Abstract:
The present invention relates to an injection device for administering doses of liquid drug. The injection device comprises a user operable dose adjustment structure configured to adjust, in a prepared state of the device, a dose of liquid drug of a first size to set a dose of a second size. The present injection device is particularly suitable for self-injection of liquid drugs such as insulin for treating diabetes by the user or patient.

Description:
[0001]    The present invention relates to an injection device for administering doses of liquid drug. The injection device is particularly suitable for self-injection of liquid drugs, such as insulin for treating diabetes, by the user or patient. 
       BACKGROUND OF THE INVENTION 
       [0002]    Within some therapy areas the tendency of a patient to adhere to the prescribed therapy is dependent on the simplicity of the specific treatment regimen. For example, many people with type 2 diabetes are diagnosed with the disease at a relatively high age where they are less prone to accept a treatment that intervenes too much with their normal way of living. Most of these people do not like constantly being reminded of their disease and, as a consequence, they do not want to be entangled in complex treatment patterns or waste time on learning to operate cumbersome delivery systems. Basically, people with diabetes need to keep track of, and minimise, their glucose excursions. Insulin is a well-known glucose lowering agent which has to be administered parenterally to be effective in the body. At present, the most common way of administering insulin to a patient is by subcutaneous injections. Such injections have previously been performed using a vial and a syringe, but in recent years so-called injection devices, or injection pens, have gained more and more attention in the marketplace. Many people have found these injection devices easier to handle, particularly as they do not require the user to carry out a separate drug filling procedure before each injection. 
         [0003]    In some prior art injection devices which are suitable for self-injection, the user has to set a desired dose size using a dose setting mechanism of the injection device and subsequently inject the previously set dose using an injection mechanism of the injection device. In this case the dose size is variable, i.e. the user must set a dose size which is suitable in the specific situation each time a dose is to be injected. 
         [0004]    Other prior art injection devices are adapted to inject a dose of fixed size each time it is operated. In this case the user has to prepare the injection device in an appropriate manner to set the fixed dose size, using a dose setting or loading mechanism, and subsequently inject the dose using an injection mechanism. 
         [0005]    WO 2009/092807 discloses an injection device which is simple and intuitive to handle and therefore easy for the patient to learn using. The disclosed injection device is loaded or prepared with a predetermined dose of liquid drug by the mounting of a protective cap with a twisting operation. The injection means is automatically disabled when the protective cap is mounted on the device and automatically enabled when the protective cap is dismounted from the device. The injection device automatically sets the predetermined dose when the protective cap is mounted so as to eliminate any risk of misadjusting the dose size by the user. 
         [0006]    While the cap induced dose preparation of the disclosed injection device is desirable for its simplicity and minimization of the required number of manipulation steps for preparing the injection device, the fixed nature of the dose size may be impractical in certain situations. The user may need to adjust the size of the predetermined dose. The decision to adjust dose size is often taken right before the time of injection which may be many hours from the time where the injection device was prepared and the user condition such as a glucose level changed in the meantime. It would thus be desirable to provide an improved injection device which allows the user to make such a dose size adjustment of an already prepared or loaded injection device just before administration or injection. It would also be beneficial if the dose size adjustment can be made, in the prepared state, without spilling any drug 
         [0007]    In the following disclosure of the present invention, aspects and embodiments will be described which address one or more of the above objects or which address objects apparent from the disclosure as well as from the description of exemplary embodiments. 
       SUMMARY OF INVENTION 
       [0008]    A first aspect of the invention relates to an injection device for administering doses of liquid drug, comprising a cartridge having a movable piston arranged therein and adapted to hold the liquid drug. The injection device further comprises a dose setting structure responsive to mounting of a removable cap to place the injection device in a prepared state with a dose of a first size and a user operable dose adjustment structure configured to, in the prepared state, adjust the dose of the first size to set a dose of a second size. An injection structure of the injection device comprises a piston rod coupled to the movable piston and configured to advance the piston a predetermined axial distance inside the cartridge from a first position in the prepared state to a second position in an unprepared state corresponding to delivery of the dose of the second size. 
         [0009]    The present injection device allows the user to prepare the device with the dose of the first size by a simple mounting of the removable cap. The mounting may comprise a twisting or helical movement of the removable cap injection device therefore only requires a minimum of manipulation steps by the user. In accordance with the invention, the user operable dose adjustment structure is capable of adjusting the dose of the first size to set a dose of a second size in the prepared state of the injection device. This user is accordingly allowed to increase or decrease the size of a previously, i.e. at the time of mounting of the removable cap, set dose. This is beneficial because a decision to adjust the dose size is often taken right before the time of injection which may be many hours from the time where the injection device was prepared with the dose of the first size. The user condition such as a glucose level may have changed in the meantime. The user operable dose adjustment structure may be configured to adjust the dose size in discrete step(s) or continuously in a predetermined range within upper and lower limits for the second dose size. Depending on the user&#39;s or patient&#39;s condition at the time of drug administration, the user may choose to maintain an already set dose of the first size, in which case the first and second dose sizes are identical, or decrease/increase the dose of the first size to set a second dose of a different size. 
         [0010]    During preparation or loading of the injection device, the movable piston is displaced to the first position in response to the mounting of the removable cap. A source of energy or mechanical force is preferably charged/loaded in that connection so that the device can be fired or unloaded and the injection made by stored energy delivered by the energy source. 
         [0011]    The first position of the movable piston may be defined by a proximal clamping structure operatively coupled to the piston rod to retain the piston rod in the first position. In certain embodiments of the invention, the proximal clamping structure is fixedly attached to, or engraved in, the housing of the injection device. In certain embodiments the proximal clamping structure comprises a proximal shelf while other such embodiments comprise a circumferential slot, aperture or groove in the housing. The circumferential slot, aperture or groove may be configured to guiding a trajectory of a sliding element of the dose setting structure. 
         [0012]    The second or distal position of the movable piston is preferably defined by a distal clamping structure operatively coupled to the piston rod to arrest the piston rod in the second distal position. The distal clamping structure defines an end-of-dose stop for the moveable piston. The moveable piston is preferably rigidly connected to the piston rod at least in an axial direction of the housing of the injection device so these are advanced the same predetermined axial distance during delivery of the dose of the second size. The dose setting structure is preferably configured to sequentially advancing the piston rod in axial direction for each new dose delivery. 
