Abstract:
An auto-injector for administering a dose of a liquid medicament is presented that has a tubular chassis telescopable in a tubular case, a carrier subassembly comprising a tubular carrier slidably arranged relative to the chassis inside the case, where the carrier adapted to contain a syringe with a hollow injection needle. The injector has a drive spring and a plunger for forwarding load of the drive spring to a stopper of the syringe, wherein the syringe is lockable for joint axial translation with the carrier. There is also a trigger button arranged distally or laterally in or on the case, a control spring arranged around the carrier, and a needle extension control mechanism for coupling a proximal end of the control spring to either the carrier for advancing it for needle extension or to the chassis for needle retraction depending on the relative axial position of the carrier and the chassis.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    The present application is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/EP2012/052640 filed Feb. 16, 2012, which claims priority to European Patent Application No. 11155032.3 filed Feb. 18, 2011 and U.S. Provisional Application No. 61/445,610 filed Feb. 23, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
     
    
     TECHNICAL FIELD 
       [0002]    The invention relates to an auto-injector for administering a dose of a liquid medicament. 
       BACKGROUND 
       [0003]    Administering an injection is a process which presents a number of risks and challenges for users and healthcare professionals, both mental and physical. 
         [0004]    Injection devices (i.e. devices capable of delivering medicaments from a medication container) typically fall into two categories—manual devices and auto-injectors. 
         [0005]    In a manual device—the user must provide the mechanical energy to drive the fluid through the needle. This is typically done by some form of button/plunger that has to be continuously pressed by the user during the injection. There are numerous disadvantages to the user from this approach. If the user stops pressing the button/plunger then the injection will also stop. This means that the user can deliver an underdose if the device is not used properly (i.e. the plunger is not fully pressed to its end position). Injection forces may be too high for the user, in particular if the patient is elderly or has dexterity problems. 
         [0006]    The extension of the button/plunger may be too great. Thus it can be inconvenient for the user to reach a fully extended button. The combination of injection force and button extension can cause trembling/shaking of the hand which in turn increases discomfort as the inserted needle moves. 
         [0007]    Auto-injector devices aim to make self-administration of injected therapies easier for patients. Current therapies delivered by means of self-administered injections include drugs for diabetes (both insulin and newer GLP-1 class drugs), migraine, hormone therapies, anticoagulants etc. 
         [0008]    Auto-injectors are devices which completely or partially replace activities involved in parenteral drug delivery from standard syringes. These activities may include removal of a protective syringe cap, insertion of a needle into a patient&#39;s skin, injection of the medicament, removal of the needle, shielding of the needle and preventing reuse of the device. This overcomes many of the disadvantages of manual devices. Injection forces/button extension, hand-shaking and the likelihood of delivering an incomplete dose are reduced. Triggering may be performed by numerous means, for example a trigger button or the action of the needle reaching its injection depth. In some devices the energy to deliver the fluid is provided by a spring. 
         [0009]    US 2002/0095120 A1 discloses an automatic injection device which automatically injects a pre-measured quantity of fluid medicine when a tension spring is released. The tension spring moves an ampoule and the injection needle from a storage position to a deployed position when it is released. The content of the ampoule is thereafter expelled by the tension spring forcing a piston forward inside the ampoule. After the fluid medicine has been injected, torsion stored in the tension spring is released and the injection needle is automatically retracted back to its original storage position. 
         [0010]    High viscosity medicaments require high forces for expelling them through the relatively thin injection needle. To achieve these forces strong drive springs are needed. This can lead to a high impact felt by the user when inserting the needle into the skin and to high forces felt by the user when triggering the injection. 
       SUMMARY 
       [0011]    It is an object of the present invention to provide an improved auto-injector and an improved method for operating an auto-injector. 
         [0012]    The object is achieved by an auto-injector according to claim  1  and by a method according to claim  13 . 
         [0013]    Preferred embodiments of the invention are given in the dependent claims. 
         [0014]    In the context of this specification the term proximal refers to the direction pointing towards the patient during an injection while the term distal refers to the opposite direction pointing away from the patient. The term inwards refers to a radial direction pointing towards a longitudinal axis of the auto-injector whereas the term outwards refers to the opposite direction radially pointing away from the longitudinal axis. 
         [0015]    According to the invention an auto-injector for administering a dose of a liquid medicament comprises: 
         [0016]    a tubular chassis telescopable in a tubular case, 
         [0017]    a carrier subassembly comprising a tubular carrier slidably arranged relative to the chassis inside the case, the carrier adapted to contain a syringe with a hollow injection needle, a drive spring and a plunger for forwarding load of the drive spring to a stopper of the syringe, wherein the syringe is lockable for joint axial translation with the carrier, 
         [0018]    a trigger button arranged distally or laterally in or on the case, 
         [0019]    a control spring arranged around the carrier, 
         [0020]    a needle extension control mechanism for coupling a proximal end of the control spring to either the carrier for advancing it for needle extension or to the chassis for needle retraction depending on the relative axial position of the carrier and the chassis, 
         [0021]    a plunger release mechanism arranged for releasing the plunger when the carrier has at least almost reached a extended proximal position, 
         [0022]    a detent mechanism arranged for coupling the chassis to the carrier for joint axial translation relative to the case, wherein the detent mechanism is arranged to decouple the chassis from the carrier upon actuation of the trigger button thus allowing the carrier to move relative to the chassis so as to cause the needle extension control mechanism to switch the proximal end of the control spring to the carrier for needle extension, 
         [0023]    a syringe retraction control mechanism arranged for coupling a distal end of the control spring to either the carrier for needle refraction or to the case otherwise. 
         [0024]    The carrier subassembly with the integrated drive spring allows for employing a strong drive spring without any impact on the user when triggering the auto-injector or during needle extension since these actions are achieved or opposed by the control spring which can be specified considerably weaker than the drive spring. This allows for delivering highly viscous medicaments. 
         [0025]    There are a number of significant benefits of separating the functions between the drive spring and the control spring in this way. The auto-injector is always needle safe, i.e. the needle can be retracted before the injection is complete. The reliability of the auto-injector is improved as the components for needle advance and retraction are not loaded by the high impact of a freely expanding high force drive spring. The auto-injector is well suited to serve as a platform as the drive spring can be swapped to deliver different viscosity drugs without affecting the insertion or retraction functions. This is particularly advantageous for high viscosity fluids. 
         [0026]    Releasing the drive spring upon the needle reaching an advanced proximal position, e.g. when the needle is advanced to a corresponding injection depth, avoids a so called wet injection, i.e. medicament leaking out of the needle which is a problem in conventional art auto-injectors, where both needle extension and injection are achieved by pushing on the stopper. The auto-injector according to the invention solves the wet injection problem by the separate springs for translation of the carrier and for drug delivery. 
         [0027]    The auto-injector according to the invention has a particularly low part count compared to most conventional auto-injectors thus reducing manufacturing costs. The arrangement with separate control spring and drive spring for fluid injection allows for using one design for different viscosity liquids by just changing the drive spring, and for different volumes just by changing the length of the plunger. This is an advantage over conventional art designs where the main spring also powers needle extension and/or retraction. 
         [0028]    In the context of this specification the chassis is generally considered as being fixed in position so motion of other components is described relative to the chassis. 
         [0029]    In an initial as delivered state of the auto-injector the proximal end of the control spring is coupled to the chassis by the needle extension control mechanism while the distal end is coupled to the case by the syringe retraction control mechanism, release of the drive spring is prevented by the plunger release mechanism, decoupling of the chassis from the carrier is prevented by the detent mechanism. 
         [0030]    In order to trigger the auto-injector the case has to be translated in the proximal direction relative to the chassis against the force of the control spring. When the case has at least almost reached an advanced proximal position the detent mechanism is unlocked thereby allowing translation of the carrier relative to the chassis. Preferably this position has been reached, when the case has moved 85%-98% of its total proximal extension. The relative translation of the case and the chassis could be achieved, e.g. by fixing the chassis and moving the case. For the purpose of injection, e.g., the chassis may be fixed by pressing against an injection site, e.g. a patient&#39;s skin. Hence a user, e.g. the patient or a caregiver, could grab the case with their whole hand and push the chassis protruding from the proximal end against the injection site, thereby translating the case relative to the chassis in proximal direction and triggering the auto-injector in a way described above. 
         [0031]    The carrier now is unlocked to be translated in the proximal direction. As the carrier translates in the proximal direction relative to the case and to the chassis it thereby switches the needle extension control mechanism depending on the relative position of the carrier in the chassis so as to decouple the proximal end of the control spring from the chassis and couple it to the carrier, thereby releasing the control spring for advancing the carrier for needle extension. For the purpose of injection, e.g., the user could manually depress a trigger button coupled to the carrier forcing the carrier in the proximal direction. This would cause the needle to be extended according to the needle extension control mechanism described before. Again, for purpose of injection, the user pushing the injector against an injection site could press the trigger button thereby translating the carrier in the proximal direction relative to the case and the chassis thereby switching the needle extension control mechanism as described before. Advancing the carrier under the force of the control spring would then result in advancing the needle into the skin. 
