Abstract:
An injection device includes a syringe with a hollow needle and a stopper for sealing the syringe and displacing a medicament stored in the syringe. An arrangement for transferring a translation of a drive means to a plunger for pushing against the stopper includes a release latch pivoted at one end and connected to either the drive means or the plunger. The other end of the release latch engages the other one of the drive means or the plunger. The non-pivoted end of the release latch disengages by rotation upon contact between a ramp and another component when the stopper has displaced most of a predefined medicament dose. The release latch is long enough to provide a clearance between the plunger and the drive means when engaged to allow the plunger, stopper and needle to be retracted inside the syringe or a housing after disengaging the release latch.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/EP2011/053157 filed Mar. 3, 2011, which claims priority to European Patent Application No. 10155948.2 filed on Mar. 9, 2010. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
     FIELD OF INVENTION 
     The invention relates to an injection device. 
     BACKGROUND 
     Administering an injection is a process which presents a number of risks and challenges for users and healthcare professionals, both mental and physical. 
     Injection devices (i.e. devices capable of delivering medicaments from a medication container) typically fall into two categories—manual devices and auto-injectors. 
     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. 
     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. 
     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. 
     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. Forces required of the user/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, the action of placing the autoinjector against the skin or the action of the needle reaching its injection depth. In some devices the energy to deliver the fluid is provided by a spring. 
     Auto-injectors may be disposable or single use devices which may only be used to deliver one dose of medicament and which have to be disposed of after use. Other types of auto-injectors may be reusable. Usually they are arranged to allow a user to load and unload a standard syringe. The reusable auto-injector may be used to perform multiple parenteral drug deliveries, whereas the syringe is disposed after having been spent and unloaded from the auto-injector. The syringe may be packaged with additional parts to provide additional functionality. 
     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 in a proximal direction inside the ampoule. After the fluid medicine has been injected energy stored in the tension spring is released and the injection needle is automatically retracted back to its original storage position. 
     In order to prevent post-injection needle stick injuries, syringes with needle retraction have been developed. These syringes comprise a stopper, a plunger connected to the stopper, a hollow injection needle and a needle retraction spring. When the stopper in such a syringe has bottomed out and displaced at least nearly all of the syringe&#39;s content it grips a part of the needle protruding into the interior of the syringe. The needle retraction spring pushes the plunger in distal direction, i.e. away from the injection site. The plunger then pulls the stopper and the needle in distal direction until the needle is hidden inside the syringe. 
     GB 2 447 339 A discloses an autoinjector comprising an outer housing in which is mounted a syringe comprising a barrel for holding a volume of medicament, a needle at one end of the barrel and a plunger axially-moveable in the barrel, the autoinjector further comprising an inner housing intermediate the outer housing and the syringe and an energy source in communication with said inner housing, wherein the inner housing is moveable by the energy source between three positions, namely a first position in which the inner housing is in communication with the barrel such that, in use, the plunger and barrel are moveable axially so as to move at least part of said needle out of the outer housing; a second position in which the inner housing is in communication with the plunger but not the barrel such that, in use, said plunger is moveable axially into said barrel so as to expel medicament through the needle; and a third position in which the inner housing is in communication with neither the plunger nor the barrel such that, in use, the plunger and barrel are able to retract in order to retract the needle into the outer housing, characterised in that the plunger includes biasing means for axially biasing the barrel, before activation of the energy source, to a position forward of the part of the inner housing which acts on the barrel in said first position. 
     US 2003/105430 A1 discloses an automatic injector in which the needle is injected automatically into the injection site (e.g., a patient&#39;s skin), delivery is initiated upon activation of the injector, and the needle is retracted after the end of delivery. Preferably the needle is not seen by the user prior to, during or after injection. Prior to and after injection, the needle is withdrawn into the device so as to avoid any potential injury or health risk to the user or health care provider. The injector includes a housing and a control unit arranged to slide within the housing to move a piston rod during drug delivery and to pivot within the housing for needle retraction. The injector may also include a back rod that moves the piston rod before activation of the injector for titration and reconstitution and automatically disengages from the piston rod upon activation of the injector. A needle-locking device can be used in any number of pen-like injectors or other types of injectors or syringes. The needle-locking device includes a clip that insures that a needle assembly within an injector is in a locked position before and after use. 
     SUMMARY 
     One object of the present invention to provide an injection device with a means for transferring a translation to a plunger of a syringe arranged in the injection device and allowing the plunger to retract after the end of an injection cycle. 