         [0013]    In a number of useful embodiments of the injection device, the dose adjustment structure is configured to axially translate at least one of the distal clamping structure and the proximal clamping structure in the housing of the injection device to adjust the dose size. The dose adjustment structure is preferably configured to perform axial translation or movement of only a single one of the proximal and distal clamping structure to simply mechanical design. The axial translation of the proximal or distal clamping structure, in response to actuation of the dose adjustment structure, adjusts the predetermined axial distance by which the movable piston, and preferably the piston rod, is advanced during delivery of the dose of the second size. The user operable dose adjustment structure may comprise a circumferentially extending dose dial rotatably mounted about the housing of the injection device. The dose dial preferably comprises an inner threaded structure engaging the distal clamping structure or the proximal clamping structure to axially translate the distal or proximal clamping structure, respectively, by rotation of the dose dial. An outer surface of the dose dial may comprise a corrugated surface to improve the user&#39;s grip on the dial. In other embodiments, the dose dial is integrated with a proximally protruding injection button of the injection device as described in further detail in connection with the  FIGS. 5   a )- b ). 
         [0014]    A number of advantageous embodiments of the present injection device comprise a toothed sliding element adapted to engage mating teeth of a toothed axially extending section of the piston rod. The dose setting structure is configured to retain or arrest the toothed sliding element on the proximal clamping structure to set the first position of the piston rod. The mating teeth may be configured to allow unidirectional movement of toothed sliding element relative to the piston rod only. In this manner the toothed sliding element can move freely over the piston rod in proximal direction but is rigidly coupled to the piston rod in distal direction. Hence, the arrest of the sliding element on the proximal clamping structure also fixes a first or proximal position of the piston rod. In this embodiment, the dose adjustment structure may advantageously be configured to vary an axially extending geometry of the toothed sliding element to adjust the dose size. This may be accomplished by varying the axial position of a radially extending finger or protrusion of the sliding element that is configured for engagement with an axially fixed, i.e. non-translatable, distal clamping structure so as to adjust the predetermined axial distance by which the movable piston, and preferably the piston rod, is advanced during dose delivery. 
         [0015]    According to a preferred embodiment of the invention, the user operable dose adjustment structure comprises a clutch mechanism configured to decouple the dose setting structure from the injection structure in the prepared state so as to allow increasing or decreasing the dose of the first size without spilling liquid drug. The clutch mechanism may comprise an axially biased and toothed nut, rotatably mounted on the piston rod. The teeth of the toothed nut are configured to selectively engage or disengage mating teeth of a toothed member of the dose setting structure. The toothed member of the dose setting structure is preferably formed as a separate intermediate element configured for engagement with the sliding element, but may alternatively be integrated with the toothed sliding element. In response to the user&#39;s mounting of the removable cap to prepare the injection device, the intermediate element may be axially displaced in proximal direction whereby the mating teeth of the intermediate element and toothed nut are disengaged, for example by the action of a compressed nut spring supplying the axial bias force to the toothed nut. By this step or action, the toothed sliding element, which forms part of the dose setting structure, is decoupled or disengaged from the toothed piston rod and toothed nut, which form part of the injection structure. According to this embodiment, the clutch mechanism may be configured to decouple the dose setting structure from the injection structure during an initial step or phase of the preparation or loading sequence of the injection device. This embodiment of the clutch mechanism prevents dosage spill caused by handling errors such as partial loading of the injection device by incomplete or partial mounting of the removable cap. In this situation, a subsequent dismounting of the removable cap would lead to unloading or firing of the injection device with accompanying drug spill if the piston rod had been in operative engagement with the toothed sliding element during the loading sequence. This type of undesired drug spill can be avoided by utilization of the above-mentioned configuration of the clutch mechanism. 
         [0016]    In yet another embodiment of the invention, the clutch mechanism is formed by rotational engagement and disengagement of mating teeth structures formed in the toothed piston rod and the toothed sliding element. In this embodiment, the dose setting structure may be configured to rotate the toothed sliding element about the longitudinal axis of the housing during preparation of the device when the toothed sliding element reaches the first position. The toothed piston rod and the toothed sliding element may be engaged during axial translation of the toothed sliding element towards the first position during a preparation step of the injection device. The rotation of the toothed sliding element causes the disengagement between the mating teeth structures of the toothed piston rod and the toothed sliding element. 
         [0017]    According to one such embodiment, the toothed piston rod comprises a first axially extending segment of teeth of a first radial height occupying a first predetermined circumferential surface of the toothed piston rod. A second axially extending segment of teeth of a second radial height, smaller than the first radial height, occupies a second predetermined circumferential surface of the toothed piston rod. The engagement and disengagement is preferably provided by rendering the radial height of the teeth of the second segment sufficiently small to avoid engagement with a radially protruding tooth or teeth of the sliding element when the sliding element is arrested in the first position after rotation. Consequently, the toothed sliding element is decoupled from the toothed piston rod and rendered in an axially translatable state. The first radial height of the teeth of the first axially extending segment is on the other hand set to a value which ensures engagement between the mating teeth structures of the toothed piston rod and toothed sliding element. Therefore, the toothed sliding element can be coupled to the toothed piston rod by a suitable rotatory movement thereof in connection with a firing step of the injection device. The angle of rotation of the sliding element may naturally be adapted to fit the respective angular extensions of the first and second predetermined circumferential surfaces to ensure appropriate engagement and disengagement between the mating teeth structures of the toothed piston rod and toothed sliding element is accomplished. In a number of preferred embodiments, the angle of rotation of the toothed sliding element relative to the toothed piston rod lies between 10 degrees and 180 degrees such as between 20 and 90 degrees. 
         [0018]    The skilled person will understand that different types of energy sources may be applied for advancing the injection structure from the first to the second position in connection with dose delivery. In a preferred embodiment, the energy source driving the injection structure comprises a compression spring. The compression spring may be operatively coupled between the toothed sliding element and the housing of the injection device. The mounting of the removable cap to prepare the injection device causes axial compression of, and energy storage in, the compression spring due to the axial translation in proximal direction of the toothed sliding element. 
         [0019]    In another preferred embodiment of the invention, the dose setting structure comprises a torsionally pre-tensioned spring operatively coupled between the sliding element and the housing. The torsionally pre-tensioned spring is configured to rotate the toothed sliding element into engagement with the proximal clamping structure at the first position of the toothed sliding element. In some of these embodiments, the proximal clamping structure may comprise the axially translatable shelf, the axial position of which can be moved by actuation of the dose adjustment structure to adjust the dose size. In other embodiments, the axial position of the proximal clamping structure may be fixed relative to the housing and comprise a circumferentially extending slot, groove or channel in an annular wall section of the housing. The circumferentially extending slot, groove or channel is configured to guide the rotation or rotary movement of the sliding element about the longitudinal housing axis for example by engagement with a matingly shaped finger or protrusion of the toothed sliding element. The rotation of the toothed sliding element ensures that the sliding element is safely retained or arrested at the proximal clamping structure in the prepared state so as to minimize any risk of unintended firing of the injection structure. The rotary movement ensures that this indication is provided only after the sliding element has been safely retained at the proximal clamping structure. In addition, the rotary movement of the toothed sliding element may be used to release, rotate and axially translate an injection button arranged in operative engagement with the toothed sliding element such as to indicate a prepared state of the injection device. The injection button may be axially translated a pre-set distance in proximal direction to move from a depressed state, indicating an unprepared state of the injection device, to a protruding state indicating the prepared state of the injection device. The dose setting means may be configured to render the injection button partly, or preferably entirely, contained within the housing contour in its depressed state. In the prepared state of the injection device, the injection button may in response to user actuation or depression thereof be configured to operatively engage and rotate the toothed sliding element a predetermined distance along the proximal clamping structure. The predetermined distance is preferably designed such that the rotation of the toothed sliding element is terminated when it reaches an axially extending slot in the annular wall section of the housing. The axially extending slot guides further distal advancement of the sliding element in axial direction driven by the spring force from the compressed helical spring. 
