Patent Publication Number: US-2022233778-A1

Title: Feedback Mechanism for an Injection Device

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is a divisional of U.S. patent application Ser. No. 16/346,250, filed on Apr. 30, 2019, which is the national stage entry of International Patent Application No. PCT/EP2017/076056, filed on Oct. 12, 2017, and claims priority to Application No. EP 16196676.7, filed on Nov. 1, 2016, the disclosures of which are incorporated herein by reference. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates to a feedback mechanism for an injection device. 
     BACKGROUND 
     Injection devices, such as auto-injectors, typically have a syringe into which a plunger is pushed to dispense medicament from the syringe into the patient via a needle. The injection process is completed when the plunger has been pushed the appropriate distance into the syringe. It is known to provide a feedback mechanism for indicating to the user when the appropriate volume of medicament has been injected. 
     SUMMARY 
     It is an object of the present disclosure to provide a feedback mechanism for an injection device that provides feedback to a user. 
     According to a first aspect, there is provided a feedback mechanism for an injection device, said injection device being configured to deliver a medicament to a user, the feedback mechanism comprising:
         a piston and a fluid chamber, the piston being adapted to move into the fluid chamber during use of the injection device;   a damper arranged to damp movement of the piston; and,   an indicator arranged to provide feedback to said user after the piston has moved a pre-determined distance into the fluid chamber.       

     The feedback mechanism may further comprise a biasing member arranged to urge the piston into the fluid chamber during use. 
     The damper may comprise a rotary agitator disposed within the fluid chamber, and wherein movement of the piston into the fluid chamber may cause rotation of the rotary agitator such that the movement of the piston is damped by the rotary agitator. 
     The piston may comprise the rotatory agitator. 
     The piston may comprise a plate that extends across the fluid chamber, and the damper may comprise one or more orifices located in the plate through which fluid flows as the piston moves into the fluid chamber. 
     The feedback mechanism may further comprise a recipient chamber into which fluid is urged as the piston moves into the fluid chamber, and wherein the damper may comprise an orifice arranged between the fluid chamber and the recipient chamber. 
     The recipient chamber may comprise a slider that is moved by fluid passing into the recipient chamber, and wherein the slider may be configured to engage the indicator after the slider has moved a predetermined distance, and wherein the indicator may provide feedback to said user after being engaged. 
     The indicator may be disposed between the piston and a part of said injection device, such that movement of the piston into the fluid chamber causes the indicator to be engaged by the piston and/or said part of said injection device, and wherein the indicator may provide feedback to said user after being engaged. 
     The indicator may comprise a sound generator that generates an audible sound. 
     The sound generator may comprise a pre-stressed element that generates an audible sound when deflected. 
     According to a further aspect, there is also provided an injection device comprising a medicament delivery mechanism comprising a reservoir and a plunger that moves to displace medicament from the reservoir for delivery to a user during use of the injection device; and, the feedback mechanism described above. 
     The injection device may further comprise a biasing member arranged to push the plunger into the reservoir during use. 
     The biasing member may be arranged to act on the piston, and wherein the piston and plunger may be arranged such that force applied to the piston is transferred to the plunger via the fluid chamber. 
     The damper may comprise an orifice formed in the plunger. 
     The injection device may further comprise a housing, and wherein the damper may comprise an orifice formed in the housing. 
     The indicator may comprise a pre-stressed element that generates an audible sound when deflected, the pre-stressed element being mounted to the plunger and arranged to be deflected as the plunger moves to displace medicament. 
     The plunger may comprise an arm to which the pre-stressed element is mounted, the arm being arranged to engage a feature of the piston as the piston moves into the fluid chamber, and wherein the arm is arranged to deflect the pre-stressed element after engaging with the feature of the piston. 
     The injection device may be configured such that the piston begins moving into the fluid chamber after the plunger has moved a pre-determined distance into the reservoir. 
     The injection device may further comprise a locking mechanism arranged to hold the piston until the plunger has reached a pre-determined position, and to then release the piston such that the piston can move into the fluid chamber. 
     The reservoir may contain a medicament. 
     According to a further aspect, there is also provided a method of using an injection device, the method comprising:
         delivering a medicament to a user;   moving a piston into a fluid chamber;   damping said movement of the piston; and,   providing feedback to said user after the piston has moved a pre-determined distance into the fluid chamber.       