     This object is achieved by an injection device according to claim  1 . 
     Preferred embodiments of the invention are given in the dependent claims. 
     According to the invention an injection device comprises a syringe with a hollow needle and a stopper for sealing the syringe and displacing a medicament stored in the syringe, the injection device further comprising a drive means, a plunger arranged for pushing against the stopper and an arrangement for transferring a translation of the drive means to the plunger. The arrangement comprises an elongate release latch member. The release latch member is pivoted at one end which is connected to either the drive means or the plunger. Another end of the release latch member is arranged for engaging the respective other one of the drive means or the plunger. The release latch member is arranged to have its non-pivoted other end disengaged by rotation due to contact between at least one ramp and another component when the stopper has at least nearly displaced all of a predefined dose of the medicament. Force propagation from the drive means to the plunger is thus interrupted so a needle retraction spring may retract the needle. The ramp may be arranged at the release latch member or at another part moving relative to the release latch member during the translation. The other component may be another ramp or a pin. A length of the release latch member is specified so as to provide a clearance between the plunger and the drive means when the release latch member is engaged in order to allow at least the plunger, the stopper and a hollow needle of the syringe to be retracted at least far enough to hide the needle inside the syringe or inside a housing after disengaging the release latch member. 
     If the arrangement is used with a so called needle retraction syringe, such as a Unilife® syringe, the needle is hidden inside the syringe after delivery of the predefined dose. In this case it is sufficient to allow retraction of the plunger, the stopper, and the needle. 
     If a different syringe type with a fixed needle is used, the plunger and the entire syringe along with the needle and the stopper have to be retracted so as to hide the needle inside the housing. 
     Preferably the release latch member is pivoted at the end connected to the drive means. This allows for using standard syringes with needle retraction functionality without having to attach the release latch member to their plunger. Instead the release latch member may be part of a reusable injection device, e.g. an auto-injector containing a replaceable syringe. 
     The predefined dose of the medicament is preferably the entire content of the syringe. 
     In one embodiment the release latch member is arranged to be disengaged depending on a distance travelled until at least the entire predefined dose has been delivered. This may be achieved by ramp engagement of the release latch member to a housing or chassis which translated relative to the release latch member and the plunger. 
     In a preferred embodiment the release latch member is arranged to be disengaged depending on a time elapsed from a beginning of the translation. This may be achieved by a damper unit arranged in series with the drive means and the release latch member. The damper unit may comprise a plunger spring and a viscous damper. The plunger spring is arranged for being compressed when subjected to the force of the drive means acting against a counteracting force of the stopper, which depends on friction between the stopper and the inner wall of the syringe and on the hydrostatic resistance of the liquid medicament being displaced through the hollow needle. Compression of the plunger spring is delayed by the viscous damper. At the beginning of the translation the plunger spring is in an expanded state, but during the translation it is slowly compressed. A coefficient of damping of the damper is specified such that a time taken to fully compress the plunger spring is greater than a time required to displace the predefined dose. The release latch member may be pivoted in a proximal end of the damper unit, and arranged to be rotated out of engagement with the plunger by a distal end of the damper unit when the plunger spring is fully compressed. Force propagation from the drive spring to the plunger is thus interrupted and the needle retraction spring may retract the needle. Provided the predefined dose is the entire content, both problems are solved, reliably retracting the hollow needle to a safe position and fully emptying the syringe which is particularly desirable with expensive drugs. Emptying the syringe is also important for dosage accuracy. 
     The function of the plunger spring is to reset the damper after use in order to prepare it for another injection cycle. However, in a single use device the damper unit may be implemented without a plunger spring. 
     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. 
     Preferably, the viscous damper may comprise a piston fixed to a drive collar by a connecting rod. The drive collar is arranged at a proximal end of the drive means. The piston has a greater diameter than the connecting rod. A hollow cylinder with an internal diameter slightly greater than the diameter of the piston may be arranged around the piston thus allowing the piston and cylinder to reciprocate. A proximal end face of the cylinder may be fully closed and a distal end face of the cylinder may be arranged to seal the cylinder against the connecting rod. Thus, the interior of the cylinder may be divided into two separate cavities by the piston. At least one transfer port may be provided through the piston in a manner to allow a fluid to flow between the distal side of the piston and the proximal side, i.e. from one cavity into the other. The size and number of the transfer ports and the viscosity of the fluid in the cylinder determine the damping characteristics of the viscous damper. 