         [0020]    In an advantageous embodiment, the above-mentioned torsionally pre-tensioned spring and the compression spring are integrally formed as a single helical compression spring, thus minimizing the number of separate components of the injection device and simplifying assembly or manufacturing processes. In this embodiment, the axially extending slot in the annular wall section of the housing may be adapted to guide the axial movement in proximal direction of the toothed sliding element in connection with preparation of the injection device. The rotational movement of the toothed sliding element may, as mentioned above, be guided by the circumferentially extending slot in the annular wall structure. The axially extending slot and the circumferentially extending slot may be combined to form an L-shaped slot structure. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0021]    Preferred embodiments of the invention will be described in additional detail in connection with the appended drawings, in which: 
           [0022]      FIGS. 1   a ) and  1   b ) are respective central axial cross-sectional views of an injection device in accordance with a first embodiment of the invention, 
           [0023]      FIGS. 2   a ) and  2   b ) illustrate first and second steps, respectively, of a preparation and firing sequence of the injection device depicted on  FIG. 1 , 
           [0024]      FIGS. 2   c ) and  d ) illustrate third and fourth steps, respectively, of the preparation and firing sequence of the injection device depicted on  FIG. 1 , 
           [0025]      FIGS. 2   e ) and  f ) illustrate fifth and sixth steps, respectively, of the preparation and firing sequence of the injection device depicted on  FIG. 1 , 
           [0026]      FIGS. 3   a ) and  3   b ) depict a user operable dose adjustment structure in respective cross-sectional views to illustrate steps of a dose adjustment function of the injection device depicted on  FIG. 1 , 
           [0027]      FIGS. 4   a ) and  4   b ) are respective central cross-sectional views of a user operable dose adjustment structure of an injection device in accordance with a second embodiment of the invention, 
           [0028]      FIGS. 5   a ) and  5   b ) are respective central axial cross-sectional views of an injection device in accordance with a third embodiment of the invention, 
           [0029]      FIGS. 6   a ) and  6   b ) illustrate first and second steps, respectively, of a preparation and firing sequence of the injection device depicted on  FIG. 5  in accordance with the third embodiment of the invention, 
           [0030]      FIGS. 6   c ) and  6   d ) illustrate third and fourth steps, respectively, of the preparation and firing sequence of the injection device depicted on  FIG. 5  in accordance with the third embodiment of the invention, 
           [0031]      FIGS. 6   e ) and  6   f ) illustrate fifth and sixth steps, respectively, of the preparation and firing sequence of the injection device depicted on  FIG. 5  in accordance with the third embodiment of the invention, 
           [0032]      FIG. 6   g ) illustrates a seventh step of the preparation and firing sequence of the injection device depicted on  FIG. 5  in accordance with the third embodiment of the invention, 
           [0033]      FIG. 7   a ) is a central cross-sectional view of a user operable dose adjustment structure of the injection device depicted on  FIG. 5  in accordance with the third embodiment of the invention, 
           [0034]      FIG. 7   b ) is a perspective view of a sliding element with a variable axial dimension mounted in the user operable dose adjustment structure depicted on  FIG. 5   a ), 
           [0035]      FIG. 7   c ) is a central cross-sectional view of an end-of-content feature of the injection device depicted on  FIG. 5   a )- b ) under normal operating conditions; and 
           [0036]      FIG. 7   d ) is a central cross-sectional view of the end-of-content feature of the injection device depicted on  FIG. 5   a )- b ) in an end of content mode. 
       
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       [0037]      FIGS. 1   a ) and  1   b ) are respective central axial cross-sectional views of an injection device  1  in accordance with a first embodiment of the invention wherein the depicted cross-sectional views are made at an angular separation of 90 degrees by rotation of the injection device  1  about a central longitudinal axis  3 . 
         [0038]    The injection device  1  is illustrated in a prepared or loaded state ready to deliver a dose of liquid drug to a user or patient by self-administration. The injection device  1  comprises a tubular housing  20 , a cartridge  85  holding a volume of liquid drug and an injection button  5  protruding axially from the tubular housing  5 . An injection needle (not shown) is attached to a distal portion of the cartridge  85  for subcutaneous injection of a predetermined dose of liquid drug in accordance with the user&#39;s setting of a dose size. A toothed elongate piston rod  30  is rigidly attached or coupled to a movable piston  70  via a piston foot  65 . The movable piston  70  is arranged within an interior volume of the cartridge  85 . Consequently, advancing the toothed piston rod  30  a predetermined distance axially in distal direction will cause a corresponding axial displacement of the movable piston  70  and cause a dose of the liquid drug to be expelled via the injection needle. A dose setting structure is responsive to mounting of a removable cap  80  to place the injection device  1  in the prepared or loaded state with a dose of liquid drug of a first size. The dose setting structure comprises an intermediate element in the form of a pusher  50  configured for engagement with the removable cap  80  and axially displaceable by mounting of the removable cap  80 . The pusher  50  is configured for engaging a sliding element  35  and axially displacing the sliding element  35  in proximal direction, i.e. towards the injection button  5 . The displacement of the sliding element  35  leads to a loading or preparation of the injection device  1  with a dose of liquid drug of the first size as explained in further detail below. The sliding element  35  comprises teeth arranged on an inner surface and configured to engaging mating teeth of the toothed elongate piston rod  30 . The mating teeth of the sliding element  35  and toothed elongate piston rod  30  are configured to solely allow unidirectional displacement of the sliding element  35  relative to the toothed elongate piston rod  30  or piston rod. Only proximal displacement of the sliding element  35  relative to the piston rod  30  is allowed. Consequently, the mating teeth of piston rod  30  and the sliding element  35  are brought into operative engagement when the latter moves in an opposite direction, i.e. a distal direction towards the second or distal position defined by an adjustable shelf  60 . 
         [0039]    The sliding element  35  is coupled to a helical compression spring  25  co-axially arranged around a tubular neck or portion of the sliding element  35 . The compression spring  25  is torsionally pre-tensioned and compressible by proximal displacement of the sliding element  35  during a loading sequence or operation of the injection device  1 . The loading sequence therefore causes potential energy or spring force to be stored in the compression spring  25  for release in connection with forward firing or advancement of the piston rod  30  and movable piston  70  during injection of the set dose of liquid drug. One end portion of the compression spring  25  engages the sliding element  35  and an opposing end portion engages a spring base  15  rigidly attached to the housing  20 . 