     These and other aspects will be apparent from and elucidated with reference to the embodiments described hereinafter. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       Embodiments will now be described, by way of example only, with reference to the accompanying drawings, in which: 
         FIG. 1A  is a schematic side view of an injection device and a removable cap; 
         FIG. 1B  is a schematic side view of the injection device of  FIG. 1A , with the cap removed from the housing; 
         FIG. 2A  is a cross-sectional side view of an injection device having a damper and an indicator, shown before the injection device has been used; 
         FIG. 2B  is a cross-sectional side view of the injection device of  FIG. 2A , after the injection device has been used; 
         FIG. 3A  is a cross-sectional side view of an injection device having a damper, an indicator and a locking mechanism, shown before the injection device has been used; 
         FIG. 3B  is a magnified cross-sectional side view of the locking mechanism of the injection device of  FIG. 3A ; 
         FIG. 4  is a cross-sectional side view of another injection device having a damper and an indicator, shown before the injection device has been used; 
         FIG. 5A  is a cross-sectional side view of another injection device having a damper and an indicator, shown before the injection device has been used; 
         FIG. 5B  is a cross-sectional side view of the injection device of  FIG. 5A , after the injection device has been used; 
         FIG. 6A  is a cross-sectional side view of another injection device having a damper and an indicator, shown before the injection device has been used; 
         FIG. 6B  is a cross-sectional side view of the injection device of  FIG. 6A , after the injection device has been used; 
         FIG. 7A  is a cross-sectional side view of another injection device having a damper and an indicator, shown before the injection device has been used; and, 
         FIG. 7B  is a cross-sectional side view of the injection device of  FIG. 6A , after the injection device has been used. 
     
    
    
     DETAILED DESCRIPTION 
     A drug delivery device, as described herein, may be configured to inject a medicament into a patient. For example, delivery could be sub-cutaneous, intra-muscular, or intravenous. The user of such a device could be a patient or care-giver, such as a nurse or physician, and can include various types of safety syringe, pen-injector, or auto-injector. The device can include a cartridge-based system that requires piercing a sealed ampule before use. Volumes of medicament delivered with these various devices can range from about 0.5 ml to about 2 ml. Yet another device can include a large volume device (“LVD”) or patch pump, configured to adhere to a patient&#39;s skin for a period of time (e.g., about 5, 15, 30, 60, or 120 minutes) to deliver a “large” volume of medicament (typically about 2 ml to about 10 ni). 
     In combination with a specific medicament, the presently described devices may also be customized in order to operate within required specifications. For example, the device may be customized to inject a medicament within a certain time period (e.g., about 3 to about 20 seconds for auto-injectors, and about 10 minutes to about 60 minutes for an LVD). Other specifications can include a low or minimal level of discomfort, or to certain conditions related to human factors, shelf-life, expiry, biocompatibility, environmental considerations, etc. Such variations can arise due to various factors, such as, for example, a drug ranging in viscosity from about 3 cP to about 50 cP. Consequently, a drug delivery device will often include a hollow needle ranging from about 25 to about 31 Gauge in size. Common sizes are 17 and 29 Gauge. 
     The delivery devices described herein can also include one or more automated functions. For example, one or more of needle insertion, medicament injection, and needle retraction can be automated. Energy for one or more automation steps can be provided by one or more energy sources. Energy sources can include, for example, mechanical, pneumatic, chemical, or electrical energy. For example, mechanical energy sources can include springs, levers, elastomers, or other mechanical mechanisms to store or release energy. One or more energy sources can be combined into a single device. Devices can further include gears, valves, or other mechanisms to convert energy into movement of one or more components of a device. 
     The one or more automated functions of an auto-injector may each be activated via an activation mechanism. Such an activation mechanism can include an actuator, for example, one or more of a button, a lever, a needle sleeve, or other activation component. Activation of an automated function may be a one-step or multi-step process. That is, a user may need to activate one or more activation components in order to cause the automated function. For example, in a one-step process, a user may depress a needle sleeve against their body in order to cause injection of a medicament. Other devices may require a multi-step activation of an automated function. For example, a user may be required to depress a button and retract a needle shield in order to cause injection. 
     In addition, activation of one automated function may activate one or more subsequent automated functions, thereby forming an activation sequence. For example, activation of a first automated function may activate at least two of needle insertion, medicament injection, and needle retraction. Some devices may also require a specific sequence of steps to cause the one or more automated functions to occur. Other devices may operate with a sequence of independent steps. 
     Some delivery devices can include one or more functions of a safety syringe, pen-injector, or auto-injector. For example, a delivery device could include a mechanical energy source configured to automatically inject a medicament (as typically found in an auto-injector) and a dose setting mechanism (as typically found in a pen-injector). 
     According to some embodiments of the present disclosure, an exemplary drug delivery device  10  is shown in  FIGS. 1A &amp; 1B . Device  10 , as described above, is configured to inject a medicament into a patient&#39;s body. Device  10  includes a housing  11  which typically contains a syringe  18  containing the medicament to be injected and the components required to facilitate one or more steps of the delivery process. A cap  12  is also provided that can be detachably mounted to the housing  11 . Typically, a user must remove cap  12  from housing  11  before device  10  can be operated. 
     As shown, housing  11  is substantially cylindrical and has a substantially constant diameter along the longitudinal axis A-A. The housing  11  has a distal region D and a proximal region P. The term “distal” refers to a location that is relatively closer to a site of injection, and the term “proximal” refers to a location that is relatively further away from the injection site. 
     Device  10  can also include a needle sleeve  19  coupled to housing  11  to permit movement of sleeve  19  relative to housing  11 . For example, sleeve  19  can move in a longitudinal direction parallel to longitudinal axis A-A. Specifically, movement of sleeve  19  in a proximal direction can permit a needle  17  to extend from distal region D of housing  11 . 