         [0032]    Alternatively the control spring could initially be coupled to the carrier by the needle extension control mechanism so that the carrier would be immediately advanced when the detent mechanism is unlocked by translation of the case into the advanced position. 
         [0033]    As the needle translates with the carrier subassembly to an extended proximal position, where it is no longer needle safe, the drive spring is released by the plunger release mechanism thereby allowing the drive spring to advance the plunger and the stopper for at least partially expelling the medicament. This release of the drive spring is preferably triggered by the carrier reaching a predefined relative position within the case. This position is reached, when the carrier has at least almost reached the extended proximal position. Preferably, this position is at 85% to 98% proximal extension. If, for example, the extension length is 1 cm the position would fall into the range of 8.5 mm-9.8 mm proximal extension length 
         [0034]    For the purpose of injection the extended proximal position may correspond to an intended injection depth. Hence the drive spring could be released by the plunger release mechanism once the injection depth is substantially reached thereby allowing the drive spring to advance the plunger and the stopper for at least partially delivering the medicament. 
         [0035]    If the auto-injector is removed from the injection site after the stopper has bottomed out in the syringe or at any point during injection, the case is translated in the distal direction under load of the control spring relative to the carrier subassembly. 
         [0036]    The needle retraction is triggered by moving the case in distal direction relative to the chassis and the carrier under the force of the control spring. As the case reaches a defined position relative to the carrier the proximal end of the control spring is decoupled from the carrier and coupled to the chassis by the needle extension control mechanism. Furthermore the distal end of the control spring is decoupled from the trigger sleeve and coupled to the carrier by the syringe retraction control mechanism. The sequencing of this switching is critical as retraction will fail if both collars are attached to the carrier at the same time. This is overcome by separating the switching of the collars by a significant displacement of the case, which provides for first switching the needle extension control mechanism and then the syringe retraction control mechanism, e.g. 
         [0037]    As the control spring now pushes against the chassis in the proximal direction and against the carrier in the distal direction the carrier subassembly is retracted into the chassis into a needle safe position by the control spring, where the proximal end of the needle is covered. As this retraction is triggered by the relative position between case, chassis, and carrier, it is particularly independent from expelling the medicament. For the purpose of injection this position of the case relative to the carrier could be reached, e.g. if the auto-injector is removed from the injection site. When, e.g., the user still grabbing the case with their whole hand and pushing the chassis protruding from the proximal end against the injection site move their hand in distal direction, the case will be moved in distal direction relative to the carrier and the chassis and the mechanism will be triggered as described before. The needle will thus be retracted from the injection site under the force of the control spring. 
         [0038]    According to one embodiment the needle extension control mechanism may comprise a first collar biased by the control spring in the proximal direction, wherein at least one resilient beam is proximally arranged on the first collar, wherein respective recesses are arranged in the carrier and case, wherein a transversal extension of a head of the resilient beam is wider than a gap between the carrier and the chassis causing the head of the resilient beam to abut a distal face on the recess in the chassis while being prevented from deflecting in an inward direction by the carrier or to abut a distal face on the recess in the carrier while being prevented from deflecting in an outward direction by the chassis thereby forwarding load from the control spring to the carrier for needle extension, wherein the resilient beam is arranged to be switched between the chassis and the carrier by ramped engagement of the head to the distal faces under load of the control spring depending on the relative longitudinal position between the chassis and the carrier. As the head of the resilient beam may be inwardly and outwardly ramped it may be referred to as an arrowhead. 
         [0039]    The plunger release mechanism may comprise at least one resilient arm on the carrier arranged to be in a ramped engagement to the plunger so as to disengage them under load of the drive spring, wherein a peg protrudes from a distal end face of the trigger button in the proximal direction in a manner to support the resilient arm preventing disengagement of the carrier from the plunger and thus release of the drive spring when the carrier is in a distal position. The trigger button is arranged to remain in position relative to the case when the carrier is translated for advancing the needle. That means, the trigger button, initially coupled to the carrier, pushes the carrier in the proximal direction when depressed. As soon as the control spring takes over further advancing the carrier the trigger button may abut the case and decouple from the carrier, staying in position as the carrier moves on. Hence the resilient arm is pulled away from the peg thus allowing deflection of the resilient arm due to the ramped engagement under load of the drive spring for disengaging the plunger from the carrier and releasing the drive spring for drug delivery when the carrier has reached a predefined position during needle advancement. 
         [0040]    The detent mechanism may be arranged to provide a resistive force which has to be overcome to advance the carrier in the proximal direction for needle extension. The carrier may be coupled to a trigger button and the force pushing the trigger button has to exceed the resistive force of the detent mechanism. E.g., once the user applies a force on the trigger button which exceeds a pre-determined value the detent mechanism releases, initiating the injection cycle. If the pre-determined value is not overcome the detent mechanism pushes the carrier and trigger button back into their prior position. This ensures that the auto-injector is always in a defined state, either triggered or not triggered, not half triggered by the user hesitating. 
         [0041]    The detent mechanism may also be arranged to provide a resistive force resisting translation of the carrier in the distal direction relative to the chassis for keeping the carrier in a defined position in a transitional state with both ends of the control spring decoupled from the carrier. This transitional state may be required for retracting the needle on removal from the injection site. As the carrier is biased against the injection site by the control spring before removal from the injection site it has to be decoupled from the proximal end of the control spring and coupled to the distal end for retraction. The sequencing of this switching is critical as retraction will fail if both ends of the control spring are attached to the carrier at the same time. This is overcome by separating the switching of the ends by a significant displacement of the case, which moves in the distal direction relative to the chassis on removal of the injection site under load of the control spring. As the switching of the distal end of the control spring to the carrier depends on the relative position of the case to the carrier the carrier has to be fixed in the transitional state which is achieved by the detent mechanism. 
         [0042]    In one embodiment the detent mechanism comprises a resilient beam on the chassis and a rhomboid ramp member on the carrier, the resilient beam being essentially straight when relaxed and having a first beam head arranged to interact in a ramped engagement with a proximal fourth ramp or a distal fifth ramp on the rhomboid ramp member in such a manner that application of a translative force on the carrier relative to the chassis in the proximal direction with the first beam head engaged to the fourth ramp deflects the resilient beam in one transversal direction, e.g. outwards when a predetermined value of the translative force, at least depending on the resilience of the resilient beam, is overcome so as to allow the first beam head to travel along one transversal side of the rhomboid ramp member on continued relative translation of the components. The beam head may protrude transversally from the resilient beam in a manner to distort the resilient beam by lever action when pushed against the rhomboid ramp member thereby also defining the predetermined value of the translative force to be overcome by the carrier. Furthermore, the contacting faces of the first beam head and the rhomboid ramp member may have their friction adapted to define the required force by appropriately choosing their shape and material properties. The resilient beam is allowed to relax when the first beam head has reached the fifth ramp thereby engaging it in a manner that application of a translative force on the carrier in the distal direction deflects the resilient beam in the other transversal direction, e.g. inwards when a predetermined value of the translative force, at least depending on the resilience of the resilient beam, is overcome so as to allow the first beam head to travel along the other transversal side of the rhomboid ramp member on continued translation of the carrier. The first beam head may also be allowed to relax behind the fourth ramp at the end of this motion for preventing the carrier from being advanced again, e.g. when the auto-injector is being heavily shaken after use. 
         [0043]    It goes without saying that the positions of the resilient beam on the chassis and the rhomboid ramp member on the carrier may be switched without altering the function of the detent mechanism. 
         [0044]    When the auto-injector or the syringe is assembled a protective needle sheath may be attached to the needle for keeping the needle sterile and preventing both, damage to the needle during assembly and handling and access of a user to the needle for avoiding finger stick injuries. Removal of the protective needle sheath prior to an injection usually requires a relatively high force for pulling the protective needle sheath off the needle and needle hub in the proximal direction. In order to maintain pre injection needle safety and prevent exposure of the needle translation of the syringe in the proximal direction due to this force has to be avoided. For this purpose the case may be arranged to lock the detent mechanism prior to being translated in the proximal direction relative to the chassis when the chassis is being pressed against the injection site so as to avoid translation of the carrier. This may be achieved by a rib in the case preventing deflection of the resilient beam of the detent mechanism by supporting it outwardly. Translation of the case is translated into the advanced position in the proximal direction on contact to the injection site is arranged to unlock the detent mechanism rendering it operable. This may be achieved by the rib being moved with the case so as to no longer outwardly supporting the resilient beam of the detent mechanism. In order to ensure that the case is not moved in the proximal direction unlocking the detent mechanism before the protective needle sheath is removed a cap may be attached to the proximal end of the case so as to make the chassis inaccessible before the cap is removed. The cap preferably engages the protective needle sheath by means of a barb in a manner to remove the protective needle sheath when the cap is being pulled off the auto-injector. In order to facilitate removal of the cap it may have a profiled surface mating with a surface on the case so that the cap is pulled off when rotated. The barb may be connected to the cap in a manner allowing them to rotate independently so as to avoid torque on the protective needle sheath when the cap is rotated in order not to distort the needle inside the protective needle sheath. 