         [0040]    The injection device  1  furthermore comprises user operable dose adjustment structure comprising dose dial  55  and configured to, in the prepared or load state, increase or decrease the dose of the first size to set a dose of a second size. The dose dial  55  is configured to adjust a position, relative to the housing  20 , of an axially translatable distal clamping structure in form of the adjustable shelf  60  so as to vary the dose size in accordance with the user&#39;s adjustment of the dose dial  55  as explained in further detail below. The user operable dose adjustment structure additionally comprises a clutch mechanism configured to decouple the dose setting structure from the injection structure in the prepared state. The clutch mechanism comprises the pusher  50  which is configured to selectively engage or disengage a toothed nut  40  operatively coupled to the piston rod  30  as as explained in further detail below in connection with  FIGS. 2   b )- 2   f ). 
         [0041]    The injection button  5  is configured to noticeably project from the housing  1  in the prepared state of the injection device  1  as depicted on  FIGS. 1   a ) and  1   b ) to indicate a current state of the injection device to the user or patient. By depression of the injection button  5  a firing sequence is initiated where the sliding element  35  is released from a a proximal clamping structure and the piston rod  30  advanced from a first or proximal position relative to the housing  1  to the second or distal position in an unprepared or unloaded state of the injection device  1 . An axial distance between the first and second positions accordingly corresponds to the delivery of the dose of the second size. 
         [0042]    The clutch mechanism comprises a toothed nut  40 , a nut spring  45  and a toothed inner peripheral surface of the pusher  50 . The clutch mechanism is configured to decouple the dose setting structure from the injection structure in the prepared state of the injection device so as to allow dose adjustment in the prepared state by actuation of the dose dial  55  without advancing the toothed piston rod  30  and the moveable piston  70  and spillage of liquid drug as explained in further detail below. 
         [0043]      FIG. 2   a ) illustrates a first step of the loading and firing sequence where the injection device  1  depicted on  FIG. 1  is loaded or prepared. In connection with the first step, loading or preparation is initiated by the user by twisting the replaceable cap  80  onto the injection device  1  following a helical trajectory as indicated by arrow  72 . 
         [0044]      FIG. 2   b ) illustrates the second step of the loading and firing sequence where the injection device  1  is loaded or prepared. The pusher  50  is the first portion of the dose setting structure to move in response to the mounting of the removable cap  80 . As previously explained, the piston rod  30  can only move in one direction, distally, relative to the housing  20  of the injection device. This effect is created by a pair of one way snaps mounted in the housing  20  and engaging the teeth on piston rod  30 . The pusher  50  is rotationally locked to the housing  20 . The pusher  50  is axially displaced by the twisting operation of the removable cap  80 , but the toothed nut  40 , which is rotatably mounted on the piston rod  30 , stands still due to an inner thread (not shown) that engages a mating thread on the piston rod  30 . The disengagement between the toothed nut  40  and the pusher  50  allows the toothed nut  40  to rotate as it is pushed proximally/upwards by the pusher  50  and the nut spring  45 . The toothed nut  40  will start to rotate due to the threaded non-locking interface with the mating teeth on the piston rod  30 . 
         [0045]    The teeth of the toothed nut  40  are arranged around a circumferential outer perimeter of the toothed nut  40 . The teeth of the pusher  50 , which are arranged on an inner tubular surface of the pusher  50  as explained above, are forced to disengage the mating teeth on the toothed nut  40  by this translation due to an axially directed biasing force supplied by the nut spring  45 . The toothed nut  40  can now rotate freely about the piston rod  30 . In effect, the dose setting structure has been decoupled from the injection structure because the piston rod  30  is no longer operatively coupled to the sliding element  35 . 
         [0046]      FIG. 2   c ) illustrates the third step of the loading and firing sequence where the injection device  1  is undergoing loading or preparation. In this step, the helical compression spring  25  is compressed and loaded with axial spring force and a torque. The axial force is later on used to supply dose delivery force or energy during a user initiated firing or dose delivery sequence as explained below. The torque is obtained by torsionally pre-tensioning the helical compression spring  25  and using this torque to radially rotate the sliding element  35  into engagement with a proximal clamping structure at a first or proximal position of the piston rod  30 . The helical twisting of the removable cap  80  is configured to axially translate the pusher  50  and the sliding element  35  to a first position guided by an axial slot (not shown) in a tubular wall section of the housing  20 . At the first position, a circumferentially and essentially horizontally extending slot or channel  32  in the tubular wall section guides rotary movement of the sliding element  35  about a longitudinal housing axis  3  (refer to  FIG. 1   a )). The combination of the axial slot and the circumferentially extending slot  32  forms an L-shaped slot in the housing  20 . The toothed nut  40  is free to rotate in the non self-.locking thread engaging the piston rod  30  when the pusher  50  and the sliding element  35  translate. 
         [0047]      FIG. 2   d ) illustrates the fourth step of the loading and firing sequence where the injection device  1  is loaded or prepared. The sliding element  35  will rotate because of the freedom in the housing  20  and the torque generated by the pretensioned helical compression spring  25 . Furthermore, the injection button  5  is rotated and axially translated, in response to the axial displacement and rotation of the sliding element  35 , from an unloaded or unprepared state indicated by its non-protruding placement inside the housing  20  of injection device to a loaded or prepared state indicated by the protruding placement depicted in  FIG. 2   d ). Consequently, after completion of step  4 , the injection device is rendered in the prepared state with the removable cap  80  mounted on the injection device. The sliding element  35  rests in the circumferentially extending slot  32  in the housing  20  with the sliding element  35  decoupled from the pusher  50 . It is now possible to adjust the axial position of the adjustable shelf  60  which effectively defines the second position or end-step of the sliding element  35 . Since the first position of the sliding element, as defined by the circumferentially extending slot  32 , remains fixed, the predetermined axial distance which the sliding element  35  and piston rod  30  travels during the dose delivery is varied. This leads in turn to the desired adjustment of the size of the initially set dose. 
         [0048]      FIG. 2   e ) illustrates the fifth step of the loading and firing sequence where the injection device  1  is fired or unloaded. The sliding element  35  rests in the circumferentially extending slot  32  in the housing  20  when the removable cap  80  is removed by the user as explained above. Furthermore, the pusher  50  is configured to translate a small distance axially and engage with the toothed nut  40  so as to rotationally lock to, or engage, the toothed nut  40  by virtue of the mating sets of teeth arranged on the pusher  50  and the toothed nut  40  as explained above. The engagement can be made in a manner where the interacting teeth make an incremental rotation of the toothed nut  40  to compensate for possible tolerances caused by small variations in the user&#39;s mounting process of the replaceable cap  80 . This will improve the dose accuracy. 