     Insertion of needle  17  can occur via several mechanisms. For example, needle  17  may be fixedly located relative to housing  11  and initially be located within an extended needle sleeve  19 . Proximal movement of sleeve  19  by placing a distal end of sleeve  19  against a patient&#39;s body and moving housing  11  in a distal direction will uncover the distal end of needle  17 . Such relative movement allows the distal end of needle  17  to extend into the patient&#39;s body. Such insertion is termed “manual” insertion as needle  17  is manually inserted via the patient&#39;s manual movement of housing  11  relative to sleeve  19 . 
     Another form of insertion is “automated”, whereby needle  17  moves relative to housing  11 . Such insertion can be triggered by movement of sleeve  19  or by another form of activation, such as, for example, a button  13 . As shown in  FIGS. 1A &amp; 1B , button  13  is located at a proximal end of housing  11 . However, in other embodiments, button  13  could be located on a side of housing  11 . 
     Other manual or automated features can include drug injection or needle retraction, or both. Injection is the process by which a bung  14  is moved from a proximal location within a syringe  18  to a more distal location within the syringe  18  in order to force a medicament from the syringe  18  through needle  17 . In some embodiments, a drive spring (not shown) is under compression before device  10  is activated. A proximal end of the drive spring can be fixed within proximal region P of housing  11 , and a distal end of the drive spring can be configured to apply a compressive force to a proximal surface of bung  14 . Following activation, at least part of the energy stored in the drive spring can be applied to the proximal surface of bung  14 . This compressive force can act on bung  14  to move it in a distal direction. Such distal movement acts to compress the liquid medicament within the syringe  18 , forcing it out of needle  17 . 
     Following injection, needle  17  can be retracted within sleeve  19  or housing  11 . Retraction can occur when sleeve  19  moves distally as a user removes device  10  from a patient&#39;s body. This can occur as needle  17  remains fixedly located relative to housing  11 . Once a distal end of sleeve  19  has moved past a distal end of needle  17 , and needle  17  is covered, sleeve  19  can be locked. Such locking can include locking any proximal movement of sleeve  19  relative to housing  11 . 
     Another form of needle retraction can occur if needle  17  is moved relative to housing  11 . Such movement can occur if the syringe  18  within housing  11  is moved in a proximal direction relative to housing  11 . This proximal movement can be achieved by using a retraction spring (not shown), located in distal region D. A compressed retraction spring, when activated, can supply sufficient force to the syringe  18  to move it in a proximal direction. Following sufficient retraction, any relative movement between needle  17  and housing  11  can be locked with a locking mechanism. In addition, button  13  or other components of device  10  can be locked as required. 
       FIG. 2A  and  FIG. 2B  show an example injection device  20  that includes a syringe  18 , similar to as described above with reference to  FIG. 1A  and  FIG. 1B . The injection device  20  of  FIG. 2A  also includes a housing (not shown). 
     As illustrated, the injection device  20  also includes a plunger  21  that acts on the bung  14  to move the bung  14  into the syringe  18  and dispense medicament through the needle  17 . A drive spring  22  is provided to push the plunger  21  against the bung  14  and into the syringe  18  during use of the injection device  20 . The drive spring  22  may be pre-loaded, and a release mechanism may be provided to release the plunger  21  such that the drive spring  22  can push the plunger  21  and bung  14  to dispense medicament, as described previously. It will be appreciated that the bung  14  may be omitted and the end  23  of the plunger  21  may act as a bung within the syringe  18 . 
     The injection device  20  of  FIG. 2A  also includes a delay mechanism that provides delayed user feedback at a time after the plunger  21  has moved into the syringe  18 . This delayed feedback informs the user that the medicament has been dispensed, and the delay provides time for the medicament to have dispersed from the injection site. 
     As illustrated, the injection device  20  of this example includes a damper, in this example a piston  24  and fluid chamber  25  that are located within the plunger  21 . The plunger  21  is elongate and has a cylindrical bore  26  with an opening  27  at the distal end of the plunger  21 , in which the piston  24  and fluid chamber  25  are located. 
     As shown, the piston  24  of this example is formed of a disc  28  and an opposite end  29 , and a web  30  connecting the disc  28  and the opposite end  29 . The web  30  provides free space in the area surrounding the web  30  between the disc  28  and the opposite end  29 . Also provided is a sealing plate  31  fixed in the cylindrical bore  26 , including a seal  32 . The sealing plate  31  includes an aperture through which the web  30  of the piston  24  extends, such that the disc  28  is on a first (proximal) side of the sealing plate  31  and the opposite end  29  is on a second (distal) side of the sealing plate  31 . The fluid chamber  25  is defined between the sealing plate  31  and the end of the cylindrical bore  26  within the plunger  21 . 
     In this way, the disc  28  is located within the fluid chamber  25 . The drive spring  22  acts between the opposite end  29  of the piston  24  and the housing (not shown) of the injection device  20 . The drive spring  22  pushes the piston  24  towards the fluid chamber  25 . 