     A gasket ring may be arranged to seal the piston against the cylinder in order to avoid uncontrolled leaking of the fluid between the cavities which might lead to less repeatable damping characteristics. 
     Another gasket ring may be arranged to seal the connecting rod against the distal end face of the cylinder in order to avoid fluid leaking out of the damper which would otherwise in a drift of the damping characteristics due to disappearing liquid and to pollution of the interior of the auto-injector. An air space may be provided in the cylinder, e.g. by only partially filling it with the damping fluid in order to compensate for the volume of the connecting rod as it goes into the cylinder. Otherwise the viscous damper could lock since the volume of fluid displaced by the piston on its proximal side is greater than the volume increase on the distal side due to the volume of the connecting rod. Air or another gas provided in the cylinder in addition to the viscous fluid can be compressed in order to compensate this disparity in volume change. A hydraulic lock situation is thus avoided. 
     The plunger spring may be arranged in a longitudinal bore in the connecting rod and grounded at its distal end in the drive collar. The proximal end of the plunger spring may bear against the proximal face of the cylinder from inside. Thus, the damper unit is arranged as a compact unit. 
     Preferably the arrangement for transferring a translation of a drive means to a plunger is applied in an auto-injector. 
     A reusable auto-injector for administering a dose of a liquid medicament may comprise:
         an elongate housing arranged to contain the syringe with a hollow needle and a stopper for sealing the syringe and displacing the medicament, the housing having a distal end and a proximal end with an orifice intended to be applied against the injection site, wherein the syringe is slidably arranged with respect to the housing, wherein a plunger is arranged for transferring a translation to the stopper,   a drive spring capable of, upon activation:
           pushing the needle from a covered position inside the housing into an advanced position through the orifice and past the proximal end, and   operating the syringe to supply the dose of medicament, and   
           activating means, i.e. the trigger button arranged to lock the drive spring in a compressed state prior to manual operation and capable of, upon manual operation, releasing the drive spring for injection.       

     The elongate housing may comprise the distal portion and the proximal portion connected by a hinge, the hinge having a rotational axis offset from a longitudinal axis of the auto-injector and oriented transversally with respect to the longitudinal axis. The portions are rotatable about the hinge relative to each other between an aligned position with their longitudinal axes aligned and a maximum opening angle. The drive spring may be compressed by rotating the portions out of the aligned position towards the maximum opening angle. The activating means are arranged to lock the drive spring in the compressed state when the portions are rotated at least almost by the maximum opening angle. A loading bay for holding the syringe is arranged in the proximal portion, the loading bay accessible from its distal end for loading or unloading the syringe when the portions are rotated out of the aligned position, e.g. when they are rotated by least almost the maximum opening angle. 
     An alternative embodiment of the auto-injector may have the two portions connectable by other means than the hinge, e.g. a screw connection or a bayonet fit. 
     When referring to the proximal and distal portion of the auto-injector in this specification their respective distal and proximal ends are those that point in the respective direction during an injection, i.e. with the portions aligned. In the terminology of this specification the distal end of the distal portion remains the distal end even if the portions are rotated by the maximum opening angle in such a manner that the distal end of the distal portion essentially points in the same direction as the proximal end of the proximal portion in this situation. 
     The said auto-injector is a reusable auto-injector, which may be split in two by rotating the portions about the hinge. On the one hand this rotating action serves for cocking the drive spring, on the other hand it provides access to the loading bay in order to remove a spent syringe and insert a new, unused one. The auto-injector involves less user actions to reset it for another drug delivery compared to conventional reusable auto-injectors. Conventional auto-injectors usually require the user to dismantle it after use, load a new syringe, reset the drive spring and reassemble the auto-injector. 
     Once the activating means has been operated to release the drive spring the auto-injector will advance the syringe and needle thereby inserting the needle into the injection site, e.g. a patient&#39;s skin. Furthermore the auto-injector will automatically empty the syringe in order to deliver the medicament. 