         [0045]    The distally arranged trigger button may be at least initially coupled to the carrier, wherein the case is arranged to abut the trigger button in the initial state preventing depression of the trigger button. On translation of the case into the advanced position when the chassis is being pressed against the injection site the trigger button remains coupled to the carrier thus emerging from the case which has been moved relative to the chassis, carrier and trigger button so as to allow depression of the trigger button for starting an injection cycle. Thus a sequence of operation is defined for the auto-injector to be actuated, first pressing it against the injection site and then to push the trigger button. This reduces the risk of finger stick injuries particularly if the user were to be confused which end of the auto-injector to apply against their skin. Without a sequence the user would risk inserting the needle into their thumb which is significantly less probable with the forced sequence. 
         [0046]    The syringe retraction control mechanism may comprise a second collar bearing against the distal end of the control spring and having a resilient proximal beam with a second beam head having an inward boss. The second beam head is arranged to be in a ramped engagement with a second case detent in the case in a manner ramping the second beam head in the inward direction under load of the control spring in the distal direction. The inward boss is arranged to inwardly abut the carrier for preventing inward deflection of the second beam head and keep the second collar locked to the case. A third recess is arranged in the carrier for allowing the inward boss to be inwardly deflected on translation of the case in the distal direction relative to the carrier on removal of the auto-injector from the injection site. 
         [0047]    In an alternative embodiment the first collar and/or the second collar may also be threaded to one of the components which they are intended to couple to the control spring wherein the case would be arranged to prevent the threads from decoupling in some relative longitudinal positions while allowing the collar to rotate out of the threaded engagement in other relative longitudinal positions so as to allow the collars to switch to the respective other component to be coupled to the control spring. 
         [0048]    In an alternative embodiment the trigger button may be arranged distally, wherein the case is arranged as a wrap-over sleeve trigger having a closed distal end face covering the trigger button. In an initial state a clearance is provided between the distal end face of the sleeve trigger and the trigger button allowing for some travel of the sleeve trigger against the bias of the control spring in the proximal direction in a first phase before abutting the trigger button. As soon as the sleeve trigger has contacted the trigger button the trigger button is pushed by the sleeve trigger on further translation in a second phase. This embodiment allows for keeping the majority of the components of the auto-injector while only the described features need modification allowing to customize a platform device to particular requirements. An auto-injector with a sleeve trigger is particularly well suited for people with dexterity problems since, as opposed to conventional art auto-injectors, triggering does not require operation of small buttons by single fingers. Instead, the whole hand is used. 
         [0049]    Retraction of the needle requires the user to lift the auto-injector far enough from the injection site to allow the case or sleeve trigger to translate back in the distal direction to switch the control spring. As it may be difficult for the user to know if the injection is finished or not a releasable feedback component may be provided, capable of, upon release, generating an audible and/or tactile feedback to the user, wherein the feedback component is arranged to be released when the plunger reaches a position relative to the syringe in which the stopper is located in proximity of a proximal end of the syringe, i.e. , e.g., when the injection is at least almost finished. The released feedback component then impacts on a housing component, such as the case, sleeve trigger or trigger button indicating the end of the injection. Impacting a directly accessible component allows for high perceptibility of the noise and direct access to the user&#39;s hand or finger for generating the tactile feedback. Preferably the feedback component may impact the trigger button which may be shaped as a drum for providing a loud noise. 
         [0050]    The needle extension length or depth is preferably defined by the carrier relative to the chassis not relative to the case, so if the user flinches or fails to hold the auto-injector hard against the injection site, only the case will move in the distal direction while the injection depth remains constant. As long as this case motion does not exceed a set distance the case does not yet switch the control spring for needle retraction. 
         [0051]    The auto-injector may be operated by a number of key mechanical operations: 
         [0052]    The case is advanced relative to the chassis compressing the control spring giving the user the impression of depressing a skin interlock sleeve. All other components remain in the same place during case advance resulting in the trigger button appearing from the distal end of the case. 
         [0053]    The user pushes the trigger button which can now be operated. Button depression directly moves the carrier and hence the drive sub-assembly in the proximal direction a set distance until the control spring takes over via the first collar and fully extends the needle, e.g. inserts the needle into the injection site. 
         [0054]    The trigger button stops on the distal end of the case as the carrier continues translating in the proximal direction. The motion of the carrier relative to the trigger button is used to release the drive spring just before full insertion depth is reached, e.g. by pulling a peg on the trigger button out of the carrier thus allowing the plunger to move. The drive spring drives the plunger down the syringe barrel expelling the medicament. 
         [0055]    A feedback mechanism is released when the plunger is near the end of travel shortly before the stopper bottoms out in the syringe, providing audible and/or tactile indicator of the end of injection to the user. 
         [0056]    The needle remains fully extended until the user moves the case back a set distance relative to the chassis at which point the second collar decouples from the case and couples to the carrier while the first collar decouples from the carrier and couples to the chassis thus allowing the control spring to retract the carrier and hence the needle. 
         [0057]    The auto-injector may preferably be used for subcutaneous or intra-muscular injection, particularly for delivering one of an analgetic, an anticoagulant, insulin, an insulin derivate, heparin, Lovenox, a vaccine, a growth hormone, a peptide hormone, a proteine, antibodies and complex carbohydrates. The auto-injector may preferably be adapted to be used for injecting a liquid medicament with high viscosity, e.g. liquid solutions of antibody medicaments. 
         [0058]    The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
         [0059]    wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, a antibody, an enzyme, an antibody, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, 
         [0060]    wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, 
         [0061]    wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, 
         [0062]    wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exedin-3 or exedin-4 or an analogue or derivative of exedin-3 or exedin-4. 
         [0063]    Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
         [0064]    Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(w-carboxyheptadecanoyl) human insulin. 
         [0065]    Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-S er-Asp-Leu-S er-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
         [0066]    Exendin-4 derivatives are for example selected from the following list of compounds:
   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(02)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(02)25, IsoAsp28] Exendin-4(1-39); or   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(02)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(02)25, IsoAsp28] Exendin-4(1-39),   wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;   or an Exendin-4 derivative of the sequence   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(02)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(02)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;   or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exedin-4 derivative.   
 
         [0116]    Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
         [0117]    A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
         [0118]    Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C 1 -C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
         [0119]    Pharmaceutically acceptable solvates are for example hydrates. 
         [0120]    The drive spring and control spring may be compression springs. However, they may likewise be any kind of stored energy means such as torsion springs, gas springs etc. 
         [0121]    Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0122]    The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus, are not limitive of the present invention, and wherein: 
           [0123]      FIG. 1  shows two longitudinal sections of an auto-injector in different section planes in a state prior to use, 
           [0124]      FIG. 2  shows two longitudinal sections of the auto-injector after removal of a cap and a protective needle sheath, 
           [0125]      FIG. 3  shows two longitudinal sections of the auto-injector with the case moved in proximal direction relative to the chassis, 
           [0126]      FIG. 4  shows two longitudinal sections of the auto-injector with a trigger button depressed, 
           [0127]      FIG. 5  shows two longitudinal sections of the auto-injector during needle extension, 
           [0128]      FIG. 6  shows two longitudinal sections of the auto-injector with the needle in extended proximal position, 
           [0129]      FIG. 7  shows two longitudinal sections of the auto-injector during expelling the medicament, 
           [0130]      FIG. 8  shows two longitudinal sections of the auto-injector where the stopper is located in proximity of a proximal end of the syringe, 
           [0131]      FIG. 9  shows two longitudinal sections of the auto-injector where the case is moved in distal direction relative to the chassis, 
           [0132]      FIG. 10  shows two longitudinal sections of the auto-injector with the needle retracted into a needle safe position, 
           [0133]      FIG. 11  shows schematic views of a detent mechanism for controlling movement of a carrier relative to a chassis of the auto-injector in four different states, 
           [0134]      FIG. 12  shows schematic views of a needle extension control mechanism for controlling movement of a first collar in six different states, 
           [0135]      FIG. 13  shows schematic views of a syringe retraction control mechanism in three different states 
           [0136]      FIG. 14  shows schematic views of a feedback release mechanism for audibly and/or tactily indicating the end of injection in three different states, 
           [0137]      FIG. 15  shows schematic views of a plunger release mechanism in three different states, 
           [0138]      FIG. 16  shows schematic views of a button release mechanism in three different states, 
           [0139]      FIG. 17  is an isometric view of an alternative embodiment of the plunger release mechanism, 
           [0140]      FIG. 18  is a longitudinal section of an alternative embodiment of the button release mechanism, 
           [0141]      FIG. 19  shows longitudinal sections of an alternative embodiment of the detent mechanism, 
           [0142]      FIG. 20  is a longitudinal section of a third embodiment of the detent mechanism, 
           [0143]      FIG. 21  is a longitudinal section of an alternative embodiment of the feedback release mechanism, 
           [0144]      FIG. 22  shows longitudinal sections of an alternative embodiment of the needle extension control mechanism, also arranged to perform the function of the detent mechanism on needle retraction and needle extension, 
           [0145]      FIG. 23  is an isometric view of the needle extension control mechanism of  FIG. 22 , 
           [0146]      FIG. 24  shows longitudinal sections of a third embodiment of the needle extension control mechanism, also arranged to perform the functions of the detent mechanism, 
           [0147]      FIG. 25  is an isometric view of the needle extension control mechanism of  FIG. 24 , 
           [0148]      FIG. 26  shows longitudinal sections of a third embodiment of the feedback release mechanism, and 
           [0149]      FIG. 27  is another embodiment of the auto-injector having a wrap-over sleeve trigger instead of a trigger button. 