     An indicator, in this example a sound generator  33 , is located between the sealing plate  31  and the opposite end  29  of the piston  24 . In this example, the sound generator  33  is fixed to the proximal side of the sealing plate  31 , but it may alternatively be fixed to the piston  24 . The sound generator  33  comprises a pre-stressed member that generates a sound when deflected (as explained below), which provides the user with an audible indication. 
     During use of the injection device  20  the drive spring  22  pushes the piston  24 , which in turn applies a compressive force to the fluid chamber  25 , which in turn urges the plunger  21  against the bung  14  and into the syringe  18 . That is, the force of the drive spring  22  is provided to the plunger  21  via the piston  24  and fluid chamber  25 . 
     The disc  28  of the piston  24  is provided with at least one orifice  34  through which the fluid in the fluid chamber  25  passes as the piston  24  is urged in a proximal direction by the drive spring  22 . The orifice(s)  34  allows fluid to pass through the disc  28 , from a proximal side to a distal side, and therefore allows the piston  24  to move proximally. As the piston  24  moves proximally, the web  30  slides within the aperture of the sealing plate  31  and fluid gradually moves into the space between the sealing plate  31  and the disc  28  of the piston  24 . 
     The orifice(s)  34  is of restricted size to limit the rate at which fluid can pass through the orifice(s)  34  as the drive spring  22  pushes against the piston  24 . The orifice(s)  34  thereby form a damper that damps movement of the piston  24  into the fluid chamber  25 . 
     The rate at which the piston  24  is able to move in a proximal direction depends on the rate at which the fluid can pass through the orifice(s)  34 , which is dependent on the viscosity of the fluid and the size and number of the orifice(s)  34 , as well as the force applied by the drive spring  22 . 
     As illustrated in  FIG. 2B , when the piston  24  has moved completely or almost completely into the fluid chamber  25  the sound generator  33  is deflected by the opposite end  29  and/or the sealing plate  31 . Deflection of the sound generator  33  creates an audible sound that provides the user with an indication. 
     In this example, the rate of fluid movement through the orifice(s)  34  is configured such that the piston  24  reaches the point at which the sound generator  33  is deflected at a time after the plunger  21  has reached the end of its movement into the syringe  18 . In particular, for the given force of the drive spring  22  the time taken for the bung  14  to be pushed into the syringe  18  is less than the time taken for the piston  24  to be pushed into the fluid chamber  25  and the sound generator  33  to be deflected. 
     Therefore, the user is provided with the indication at a time after the medicament has been dispensed from the syringe  18 . This delayed feedback provides for dispersion of the medicament from the injection site. 
     The duration of the delay may be, for example, more than 2 seconds, or more than 5 seconds, or more than 10 seconds, or between 10 and 30 seconds, or between 10 and 20 seconds. 
       FIG. 3A  and  FIG. 3B  show an example injection device  35  that is similar to that described with reference to  FIG. 2A  and  FIG. 2B . In this example, the injection device  35  also has a locking mechanism that holds the piston  24  in a locked position until the plunger  21  and bung  14  have been moved a pre-determined distance into the syringe  18 . 
     The locking mechanism includes locking arms  36  that are pivotally attached to the plunger  21  at pivots  38  and engage a distal side of the opposite end  29  of the piston  24 , as shown in  FIG. 3A  and  FIG. 3B . A stop  37  is provided for each locking arm  36 , the stops  37  being located on the plunger  21  and the stops  37  are arranged to prevent rotation of the locking arms  36  as the plunger  21  and bung  14  are moved into the syringe  18 . 
     In particular, as the drive spring  22  acts on the piston  24  force is transferred to the plunger  21  via the locking arms  36  and stops  37 , rather than via the disc  28  and fluid chamber  25 . Therefore, the locking arms  36  remain in the position illustrated in  FIG. 3A  and  FIG. 3B  while the plunger  21  and bung  14  move into the syringe  18  to dispense medicament. 
     At or towards the end of the movement of the plunger  21  into the syringe  18  the locking arms  36  abut against the annular end  39  of the syringe  18 . The leverage caused by the locking arms  36  abutting against the annular end  39  of the syringe  18  causes the locking arms  36  to either break or deform the stops  37 , allowing the locking arms  36  to rotate and release the engagement between the piston  24  and plunger  21 . Thereafter, the force of the drive spring  22  acts to push the piston  24  into the fluid chamber  25 , eventually triggering the sound generator  33  after a delay caused by the damper (orifice(s)  34 ), as described with reference to  FIG. 2A  and  FIG. 2B . 
     The locking mechanism thereby prevents movement of the piston  24  until the plunger  21  has dispensed all or most of the medicament through the needle  17 . This is advantageous as it removes the variations in time for the fluid to pass through the orifice(s)  34  in the disc  28 , which may be caused by temperature and back pressure differences. 
     In an alternative example, the locking arms  36  may not be pivotally mounted, but may themselves be broken or deformed when they contact the annular end  39  of the syringe  18 , thereby allowing the piston  24  to move independently of the plunger  21 . 