     In a preferred embodiment a lever may be attached with one end to a fixed first pivot in the proximal portion, wherein the other end of the lever may be attached to a second pivot arranged at a sliding shuttle in the distal portion. The sliding shuttle may be translatable in longitudinal direction of the distal portion between a maximum proximal position when the portions are aligned and a maximum distal position when the portions are rotated at least almost by the maximum opening angle, which may be about 180 degrees. A drive collar arranged at a proximal end of the drive spring may be engageable by the sliding shuttle in order to compress the drive spring, i.e. the sliding shuttle pushes the drive collar in a distal direction in the distal portion as the portions are rotated out of alignment thus cocking the drive spring, whose distal end may be grounded inside the distal end of the distal portion. During that cocking process, the mechanical advantage increases as the drive spring is compressed due to the lever action. This is particularly advantageous if the drive means is a compression spring whose spring force increases with the level of compression. Thus, the user effort required to reset the auto-injector is reduced. 
     In another preferred embodiment at least one interlock mechanism may be arranged, comprising first latch features for preventing the syringe and needle from being pushed into the advanced position and further comprising second latch features for preventing a trigger button, i.e. the activating means from being pressed. The interlock mechanism serves for defining an operation sequence of an auto-injector in a manner to allow a lateral trigger button to be operated only when a proximal end of the auto-injector is pressed against an injection site. 
     The interlock mechanism may be arranged to prevent the button from being pressed as long as the auto-injector is not pressed against the injection site in order to keep the user from activating the auto-injector inadvertently. This increases needle safety and reduces the risk for needle stick injuries and for wasting the medicament without injecting it. The first latch features and the second latch features may be arranged to be disengaged by the proximal end of the auto-injector being pressed against an injection site. This skin interlock feature secures, that the device can only be triggered when it is properly positioned for an injection. 
     The skin interlock may comprise a detector sleeve arranged in the proximal portion and biased in proximal direction by a detector spring into a position with the detector sleeve protruding beyond the proximal end of the proximal portion. The interlock mechanism may be disengaged by pressing the detector sleeve against the injection site. Thus the detector sleeve is translated against the force of the detector spring in distal direction. The interlock mechanism may be arranged to disengage when the detector sleeve is pushed into the auto-injector and essentially on a level with the proximal end of the auto-injector. However, the interlock mechanism may also be arranged to disengage when the detector sleeve is pushed in and still protruding from the proximal end to a lesser extent than without being pushed. 
     Preferably the detector sleeve may comprise a longitudinal extension bar extending at least almost to the distal end of the proximal portion when the detector sleeve is pushed into the auto-injector. The first latch feature may comprise a dog and a syringe latch arm. The dog may protrude from the extension bar in a manner to disengage the syringe latch arm from the loading bay when the detector sleeve is pushed into the auto-injector. Once the first latch feature is disengaged, the loading bay with the syringe is allowed to be moved in proximal direction. When the detector sleeve is not pushed into the auto-injector, the syringe latch arm prevents the syringe from being advanced. 
     The proximal end of the latch arm and/or the dog for engaging it may comprise a ramp for easing their interaction. 
     The second latch features may comprise a dog arranged at the trigger button and a transmission bar arranged in the distal portion and slidable in longitudinal direction. A proximal end of the transmission bar may bear against a distal end of the extension bar when the portions are aligned. Consequently, translation of the detector sleeve is forwarded to the transmission bar when the portions are aligned. A recess for the dog is provided in the transmission bar. When the detector sleeve is not pushed into the auto-injector, the dog is blocked by the transmission bar. Hence, the trigger button cannot be pressed. Once the detector sleeve is pushed in, the dog may enter the recess thus allowing the trigger button to be pressed. 
     A detector means is arranged inside an elongate housing of the auto-injector at the proximal end. The detector means is slidable in longitudinal direction and biased by a detector spring into a position with the detector means protruding beyond the proximal end. A dog is arranged at the trigger button. At least one longitudinal bar is provided in the housing. At least one of the bars is slidable in longitudinal direction and coupled to the detector means for joint movement at least in distal direction. 
     The detector means may be arranged as an essentially tubular detector sleeve or as a part with at least one tooth protruding beyond the proximal end. 
     The loading bay is preferably biased in distal direction by a syringe retraction spring. The syringe refraction spring may be a compression spring arranged around the loading bay. It may be arranged to retract the syringe in a manner to hide the needle inside the proximal portion after delivering the dose of medicament by decoupling the plunger from the drive spring. This feature provides post-injection needle safety, i.e. the user is prevented from needle stick injury after removing the auto-injector from the injection site. The syringe spring may also be used to return the loading bay into the position where it is locked by the first latch features when the housing is split into for replacing the syringe. 
     The drive collar and the trigger button may be equipped with respective snap arms arranged to snap into each other when the drive spring is sufficiently compressed. The snap arms may be disengaged by pressing the trigger button. 
