The present invention relates to an injection device suitable for the delivery of a medicament to a patient. In particular, but not exclusively, the invention relates to an injection device comprising a mechanism for controlling the movement of a plunger assembly within the device.

Injection devices designed for automatic or semi-automatic delivery of a single predetermined dose of a medicament are known in the art. Such devices typically include a housing that allows the user to grip the device, a pre-filled syringe containing the medicament, and a firing mechanism. The pre-filled syringe includes a tubular glass barrel with a staked hypodermic needle at its distal end, a needle shield to shroud the needle, and a stopper slidably received in the barrel. The needle shield is typically of two-part construction, with an elastomeric inner part for receiving the needle and a rigid outer cap or cover, for example of polypropylene, which is attached to the inner part and can be gripped by a user to pull the shield off the needle. This shield arrangement is known in the art as a rigid needle shield (RNS). One or more radially- projecting flanges are provided on the proximal end of the syringe barrel, which can be used to retain the syringe in the device. One example of a pre-filled syringe with a rigid needle shield is available under the registered trade mark Hypak (Becton Dickinson, New Jersey, USA).

With the syringe in place in the housing of the device, the distal end of the housing is closed by a cap. To prepare the device for use, the cap is removed. The cap is arranged to grip the rigid needle shield, so that removal of the cap pulls the rigid needle shield off the needle. The distal end of the housing is then placed against the skin. When activated, a plunger of the firing mechanism pushes the stopper of the syringe distally towards the needle to inject the medicament. In some devices, known as auto-injectors, needle insertion is also automatic. In such devices, the needle is initially retracted in the housing and the firing mechanism also causes the syringe to move to advance the needle out of the housing and into the patient's skin before injection of the medicament. Examples of such devices are described in the Applicant's International Patent Application Publication No. WO 2012/049484 and UK Patent Application Publication No. GB 2516624.

As the use of injection devices has developed, the springs used to drive the firing mechanisms for actuating the devices have become more powerful. In some instances this has been driven by the use of finer needles or more viscous medicament compositions, which require the use of higher forces to expel the medicament. At the same time, more complex auto-injector mechanisms have also required the use of more powerful springs to drive both the advancement of the needle and the injection of the medicament.

One problem with the use of stronger drive springs is that it can lead to an unwanted noise or vibration when the driving mechanism is first actuated. That is, when the drive spring is released, it may generate sufficiently high impact forces on other components when they first engage so as to cause an audible sound and/or a recoil shock vibration. This can be uncomfortable for a patient. Furthermore, such forces also impose high stresses on the device's components and the medicament container itself, which can lead to component failure. This is particularly problematic in arrangements using glass syringes because such glass is relatively brittle.

It would therefore be desirable to provide an injection device that provides a reduced level of noise and/or vibration on actuation.

Against this background, and from a first aspect of the present invention, there is provided an injection device for injection of a medicament from a container having a container body for containing the medicament and a stopper for expelling medicament from the container, the device comprising: a housing for housing the container; a plunger assembly for moving the stopper; and a drive mechanism arranged to hold the plunger assembly in a starting position and activatable to deliver a drive force to the plunger assembly for moving the stopper in a distal direction for expelling the medicament; wherein the plunger assembly comprises a control element and an actuator moveable in the distal direction to apply the drive force to the stopper, the actuator being slidably coupled to the control element and moveable relative thereto, and wherein the movement of the actuator the distal direction is regulated by the control element. ln this way, the control element may be used to selectively dissipate some of the force applied by the drive mechanism to thereby control the rate of movement of the actuator during operation of the device. As such, even in instances where a very high drive force is applied to the actuator, the control element allows the application of this force to be regulated during selected phases of the operation of the device in order to reduce the dynamic loads applied to other components of the device by the actuator. For example, the actuator may be restrained by the control element in order to slow its acceleration immediately prior to it engaging with other components. For instance, the control element may reduce the impact applied when the stopper is first engaged. Equally, the rate of the actuator's initial acceleration may be retarded by the control means to reduce the initial shock when it is first released by the activation of the drive mechanism. The control element may thereby both reduce the impact forces applied to components of the device and dampen lateral movements of the components under high loads, which may otherwise cause adverse noises and vibrations. At the same time, because the movement of the actuator may be regulated selectively, higher spring forces may still be used to drive the plunger in the later stages of the operation of the device to allow for the injection of, for example, high viscosity drugs.