         [0049]    When the injection button  5  is depressed as indicated by the arrow adjacent to the button  5 , the sliding element  35  will also be forced to rotate due to a helical spiralling movement of the injection button  5  under engagement with an end surface of the sliding element  35 . The rotary movement of the sliding element  35  is guided by the circumferentially extending slot  32  and continues until the sliding element  35  reaches the axial slot in the housing  20 . 
         [0050]      FIG. 2   f ) illustrates the sixth step of the loading and firing sequence where the injection device  1  is fired or unloaded. When the sliding element  35  reaches the axial slot in the housing  20 , the sliding element  35  is translated axially in distal direction because of the axial force generated by the compressed helical compression spring  25 . The toothed nut  40  will translate axially in a corresponding manner because of the locked engagement with the pusher  50 . The toothed nut  40 , which is coupled to the piston rod  30  by the threaded interface, will subsequently advance the piston rod  30  and the movable piston  70  inside the cartridge  85  to make a dosing in accordance with the user selected dose size. The depicted end-of-dose or second position of the piston  70 , and corresponding end position of the piston rod  30 , is defined or set by the adjustable shelf  60  operating as the distal clamping structure or end-stop. The adjustable shelf  60  interrupts any further distal advancement of the piston  70  once the adjustable shelf  60  engages the toothed nut  40 . 
         [0051]      FIGS. 3   a ) and  3   b ) depict the user operable dose adjustment structure in respective cross-sectional views and illustrate functionality of the dose adjustment structure of the injection device  1  depicted on  FIG. 1 .  FIG. 3   a ) illustrates a current state of the injection device  1  after completion of step  4  above, i.e. the current state is the prepared state where the dose already has been set to a first size. This first size will correspond to a previously injected dose size. The user is now able to adjust the dose of the first size to set a dose of a second size in accordance with his/hers current condition by axially moving the adjustable shelf  60  either distally or proximally. The adjustable shelf  60  is translatable inside the housing  20 . The dose dial  55  is configured for rotation about the housing  20  but is unable to move axially or translate relative to the housing  20 . The dose dial  55  comprises an internal thread  62  which mates to a corresponding circumferential end structure of the adjustable shelf  60  as illustrated. The adjustable shelf  60  is accordingly forced to move axially in response to rotation of the dose dial  55 . Since the sliding element  35  is rests safely on the proximal clamping structure (the circumferentially extending slot  32 ), the axial position of the adjustable shelf  60  can be safely adjusted without inducing any corresponding displacement of the piston rod  30  and movable piston  70 . Therefore, without causing any spillage of the liquid drug. On the other hand, the adjustment of the axial position of the adjustable shelf  60  leads to the desired dose size adjustment because any positional change alters the axial distance of travel of the piston rod  30  and piston movable piston  70  during the firing sequence or dose delivery. 
         [0052]      FIG. 4   a ) is a central cross-sectional view of a user operable dose adjustment structure of an injection device  400  in accordance with a second embodiment of the invention. The injection device  400  has many features in common with the above-described first embodiment of the injection device. However, the dose adjustment structure of the first embodiment utilized axial movement of a distal clamping structure (the adjustable shelf  60 ) to adjust the desired dose size in the prepared state of the injection device  1 . The present injection device  400  utilizes axial movement of a proximal clamping structure (for example an adjustable shelf) to adjust the dose size in the prepared state of the injection device  400 . A distal clamping structure or end-stop remains fixed. Furthermore, the present injection device  400  utilizes a different type of clutch mechanism to decouple a dose setting structure from an injection structure in the prepared state of the injection device where the clutch mechanism is formed integrally with a toothed piston rod  430  and a sliding element  435 . 
         [0053]      FIG. 4   a ) shows the injection device  400  in the prepared state ready to deliver a dose of liquid drug to a user or patient by self-administration when the user depresses an injection button (not shown) similar in structure to the one depicted on  FIG. 1 . The injection device  400  comprises a tubular housing  420 , a cartridge  485  holding a volume of liquid drug. The injection button (not shown) is protruding axially from a proximal end of the housing  420 . An injection needle (not shown) is attached to a distal portion of the cartridge  485  for subcutaneous injection of a predetermined dose of liquid drug in accordance with the user&#39;s setting of a dose size. The toothed elongate piston rod  430  is rigidly attached to a movable piston  470 . The movable piston  470  is arranged within an interior volume of the cartridge  485 . Consequently, advancing the piston rod  430  a predetermined distance axially in distal direction will cause a corresponding axial displacement of the piston  470  and cause the liquid drug to be expelled via the injection needle (not shown). A dose setting structure is responsive to mounting of a removable cap  480  to place the injection device  400  in the illustrated prepared or loaded state with a dose of liquid drug of a first size. The dose setting structure comprises a pusher  450  configured for engagement with the removable cap  480  and axially displaceable by mounting of the removable cap  480 . The pusher  450  is configured for engaging a sliding element  435  and axially displaces the sliding element  435  in proximal direction, i.e. the direction indicated by arrow  490  which is towards the injection button. The displacement of the sliding element  435  in proximal direction leads to the loading of the injection device  400  with a dose of liquid drug of a first size as explained in further detail below. The sliding element  435  comprises teeth engaging mating teeth of the piston rod  430 . The mating teeth of the sliding element and piston rod are configured to solely allow unidirectional displacement in the proximal direction of the sliding element  435  relative to the piston rod  430 . Consequently, the piston rod  430  is advanced together with the sliding element  435  when the latter is advanced in the opposite direction, i.e. a distal direction towards a second or distal position defined by the fixed distal clamping structure or end-stop as explained below in connection with  FIG. 4   b ). The sliding element  435  is coupled to, or engages, a helical compression spring  425  co-axially arranged around a tubular portion or neck of the sliding element  435 . An opposite end of the helical compression spring  425  is operatively coupled to the housing  420  in similar manner to the first embodiment of the injection device. The injection device  400  furthermore comprises a user operable dose adjustment structure actuated by the dose dial  455  and configured to, in the prepared or load state, increase or decrease the dose of the first size to set a dose of a second size. The dose dial  455  is configured to adjust a position of an axially translatable proximal clamping structure in form of a proximal adjustable shelf  460  so as to vary the set dose size in accordance with the user&#39;s adjustment of the dose dial  455  as explained in further detail below in connection with  FIG. 4   b ). 