     Usually the hollow needle is equipped with a protective needle shield for keeping the needle sterile and preventing it from being mechanically damaged. The protective needle shield is attached to the needle when the syringe is assembled. 
     In order to prepare the auto-injector for delivering a dose the protective needle shield has to be removed from the needle. 
     In one embodiment of the invention a cap may be arrangeable at the proximal end of the proximal portion. In the cap barbs may be provided for gripping the protective needle shield. When the cap is removed from the housing in preparation of an injection the protective needle shield is reliably removed without exposing the user to too high a risk to injure themselves. 
     The barbs may be arranged to snap into a circumferential notch or behind a shoulder of the protective needle shield. 
     Preferably the barbs are arranged to be constrained by the detector sleeve from moving radially outward and inadvertently disengaging the protective needle cap as long as the cap is attached to the auto-injector. 
     The cap may be attachable to the housing by a screw connection. This allows for a low force removal of the protective needle shield. 
     The housing may have at least one viewing window for inspecting the syringe, or be manufactured from a transparent material. 
     The auto-injector may preferably be used for subcutaneous or intra-muscular injection, particularly for delivering one of an analgesic, an anticoagulant, insulin, an insulin derivate, heparin, Lovenox, a vaccine, a growth hormone, a peptide hormone, a protein, antibodies and complex carbohydrates. 
     The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
     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, 
     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, 
     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, 
     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. 
     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. 
     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-(ω-carboxyheptadecanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-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. 
     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(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)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(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)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(O2)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(O2)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.   

     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. 
     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. 
     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 C1-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. 
     Pharmaceutically acceptable solvates are for example hydrates. 
     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 
       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: 
         FIG. 1  is a longitudinal section of a reusable auto-injector, 
         FIG. 2  is a longitudinal section of the auto-injector during loading of a syringe, 
         FIG. 3  is the auto-injector in a resetting step after loading, 
         FIG. 4  is the auto-injector during removal of a cap and a rigid needle shield, 
         FIG. 5  shows the cap and rigid needle shield in different stages of operation, 
         FIG. 6  is the auto-injector pressed against an injection site after the cap and rigid needle shields have been removed, 
         FIG. 7  is a perspective detail view of a syringe interlock with a protective sleeve, 
         FIG. 8  is a perspective detail view of a trigger button interlock with the protective sleeve, 
         FIG. 9  is the auto-injector during actuation by means of the trigger button, 
         FIG. 10  is a perspective detail view of a loading bay, 
         FIG. 11  is another perspective detail view of the loading bay, 
         FIG. 12  is the auto-injector near the end of an injection stroke, 
         FIG. 13  is a detail view of a damped delay member near the end of the injection stroke, 
         FIG. 14  is a detail view of the damped delay member decoupled from the syringe after the end of the injection, 
         FIG. 15  is a perspective view of the damped delay member of  FIG. 13 , 
         FIG. 16  is a perspective view of the damped delay member of  FIG. 14 , 
         FIG. 17  is the auto-injector when being removed from the injection site, and 
         FIG. 18  is the auto-injector during removal of the spent syringe. 
     
    
    
     Corresponding parts are marked with the same reference symbols in all figures. 
     DETAILED DESCRIPTION 
       FIG. 1  is a longitudinal section of a reusable auto-injector  1 . The auto-injector  1  comprises an elongate housing  2 . A disposable syringe  3 , e.g. a Uni-Life syringe, with a hollow needle  4  is arranged in a proximal portion of the auto-injector  1 . When the syringe  3  is assembled a protective needle shield  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 loading bay  7 . A drive spring  8  in the shape of a compression spring is arranged in a distal portion of the auto-injector  1 . A plunger  9  is arranged for forwarding the spring force of the drive spring  8 . The drive spring  8  is used for providing axial motion for advancing the syringe  3 , inserting the needle  4  into the injection site, i.e. a patient&#39;s skin and injecting a dose of medicament M. 
     In the present embodiment the needle  4  is withdrawn into the syringe  3  once fully emptied. However, a post-injection needle safety function may be alternatively integrated into the auto-injector  1  instead of the syringe  3 . 
     The elongate housing  2  comprises an essentially tubular distal portion  2 . 1  and an essentially tubular proximal portion  2 . 2  connected by a hinge  10  so the portions  2 . 1 ,  2 . 2  may be operated similar to a break barrel air rifle. 