Preferably, the drive mechanism is activatable to move the actuator distally from a starting position through a drive stroke, wherein the control element regulates the movement of the actuator during at least part of the drive stroke.

In embodiments, the control element comprises a rod. In this way, the control element may extend axially through the interior of the housing and help guide movement of the actuator though its slidable coupling extending along the length of the rod.

Preferably, the drive mechanism comprises a spring for applying the drive force to the plunger assembly.

Preferably, the control element comprises an interface surface for applying a frictional retardation force to the actuator when the actuator is slidably moved over the interface surface by the drive force. In this way, the frictional forces dissipate some of the energy applied by the drive mechanism, thereby slowing the movement of the actuator.

In embodiments, the control element is slidably received within a bore of the actuator and the interface surface is engagable with a wall of the actuator defining the bore when the actuator is moved relative to the control element. In this way, the actuator is coupled around the control element and may slide distally down, with the cross sectional profile of the control element allowing the movement of the actuator to be regulated. That is, thicker and/or high friction sections of the control element may be used to slow the passage of the actuator by increasing the frictional forces generated between the interface surface and the wall of the actuator. Conversely, thinner and/or low friction sections may be used to allow the actuator to accelerate under the drive force.

In embodiments, the interface surface comprises one or more frictional elements for engaging with the actuator. In this way, the frictional elements may be provided as projections or spurs, or as series of O-rings on the control element for increasing the frictional forces applied to the actuator.

In embodiments, the interface surface comprises one or more relief formations. In this way, the relief formations may allow the interface surface to compress and deform for preventing the stalling of the actuator as it moves over the interface.

Preferably, the interface surface comprises rubber. This may provide a high friction surface for retarding movement of the actuator. The rubber may be provided over the body of the control element by, for example, an over-moulding or twin-shot process. Other materials for providing compressible or high friction surfaces may alternatively be used, such as a thermoplastic elastomer.

Preferably, the interface surface is profiled to vary the frictional retardation force applied to the actuator as the actuator slidably moves relative to the control element.

In embodiments, the control element comprises a latching formation releasably connected to the housing, and wherein, when the actuator is moved the distal direction by the drive mechanism, the actuator engages with the control element for disengaging the latching formation from the housing under a load applied by the drive force. In this way, the force required to delatch the control element may regulate the movement of the actuator the distal direction. That is, initially the relative movement between the actuator and the control element may allow the actuator to first accelerate, but at a predetermined position in during the operation of the device, the actuator engages with the control element to transfer a sufficient dynamic load to the releasable connection to detach the control element. In the process of overcoming the frictional and/or mechanical locking connecting the control element to the housing, the actuator is thereby slowed to regulate its movement.

Preferably, the latching formation is releasably connected to the housing by latch members and, when the actuator engages with the control element for disengaging the latching formation, the load applied by the actuator causes deformation of the latch members. In this way, the force required to deform the latch members dissipates energy from the drive mechanism, thereby slowing the actuator.

Preferably, the control element comprises an abutment engagable by the actuator for preventing further distal movement of the actuator relative to the control element, wherein engagement of the actuator and the abutment applies the load for disengaging the latching formation from the housing. In this way, the position of the abutment provides a fixed point at which actuator and control element become connected so that there is no further slippage between them. The full force of the actuator is thereby transferred as a dynamic load on the latching formation to disengage the control element.

Preferably, the abutment comprises a rubber surface for damping the impact of the engagement of the actuator. This helps to dissipate some of the impact forces to minimise the sound and vibrations arising from this engagement.

Preferably, the control element is profiled to reduce a frictional retardation force acting on the actuator for accelerating the actuator under the drive force prior to its engagement with the abutment. In this way, even if the acceleration of the actuator has been initially slowed during the start of the operation of the device, the actuator can be allowed to accelerate a distance before it impacts with the abutment in order to generate a sufficient dynamic load for detaching the control element from the housing. That is, the distance over which the actuator accelerates may be selected to generate just enough dynamic load for detaching the control element, without applying excessive impact forces.

Preferably, the control element comprises a distal head, and wherein, when the control element is released from the housing, the control element moves distally with the actuator for engaging the distal head with the stopper to apply the drive force to move the stopper for expelling the medicament. In this way, the control element is used to transfer the drive force from the actuator to the stopper. ln embodiments, activation of the drive mechanism moves the container in a distal direction relative to the housing for advancing a needle of the container into an injection site before injection of the medicament. In this way, embodiments of the invention may be provided as auto-injector arrangements. In embodiments, the injection device may further comprise a pre-filled container comprising a syringe containing the medicament, a needle disposed at a distal end of the syringe, a removable needle shield, and a stopper for expelling medicament through the needle.