       FIG. 4  shows an alternative example injection device  40  that includes a syringe  18  and a bung  14 , similar to as described above with reference to  FIG. 2A ,  FIG. 2B , and  FIG. 3 . 
     The injection device  40  of this example also comprises a drive spring  22  that acts on a piston  41  which in turn acts on a plunger  42  to drive the plunger  42  into the syringe  18 . A locking mechanism locks in the piston  41  to the plunger  42  until the plunger  42  has moved into the syringe  18 , in the same way as described above with reference to  FIG. 3 . In particular, locking arms  36  are pivotally attached to the plunger  42  at pivots  38  and engage with the piston  41  until they contact the annular end  39  of the syringe  18 . At this point, the stops  37  are broken and the locking arms  36  can rotate and release the piston  41  from the plunger  42 . Thereafter, the drive spring  22  acts to push the piston  41  into a fluid chamber  25  formed within a cylindrical bore  43  of the plunger  42  and closed by a sealing plate  31 . 
     The sealing plate  31  is located in the plunger  42  and the piston  41  includes a web  44  that passes through an aperture in the sealing plate  31 , similarly to the example of  FIG. 3A  and  FIG. 3B . The drive spring  22  abuts against a proximal end  45  of the piston  41 , and a sound generator  33 , in this example a pre-stressed member, is located between the proximal end  45  and the sealing plate  31 . The distal end of the piston  41 , located in the fluid reservoir  25 , includes a damper in the form of a rotary agitator  46 . 
     The rotary agitator  46  comprises one or more fins, paddles, or angled plates that create resistance as the rotary agitator  46  rotates within the fluid in the fluid chamber  25 . 
     The proximal end  45  of the piston  41  includes at least one protrusion  47  that engages with a thread  48  formed in the cylindrical bore  43  of the plunger  42 . The thread  48  is helical along the cylindrical bore  43 , and so to move axially within the injection device  40  the piston  41  must rotate so that the protrusion(s)  47  move along the thread  48 . 
     Therefore, after the locking arms  36  have released the piston  41  from the plunger  42 , and the drive spring  22  is pushing the piston  41  in a distal direction, the piston  41  rotates within the plunger  42 . This rotation is damped by the rotation of the rotary agitator  46  within the fluid chamber  25 . This resistance delays the progress of the piston  41  in a distal direction. 
     Once the piston  41  has been pushed/rotated towards the end of the fluid chamber  25  the sound generator  33  is compressed between the proximal end  45  of the piston  41  and the sealing plate  31 , and is deflected. The sound generator generates an audible sound as it is deflected, providing the user with an audible indication. 
     The duration of the delay between the start of the movement of the piston  41  and the compression of the sound generator  33  may be, for example, more than 2 seconds, or more than 5 seconds, or more than 10 seconds, or between 10 and 30 seconds, or between 10 and 20 seconds. 
     In this example, the piston  41  only starts moving into the fluid chamber  25  after the bung  14  is at or near the end of the syringe  18 , and so the indication is provided to the user at a time after the medicament has been injected. This allows time for the medicament to disperse from the injection site. 
     In an alternative example, the locking mechanism (locking arms) are omitted, and the damping provided by the rotary agitator  46  and fluid chamber  25  is increased such that, for a given force from the drive spring  22 , the time taken for the piston  41  to move from the initial position to the position in which the sound generator  33  is triggered is greater than the time required to move the bung  14  to the end of the syringe  18  and dispense all of the medicament. In this way, the audible indication is provided at a time after the medicament has been dispensed, allowing for dispersal of the medicament from the injection site. 
       FIG. 5A  shows an alternative example injection device  50  that includes a bung  14  and syringe  18 , similar to as described previously. In particular, the injection device  50  has a syringe  18  and a bung  14  that is pushed into the syringe  18  by a plunger  51 . In this example, a piston  52  is located between the plunger  51  and the bung  14 , and the piston  52  is received in a recess  53  in the distal end  54  of the plunger  51 . A fluid chamber  25  is defined in the recess  53  and the piston  52  seals the fluid chamber  25 . The drive spring  22  urges the plunger  51  against the piston  52 , which in turn is urged against the bung  14 . 
     The plunger  51  includes a cylindrical bore  55  extending from the proximal end  56  of the plunger  51 , and the recess  53  is located in the distal end  54  of the plunger  51 . A wall  57  separates the cylindrical bore  55  and the recess  53  and the wall  57  includes at least one orifice  58  through which fluid passes as the piston  52  moves into the recess  53  to compress the fluid chamber  25 . The fluid in the fluid chamber  25  and orifice  58  create a damper that damps movement of the piston  52  into the fluid chamber  25 . 