         [0054]      FIG. 4   b ) is a perspective view of the user operable dose adjustment structure of the injection device  400  in partial cross-section. As previously mentioned, the injection device  400  is placed in its prepared state where the sliding element  435  rests on the proximal adjustable shelf  460  and the helical compression spring  425  is axially compressed. The sliding element  435  comprises an axially extending finger  437  which rests on an upper plane surface  462  of the adjustable proximal shelf  460  so as to define a first or proximal position of the piston rod  430 . The piston rod  430  comprises a first axially extending segment of teeth  434  extending across a first predetermined circumferential surface of the toothed piston rod  430 . The teeth have a first radial height. Another axially extending segment of teeth  432  is placed adjacently to the first axially extending segment of teeth  434  so as to occupy a second predetermined circumferential surface of the piston rod  430 . The teeth of the second segment  432  have a radial height which is smaller than the first radial height. A radially protruding tooth  439  of the sliding element  430  is configured for engagement with individual teeth of the first axially extending segment of teeth  434 . However, in the illustrated state the radially protruding tooth  439  is placed at the teeth of the second segment  432  which have a radial height sufficiently small to avoid engagement with the radially protruding tooth  439  of the sliding element  435 . Consequently, the sliding element  435  is decoupled from the piston rod  430  and rendered axially translatable by movement or adjustment of the axial position of the upper plane surface  462  of the adjustable proximal shelf  460 . The axial position of the sliding element  435  can accordingly be adjusted without adjusting the axial position of the piston rod  430  and the moveable piston  470  so as to avoid drug spillage during dose size adjustment. 
         [0055]    During firing of the injection device  400 , the sliding element  435  is firstly rotated about the longitudinal housing axis  403  of the injection device which causes the axially extending finger  437  or finger to travel across the upper plane surface  462  of the adjustable proximal shelf  460  in rotary movement until the finger  437  reaches a slot or aperture  436  in the upper plane surface  462 . During this rotary movement of the sliding element  435 , the radially protruding tooth  439  is rotated as well until it is placed at the first axially extending segment of teeth  434  or first segment of teeth of the toothed piston rod  430 . Due to the larger radial height of the teeth of the first segment of teeth  434 , the radially protruding tooth  439  of the sliding element is now brought into a locked engagement with the teeth of the first segment of teeth  434 . Consequently, the sliding element  435  is now coupled to the piston rod  430  such that piston rod will translate axially together with the sliding element  435  in the distal direction towards the second position of the piston rod and piston. The skilled person will appreciate that an integrally formed clutch mechanism resides in the described cooperation between the sliding element  435  and the piston rod  430 . This integrally formed clutch mechanism operates by rotational engagement and disengagement of the mating teeth structures  432 ,  434 ,  439  formed in respective ones of the toothed piston rod  430  and the slider element  435 . 
         [0056]    Once the finger  437  has reached the slot or aperture  436  in the adjustable upper shelf  460 , the spring force or energy stored in the axially compressed helical compression spring  425  will advance the sliding element  435  and the piston rod  430  (now brought into engagement by the clutch mechanism) in axial direction. The sliding element  435  and the piston rod  430  will advance together until the finger  437  contacts or engages a non-adjustable or fixed lower shelf  464  which blocks further axial advancement of the sliding element  435  and the piston rod  430 . The fixed lower shelf  464  therefore defines an end-of-dose or the second position of the piston  470  and corresponding second or distal position of the piston rod  430  after delivery of the set dose size. 
         [0057]    The depicted user operable dose adjustment structure of the injection device  400  allows the user to increase or decrease a dose of a first size to set a dose of a second size by axially moving the adjustable proximal shelf  460  either distally or proximally to respectively decrease or increase the dose size. The adjustable proximal shelf  460  is translatable inside the housing  420 . The tubular dose dial  455  is configured for rotation about the housing  420  but unable to move axially relative to the housing  420 . The dose dial  455  comprises an internal thread which mates to a corresponding circumferential end structure of the adjustable shelf  460  in a manner similar to the above-described dose dial  55  (refer to  FIG. 3   b )) of the first embodiment. The adjustable shelf  460  is accordingly forced to move axially in response to rotation of the dose dial  455 . Even though the sliding element  435  rests on the upper plane surface  462  of the adjustable shelf  460  as illustrated on  FIG. 4   b ), the sliding element  435  is decoupled from the piston rod  430  by the operation of the clutch mechanism as described above. Therefore, the position of the adjustable shelf  460  can be adjusted axially without inducing any corresponding movement of the piston rod  430  and movable piston  470 . The position of the adjustable shelf  460 , and therefore the dose size, can accordingly be adjusted without spillage of liquid drug. Furthermore, the adjustment of the axial position of the adjustable shelf  460  leads to the desired dose size adjustment because the positional change alters the axial distance of travel of the piston rod  430  and piston movable piston  470 . 
         [0058]    The loading or preparation of the injection device  400  is generally similar to the one for the first injection device  1  described above in connection with  FIGS. 2   a )- d ) albeit with a different operation of the clutch mechanism. The helical compression spring  425  is torsionally pre-tensioned and compressible by proximal displacement of the sliding element  435  during the loading sequence of the injection device  400 . The torque obtained from the torsionally pre-tensioned helical compression spring  425  is used to rotate the the sliding element  435  once the adjustable proximal shelf  460  is reached and bring the finger  437  into engagement with the upper plane surface  462  in connection with the mounting of removable cap  480  by helical twisting. Once the removable cap  480  has been mounted, the injection device  400  is automatically rendered in a prepared state with a dose of the first size where the finger  437  of the sliding element  435  rests safely on the upper plane surface  462  of the adjustable upper shelf  460 .  FIGS. 5   a ) and  5   b ) are respective central axial cross-sectional views of an injection device  501  in accordance with a third embodiment of the invention wherein the depicted cross-sectional views are shown at an angular separation of 90 degrees by rotation of the injection device  501  about a central longitudinal axis  503 . 
         [0059]    The injection device  501  has many features in common with the above-described first embodiment of the injection device  1  on  FIG. 1 . The dose adjustment structure of the first embodiment utilized axial movement of a distal clamping structure (the adjustable shelf  60 ) to adjust the desired dose size in the prepared state of the injection device  1 . In contrast, the dose adjustment structure of the present injection device  501  is configured to vary an axially extending geometry of a toothed sliding element  535  to adjust the dose size in the prepared state. In the present injection device  501 , the respective axial positions of a distal clamping structure and a proximal clamping structure remain fixed. Furthermore, a user operable dose dial is integrated with an injection button of the injection device  501  as explained in further details below. 