Aspects and embodiments of the present invention may be used for the delivery of medicaments comprising or including pharmaceutical products (active ingredients).

Pharmaceutical products (active ingredients) contemplated for use include small molecules, vaccines, live or attenuated cells, oligonucleotides, DNA, peptides, antibodies, and recombinant or naturally occurring proteins, whether human or animal, useful for prophylactic, therapeutic or diagnostic application. The active ingredient can be natural, synthetic, semi-synthetic or derivatives thereof. In addition, active ingredients of the present invention can be perceptible. A wide range of active ingredients are contemplated. These include but are not limited to hormones, cytokines, hematopoietic factors, growth factors, antiobesity factors, trophic factors, anti-inflammatory factors, and enzymes. One skilled in the art will readily be able to adapt a desired active ingredient to the necessary formulations encompassed by the present invention.

Active ingredients can include but are not limited to insulin, gastrin, prolactin, human growth hormone (hGH), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), human parathyroid hormone (PTH), glucagon, glucagons-like peptide 1 (GLP-1 ), glucagons- like peptide 2 (GLP-2), insulin-like growth factors (IGFs) such as insulin growth factor I (IGF I), insulin growth factor II (IGF II), growth hormone-releasing factor (GRF), human chorionic gonadotropin (HCG), gonadotropin-releasing hormone, motilin, interferons (alpha, beta, gamma), interleukins (e.g., IL-1 , IL-2, IL-4, IL-5, IL-6, IL-9, IL- 1 1 , IL-12, IL-13, IL-15, IL-16, IL-1 , IL-18, IL-20 or IL-21 ), interleukin-1 receptor antagonists (IL-lra), tumor necrosis factor (TNF), tumor necrosis factor-binding protein (TNF-bp), CD40L, CD30L, erythropoietin (EPO), plasminogen activator inhibitor 1 , plasminogen activator inhibitor 2, von Willebrandt factor, thrombopoietin, angiopoietin, granulocyte-colony stimulating factor (G-CSF), stem cell factor (SCF), leptin (OB protein), brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), neurotrophic factor 3 (NT3), fibroblast growth factors (FGF), neurotrophic growth factor (NGF), bone growth factors such as osteoprotegerin (OPG), transforming growth factors, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), macrophage colony stimulating factor (M-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), megakaryocyte derived growth factor (MGDF), keratinocyte growth factor (KGF), platelet-derived growth factor (PGDF), novel erythropoiesis stimulating protein (NESP), bone morphogenetic protein (BMP), superoxide dismutase (SOD), tissue plasminogen activator (TPA), pro- urokinase, urokinase, streptokinase, kallikrein, a protease inhibitor e.g. aprotinin, an enzyme such as asparaginase, arginase, arginine deaminase, adenosine deaminase, ribonuclease, catalase, uricase, bilirubin oxidase, trypsin, papain, alkaline phosphatase, glucoronidase, purine nucleoside phosphorylase or batroxobin, an opioid, e.g. endorphins, enkephalins or non-natural opioids, a neuropeptide, neuropeptide Y, calcitonin, cholecystokinins, corticotrophin-releasing factor, vasopressin, oxytocin, antidiuretic hormones, thyrotropin releasing hormone, relaxin, peptideYY, pancreastic polypeptide, CART (cocaine and amphetamine regulated transcript), a CART related peptide, perilipin, melanocortins (melanocyte-stimulating hormones) such as MSH, melanin-concentrating hormones, natriuretic peptides, adrenomedullin, endothelin, secretin, amylin, vasoactive intestinal peptide (VIP), pituary adenylate cyclase activating polypeptide (PACAP), bombesin, bombesin-like peptides, thymosin, heparin-binding protein, soluble CD4, hypothalmic releasing factor, melanotonins, and human antibodies and humanized antibodies. The term proteins, as used herein, includes peptides, polypeptides, consensus molecules, analogs, derivatives or combinations thereof.