       
    
    
       [0150]    Corresponding parts are marked with the same reference symbols in all figures. 
       DETAILED DESCRIPTION 
       [0151]    A ramped engagement in the terminology of this specification is an engagement between two components with at least one of them having a ramp for engaging the other component in such a manner that one of the components is flexed aside when the components are axially pushed against each other provided this component is not prevented from flexing aside. 
         [0152]    Figures la and lb show two longitudinal sections of an auto-injector  1  in different section planes, the different section planes approximately 90° rotated to each other, wherein the auto-injector  1  is in an initial state prior to starting an injection. The auto-injector  1  comprises a chassis  2 . In the following the chassis  2  is generally considered as being fixed in position so motion of other components is described relative to the chassis  2 . A syringe  3 , e.g. a Hypak syringe, with a hollow injection needle  4  is arranged in a proximal part of the auto-injector  1 . When the auto-injector  1  or the syringe  3  is assembled a protective needle sheath  5  is attached to the needle  4 . A stopper  6  is arranged for sealing the syringe  3  distally and for displacing a liquid medicament M through the hollow needle  4 . The syringe  3  is held in a tubular carrier  7  and supported at its proximal end therein. The carrier  7  is slidably arranged in the chassis  2 . 
         [0153]    A drive spring  8  in the shape of a compression spring is arranged in a distal part of the carrier  7 . A plunger  9  serves for forwarding the force of the drive spring  8  to the stopper  6 . 
         [0154]    The drive spring  8  is loaded between a distal carrier end face  10  of the carrier  7  and a thrust face  11  arranged distally on the plunger  9 . 
         [0155]    The carrier  7  is a key element housing the syringe  3 , the drive spring  8  and the plunger  9 , which are the components required to expel the medicament M from the syringe  3 . These components can therefore be referred to as a drive sub-assembly. 
         [0156]    The chassis  2  and the carrier  7  are arranged within a tubular case  12 . A trigger button  13  is arranged at a distal end of the case  12 . In a plunger release mechanism  27  a peg  14  protrudes from a distal end face of the trigger button  13  in the proximal direction P between two resilient arms  15  originating from the distal carrier end face  10  thus preventing them from flexing towards each other in an initial state A illustrated in  FIG. 15A . In  FIG. 15A  only one of the resilient arms  15  is shown to illustrate the principle. Outwardly the resilient arms  15  are caught in respective first recesses  16  in a distal plunger sleeve  17  attached distally to the thrust face  11  and arranged inside the drive spring  8 . The engagement of the resilient arms  15  in the first recesses  16  prevents axial translation of the plunger  9  relative to the carrier  7 . The resilient arms  15  are ramped in a manner to flex them inwards on relative motion between the plunger  9  and the carrier  7  under load of the drive spring  8 , which is prevented by the peg  14  in the initial state A. 
         [0157]    The carrier  7  is locked to the chassis  2  for preventing relative translation by a detent mechanism  18  illustrated in more detail in  FIGS. 11A to 11D . 
         [0158]    The trigger button  13  is initially engaged to the case  12  by a button release mechanism  26  and cannot be depressed. The button release mechanism  26  is illustrated in detail in  FIGS. 16A to 16C . Referring now to  FIG. 16A  the button release mechanism  26  comprises a resilient proximal beam  13 . 1  on the trigger button  13 , the proximal beam  13 . 1  having an outward first ramp  13 . 2  and an inward second ramp  13 . 3 . In an initial state A illustrated in FIG.  16 A the outward first ramp  13 . 2  is engaged in a ramped first case detent  12 . 1  preventing the trigger button  13  from moving out of the distal end D. The trigger button  13  proximally abuts both the case  12  and the carrier  7  hence being prevented from being depressed in the proximal direction P. 
         [0159]    Referring again to  FIGS. 1A and 1B  a control spring  19  in the shape of another compression spring is arranged around the carrier  7  and acts between a proximal first collar  20  and a distal second collar  21 . The control spring  19  is used to move the carrier  7  and hence the drive sub-assembly in the proximal direction P for needle extension or in the distal direction D for needle retraction. 
         [0160]    In the state as delivered as shown in  FIGS. 1   a  and  1   b  a cap  22  is attached to the proximal end of the case  12  and the protective needle sheath  5  is still in place over the needle  4  and the needle hub. An inner sleeve  22 . 1  of the cap  22  is arranged inside the chassis  2  and over the protective needle sheath  5 . In the inner sleeve  22 . 1  a barb  23  is attached. The barb  23  is engaged to the protective needle sheath  5  for joint axial translation. 
         [0161]    A sequence of operation of the auto-injector  1  is as follows: 
         [0162]    A user pulls the cap  22  from the proximal end of the case  12 . The barb  23  joins the protective needle sheath  5  to the cap  22 . Hence, the protective needle sheath  5  is also removed on removal of the cap  22 .  FIGS. 2   a  and  2   b  show the auto-injector  1  with the cap  22  and needle sheath  5  removed. The carrier  7  and syringe  3  are prevented from moving in the proximal direction P by the detent mechanism  18  being in a state A as in  FIG. 11A . Referring now to  FIG. 11A , the detent mechanism  18  comprises a resilient beam  2 . 1  on the chassis  2  with an inwardly protruding first beam head  2 . 2 . The first beam head  2 . 2  has a proximal third ramp  2 . 3 . The detent mechanism  18  further comprises a rhomboid ramp member  7 . 1  on the carrier  7  having a proximal fourth ramp  7 . 2  and a distal fifth ramp  7 . 3 . In state A a rounded off distal side of the first beam head  2 . 2  abuts the ramp member  7 . 1  in the distal direction D resisting movement of the carrier  7  in the proximal direction P relative to the chassis  2 . A rib on the case  12  is provided for preventing outward deflection of the resilient beam  2 . 1  thereby also preventing motion of the carrier  7  relative to the chassis  2 . 
         [0163]    Referring again to  FIGS. 2A and 2B  the user grabs the case  12  and places the chassis  2  protruding from the case  12  at the proximal end P against an injection site, e.g. a patient&#39;s skin. As the auto-injector  1  is pressed against the injection site the case  12  translates in the proximal direction P relative to the chassis  2  into an advanced position as illustrated in  FIGS. 3A and 3B . The second collar  21  is locked to the case  12  and is moved with the case  12  relative to the chassis  2  and relative to nearly all other components of the auto-injector  1  thus slightly compressing the control spring  19  against the first collar  20  which is prevented from moving in the proximal direction P by the chassis  2  due to a needle extension control mechanism  24  being in a state A illustrated in detail in  FIG. 12A . Referring now to  FIG. 12A , a resilient member in the shape of an arrowhead  20 . 1  is proximally arranged on the first collar  20 . The first collar  20  with the arrowhead  20 . 1  is being forced in the proximal direction P under load of the compressed control spring  19 . An outward sixth ramp  20 . 2  on the arrowhead  20 . 1  interacts with a second distal seventh ramp  2 . 4  on the chassis  2  ramping the arrowhead  20 . 1  in an inward direction I which is prevented by the arrowhead  20 . 1  inwardly abutting the carrier  7 . Hence, the first collar  20  cannot translate in the proximal direction P. 
