 to shroud the needle tip 15 thereof.

In this 'end of use' position, the front cylinder 30 has been advanced to a stop point, in which the rear radially spaced notches 36 of the front cylinder locate at the furthest forward extent within the axial slots 42 of the inner housing (as shown at Figure 6b). Also at this stop point, central radially spaced tabs 34 on the front cylinder 30 spring out and lock the front cylinder 30 in its 'at rest' position. In this 'locking position' it will be appreciated that syringe 10 is also locked such that the needle tip 15 does not protrude from the needle delivery aperture 25, but rather is safely shrouded away. Other 'end of use' locking arrangements are disclosed in Applicant's co-pending PCT publication no. WO2009/081103, the entire contents of which are incorporated herein by reference.

An alternative locking arrangement may be achieved by use of a slightly modified version of the syringe barrel sleeve 135 as shown in Figure 19; front cylinder 130 as shown in Figures 20 and 21; and inner housing sleeve 140 as shown in Figure 20. Other than the modifications described below these modified parts 130, 135, 140 are identical to those previously described for the first auto-injector device 1 and these modified parts 130, 135, 140 may thus, be incorporated in that device 1 without further modification thereof.

Thus, in more detail the modified syringe barrel sleeve 135 of Figure 19 is provided at its rear 137 flange with pair of diametrically oppositely located trailing latch arms 185, each with latch ramp 187. The inner housing sleeve 140 of Figure 20 is provided with an additional latch slot 141, which is sized, shaped and located for receipt of end latch ramp 187 of the modified barrel sleeve 135. The modified front cylinder of Figures 20 and 21 is provided with a cut out latch slot 133, which is also sized, shaped and located for receipt of end latch ramp 187 of the modified barrel sleeve 135. It will appreciated that in the assembly of Figure 20, the latch slots 133, 141 of the modified front cylinder 130 and modified inner housing sleeve 140 rest co-axially with each other, both receiving the end latch ramp 187 of the modified barrel sleeve, which thus couples these parts 130, 140 together and acts to restrict their axial motion relative to each other. All other aspects of the modified barrel sleeve 135, front cylinder 130 and inner housing sleeve 140 correspond to their earlier described unmodified parts 35, 30, 40 and are thus, not described in more detail. Figures 21 and 22 show in more detail the locking interrelationship of the modified parts 135, 130, 140 in the 'end of use' position of the auto -injector device 1 (also generally corresponding to Figures 14f and 18d). In this position, the front cylinder 130 has been advanced relative to the inner housing sleeve 140 and locked into its needle shrouding position, as previously described. Also in this position, end latch ramps 187 of the latch arms 185 of the modified barrel sleeve 135 abut up against the forward wall of the latch slot 141 of the modified inner housing sleeve 140. Further, front wall 95 of shuttle 90 also abuts tip 188 of each latch arm 187. Thus overall, the modified barrel sleeve 135, and hence the syringe 10 carried thereby, is held in restrained relationship with modified inner housing 140 and shuttle 90 such as to prevent any further forward movement thereof. The syringe 10 is thus, effectively prevented from advancing out from its shrouded position, thereby removing any danger of possible inadvertent contact of the used needle 14, 15 with a user.

Figures 25a to 25e show sectional views of a modified auto-injector device 101 incorporating the modified inner plunger rod of Figures 23 and 24 during sequential use steps thereof. It will be appreciated that these views correspond roughly to the configurations shown at Figures 14a, 14c, 14d, 14e and 14f for the unmodified device 1. Other than using the plunger rod parts of Figures 23 and 24, this modified device 101 generally corresponds in form, features and usage mode to those of the unmodified device 1 , and for succinctness fuller description of its use is therefore not provided.

The auto-injector of the invention is suitable for the injected delivery of drug, particularly for the treatment and/or prophylaxis of a number of diseases, disorders or conditions, including infections (viral, e.g. HIV infection, bacterial, fungal and parasitic); endotoxic shock associated with infection; inflammatory diseases/autoimmunity such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), ankylosing spondilitis, COPD, asthma, Alzheimer's Disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome and psoriasis; immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barr syndrome; graft-versus-host disease; organ transplant rejection; pain; cancer (including solid tumours such as melanomas, hepatoblastomas, sarcomas, squamous cell carcinomas, transitional cell cancers, ovarian cancers and hematologic malignancies, acute myelogenous leukaemia, chronic myelogenous leukemia, gastric cancer and colon cancer); congenital disorders, e.g. cystic fibrosis and sickle cell anaemia; growth disorders; epilepsy; treatment of infertility; heart disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis and intravascular coagulation; bone disorders such as osteopenia and osteoporosis; and metabolic/idiopathic disease, e.g. diabetes.