     On the proximal side of the wall  57  (opposite to the fluid chamber  25 ) is a spacer  59  that defines a recipient chamber  60  that is in fluid communication with the orifice  58 , such that fluid passing from the fluid chamber  25  through the orifice  58  passes into the recipient chamber  60 . The recipient chamber  60  includes an air outlet  61  so that the air displaced by the fluid can escape. The drive spring  22  pushes on the spacer  59  and in turn the wall  57 , and so drives the plunger  51  towards the bung  14  and piston  52 . In so doing the piston  52  is moved into the fluid chamber  25  and fluid is forced through the orifice  58  into the recipient chamber  60 . The rate of movement of fluid through the orifice  58  determines the rate at which the piston  52  moves into the recess  53 . Therefore, by defining the fluid viscosity and size and number of orifices  58 , the rate at which the piston  52  moves into the recess  53  can be defined. 
     The injection device  50  of this example also includes an indicator, in this example a sound generator. As illustrated, the sound generator includes a pre-stressed member  62  that is located on the plunger  51  and moves with the plunger  51  as the plunger  51  moves towards the syringe  18 . 
     As illustrated, the plunger  51  also includes a clip  63  that holds the pre-stressed member  62  in a first state as the plunger  51  moves into the syringe  18 . The clip includes an arm  64  and a head  65 , and the head  65  is in contact with, and urged against, the side of the piston  52 . The head  65  may be urged against the side of the piston  52  by a biasing member (not shown) or by the force provided by the pre-stressed member  62 . 
     The piston  52  includes a notch  66  adapted to receive the head  65  of the clip  63  once the piston  52  has moved a pre-determined distance into the fluid chamber  25 . As illustrated in  FIG. 5A , in an initial position the head  65  of the clip  63  is located proximally of the notch  66 , and as the drive spring  22  causes the piston  52  to move into the fluid chamber  25  the head  65  and notch  66  come into alignment, as shown in  FIG. 5B . Once aligned, the arm  64  deflects inwards and the pre-stressed member  62  is deflected, generating an audible sound that provides an indication to the user. 
     The viscosity of the fluid and the size and number of orifices  58  are selected such that the drive spring  22  pushes the bung  14  completely into the syringe  18 , to dispense all of the medicament, before the piston  52  reaches the point at which the audible indication is generated. In this way, the feedback is provided at a time after the medicament has been injected, allowing for the medicament to disperse from the injection site. 
     The arrangement of the damper creates a delay between the start of the movement of the piston  52  into the fluid chamber  25 , and the time at which the sound generator  62  generates a sound. The duration of the delay may be, for example, more than 2 seconds, or more than 5 seconds, or more than 10 seconds, or between 10 and 30 seconds, or between 10 and 20 seconds. 
       FIG. 6A  shows an alternative example injection device  70  similar to the example described with reference to  FIG. 5 . In particular, the injection device  70  has a syringe  18  and a bung  14  that is pushed into the syringe  18  by a plunger  71 . A piston  72  is located between the plunger  71  and the bung  14 , and the piston  72  is received in a recess  73  in the distal end  74  of the plunger  71 . The recess  73  forms a fluid chamber  25  and the piston  72  seals the fluid chamber  25 . 
     The plunger  71  includes a cylindrical bore  75  extending from the proximal end  76  of the plunger  71 , and the recess  73  is located in the distal end  74  of the plunger  71 . A wall  77  separates the cylindrical bore  75  and the recess  73 , and the wall  77  includes an orifice  78  through which fluid passes as the piston  72  moves into the fluid chamber  25 . 
     An elongate recipient chamber  79  is formed on the proximal side of the wall  79  (opposite to the fluid chamber  25 ), such that fluid passing from the fluid chamber  25  through the orifice  78  passes into the recipient chamber  79 . A slider  80  is located within the elongate recipient chamber  79  and the slider  80  is initially in a distal position, proximate to the wall  77 . 
     The drive spring  22  pushes on the wall  77  and so drives the plunger  71  towards the bung  14  and syringe  18 . In so doing the piston  72  is moved into the fluid chamber  25  and fluid is forced through the orifice  78  into the elongate recipient chamber  79 . The rate of movement through the orifice  78  defines the rate at which the piston  72  moves into the fluid chamber  25 . Therefore, by defining the fluid viscosity and size and number of orifices  78 , the rate at which the piston  72  moves into the fluid chamber  25  can be defined. 
     The injection device  70  of this example also includes an indicator, in this example a sound generator. As illustrated, the sound generator includes a pre-stressed member  81  that is located at the proximal end of the elongate recipient chamber  79 , opposite to the orifice  78 . The pre-stressed member  81  is initially in deflected state, as shown in  FIG. 6A . 
     As the drive spring  22  pushes the plunger  71  against the piston  72  and bung  14  the piston  72  gradually moves into the fluid chamber  25  and fluid is pushed through the orifice  78  into the elongate recipient chamber  79 . As fluid passes into the elongate recipient chamber  79  it pushes the slider  80  in a proximal direction, towards the pre-stressed member  81 . Eventually, as shown in  FIG. 6B , the slider  80  contacts the pre-stressed member  81  and deflects the pre-stressed member  81 , generating an audible sound which provides an indication to the user. 