         [0164]    Referring again to  FIGS. 3A and 3B  the second collar  21  is locked to the case due to a syringe refraction control mechanism  25  being in a state A illustrated in detail in  FIG. 13A . Referring now to  FIG. 13A , the syringe retraction control mechanism  25  comprises a resilient proximal beam  21 . 1  on the second collar  21 , the proximal beam  21 . 1  having a second beam head  21 . 2  having an inward boss  21 . 3  and a distal outward eighth ramp  21 . 4 . The distal outward eighth ramp  21 . 4  is engaged in a ramped second case detent  12 . 2  in a manner ramping the second beam head  21 . 1  in the inward direction I with the second collar  21  under load of the control spring  19  in the distal direction D which is prevented by the inward boss  21 . 3  inwardly abutting the carrier  7 . 
         [0165]    Referring again to  FIGS. 3A and 3B , if the user was to move the case  12  away from the injection site, the control spring  19  expands returning the auto-injector  1  to the initial condition after removal of the cap  22  as illustrated in  FIGS. 2A and 2B . 
         [0166]    In the state as in  FIGS. 3A and 3B  the carrier  7  continues to be prevented from moving in the proximal direction P by the detent mechanism  18 , however with the case  12  in its advanced position the detent mechanism  18  is unlocked as the rib on the case  12  has also moved and no longer prevents outward deflection of the resilient beam  2 . 1 . Movement of the case  12  relative to the carrier  7 , which is locked to the chassis  2  by the detent mechanism  18 , causes the button release mechanism  26  to switch to a state B illustrated in  FIG. 16B . The trigger button  13  cannot translate with the case  12  in the proximal direction P as it is abutted against the carrier  7 . The ramp on the first case detent  12 . 1  interacts with the outward first ramp  13 . 2  on the proximal beam  13 . 1  on the trigger button  13  deflecting the proximal beam  13 . 1  in the inward direction I thus engaging the inward second ramp  13 . 3  on the proximal beam  13 . 1  in a ramped carrier detent  7 . 4  arranged in the carrier  7 . As the case  12  is translated further in the proximal direction P it supports the proximal beam  13 . 1  outwardly thus locking the trigger button  13  to the carrier  7 . The trigger button  13  now protrudes from the distal end D of the chassis  12  and is ready to be pressed. 
         [0167]    In the state as in  FIGS. 3A and 3B  the user depresses the trigger button  13  in the proximal direction P. As the trigger button  13  abuts against the carrier  7  the carrier  7  is pushing in the proximal direction P against the chassis  2 , the carrier  7  and the chassis  2  interacting in the detent mechanism  18 . The force exerted by the user pressing the trigger button  13  is resolved through the chassis  2  onto the injection site, not between the trigger button  13  and the case  12 . The detent mechanism  18  provides a resistive force when the user pushes the trigger button  13 . Once the user applies a force which exceeds a pre-determined value the detent mechanism  18  releases, initiating the injection cycle. Referring now to  FIG. 11B  showing the detent mechanism  18  in a state B, the resilient beam  2 . 1  on the chassis  2  begins to bow under load from the rhomboid ramp member  7 . 1  on the carrier  7 , storing elastic energy. Despite the proximal fourth ramp  7 . 2  on the ramp member  7 . 1  friction between the contacting faces of the first beam head  2 . 2  and the proximal fourth ramp  7 . 2  prevents movement of the first beam head  2 . 2  in the outward direction  0  until the straightening force in the resiliently deformed beam  2 . 1  is sufficiently large to overcome it. At this point the resilient beam  2 . 1  is deflected in the outward direction  0  moving out of the way of the carrier  7  thus allowing the carrier  7  to translate in the proximal direction P. When the carrier  7  travels sufficiently far in the proximal direction P the rhomboid ramp member  7 . 1  on the carrier  7  passes under the first beam head  2 . 2  thus allowing it to relax and move back in the inward direction I distally behind the rhomboid ramp member  7 . 1  in a state C illustrated in  FIG. 11  C at the same time constraining translation of the carrier  7  in the distal direction D relative to the chassis  2 . 
         [0168]    Once the carrier  7  slides far enough in the proximal direction P relative to the first collar  20  the needle extension control mechanism  24  is switched to a state B as illustrated in  FIG. 12B . In  FIG. 12B  the carrier  7  has been translated in the proximal direction P in such a manner that the arrowhead  20 . 1  on the first collar  20  is no longer inwardly supported. This may be achieved by a second recess  7 . 5  in the carrier  7 . The arrowhead  20 . 1  is now deflected in the inward direction I into the second recess  7 . 5  under load of the control spring  19  arriving at a state C as illustrated in  FIG. 12C . The first collar  20  is now decoupled from the chassis  2 . Instead, the arrowhead  20 . 1  couples the first collar  20  to the carrier  7  by an inward ninth ramp  20 . 3  engaging a distal tenth ramp  7 . 6  on the carrier  7  at the proximal end of the second recess  7 . 5 . Hence, the control spring  19  continues moving the carrier  7  in the proximal direction P from this point. Whilst the user advances the needle  4  by a proportion of its travel, the control spring  19  takes over insertion before the needle  4  protrudes from the proximal end P. Therefore the user experience is that of pressing a button, rather than manually inserting a needle. 
         [0169]    The detent mechanism  18  relies on the user applying a force rather than a displacement. Once the force applied exceeds the force required to switch the detent the user will push the trigger button  13  fully, ensuring that the first collar  20  will always switch. If the user fails to pass the detent, the trigger button  13  returns to its unused state ready for use as illustrated in  FIGS. 3A and 3B . This feature avoids the auto-injector  1  arriving in an undefined state. 
         [0170]      FIGS. 4A and 4B  show the auto-injector  1  with the trigger button  13  depressed sufficiently for the control spring  19  to couple on to the carrier  7  and continue moving the carrier  7  forwards, but not yet abutting the case  12 . 
         [0171]    The carrier  7  coupled to the first collar  20  is translated in the proximal direction P driven by the control spring  19 . As the syringe  3  is arranged for joint axial translation with the carrier  3  the syringe  3  and needle  4  are also translated resulting in the needle  4  protruding from the proximal end P and being inserted into the injection site. The trigger button  13  returns to its initial position relative to the case  12  and latches back to the case  12  from the carrier  7  as in state A in  FIG. 16  A. The carrier  7  translates further in the proximal direction P preventing inward deflection of the proximal beam  13 . 1  so the outward first ramp  13 . 2  cannot disengage from the first case detent  12 . 1 . 
         [0172]    Immediately prior to the needle  4  reaching full insertion depth as illustrated in  FIGS. 5A and 5B  the peg  14  on the trigger button  13  is completely pulled out from between the resilient arms  15  on the carrier  7 . Hence, the plunger release mechanism  27  arrives in a state B shown in  FIG. 15B  with the resilient arms  15  no longer inwardly supported by the peg  14 . Due to the ramped engagement of the resilient arms  15  in the first recess  16  they are deflected in the inward direction I under load of the drive spring  8  arriving in a state B illustrated in  FIG. 15C . 
         [0173]    Hence, the plunger  9  is released from the carrier  7  and driven in the proximal direction P by the drive spring  8 , ready to expel the medicament M. The force to pull the peg  14  out from between the resilient arms  15  is provided by the control spring  19  while the force required to deflect the resilient arms  15  out of engagement to the plunger  9  is provided by the drive spring  8 . 
         [0174]    While the plunger  9  moves and closes a gap to the stopper  6  the movement of the carrier  7  in the proximal direction P is completed by the control spring  19  pushing the first collar  20 . As the carrier  7  moves with respect to the chassis  2  during needle extension the needle extension mechanism  24  arrives in a state D illustrated in  FIG. 12D . The arrowhead  20 . 1  has moved with the carrier  7  and is still kept inwardly deflected by the chassis  2  thus preventing the first collar  20  from disengaging the carrier  7 . The arrowhead  20 . 1  must be able to deflect in the outward direction  0  to allow retraction which will be discussed below. In order to allow outward deflection the arrowhead  20 . 1  travels proximally beyond the part of the chassis  2  shown in  FIGS. 12A to 12F  next to an aperture  2 . 5  in the chassis  2 . However, as long as the case  12  is being kept pressed against the injection site and not allowed to return in the distal direction D beyond a predefined distance under load of the control spring  19  the arrowhead  20 . 1  will be kept from deflecting in the outward direction  0  by a first rib  12 . 3  on the case  12  (not illustrated in  FIGS. 12A  to F, see  FIGS. 5A to 8A ) during about the second half of its motion for needle extension. 
         [0175]    The needle  4  is now fully inserted into the injection site as illustrated in  FIGS. 6A and 6B . The time between the trigger button  13  pressed and the needle  4  being fully inserted is very short, however several mechanical operations take place in this time. The needle extension depth is defined by the carrier  7  relative to the chassis  2  not relative to the case  12 , so if the user flinches or fails to hold the auto-injector  1  hard against the skin, only the case  12  will move in the distal direction D while the injection depth remains constant. 