Appropriate drugs may thus be selected from biologically active agents, including chemical entities, polysaccharides, steroids and, especially, naturally occurring and recombinant proteins, including glycoproteins, polypeptides and oligopeptides and polymeric derivatives thereof. Particular proteins, polypeptides and oligopeptides include hormones, such as insulin, epinephrine, norepinephrine, adrenocorticotrophin, somatotropin, erythropoietin and oxytocin; cytokines, such as lymphokines, chemokines and interleukins and receptors therefor, e.g. interleukin (IL)-I α , IL-1β, IL-1R, IL-2, IL-3, IL-4, IL-5, IL-6, IL-13, IL17, interferon (IFN)-α, IFN-β, IFN-γ, granulocyte monocyte colony stimulating factor, tumour necrosis factor-α; growth factors, such as nerve growth factor and platelet-derived growth factor; enzymes, such as tissue plasminogen activator; and, especially, immunoglobulins. Immunoglobulins include whole antibodies and functionally active fragments and/or derivatives thereof, for example polyclonal, monoclonal, recombinant, multi-valent, mono- or multi-specific, humanised or chimeric antibodies, single chain antibodies, Fab fragments, Fab" and F(ab')₂ fragments. Polymeric derivatives of such proteins, polypeptides and oligopeptides include derivatives formed between the protein, polypeptide or oligopeptide and a naturally occurring or synthetic polymer, e.g. a polysaccharide or a polyalylklene polymer such as a poly(ethyleneglycol) [PEG] or derivative thereof, e.g. methoxypoly(ethyleneglycol) [mPEG]. Particular agents include growth hormones and hormones for the treatment of infertility. Other particular agents are for the treatment of epilepsy such as brivaracetam and seletracetam.

The auto-injector device herein has been found to be of particular utility where the drug is an immunoglobulin or a fragment thereof, especially a PEGylated or mPEGylated antibody fragment.

The liquid drug formulations herein are typically aqueous formulations, which comprise the drug in solution and additionally other optional formulation components, which may include buffers (e.g. lactate, acetate), NaCI, and pH modifiers (e.g. NaOH).

The auto-injector device herein has been found to be of particular utility wherein the concentration of the drug (e.g. a therapeutic biologic type drug) in the liquid drug formulation is quite high. In particular, where the drug is a pegylated antibody the auto-injector device has been found to be of particular utility wherein the concentration of the drug is greater than 100mg/ml, particularly greater than 150mg/ml such as 200mg/ml.

It will be understood that the present disclosure is for the purpose of illustration only and the invention extends to modifications, variations and improvements thereto. The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described therein. They may take the form of product, method or use claims and may include, by way of example and without limitation, one or more of the following claims:

Claims

1. An auto-injector comprising

a barrel for containing a volume of a liquid drug formulation;

a plunger that is axially movable within the barrel,

a drive transfer element for transferring axial drive; and

a first coupling for coupling said drive transfer element to said syringe barrel of the syringe;

2. An auto-injector according to claim 1 , wherein the drive transfer element is arranged to transfer axial drive to the syringe barrel via the plunger of the syringe and the friction clutch coupling acts to vary the frictional coupling contact between the plunger of the syringe and the syringe barrel.

3. An auto-injector according to either of claims 1 or 2, wherein the friction clutch coupling comprises a shape modifier element for modifying the shape of the syringe plunger, thereby affecting the degree of frictional contact thereof with the syringe barrel.

4. An auto-injector according to any of claims 1 to 3, wherein the drive transfer element comprises a syringe plunger rod, which interacts with the plunger of the syringe, and the shape modifier element is provided to said syringe plunger rod.

5. An auto-injector according to claim 4, wherein said shape modifier element comprises a movable plunger rod sleeve provided to the syringe plunger rod.

6. An auto-injector according to either of claims 4 or 5, wherein a damping element is provided such that initial movement of the plunger rod is damped relative to movement of the plunger rod sleeve such that opposing frictional forces are initially established therebetween.

7. An auto-injector according to claim 6, wherein said damping element is provided between the plunger rod and part of the housing.

8. An auto-injector according to claim 7, wherein the damping element comprises an O-ring provided between the plunger rod and a boss provided to the housing, thereby providing a damping relationship therebetween.