     The viscosity of the fluid and the size of the orifice  78  can be selected such that the drive spring  22  pushes the bung  14  completely into the syringe  18 , to dispense all of the medicament, before the slider  80  reaches the pre-stressed element  81 . In this way, there is a delay between time at which the medicament has been completely dispensed and the time at which the sound generator  81  is contacted by the slider  80 , allowing time for the medicament to disperse from the injection site. 
     The duration of the delay may be, for example, more than 2 seconds, or more than 5 seconds, or more than 10 seconds, or between 10 and 30 seconds, or between 10 and 20 seconds. 
       FIG. 7A  and  FIG. 7B  show a further example injection device  82 . The injection device  82  includes a plunger  83 , a carrier  84 , and rotatable locking arms  85  that hold the carrier  84  until the plunger  83  has been moved a distance into the syringe (not shown). As shown in  FIG. 7B , once the carrier  84  is released the drive spring  22  urges the carrier  84  in a proximal direction. 
     The locking arms  85  are pivotally mounted to the housing  87  of the injection device  82  at pivots  86 . The locking arms  85  include deflected ends  88  that hold the carrier  84  as the drive spring  22  pushes against the carrier  84 . In the initial position, shown in  FIG. 7A , the locking arms are prevented from rotating by the presence of the plunger  83 . As shown in  FIG. 7B , once the drive spring  22  has moved the plunger  83  into the syringe (not shown), the arms  83  can rotate and release the carrier  84 . 
     In this example, the proximal end  89  of the housing  87  has a cylindrical protrusion  90  and a piston  91  is provided within the cylindrical protrusion  90  to define a fluid chamber  92 . A seal  93  is provided between the piston  91  and the cylindrical protrusion  90 . The proximal end  89  of the housing  87 , within the cylindrical protrusion  90 , includes an orifice  94 . A second chamber  95  is provided on the opposite side of the orifice  94  to the fluid chamber  92 . The second chamber  95  is optionally provided with an air outlet  96 . 
     As shown in  FIG. 7B , when the carrier  84  is released by the locking arms  84 , after the plunger  83  has moved distally, the drive spring  22  urges the carrier  84  against the piston  91 , which is pushed into the fluid chamber  92  and urges fluid through the orifice  94  and into the second chamber  95 . Air may be displaced from the second chamber  95  through the air outlet  96 . 
     A seal  97  may initially be provided over the orifice  94  to prevent movement of the fluid into the second chamber  95  before the carrier  84  has been released. 
     The second chamber  95  may additionally be transparent, so that the user can see the fluid entering the second chamber  95  as an indication that the plunger  83  has completed its movement into the syringe (not shown). The fluid may be coloured. The fluid may be a liquid, for example water. 
     The orifice  94  damps movement of the piston  91  into the fluid chamber  92 . 
     As illustrated in  FIG. 7A  and  FIG. 7B , the piston  91  may trigger an audible indication to the user. In this example, the piston  91  comprises an arm  98  that protrudes from the piston  91  and engages a sound generator. The sound generator is a pre-stressed element  99  that is held in a deflected position by the arm  98  until the piston  91  moves into the fluid chamber  92 , at which point the arm  98  disengages the pre-stressed element  99 , which returns to its natural shape. This changing of shape of the pre-stressed element  99  generates an audible sound, which provides the user with an indication that enough time has elapsed for the medicament to have dispersed from the injection site. In particular the arm  98  does not disengage the pre-stressed element  99  until a volume of fluid has passed into the second chamber  95 , which is delayed by the damping action of the orifice  94 , thereby providing a delay in the feedback. The duration of the delay may be, for example, more than 2 seconds, or more than 5 seconds, or more than 10 seconds, or between 10 and 30 seconds, or between 10 and 20 seconds. 
     The locking arms  85  only release the carrier  84  after the plunger  83  has been moved a pre-determined distance into the syringe (not shown), and the arrangement of the piston  91 , fluid chamber  92  and pre-stressed element  99  then creates a further delay before the audible indication is generated, providing time for the medicament to disperse from the injection site. In any of the above-described injection devices it will be appreciated that the drive spring may be omitted if the injection device is adapted to be manually operated. For example, the injection device may be provided with a lever or button that the user manually operates to push the plunger into the syringe. In this case, the force provided by the user may be used to compress the fluid reservoir. 
     In any of the above-described examples, the damping effect that provides the delay before the feedback is generated may be increased by using a highly viscous, or non-Newtonian fluid. This reduces the rate at which the fluid can pass through the outlet during compression of the fluid reservoir. 
     The terms “drug” or “medicament” are used herein to describe one or more pharmaceutically active compounds. As described below, a drug or medicament can include at least one small or large molecule, or combinations thereof, in various types of formulations, for the treatment of one or more diseases. Exemplary pharmaceutically active compounds may include small molecules; polypeptides, peptides and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids may be incorporated into molecular delivery systems such as vectors, plasmids, or liposomes. Mixtures of one or more of these drugs are also contemplated. 