         [0060]    The injection device  501  is illustrated in an unprepared or unloaded state after delivery of a dose of liquid drug to a user or patient by self-administration. The injection device  501  comprises a tubular housing  520 , a cartridge  585  holding a volume of liquid drug and an injection button  505  protruding axially from the housing  520 . An injection needle (not shown) is attached to a distal portion of the cartridge  585  for subcutaneous injection of a predetermined dose of liquid drug in accordance with the user&#39;s setting of a dose size. A toothed elongate piston rod  530  is rigidly attached to a movable piston  570  via a piston foot  565 . The movable piston  570  is arranged within an interior volume of the cartridge  585 . Consequently, advancing the toothed piston rod  530  a predetermined distance axially in distal direction will cause a corresponding axial displacement of the piston  570  and cause a dose of the liquid drug to be expelled via the injection needle. A dose setting structure is responsive to the mounting of a removable cap  580  to place the injection device  501  in a prepared or loaded state with a dose of liquid drug of a first size. The dose setting structure comprises a pusher  550  configured for engagement with the removable cap  580  and axially displaceable by mounting of the removable cap  580 . The pusher  550  is configured for engaging a sliding element  535  and axially displaces the sliding element  535  in proximal direction, i.e. towards the injection button  505 . The displacement of the sliding element  535  leads to a loading or preparation of the injection device  501  with a dose of liquid drug of the first size as explained in further detail below. The sliding element  535  comprises teeth engaging mating teeth of the toothed elongate piston rod  530  or piston rod. The mating teeth of the sliding element  35  and the piston rod  530  are configured to solely allow unidirectional displacement in proximal direction of the sliding element  535  relative to the toothed elongate piston rod  530  or piston rod. Consequently, the piston rod  530  is advanced together with the sliding element  535  when the latter moves in an opposite direction, i.e. a distal direction towards the second or distal position defined by the fixed distal clamping structure formed as a cut-out or shelf in the housing  520 . 
         [0061]    The sliding element  535  is coupled to a helical compression spring  525  co-axially arranged around a tubular portion of the sliding element  535 . The compression spring  525  is torsionally pre-tensioned and compressible by proximal displacement of the sliding element  535  during a loading sequence of the injection device  501 . The loading sequences therefore causes potential energy or compression force to be stored in the helical compression spring  525  for release in connection with forward firing or advancement of the piston rod  530  and movable piston  570  during injection of the liquid drug. One end portion of the compression spring  525  engages the sliding element  535  and an opposing end portion engages a spring base  515  rigidly attached to the housing  520 . 
         [0062]    The injection device  501  furthermore comprises user operable dose adjustment structure or dose dial  555  configured to, in the prepared or load state, increase or decrease the dose of the first size to set a dose of a second size. The dose dial  555  is configured to adjust an axial position of an axially translatable finger (refer to item  537  on  FIGS. 7   a )- b ) so as to vary the dose size in accordance with the user&#39;s adjustment of the dose dial  555  as explained in further detail below. A fixed position distal clamping structure  560  or distal shelf is formed in the housing  520  and defines an end-stop for advancement of the axially translatable finger of the sliding element  535 . 
         [0063]    The user operable dose adjustment structure additionally comprises a clutch mechanism configured to decouple the dose setting structure from the injection structure in the prepared state. The clutch mechanism comprises a pusher  550  configured to selectively engage or disengage a toothed nut  540  operatively coupled to the piston rod  530  as as explained in further detail below in connection with  FIGS. 6   b )- 6   f ). 
         [0064]    The injection button  505  is configured to noticeably project from the housing  520  in the prepared state of the injection device  501  as depicted on  FIG. 6   d ) to indicate a current state of the injection device  501  to the user or patient. By depression of the injection button  505  in the prepared state, a firing sequence is initiated where the sliding element  535  is released from the proximal clamping structure and the piston rod  530  advanced from a first or proximal position relative to the housing  501  to the second or distal position in an unprepared or unloaded state of the injection device  501 . A predetermined axial distance between the first and second positions accordingly corresponds to the delivery of the dose of the second size. 
         [0065]    The clutch mechanism comprises a toothed nut  540 , a nut spring  545  and a toothed inner peripheral surface of the pusher  550 . The clutch mechanism is configured to decouple the dose setting structure from the injection structure in the prepared state of the injection device so as to allow dose adjustment in the prepared state by actuation of the dose dial  555  without advancing the toothed piston rod  530  and piston  570  and spillage of liquid drug as explained in further detail below. 
         [0066]      FIG. 6   a ) illustrates a first step of a loading and firing sequence of the injection device  501  where the device is loaded or prepared. In connection with the first step, loading or preparation is initiated by the user by twisting the replaceable cap  580  onto the injection device  501  following a helical trajectory as indicated by arrow  672 . 
         [0067]      FIG. 6   b ) illustrates a second step of a loading and firing sequence of the injection device  501  where the device is loaded or prepared. The pusher  550  is the first portion of the dose setting structure to move in response to mounting of the removable cap  580 . As previously explained, the piston rod  530  can only move axially in one direction, a distal direction, relative to the housing  520  of the injection device. This effect is created by a pair of one way snaps  552  mounted in the housing  520  and engaging the teeth on piston rod  530 . The pusher  550  is rotationally locked to the housing  520 . The pusher  550  is axially displaced by the twisting operation of the removable cap  580 , but the toothed nut  540 , which is rotatably mounted on the piston rod  530 , stands still due to an inner thread (not shown) that engages a mating thread on the piston rod  530 . The disengagement between the toothed nut  540  and the pusher  550  allows the toothed nut  540  to rotate as it is pushed proximally/upwards by the pusher  550  and the nut spring  545 . The toothed nut  540  will start to rotate about the piston rod  530  due to the threaded non-locking interface with the mating teeth on the piston rod  530 . 
         [0068]    The teeth of the toothed nut  540  are arranged around a circumferential outer perimeter of the toothed nut  540 . The teeth of the pusher  550 , which are arranged on an inner tubular surface of the pusher  550  as explained above, are forced to disengage the mating teeth on the toothed nut  540  by this translation due to an axially directed biasing force supplied by the nut spring  45 . The toothed nut  540  can now rotate freely about the piston rod  530 . In effect, the dose setting structure has been decoupled from the injection structure because the piston rod  530  is no longer operatively coupled to the sliding element  535 . 
         [0069]      FIG. 6   c ) illustrates third step of the loading and firing sequence of the injection device  501  where the device is loaded or prepared. In this step, the helical compression spring  525  is compressed and loaded with axial force and a torque. The axial force is later on used to supply dose delivery force or energy during a user initiated firing or dose delivery sequence as explained below. The torque is obtained by torsionally pre-tensioning the helical compression spring  525  and using this torque to rotate the sliding element  535  about the axis of the housing  501  into engagement with a proximal clamping structure at a first or proximal position of the piston rod  530 . The helical twisting of the removable cap  580  is configured to axially translate the pusher  550  and the sliding element  535  to a first position guided by an axial slot  532  (depicted on  FIG. 6   d )) in a annular wall section of the housing  520 . At the first position, the circumferentially extending slot or channel  532  in the tubular wall section guides rotary movement of the sliding element  535  about the longitudinal housing axis  503 . The combination of the axial slot and the circumferentially extending slot  532  forms an L-shaped slot in the housing  520 . The toothed nut  540  is free to rotate in the non-self locking thread engaging the piston rod  530  when the pusher  550  and the sliding element  535  translate. 