9. An auto-injector according to any of claims 2 to 8, wherein the syringe plunger comprises a frictional material arranged for frictional interaction with the side wall of the syringe barrel.

10. An auto-injector according to claim 9, wherein said friction material is compressible in nature.

11. An auto-injector according to either of claims 9 or 10, wherein the syringe plunger comprises a natural or synthetic rubber polymer material.

12. An auto-injector according to any of claims 1 to 11 additionally comprising a drive shuttle element arranged for receipt of axial drive and in reversible coupling relationship with the drive transfer element.

13. An auto-injector according to claim 12, wherein the drive shuttle element has an axially symmetric form.

14. An auto-injector according to claim 13, wherein the drive shuttle has a cylindrical form and the drive transfer element is received within said cylindrical form.

15. An auto-injector according to any of claims 12 to 14, wherein the drive shuttle element is provided with one or more followers (e.g. pegs or notches) arranged for track-follower receipt by one or more tracks (e.g. grooves or slots) of the drive transfer element, thereby reversibly coupling the movement of the drive transfer element to that of the driven shuttle.

16. An auto-injector according to claim 15, wherein the track-follower relationship is arranged such that when the plunger is in the fully plunged position within the syringe the drive shuttle decouples from the drive transfer element such that axial drive is no longer transferable

17. An auto-injector according to claim 16, wherein the track-follower relationship is arranged such that at said fully plunged position the drive shuttle rotates to enable decoupling thereof from the drive transfer element.

18. An auto-injector according to claim 17, wherein said rotation is guided by a curve provided to a second track-follower relationship between the drive shuttle and the housing.

19. An auto-injector according to any of claims 1 to 18 additionally comprising a movable shroud element.

20. An auto-injector according to claim 19, wherein said movable needle shroud element is arranged for receipt of axial drive by means of a reversible coupling arranged to come into coupling relationship only when the plunger moves to a fully plunged position within the syringe barrel.

21. An auto-injector according to any of claims 1 to 20 additionally comprising an energy store for storing energy that is releasable to provide the axial drive.

22. An auto-injector according to claim 21 , wherein said energy store comprises a drive spring.

23. An auto-injector according to claim 22, wherein the energy store comprises a container of compressed liquid or gas.

24. An auto-injector according to any of claims 1 to 23, wherein the housing receives a syringe containing a liquid drug formulation.

25. An auto-injector according to claim 24, wherein the barrel of said syringe has a volume corresponding to a single dose of said liquid drug formulation.

26. An auto-injector according to either of claims 24 or 25, wherein said liquid drug formulation is arranged for rest at from 2-8°C and for injected delivery at from 18-30⁰C.

27. An auto-injector according to claim 26, wherein the liquid drug formulation has a viscosity of less than 120 mPa.s at a delivery temperature of 20⁰C.

28. An auto-injector according to any of claims 24 to 27, wherein the liquid drug formulation comprises an aqueous formulation of a therapeutic biologic type drug.

29. An auto-injector according to claim 28, wherein said biologic type drug comprises an immunoglobulin or a fragment thereof.

30. An auto-injector according to claim 28, wherein said biologic type drug comprises a PEGylated or mPEGylated antibody fragment.

31. An auto-injector according to any of claims 28 to 30, wherein said aqueous formulation comprise additional formulation component selected from the group consisting of buffers, NaCI, and pH modifiers.

32. An auto-injector according to any of claims 28 to 31 , wherein the concentration of the drug in the liquid drug formulation is greater than 100mg/ml.

33. A kit of parts comprising an auto-injector according to any of claims 1 to 23; and a syringe containing a liquid drug formulation.

34. An auto-injector comprising

a barrel for containing a volume of a liquid drug formulation;

a plunger that is axially movable within the barrel,

a source of axial drive;

a drive transfer element for transferring said axial drive;

a movable needle shroud element; a first coupling for coupling said drive transfer element to said syringe barrel of the syringe, wherein said first coupling is a reversible coupling arranged for decoupling when the syringe moves to the use position;

35. An auto-injector device according to claim 34, wherein said second coupling is a reversible coupling arranged for decoupling when the plunger moves to a fully plunged position within the syringe barrel.

36. An auto-injector device according to either of claims 34 or 35, wherein any or all of the first, second and third couplings are comprised within a common coupling element.

37. An auto-injector device according to any of claims 34 to 36, wherein said first coupling is a friction clutch coupling arranged for decoupling by declutching thereof when the syringe moves to the use position.