       FIG. 2  shows how the disposable syringe is loaded into the auto-injector  1 . The housing  2  is breached around the hinge  10  so the portions  2 . 1 ,  2 . 2  are not aligned any more. The syringe  3  may now be inserted into the loading bay  7  through the distal opening of the proximal portion  2 . 2 . A lever  11  is attached with one end to a fixed first pivot  12  in the proximal portion  2 . 2  of the housing  2 . The other end of the lever  11  is attached to a second pivot  13  arranged at a sliding shuttle  14  in the distal portion  2 . 1 , the sliding shuttle  14  moveable in longitudinal direction. When the portions  2 . 1 ,  2 . 2  are aligned as in  FIG. 1  the sliding shuttle  14  is held in a maximum proximal position by the lever  11 . When the housing  2  is breached around the hinge as in  FIG. 2  the lever  11  forces the sliding shuttle  14  to move in distal direction D as shown in  FIG. 2 . In  FIG. 2  the drive spring  8  is already in a compressed state. However, if the auto-injector  1  is breached open following an injection the then relaxed drive spring  8  is cocked by the lever  11  since the sliding shuttle  14  bears against a drive collar  15  arranged at a proximal end of the drive spring  8  (cf.  FIG. 18 ). When the sliding shuttle  14  has pushed the drive collar  15  to a maximum distal position a snap arm  15 . 1  of the drive collar snaps behind a snap arm  16 . 1 . of a trigger button  16 . This lever action resets the auto-injector  1  for another injection cycle. 
     After cocking the drive spring and inserting the syringe  3  in the manner described the user closes the auto-injector  1  by rotating the distal portion  2 . 1  about the hinge  10  until its longitudinal axis is aligned to the longitudinal axis of the proximal portion  2 . 2  as shown in  FIG. 3 . As the auto-injector  1  is closed, the sliding shuttle  14  translates in proximal direction P within the distal portion  2 . 1 . A locking mechanism (not illustrated) may be provided for locking the two portions  2 . 1 ,  2 . 2  in a coaxial position. An example mechanism may comprise a cylindrical sleeve mounted around the external surface of the housing  2  constrained to translate along the longitudinal axis. To lock the auto-injector  1 , once the syringe  3  had been loaded, the sleeve may be positioned across the joint between the distal portion  2 . 1  and the proximal portion  2 . 2  thereby preventing rotation about the hinge  10 . The sleeve may be sprung loaded such that it automatically locks the portions  2 . 1 ,  2 . 2  coaxially upon aligning them. 
     In  FIG. 4  the auto-injector  1  is shown during removal of a cap  17  which had been attached to a proximal end P of the proximal portion  2 . 2 . Barbs  17 . 1  on the cap (see  FIG. 5   a, b ) constrained from moving outward by a detector sleeve  18  slidably arranged at the proximal end P inside the proximal portion  2 . 2  grip the protective needle shield  5  thus removing the protective needle shield  5  with the cap  17 . Once the cap  17  is removed, the barbs  17 . 1  are no longer constrained so the protective needle shield  5  is released and may be easily removed from the cap  5  (see  FIG. 5   c ). 
       FIGS. 6 ,  7  and  8  show details of an interlock mechanism for defining a sequence of operation of the auto-injector  1 . 
     Following the removal of the cap  17  the user places the proximal end of the auto-injector  1  against an injection site, i.e. the user&#39;s skin. This causes the detector sleeve  18  to translate in distal direction against the bias of a detector spring  19  (see  FIG. 6 ). As the detector sleeve  17  translates, first latch features and second latch features are released. The first and second latch features prevent the user from accidentally actuating the auto-injector  1  when it is not in contact with the injection site and during a loading and cocking step. 
     The first latch features comprise a syringe latch arm  20  transversally pivoted about halfway between its ends, the distal end having a nose  20 . 1  for engaging behind a shoulder  7 . 1  arranged at the loading bay  7  in a manner to prevent the loading bay  7  from being moved in proximal direction P (see  FIG. 7  for details). The proximal end of the syringe latch arm  20  comprises a ramp  20 . 2 . The detector sleeve  18  comprises a longitudinal extension bar  18 . 1  extending at least almost to the distal end of the proximal portion  2 . 2  when the detector sleeve  18  is pushed into the auto-injector  1  and essentially on a level with the proximal end P. A dog  18 . 2  protrudes inwardly from the extension bar  18 . 1  in a manner to engage the ramp  20 . 2  when the detector sleeve  18  is pushed into the auto-injector  1 , thereby pushing the proximal end of the syringe latch arm  20  inwardly and the distal end of the syringe latch arm  20  outwardly so the nose  20 . 1  is disengaged from the shoulder  7 . 1 . Thus the loading bay  7  is no longer constrained from being moved in proximal direction P. As long as the detector sleeve  18  is not pushed back the dog  18 . 2  does not interact with the ramp  20 . 2 . A spring may be arranged for keeping the nose  20 . 1  engaged with the shoulder  7 . 1  in this situation (not illustrated). 