         [0070]      FIG. 6   d ) illustrates the fourth step of the loading and firing sequence where the injection device  501  is loaded or prepared. The sliding element  535  will rotate because of the freedom in the housing and the torque generated by the helical compression spring  525 . Furthermore, the injection button  505  is rotated and axially translated, in response to the axial displacement and rotation of the sliding element  535 , from an unloaded or unprepared state indicated by its non-protruding placement inside the housing  520  of injection device to a loaded or prepared state indicated by the protruding placement depicted in  FIG. 6   d ). Consequently, after completion of step  4 , the injection device  501  is rendered in its prepared or loaded state with the removable cap mounted on the injection device  501 . The sliding element  535  rests in the circumferentially extending slot  532  in the housing  520  with the sliding element  535  decoupled from the pusher  550 . It is now possible to adjust an axial position of the axially translatable finger (refer to item  537  on  FIGS. 7   a )- b ) movably mounted in the sliding element  535 . The adjustment of the axial position of the finger leads to an adjustment of the size of the dose as explained in further detail below. The adjustment of the dose size is accomplished by actuating the dose dial  555  by the user or patient as explained in further detail below in connection with  FIGS. 7   a )- b ). 
         [0071]      FIG. 6   e ) illustrates the fifth step of the loading and firing sequence of the injection device  501  where the device  501  fired or unloaded. The sliding element  535  rests in the circumferentially extending slot  532  in the housing  520  when the removable cap  580  is removed by the user as explained above. When the injection button  505  is depressed as indicated by the arrow adjacent to the button  505 , a first movement of the injection button  505  will disengage mating teeth structures arranged on the injection button  505  and dose adjustment structure. The injection button  505  comprises a radially and inwardly projecting toothed annular structure coupled to mating teeth extending radially outwardly from a tubular proximal end section  539  of the sliding element  535 . After the first movement, the sliding element  535  is able to rotate freely. 
         [0072]      FIG. 6   f ) illustrates the sixth step of the loading and firing sequence where the injection device  501  is fired or unloaded. In connection with the first movement of the injection button  505 , the pusher  550  will translate a small distance axially and engage with the toothed nut  450  so as to rotationally lock to, or engage, the toothed nut  540  by virtue of the mating sets of teeth arranged on the pusher  550  and the toothed nut  540  as explained above. 
         [0073]    When the injection button  505  is depressed further as indicated by the arrow adjacent to the button  505 , the sliding element  535  is also forced to rotate due to a helical spiralling movement of the injection button  505  under engagement with the end surface of the sliding element  535 . The rotary movement of the sliding element  535  is guided by the circumferentially extending slot  532  and continues until the sliding element  535  reaches the axial slot (not shown) in the housing  520 . 
         [0074]      FIG. 6   g ) illustrates the sixth step of the loading and firing sequence where the injection device  501  is fired or unloaded. When the sliding element  535  reaches the axial slot in the housing  520 , the sliding element  535  is translated axially in distal direction because of the axial force generated by the compressed helical compression spring  525 . The toothed nut  540  will translate axially in a corresponding manner because of the locked engagement with the pusher  550 . The toothed nut  540  will subsequently advance the piston rod  530  axially and distally since these components are axially locked to each other. The advancement of the piston rod  530  will lead to a corresponding advancement of the movable piston  570  inside the cartridge  585  so as to make a dosing in accordance with the user selected dose size. The depicted end-of-dose or second position of the piston rod  530  is reached once the axially translatable finger (not shown) reaches the distal shelf or end-stop  560  engraved into the housing  520  as explained below in further detail in connection with  FIG. 7   a ). 
         [0075]      FIG. 7   a ) is a central cross-sectional view of a user operable dose adjustment structure of the injection device  501  depicted on  FIG. 5 . As previously explained, the dose dial  555  is integrated with the injection button  505 . Adjustment of an already set first dose size, i.e. set during the above-described loading steps of the injection device, is achieved by rotation of the dose dial  555 . As previously explained, a radially and inwardly projecting toothed annular structure of the injection button is coupled to the radially and outwardly projecting teeth arranged on the tubular proximal end section  539  of the sliding element  535 . Rotation of the dose dial  555  causes axial translation or movement of the position of the finger  537  as indicated by the axially pointing arrows  538  on  FIG. 7  b) due to a threaded interface  536  between a lower tubular portion of the sliding element  535  and the finger  537  in connection with the allocated space in the housing for axial movement of the latter as illustrated. Axial movement of the finger  537  changes the axial distance AD between the finger  537  and the fixed position distal shelf  560 , which defines an end-stop for the finger  537  at engagement as explained above. The end-stop also functions as an end-stop for the residual part of the sliding element  535  and therefore defines a second or distal position of the piston rod  530  after dose delivery due to the interlocked engagement between the sliding element  535  and piston rod  530  during distal advancement in connection with the above-described firing or delivery sequence. In the illustrated situation, the axial distance travelled by the piston rod  530  from the first or proximal position in the prepared state to the second position in the unprepared state is 
         [0076]    AD and corresponds to the delivery of the set dose after a possible user adjustment of an initially set first dose size by manipulation of the dose dial  555 . Therefore, adjustment of the axial position of the finger  537  will adjust the travel distance AD of the piston rod  530  in a corresponding manner and adjust the size of the delivered dose of liquid drug.  FIG. 7   c ) is a central cross-sectional view of an end-of-content feature of the injection device depicted on  FIGS. 5   a )- b ) under normal operating conditions. Under the normal operating conditions, the piston rod  530  is sequentially advanced in axial direction for each new dose delivery. As explained above, the sliding  535  element rotates about the central axis when it reaches the circumferentially extending slot or channel in the tubular wall section of the housing in connection with the loading sequence and the firing sequence. However, in the end of content mode depicted on  FIG. 7   d ), the sliding element  535  is prevented from further rotation. A projection  531  arranged in an end portion of the piston rod  530  engages a mating cut out in the finger  537  of the sliding element  535  and locks the piston rod  530  for rotation. If the removable cap is mounted on the injection device by the user in this end of content mode, the sliding element  535  will translate and seek to rotate when it is possible. However, the finger  537  forms part of the sliding element  535  and is rotationally locked thereto. If the injection device is in the end of content mode, the sliding element  535  is blocked for rotation because the finger  537  and the piston rod  530  are unable to rotate. Since the injection button  505  is advanced to its projecting position, indicating a prepared or loaded state of the injection device, by rotation of the sliding element  535 , the injection button  505  will stay in the illustrated depressed state (not protruding from the housing  520 ) and indicate to the user that the injection device has been emptied. 
         [0077]    While the above-described injection devices have been designed as disposable devices, the skilled person will understand that the each of the disclosed injection devices by suitable modifications could be provided with suitable means for cartridge replacement to provide a durable injection device.