         [0176]    As soon as the plunger  9  has closed the gap to the stopper  6  under force of the drive spring  8  the stopper  6  is pushed in the proximal direction P within the syringe  3  displacing the medicament M through the needle  4 . 
         [0177]    Immediately prior to the end of expelling the medicament with the stopper  6  having almost bottomed out in the syringe  3  as illustrated in  FIGS. 7A and 7B  a feedback component  28  is released. The stack up of tolerances, most notably due to the syringe  3  requires that the feedback must always be released prior to fully expelling the medicament. Otherwise, with certain combinations of parts, the feedback would not always release. The feedback component  28  comprises an elongate portion  28 . 1  arranged within the distal plunger sleeve  17  and a distal end plate  28 . 2  arranged between the carrier end face  10  and an end face of the trigger button  13 . Two second resilient arms  30  originate from the distal carrier end face  10  and extend in the proximal direction P. A feedback spring  29  is arranged to bias the feedback component  28  in the distal direction D relative to the carrier  7  by proximally bearing against a rib on the second resilient arms  30  and distally against the feedback component  28  (not illustrated). 
         [0178]    Note: the feedback component  28  is not illustrated in  FIGS. 16A , B and C for clarity since it does not affect the function of the button release mechanism  26 . A feedback release mechanism  31  for releasing the feedback component  28  is schematically illustrated in  FIGS. 14A ,  14 B and  14 C. Referring now to  FIG. 14A , the feedback release mechanism  31  comprises the second resilient arms  30 . A ramped inward boss  30 . 1  is arranged on each second resilient arm  30  which is engaged to a respective outward eleventh ramp  28 . 3  on the elongate portion  28 . 1  of the feedback component  28  in such a manner that the second resilient arm  30  is deflected in the outward direction O under load of the feedback spring  29 . In an initial state A of the feedback release mechanism  31  the second resilient arms  30  are prevented from being outwardly deflected by outward support of the distal plunger sleeve  17  thus preventing translation of the feedback component  28  relative to the carrier  7 . The feedback release mechanism  31  remains in state A until immediately prior to fully expelling the medicament with the stopper  6  having almost bottomed out in the syringe  3  as illustrated in  FIGS. 7A and 7B . At this point the plunger  9  has been translated in the proximal direction P relative to the carrier  7  to such an extent that the second resilient arms  30  are no longer supported by the distal plunger sleeve  17 . The feedback release mechanism  31  has thus arrived in a state B illustrated in  FIG. 14B . Due to the ramped engagement between the ramped inward boss  30 . 1  and the outward eleventh ramp  28 . 3  the second resilient arm  30  is outwardly deflected under load of the feedback spring  29  thus disengaging the feedback component  28  from the carrier  7  and allowing the feedback component  28  to move in the distal direction D driven by the feedback spring  29  in a state C illustrated in  FIG. 14C . Hence, the feedback component  28  is accelerated in the distal direction D and the distal end plate  28 . 2  impacts on the inside of the trigger button  13  producing audible and tactile feedback to the user that expelling the medicament is about finished. 
         [0179]      FIGS. 8A and 8B  show the auto-injector  1  with the stopper  6  having entirely bottomed out in the syringe  3 . 
         [0180]    As mentioned above the user is able to let the case  12  move by a few millimetres in the distal direction D under the force of the control spring  19  without affecting the position of the needle  4  as long as that motion is below a predefined distance. If the user wishes to end the injection, at any time, they must allow the case  12  to move in the distal direction D beyond that distance.  FIGS. 9A and 9B  show the auto-injector  1  with the chassis extended, e.g. when lifted from the injection site with the case  12  moved all the way in the distal direction D so that the chassis  2  protrudes from the proximal end of the case  12 . As the case  12  is moved the first collar  20  releases the carrier  7  and then the second collar  21  releases from the case  12  and pulls the carrier  7  in the distal direction D. The sequencing of this switching is critical as retraction will fail if both collars  20 ,  21  are attached to the carrier  7  at the same time. This is overcome by separating the switching of the collars  20 ,  21  by a significant displacement of the case  12 . 
         [0181]    The switching of the first collar  20  is illustrated in  FIGS. 12E  and F. In  FIG. 12E  the case  12  has been allowed to move in the distal direction D under load of the control spring  19 , e.g. during removal of the auto-injector  1  from the injection site. The first rib  12 . 3  (not illustrated, see  FIG. 9A ) is removed from outwardly behind the arrowhead  20 . 1 . The first collar  20  is still being pushed in the proximal direction P by the control spring  19 . Due to the engagement of the inward ninth ramp  20 . 3  on the arrowhead  20 . 1  with the distal tenth ramp  7 . 6  on the carrier  7  the arrowhead  20 . 1  is deflected in the outward direction O into the aperture  2 . 5  of the chassis  2  (illustrated in  FIGS. 12A to 12F ), the needle extension control mechanism  24  arriving in a state E as illustrated in  FIG. 12E , decoupling the first collar  20  from the carrier  7  and latching it to the chassis  2 . 
         [0182]    As the case  12  is moving further in the distal direction D relative to the chassis, e.g. on removal from the injection site, the syringe retraction control mechanism  25  switches from its state A (cf.  FIG. 13A ) into a state B illustrated in  FIG. 13B . The case  12  and the second collar  21  locked to the case  12  move together in the distal direction D while the carrier  7  is held in place by the detent mechanism  18  in its state C as described above (cf.  FIG. 11C ). Due to this motion the inward boss  21 . 3  on the second beam head  21 . 2  of the proximal beam  21 . 1  on the second collar  21  no longer inwardly abuts the carrier  7 . Instead the inward boss  21 . 3  is deflected in the inward direction I into a third recess  7 . 7  in the carrier  7  due to the ramped engagement of the second beam head  21 . 1  to the ramped second case detent  12 . 2  under load of the control spring  19 . The syringe retraction control mechanism  25  thus arrives in a state C as illustrated in  FIG. 13C  with the second collar  21  decoupled from the case  12  and coupled to the carrier  7 . The detent mechanism  18  applies a small retarding force to the movement of the carrier  7  before the syringe retraction control mechanism  25  switches to state C as there is a small sliding force, applied by the second collar  21 , pulling the carrier  7  in the distal direction D on translation of the case  12  in the distal direction D when the needle extension control mechanism  24  has already been switched into state E. If the carrier  7  moves too far in the distal direction D before the second collar  21  switches, the case  12  runs out of travel before the inward boss  21 . 3  can deflect into the third recess  7 . 7  preventing retraction. 
         [0183]    Starting from the position C of the detent mechanism  18  (cf.  FIG. 11C ) the carrier  7  and hence the rhomboid ramp member  7 . 1  are translated in the distal direction D under load of the control spring  19 . Hence, the distal fifth ramp  7 . 3  of the rhomboid ramp member  7 . 1  engages the proximal third ramp  2 . 3  on the first beam head  2 . 2  of the resilient beam  2 . 1  in a manner deflecting the resilient beam  2 . 1  in the inward direction I. This applies the small retarding force to the movement of the carrier  7  required for ensuring the switching of the second collar  21  to the carrier  7 . The resilient beam  2 . 1  and the rhomboid ramp member  7 . 1  are offset sideways to allow the resilient beam  2 . 1  to pass without contacting the rhomboid ramp member  7 . 1  as soon as the first beam head  2 . 2  is entirely inwardly from the ramp member  7 . 1  in a state D illustrated in  FIG. 11D . 
         [0184]    The control spring  19  is grounded at its proximal end in the case by the first collar  20  being abutted against the chassis  2 . The distal end of the control spring  19  moves the second collar  21  in the distal direction D taking with it the carrier  7  and hence the syringe  3  with the needle  4  overcoming the detent mechanism  18  as illustrated in  FIG. 11D . Note that the needle  4  is retracted by the auto-injector  1  as soon as the user allows the case  12  to translate sufficiently far as opposed to auto-injectors with needle shields which require the user to remove the auto-injector from the injection site thereby themselves pulling the needle out of the skin for allowing the needle shield to advance. 
         [0185]    As the movement allowed of the feedback component  28  is limited relative to the carrier  7  it is no longer in contact with the trigger button  13  which has moved in the distal direction D with the case  12  on removal from the injection site. 
         [0186]    When the retraction begins the feedback spring  29  does not provide any retarding force. Once the feedback component  28  hits the trigger button  13  again on retraction of the carrier  7  the feedback spring  29  must be recompressed, reducing the force driving the final part of retraction. In order to ensure a reliable retraction despite this reducing force the control spring  19  must be appropriately dimensioned. 