Active ingredients include any extended half-life variants of the active ingredient listed herein or analogues thereof. Thus, the active ingredients can be any long acting variants of the active ingredient listed herein or analogues thereof. In some embodiments, the active ingredient include any extended half-life or long acting variants of hGH, insulin, glucagon, glucagons-like peptide 1 (GLP-1 ), glucagons-like peptide 2 (GLP-2), insulin-like growth factors (IGFs). In some embodiments, the active ingredient is an extended half-life or long acting variant of hGH. Examples of extended half-life or long acting variants of hGH include, but are not limited to LB03002, NNC126-0883, NNC0195-0092, MOD-4023, ACP-001 , Albutropin, somavaratan (VRS-317), and profuse GH.

Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings in which like reference numerals are used for like features, and in which:

Figures 1 (a) and 1 (b) are cross-sectional views of the injection device according to a first embodiment of the present invention on two perpendicular planes, with the plunger in a first or neutral position; Figure 2 is a perspective view of the control rod of the injection device shown in Figure 1 ;

Figures 3(a) and 3(b) are cross-sectional views of the injection device of Figure 1 , with the plunger in a second position; and

Figures 4(a) and 4(b) are cross-sectional views of the injection device of Figure 1 , with the plunger in a third position.

Figures 1 to 4 show an injection device 100 according to a first embodiment of the invention, with Figures 1 , 3 and 4 showing the device at different stages as it moves through its operation. The injection device is arranged to deliver a dose of medicament from a container, which in this example is a pre-filled syringe 10. Throughout the following description, the terms "front", "distal" and related terms are used to refer to the end of the device that is towards the patient's skin in use (i.e. the lower end of the device in Figures 1 (a) and 1 (b)), and the terms "rear", "proximal" and related terms are used to refer to the end of the device that is furthest from the skin in use (i.e. the upper end of the device in Figures 1 (a) and 1 (b)). Figures 1 (a) and 1 (b) show the injection device 100 in cross-section in two perpendicular planes, with the components in their starting position, prior to actuation of the device. The device 100 comprises an elongate two-part housing 1 for carrying the syringe 10, a spring drive mechanism 3 that is released by de-latching button 5, and a plunger assembly 2 comprising an actuator body 21 and a control rod 4. The syringe 10 is preferably of a type known in the art, for example a Hypak syringe. The syringe 10 comprises a generally tubular glass body or barrel that, at its distal end, forms into a reduced-diameter end portion that carries a staked hypodermic needle 1 1. A rigid needle shield is removably attached to the distal end portion of the syringe 10 and is provided to preserve the sterility of the needle prior to use. The barrel of the syringe is filled with a quantity of medicament and is closed by a stopper 12 that is slidably received in the barrel. The syringe 10 is held within a tubular syringe guide formation of the housing 1 , with a flange at the proximal end of the syringe 10 seated into the proximal end of the guide formation for holding the syringe 10 in place.

The plunger assembly 2 comprises an actuator body 21 and a control element in the form of control rod 4. The actuator body 21 is provided with a bell-shaped spring seat 24 that supports the distal end of the drive spring 31 1 of the drive mechanism 3. The spring seat 24 is connected to an axial sleeve 23 that forms a bore around the rod 4. The actuator body 21 further comprises a latching formation 22 that is latched to corresponding latching members 14 formed on the housing 1 to hold the plunger assembly 2 its starting position. The button 5 may be actuated to move it in a distal direction to allow formations 51 on the de-latching button 5 to disengage latching formation 21 from the latching members 14 of the housing 1 to thereby release the actuator body 21.

As shown in Figure 2, the control rod 4 comprises a rigid body 42 with a latching formation 41 at its proximal end, an engagement head 45 formed at its distal end, and an abutment 44 formed towards the engagement head 45. As shown in Figures 1 (a) and 1 (b), the control rod 4 extends through the axial sleeve 23 formed in the plunger assembly 2 so as to allow the actuator body 22 to slide distally down the control rod 4 up until it engages with the abutment 44. The latching formation 41 forms a lug that is latched into the latching members 13 provided on the distal facing side of the proximal end of the housing 1. The engagement head 45 is shaped for engagement with a recess provided in an opposing face of the stopper 12 when the device is actuated, as is discussed in more detail below. A rubber formation 43 is provided over a region of the rigid body 42 between the latching formation 41 and the abutment 44 and provides an interface surface for sliding engagement with the axial sleeve 23 of the plunger assembly 2. The rubber formation 43 comprises a number of distally extending ribbed splines that are spaced by relief cuts, which allow the splines to compress as they move through the bore of the axial sleeve 23. The interface surface provided by the rubber formation 43 provides frictional resistance against the axial sleeve 23 as the actuator 21 is slid over it. Figures 1 (a) and 1 (b) show the injection device 100 when the components are in their starting position. In this position, the spring 31 1 is compressed against spring seat 24 to bias the actuator body 21 in a distal direction. However, as shown in Figure 1 (b), the actuator body 21 is held in place by its latching formations 22 latched into corresponding latching members 14 formed on the housing 1. To actuate the device, button 5 is depressed to move it in a distal direction to allow formations 51 to disengage latching formation 22 from the latching members 14 to thereby release the actuator body 21.