     In another embodiment the latch arm  20  may have a straight end instead of the ramp in which case a ramp may be provided at the dog  18 . 2 . In yet another embodiment both the latch arm  20  and the dog  18 . 2  may have ramps. 
     The second latch features are part of a transmission bar  21  arranged in the distal portion  2 . 1  and slidable in longitudinal direction. When the portions  2 . 1 ,  2 . 2  are coaxially aligned a proximal end of the transmission bar  21  bears against a distal end of the extension bar  18 . 1 . For this purpose the transmission bar  21  may be biased by a spring in proximal direction (not illustrated). Near a distal end of the transmission bar  21  a recess  21 . 1  is provided for engaging a dog  16 . 2  arranged at the trigger button  16  (see  FIG. 8  for details). Before the detector sleeve  18  is pushed into the auto-injector  1  (cf.  FIG. 1 ) the transmission bar  21  is in a proximal position thus engaging the dog  16 . 2  in a manner to prevent the trigger button  16  from being pushed inwardly at its proximal end. The distal end of the trigger button  16  is pivoted in the distal portion  2 . 1 . When the detector sleeve  18  is pushed into the auto-injector  1  the translation is forwarded by the extension bar  18 . 1  to the transmission bar  21  so the dog  16 . 2  of the trigger button  16  finds some clearance in the recess  21 . 1  thus allowing the proximal end of the trigger button  16  to be pushed inward. 
     In order to deliver an injection the user depresses the trigger button  16 . As the proximal end of the trigger button  16  moves inward the snap arms  15 . 1 ,  16 . 1  disengage thus releasing the drive collar  15  and allowing the drive spring  8  to extend. The force from the drive spring  8  is transferred through the drive collar  15  and a release latch member  22  to the plunger  9 . The friction between the stopper  6  and the inner wall of the syringe  3  opposes relative motion between them. This friction is greater than a sum of the force of a syringe retraction spring  23  arranged between the shoulder  7 . 1  of the loading bay  7  and a protrusion  24  in the proximal portion  2 . 2  and a needle insertion force between the needle  4  and the patient&#39;s skin. Hence the needle  4  is inserted into the user&#39;s skin without medicament leaking out of the needle&#39;s tip (wet injection). An insertion depth is controlled by a finger flange or shoulder  7 . 1  of loading bay  7  contacting a stop  25  arranged in the proximal portion  2 . 2  (see  FIGS. 10 and 11 ). The stop  25  or the two stops  25  may be arranged at a proximal end of a respective longitudinal rib  25 . 1  arranged in the proximal portion  2 . 2 . The loading bay flange  7 . 1  may have recesses for rotationally fixing the loading bay flange  7 . 1  by the longitudinal ribs  25 . 1 . 
     Once the finger flange  3 . 1  contacts the stops  25 , the force of the drive spring  8  acting on the stopper  6  is sufficient to overcome friction so the emptying of the syringe contents commences. 
     The drive collar  15  is coupled to the release latch member  22  through a damper unit  26  comprising a plunger spring  26 . 1  in parallel with a viscous damper  26 . 2 . A coefficient of damping of the viscous damper  26 . 2  is specified such that a time taken to fully compress the plunger spring  26 . 1  is greater than a time required to fully empty the syringe  3 . This means the stopper  6  will always fully empty the syringe  3 . 