         [0187]    The retraction ends when the distal collar  21  meets a first back stop  12 . 4  on the case  12  as in  FIGS. 10A and 10B . The arrowhead  20 . 1  on the first collar  20  is inwardly supported by the carrier  7  in a state F illustrated in  FIG. 12F  and thus prevented from deflecting in the inward direction I. The outward sixth ramp  20 . 2  of the arrowhead  20 . 1  is engaged behind the first rib  12 . 3  on the case  12  preventing the case  12  from being pushed in the proximal direction P again. A clearance may be provided between the arrowhead  20 . 1  and the first rib  12 . 3  to allow for tolerances. 
         [0188]    The detent mechanism  18  returns to state A as in  FIG. 11A  locking the carrier  7  in position relative to the chassis  2  as it did initially, however it cannot be unlocked now as the case  12  cannot move relative to the chassis  2 . 
         [0189]    A tab  20 . 4  on the first collar  20  is now visible through an indicator window  32  in the case  12 —indicating the auto-injector  1  has been used. 
         [0190]      FIG. 17  is an isometric view of an alternative embodiment of the plunger release mechanism  27 . The plunger release mechanism  27  prevents movement of the plunger  9  in the proximal direction P relative to the carrier  7  until the carrier  7  is moved in the proximal direction P for needle extension. As opposed to the plunger release mechanism  27  of  FIG. 15 , where relative movement of the carrier  7  and trigger button  13  are used to trigger the release of the plunger  9 , the alternative embodiment of  FIG. 17  releases the plunger  9  by movement of the carrier  7  relative to the second collar  21 .  FIG. 17  illustrates the plunger release mechanism  27  prior to plunger release. The second collar  21  is shown transparent to improve clarity. The plunger  9  is being pushed in the proximal direction P by the drive spring  8 . In order for the plunger  9  to advance, it must rotate around a twelfth ramp  7 . 8  on the carrier  7 . A ramp member  9 . 1  on the plunger  9  is arranged to engage this twelfth ramp  7 . 8 . Rotation of the ramp member  9 . 1  is blocked by an inward longitudinal rib  21 . 5  on the second collar  21  splined in a longitudinal aperture  7 . 9  in the carrier  7 . The case  12  and the second collar  21  remain in the same position, i.e. coupled to each other for joint axial translation. On depression of the trigger button  13  the carrier  13  and the plunger  9  being part of the drive sub-assembly are moved in the proximal direction P, first by the user pressing the trigger button  13  and then by the control spring  19  taking over via the first collar  20  as described above. Once the carrier  7  moves sufficiently far in the proximal direction P relative to the second collar  21  the ramp member  9 . 1  on the collar  9  comes clear of the longitudinal rib  21 . 5  on the second collar  21  and can rotate past the proximal end of the longitudinal rib  21 . 5  due to its ramped engagement to the twelfth ramp  7 . 8  under load of the drive spring  8 . Hence, the drive spring  8  advances the plunger  9  in the proximal direction P for expelling the medicament M. 
         [0191]      FIG. 18  is a longitudinal section of an alternative embodiment of the button release mechanism  26 . Other than the button release mechanism  26  of  FIG. 16  which gives the appearance of a revealing trigger button  13  on skin contact by switching the ground of the trigger button  13  between the carrier  7  and the case  12 , the button release mechanism  26  of  FIG. 18  starts with the trigger button  13  locked but protruding from the distal end of the case  12 . Once the carrier  7  has moved in the distal direction D on skin contact of the chassis  2 , it is possible to depress the trigger button  13  and activate the auto-injector  1 . This ensures a sequenced operation. 
         [0192]    In the embodiment of  FIG. 18  the trigger button  13  has two proximal beams  13 . 1 , each of them having a ramped outward boss  13 . 4 . In the initial state shown in  FIG. 18  the ramped outward bosses  13 . 4  are engaged in respective fourth recesses  12 . 5  in the case  12 . Disengaging the ramped outward bosses  13 . 4  from the fourth recesses  12 . 5  is prevented by the carrier  7  inwardly supporting the proximal beams  13 . 1  in a manner to keep the proximal beams  13 . 1  from deflecting inwardly. Inward protrusions  13 . 5  on the proximal beams  13 . 1  abut against a second rib  7 . 10  on the carrier  7  in a manner preventing the carrier  7  from moving further in the proximal direction P in the initial state. Once the carrier  7  has moved in the distal direction D on skin contact of the chassis  2  a first window  7 . 11  in the carrier  7  is moved behind the inward protrusion  13 . 5  so as to allow the proximal beams  13 . 1  to be inwardly deflected due to their ramped engagement in the fourth recesses  12 . 5  on depression of the trigger button  13 . The proximal beams  13 . 1  are now outwardly supported by the case  12  and remain engaged to the carrier  7  even on retraction of the needle  4 . The trigger button  13  does therefore not return to its initial position, indicating that the auto-injector  1  has been used. 
         [0193]    The button release mechanism  26  illustrated in  FIG. 18  may preferably be combined with the plunger release mechanism  27  illustrated in  FIG. 17 . 
         [0194]      FIGS. 19A and 19B  show two longitudinal sections of an alternative embodiment of the detent mechanism  18 . The detent mechanism  18  of  FIGS. 11A to 11D , which may be referred to as a “race track” mechanism because of the first beam head  2 . 2  travelling around the rhomboid ramp member  7 . 1  has multiple functions which control the movement of the carrier  7  relative to the chassis  2 . The alternative detent mechanism  18  of  FIGS. 19A and 19B  uses three clips  7 . 12 ,  7 . 13 ,  2 . 6  to produce the same effect. 
         [0195]    The first clip  7 . 12  is arranged as an outwardly biased resilient beam on the carrier  7  extending from the carrier  7  in the proximal direction P. the first clip  7 . 12  is arranged to prevent the carrier  7  from being moved in the proximal direction P prior to the chassis  2  being depressed or rather the case  12  being translated on skin contact. The first clip  7 . 12  is composed of two sections side by side. A first section  7 . 14  prevents movement of the carrier  7  in the proximal direction P by abutting the chassis  2  in a recess. A second section  7 . 15  is arranged as an outwardly protruding clip head arranged to be ramped inwards by a ramp feature  12 . 6  on the chassis  12  for releasing the first clip  7 . 12  thereby unlocking the carrier  7  from the chassis  2  when the case  12  is being translated in the proximal direction P on skin contact. A longitudinal slot  2 . 7  in the chassis  2  is arranged for allowing the second section  7 . 15  to slide in the proximal direction P once the lock has been released. A slight friction force between the first clip  7 . 12  and the chassis  2  provides the retarding force required to ensure retraction. 
         [0196]    The second clip  7 . 13  is arranged as a resilient beam on the carrier  7  extending in the distal direction D having an outwardly protruding third beam head  7 . 16  with a proximal ramp. The third beam head  7 . 16  serves as a back stop against a third rib  2 . 9  on the chassis  2  for preventing the carrier  7  moving in the distal direction D from its initial position. The carrier  7  and chassis  2  are assembled with the second clip  7 . 13  in this position prior to inserting the syringe  3  into the carrier  7  which is facilitated by the proximal ramp on the third beam head  7 . 16 . The syringe  3  locks the clip in place by preventing inward deflection thus creating a fixed stop. 
         [0197]    The third clip  2 . 6  is a resilient beam on the chassis  2  extending in the distal direction D. A ramped fourth beam head  2 . 8  on the third clip  2 . 6  is arranged to inwardly engage in a fifth recess  7 . 17  in the carrier  7 . Once the first clip  7 . 12  is unlocked, the user can load the third clip  2 . 6  by pressing the carrier  7  in the proximal direction P on depression of the trigger button  13 . The third clip  2 . 6  is loaded in compression, i.e. it will bend outwards and release suddenly due to its ramped engagement to the carrier  7  providing the detent functionality similar to that illustrated in  FIG. 11B . 
         [0198]      FIG. 20  is a longitudinal section of a third embodiment of the detent mechanism  18  which is a variation on the embodiment of  FIGS. 19A and 19B . In this embodiment the detent function of the third clip  2 . 6  has been added into the first clip  7 . 12 . The lock between the case  12  and the carrier  7  is released in the same way, but the detent is provided by deflecting the first clip  7 . 12  inwards a second level which is achieved by the chassis  2  not having a slot  2 . 7  for the second section  7 . 15 . Instead the second section  7 . 15 , once ramped inwards by the ramp feature  12 . 6  on the case  12  has to be further ramped inwards inside the chassis  2  on axial load between the chassis  2  and the carrier  7 , suddenly releasing their engagement. 