As shown in Figures 3(a) and 3(b), the released actuator body 21 is forced distally under the drive force applied by spring 31 1. The actuator body 21 slides down over the control rod 4, with the control rod 4 held in place by its connection to the housing through its latching formation 41. As axial sleeve 23 slides over the control rod 4, it frictionally engages with the rubber formation 43, which acts to slow the advance of the actuator body since the drive force applied by the spring 31 has to overcome the counteracting frictional forces. This reduces the initial shock felt from de-latching the spring 31 because energy is dissipated by the frictional interface. The relief cuts provided in the rubber formation allow the splines to compress and deform as they pass through the sleeve 23, which aids in preventing the stalling of the actuator body 21 as it moves over the rubber.

As the actuator body 21 moves distally further towards the end of the control rod 4, the rubber formation 43 steps away from the surface of the sleeve 23, thereby allowing the actuator body 21 to accelerate a distance before it impacts the abutment 44. The distance the actuator body 21 is allowed to accelerate is calculated to generate a dynamic load delivered upon the sleeve 23 impacting the abutment 44 that is sufficient to de-latch the control rod 4 from the housing latching members 14 connecting it to the housing 1 . A layer of rubber is provided on the impact surface of the abutment 44 to dissipate some of the sound and vibration from this impact. As shown in Figures 4(a) and 4(b), following the impact of the sleeve 23 with the abutment 44, the control rod 4 de-latches from the housing 1 by deforming the latch members 13. The energy required to effect this deformation acts to temporarily slow down the actuator body 21 . Once the control rod 4 is de-latched from the housing, it is able to travel distally with the actuator body 21 to engage its engagement head 45 with the stopper 12. However, the impact applied to the stopper 12 is greatly reduced because the plunger assembly 2 has a much smaller envelope within which to accelerate before impacts. This reduced impact, in comparison to an un-dampened plunger impact, greatly reduces stresses on the syringe 10, improving both the feel and the reliability of the device.

Once the control rod 4 has engaged with the stopper 12, the operation of the device continues with the stopper being forced distally by the action of the spring 31 on the actuator body 21 . At this stage, the distal movement of the actuator body 21 is not restricted, thereby allowing the full drive force of the spring to be applied for expelling the medicament from the syringe 10. In this way, the control rod 4 allows delivery of the drive spring energy to be managed though the operation of the device to thereby regulate the application of drive forces on the device's components. This thereby allows for improved usability and reliability.

Various other modifications of the examples described above are possible. For example, in the above-described embodiment, the control rod is releasably connected to the housing in an energy dissipating arrangement. However, it will be understood that embodiments may be provided with a fixed control element, with the frictional engagement between this and the actuator being used to regulate movement. Furthermore, it may be understood that the invention may be applied to auto-injector arrangements in which the syringe is moved distally during an initial part of the actuator stroke to advance the needle into an injection site. Finally, the control element may also perform other functions, such as forming part of a priming mechanism.

Various features of the above-described examples could be substituted with structurally and/or functionally equivalent features. In particular, where parts are configured to cooperate by way of a rib, pin or other projection in engagement with a slot, channel or other recess, the projection and the recess could be provided on either part. By way of example, in the illustrative embodiment, a rubber formation is applied to the control rod. However, this interface surface may provided by O-rings. Furthermore, the invention is not limited to use with Hypak-type syringes with a rigid needle shield of the type described, but could be used with any similar syringe, with any type of needle shield. It is also conceivable that the invention could be used with other types of medicament container, such as cartridges that are designed for use with disposable needles, infusion cannulas and so on .

Further modifications and variations not explicitly described above are also possible without departing from the scope of the invention as defined in the appended claims.