     The term “drug delivery device” shall encompass any type of device or system configured to dispense a drug into a human or animal body. Without limitation, a drug delivery device may be an injection device (e.g., syringe, pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for intraocular, subcutaneous, intramuscular, or intravascular delivery), skin patch (e.g., osmotic, chemical, micro-needle), inhaler (e.g., nasal or pulmonary), implantable (e.g., coated stent, capsule), or feeding systems for the gastro-intestinal tract. The presently described drugs may be particularly useful with injection devices that include a needle, e.g., a small gauge needle. 
     The drug or medicament may be contained in a primary package or “drug container” adapted for use with a drug delivery device. The drug container may be, e.g., a cartridge, syringe, reservoir, or other vessel configured to provide a suitable chamber for storage (e.g., short- or long-term storage) of one or more pharmaceutically active compounds. For example, in some instances, the chamber may be designed to store a drug for at least one day (e.g.,  1  to at least 30 days). In some instances, the chamber may be designed to store a drug for about 1 month to about 2 years. Storage may occur at room temperature (e.g., about 20° C.), or refrigerated temperatures (e.g., from about −4° C. to about 4° C.). In some instances, the drug container may be or may include a dual-chamber cartridge configured to store two or more components of a drug formulation (e.g., a drug and a diluent, or two different types of drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components of the drug or medicament prior to and/or during dispensing into the human or animal body. For example, the two chambers may be configured such that they are in fluid communication with each other (e.g., by way of a conduit between the two chambers) and allow mixing of the two components when desired by a user prior to dispensing. Alternatively or in addition, the two chambers may be configured to allow mixing as the components are being dispensed into the human or animal body. 
     The drug delivery devices and drugs described herein can be used for the treatment and/or prophylaxis of many different types of disorders. Exemplary disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further exemplary disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis. 
     Exemplary drugs for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the term “derivative” refers to any substance which is sufficiently structurally similar to the original substance so as to have substantially similar functionality or activity (e.g., therapeutic effectiveness). 
     Exemplary insulin analogues are Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine); 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. 
     Exemplary insulin derivatives 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-gamma-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(co-carboxyhepta¬decanoyl) human insulin. Exemplary GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, for example: Lixisenatide/AVE0010/ZP10/Lyxumia, Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993 (a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN and Glucagon-Xten. 
     An exemplary oligonucleotide is, for example: mipomersen/Kynamro, a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia. 
     Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine. 
     Exemplary hormones include hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin. 
     Exemplary polysaccharides include 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 polysaccharide, 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. An example of a hyaluronic acid derivative is Hylan G-F 20/Synvisc, a sodium hyaluronate. 
     The term “antibody”, as used herein, refers to an immunoglobulin molecule or an antigen-binding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab′)2 fragments, which retain the ability to bind antigen. The antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix complement. In some embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, the antibody can be an isotype or subtype, an antibody fragment or mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region. 
     The terms “fragment” or “antibody fragment” refer to a polypeptide derived from an antibody polypeptide molecule (e.g., an antibody heavy and/or light chain polypeptide) that does not comprise a full-length antibody polypeptide, but that still comprises at least a portion of a full-length antibody polypeptide that is capable of binding to an antigen. Antibody fragments can comprise a cleaved portion of a full length antibody polypeptide, although the term is not limited to such cleaved fragments. Antibody fragments that are useful include, for example, Fab fragments, F(ab′)2 fragments, scFv (single-chain Fv) fragments, linear antibodies, monospecific or multispecific antibody fragments such as bispecific, trispecific, and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), minibodies, chelating recombinant antibodies, tribodies or bibodies, intrabodies, nanobodies, small modular immunopharmaceuticals (SMIP), binding-domain immunoglobulin fusion proteins, camelized antibodies, and VHh containing antibodies. Additional examples of antigen-binding antibody fragments are known in the art. 
     The terms “Complementarity-determining region” or “CDR” refer to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. The term “framework region” refers to amino acid sequences within the variable region of both heavy and light chain polypeptides that are not CDR sequences, and are primarily responsible for maintaining correct positioning of the CDR sequences to permit antigen binding. Although the framework regions themselves typically do not directly participate in antigen binding, as is known in the art, certain residues within the framework regions of certain antibodies can directly participate in antigen binding or can affect the ability of one or more amino acids in CDRs to interact with antigen. 
     Exemplary antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6 mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab). 
     The compounds described herein may be used in pharmaceutical formulations comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds may also be used in pharmaceutical formulations that include one or more other active pharmaceutical ingredients or in pharmaceutical formulations in which the present compound or a pharmaceutically acceptable salt thereof is the only active ingredient. Accordingly, the pharmaceutical formulations of the present disclosure encompass any formulation made by admixing a compound described herein and a pharmaceutically acceptable carrier. 
     Pharmaceutically acceptable salts of any drug described herein are also contemplated for use in drug delivery devices. 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 an alkali or alkaline earth metal, 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 known to those of skill in the arts. 
     Pharmaceutically acceptable solvates are for example hydrates or alkanolates such as methanolates or ethanolates. 
     Those of skill in the art will understand that modifications (additions and/or removals) of various components of the substances, formulations, apparatuses, methods, systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.