         [0199]      FIG. 21  is a longitudinal section of an alternative embodiment of the feedback release mechanism  31 . As opposed to the feedback release mechanism  31  of  FIG. 14  where the feedback spring  29  acts between the carrier  7  and the feedback component  28 , in the embodiment illustrated in  FIG. 21  the feedback spring  29  acts between the case  12  and the feedback component  28 . During needle extension the feedback spring  29  is compressed as the feedback component  28  moves with the carrier  7  relative to the case  12 . When the feedback component  28  is released by the plunger  9  shortly before the end of dose, the feedback component  28  moves in the distal direction D and impacts the trigger button  13 . Other than in  FIG. 14  the feedback spring  29  is not being recompressed during needle retraction since it is grounded in the case  12  not in the carrier  7 . 
         [0200]      FIGS. 22A and 22B  show longitudinal sections of an alternative embodiment of the needle extension control mechanism  24  which is also arranged to perform the detent function of the detent mechanism  18  on needle retraction and needle extension.  FIG. 23  shows a corresponding isometric view. A fourth clip  20 . 5  on the first collar  20  is arranged as a resilient beam with a beam head having an inward proximal thirteenth ramp  20 . 6  for engaging a fourth rib  7 . 18  on the carrier  7  and outwardly supported by the case  12  so as to keep the first collar  20  engaged to the carrier  7  prior to use, during needle extension and during expelling the medicament. When the case  12  moves in distal direction relative to the carrier, e.g. when the user lifts the case  12  away from the injection site at the end of injection, a sixth recess  12 . 7  in the case  12  is moved outwardly behind the fourth clip  20 . 5  allowing the fourth clip  20 . 5  to release when the carrier  7  is pulled in the distal direction D by the second collar  21 . Since the fourth clip  20 . 5  has to be ramped outwards a small force is required to release the fourth clip  20 . 5 , providing the retraction detent. 
         [0201]    A fifth clip  2 . 10  on the chassis  2  abuts a block  20 . 7  on the first collar  20  prior to use preventing the first collar  20  and hence the carrier  7  engaged to the first collar  20  from moving in the proximal direction P. In order to release, the fifth clip  2 . 10  must be deflected outwards and over the block  20 . 7 . Outward deflection of the fifth clip  2 . 10  is initially prevented by the case  12 . Once the case  12  has moved on skin contact a second window  12 . 8  in the case  12  appears outwardly from the fifth clip  2 . 10  allowing outward deflection. The fifth clip  2 . 10  is then deflected by a fourteenth ramp  7 . 19  on the carrier  7  when the carrier  7  is pushed in the proximal direction P on button depression as the fourth clip  20 . 5  does allow translation of the carrier  7  in the proximal direction P relative to the first collar  20  but not the other way round. The detent for needle extension is provided by having to deflect the fifth clip  2 . 10  when it is loaded by the control spring  19 . 
         [0202]      FIGS. 24A and 24B  show longitudinal sections of a third embodiment of the needle extension control mechanism  24 , also arranged to perform the functions of the detent mechanism  18 .  FIG. 25  is an isometric view of the needle extension control mechanism  24  of  FIG. 24 . The embodiment is similar to that illustrated in  FIGS. 22A ,  22 B and  23 . The difference is that the fifth clip  2 . 10  is arranged on the first collar  20  and the block  20 . 7  is arranged on the chassis  2 , i.e. their position has been switched, so there are two clips  2 . 10  and  20 . 5  on the first collar  20 . 
         [0203]    The fourth clip  20 . 5  is identical to that in  FIG. 22B . It keeps the first collar  20  connected to the carrier  7  until the needle retraction is triggered, ensuring full needle extension length or depth is reached and maintained until the retraction cycle is initiated by displacing the case backwards in distal direction relative to the chassis, e.g. when removing the auto-injector  1  from the skin. 
         [0204]    The fifth clip  2 . 10  provides the detent for needle extension and releases the first collar  20  from the chassis  2 , initiating needle extension. The fifth clip  2 . 10  prevents the first collar  20  and hence the carrier  7  engaged to the first collar  20  from moving in the proximal direction P prior to use by abutting the block  20 . 7  on the chassis  2 . In order to release, the fifth clip  2 . 10  must be deflected outwards and over the block  20 . 7 . Outward deflection of the fifth clip  2 . 10  is initially prevented by the case  12 . Once the case  12  has moved on skin contact the second window  12 . 8  in the case  12  appears outwardly from the fifth clip  2 . 10  allowing outward deflection. The fifth clip  2 . 10  is then deflected by the fourteenth ramp  7 . 19  on the carrier  7  when the carrier  7  is pushed in the proximal direction P on button depression as the fourth clip  20 . 5  does allow translation of the carrier  7  in the proximal direction P relative to the first collar  20  but not the other way round. The detent for needle extension is provided by having to deflect the fifth clip  2 . 10  when it is loaded by the control spring  19 . 
         [0205]      FIGS. 26A and 26B  show a longitudinal section of a third embodiment of the feedback release mechanism  31 . This embodiment works without the need for a dedicated feedback spring. The plunger  9  comprises a proximally ramped rib  9 . 2  arranged to splay two seventh clips  7 . 21  on the carrier  7  immediately prior to the end of dose. When the proximally ramped rib  9 . 2  has travelled past the seventh clips  7 . 21  they snap back and impact the plunger  9  generating a sound. The tubular shape of the carrier  7  helps to transmit the sound.  FIG. 26A  shows the feedback release mechanism  31  before release.  FIG. 26B  shows the feedback release mechanism  31  after release. Proximal faces of the seventh clips  7 . 21  on the carrier  7  are axially offset to facilitate assembly by lifting the seventh clips  7 . 21  over the distal side of the proximally ramped rib  9 . 2  one by one. 
         [0206]      FIGS. 27A and 27B  show longitudinal sections of another embodiment of the auto-injector  1  in different section planes, the different section planes approximately 90° rotated to each other, wherein the auto-injector  1  is in an initial state prior to use. The auto-injector  1  is essentially identical to the one described in  FIGS. 1 to 16 . However, other than the auto-injector of  FIGS. 1 to 16  the auto-injector  1  of this embodiment has a wrap-over sleeve trigger instead of a trigger button. 
         [0207]    The wrap-over sleeve trigger  12  is the same component as the case  12  which has a closed distal end face  12 . 10  other than the one in  FIGS. 1 to 16 . An internal trigger button  13  is arranged at the distal end inside the sleeve trigger  12 . Other than in  FIGS. 1 to 16  the trigger button  13  is not visible nor does it protrude from the case  12  in any state. In the initial state a clearance  33  is provided between the distal end face  12 . 10  of the sleeve trigger  12  and the internal trigger button  13  allowing for some travel of the sleeve trigger  12  without interfering with the trigger button  13 . 
         [0208]    As the auto-injector  1  does not differ from the auto-injector of  FIGS. 1 to 16  in other respects it is essentially operated in the same way with the following exceptions: 
         [0209]    As the chassis  2  is placed against the injection site the sleeve trigger  12  translates in the proximal direction P relative to the chassis  2  into the advanced position in a first phase of sleeve travel removing the clearance  33  between the distal end face  12 . 10  of the sleeve trigger  12  and the internal trigger button  13 . As in the embodiment of  FIGS. 1 to 16  this motion unlocks the detent mechanism  18  and the trigger button  13 . As the user continues to depress the sleeve trigger  12  in a second phase of sleeve travel thereby further advancing it in the proximal direction P the distal end face  12 . 10  hits the internal trigger button  13  thereby depressing it until the first collar  20  is released from the chassis  2  and the control spring force is coupled on to the carrier  7 . The carrier  7  then advances until the internal trigger button  13  stops on another rib in the case  12  and the plunger release mechanism  27  is released (note the peg  14  is shorter in this embodiment. 
         [0210]    From a user perspective, the detent mechanism  18  is arranged to provide a resistive force when the user reaches the second phase of sleeve travel. Internally, there is no difference to the embodiment of  FIGS. 1 to 16  at this point. 
         [0211]    Needle extension is triggered by the user fully advancing the sleeve trigger  12  in the second phase of sleeve travel thereby fully depressing the internal trigger button  13  and overcoming the detent mechanism as in the embodiment of  FIGS. 1 to 16 . 
         [0212]    As the control spring  19  takes over on button depression fully advancing the carrier  7  for needle extension the internal trigger button  13  bottoms out on an internal fifth rib  12 . 11  in the sleeve trigger  12  and the internal trigger button  13  switches back to being locked to the sleeve trigger  12  as in  FIG. 16C . 
         [0213]    The embodiment of  FIGS. 27A and 27B  may also be combined with the alternative features illustrated in  FIGS. 17 to 26 . 
         [0214]    It goes without saying that in all ramped engagements between two components described in the above embodiments there may be just one ramp on one or the other component or there may be ramps on both components without significantly influencing the effect of the ramped engagement.