     In the  FIGS. 15 and 16  the damper unit  26  is shown in detail. The viscous damper  26 . 2  comprises a piston  26 . 2 . 1  fixed to the drive collar  15  by a connecting rod  26 . 2 . 2 , the piston  26 . 2 . 1  having a greater diameter than the connecting rod  26 . 2 . 2 . A hollow cylinder  26 . 2 . 3  with an internal diameter slightly greater than the diameter of the piston  26 . 2 . 1  is arranged around the piston  26 . 2 . 1  so the piston  26 . 1 . 1  and cylinder  26 . 2 . 3  may reciprocate. A proximal end face of the cylinder  26 . 2 . 3  is fully closed. A distal end face is arranged to seal the cylinder  26 . 2 . 3  against the connecting rod  26 . 2 . 2 . A small transfer port  26 . 2 . 4  is provided through the piston  26 . 2 . 1  in longitudinal direction allowing a fluid to flow from the distal side of the piston  26 . 2 . 1  to the proximal side and vice versa. Respective gasket rings  26 . 2 . 5  and  26 . 2 . 6  are arranged to seal the piston  26 . 2 . 1  against the cylinder  26 . 2 . 3  and the connecting rod  26 . 2 . 2  against the hole in the distal end face of the cylinder  26 . 2 . 3 . The piston  26 . 2 . 1  and the distal face wall are provided with respective circumferential notches in order to hold the gasket rings  26 . 2 . 5 ,  26 . 2 . 6  in place. There may be more than one transfer port  26 . 2 . 4  through the piston  26 . 2 . 1 . The size of the transfer port  26 . 2 . 4  controls the damper characteristics. The fluid may be one of air, another gas, a liquid, grease, e.g. silicone grease. If an incompressible fluid, such as a liquid is used, an air pocket may be provided in the cylinder  26 . 2 . 3  in order to compensate for the disparity in volume change at the proximal and the distal side of the piston  26 . 2 . 1  during translation. 
     The plunger spring  26 . 1  is arranged in a longitudinal bore in the connecting rod  26 . 2 . 2  and grounded at its distal end in the drive collar  15 . The proximal end of the plunger spring  26 . 1  bears against the proximal face of the cylinder  26 . 2 . 3  from inside. Hence the cylinder  26 . 2 . 3  may be translated towards the drive collar  15  against the force of the plunger spring  26 . 1  and the plunger spring  26 . 1  may push the cylinder  26 . 2 . 3 . away from the drive collar  15 . 
     The release latch member  22  is distally pivoted in the damper unit  26 , particularly in the cylinder  26 . 2 . 3 . 
     Once the syringe  3  is fully emptied and the plunger spring  26 . 1  is fully compressed, a ramp  15 . 2  on the drive collar  15  contacts a ramp  22 . 1  on the release latch member  22  thus rotating the release latch member  22  outward and consequently decoupling the drive spring  8  from the plunger  9  (see  FIGS. 14 and 16 ). The needle  4  is withdrawn inside the syringe  3 . This may be achieved by the stopper  6  gripping the distal end of the needle  4 . The stopper  6  may be pulled in distal direction by means of a spring arranged inside the syringe  3  (not illustrated in the figures). The needle  4  is thus pulled into the syringe  3  and the plunger  9  pushed out in distal direction D into the gap vacated by the latch member. In order to enable both the withdrawal of the needle  4  and the syringe  3  sufficient space has to be provided for the distal end of the plunger  9  towards the damper unit  26 . This is achieved by appropriately selecting the length of the release latch member  22 . Due to the interrupted force propagation the plunger spring  26 . 1  will return the cylinder  26 . 2 . 3  to its initial position for further injections as shown in  FIGS. 12 and 15 . 
     The lever action described above is reversed, i.e. the distal portion  2 . 1  is rotated about the hinge  10  with respect to the proximal portion  2 . 2  thus allowing access to the loading bay  7  (see  FIG. 18 ). As the auto-injector  1  is hinged in two, the lever  11  translates the sliding shuttle  14  in distal direction of the distal portion  2 . 1 . The sliding shuttle  14  contacts the drive collar  15  and compresses the drive spring  8  in preparation for further injections. 
     Upon full opening, the snap arms  15 . 1  and  16 . 1  of the drive collar  15  and the trigger button  16  snap into each other thus preventing the drive spring  8  from expanding. The emptied syringe  3  may now be safely removed from the loading bay  7 . 
     The damper unit  26  may now return to its initial state under the force of the plunger spring  26 . 1 . 
     The detector sleeve  18  is pushed in proximal direction P of the proximal portion  2 . 2  under load of the compressed detector spring  19 . The detector spring  19  may be grounded in the protrusion  24 . 
     Although the figures illustrate a syringe  3  with a retracting needle, which ensures needle safety at all times even when changing the disposable syringe, the auto-injector  1  would also work with a fixed needle syringe, such as a Hypak syringe as well.