Abstract:
The present disclosure relates to a drive mechanism which is suitable for an injection device, especially a drug delivery device. The mechanism comprises a housing having a longitudinal axis defined by a compartment for receiving a cartridge, a plunger suitable for acting on a bung of a cartridge retained in the housing, a strained pressure spring arranged between the housing and the plunger, a retaining member coupled to the plunger, and a release member operable between a first state, in which the release member constrains the retaining member to the housing, and a second state, in which the release member is movable relative to the housing.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a U.S. national stage application under 35 USC §371 of International Application No. PCT/EP2015/078981, filed on Dec. 8, 2015, which claims priority to European Patent Application No. 14306959.9, filed on Dec. 8, 2014, the entire contents of which are incorporated herein by reference. 
     
    
     TECHNICAL FIELD 
       [0002]    The present disclosure is generally directed to a drive mechanism suitable for a handheld injection device, i.e. a drug delivery device for selecting and dispensing a number of user variable doses of a medicament. Further, the disclosure refers to a drug delivery device with such a drive mechanism. 
       BACKGROUND 
       [0003]    Drug delivery devices have application where regular injection by persons without formal medical training occurs. This may be increasingly common among patients having diabetes where self-treatment enables such patients to conduct effective management of their disease. In practice, such a drug delivery device allows a user to individually select and dispense a number of user variable doses of a medicament. Generally, the present disclosure is applicable to so called fixed dose devices which only allow dispensing of a predefined dose without the possibility to increase or decrease the set dose as well as devices where a user may individually set and amend a dose. However, it is preferred to provide a drug delivery device suitable for selecting and dispensing a number of user variable doses of a medicament with the possibility to increase or decrease the set dose. 
         [0004]    There are basically two types of drug delivery devices: resettable devices (i.e., reusable) and non-resettable (i.e., disposable). For example, disposable drug delivery devices are supplied as self-contained devices. Such self-contained devices do not have removable pre-filled cartridges. Rather, the pre-filled cartridges may not be removed and replaced from these devices without destroying the device itself. Consequently, such disposable devices need not have a resettable dose setting mechanism. The present disclosure is in general applicable for both types of devices, i.e. for disposable devices as well as for reusable devices. 
         [0005]    A further differentiation of drug delivery device types refers to the drive mechanism: There are devices which are manually driven, e.g. by a user applying a force to an injection button, devices which are driven by a spring or the like and devices which combine these two concepts, i.e. spring assisted devices which still require a user to exert an injection force. The spring-type devices involve springs which are preloaded and springs which are loaded by the user during dose selecting. Some stored-energy devices use a combination of spring preload and additional energy provided by the user, for example during dose setting. Further types of energy storage may comprise compressed fluids or electrically driven devices with a battery or the like. Although many aspects of the present disclosure are applicable for all of these types of devices, i.e. for devices with or without a drive spring or the like energy storage, the preferred embodiments require some kind of energy storage. 
         [0006]    These types of delivery devices generally comprise three primary elements: a cartridge section that includes a cartridge often contained within a housing or holder; a needle assembly connected to one end of the cartridge section; and a dosing section connected to the other end of the cartridge section. A cartridge (often referred to as an ampoule) typically includes a reservoir that is filled with a medication (e.g., insulin), a movable rubber type bung or stopper located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often necked-down, end. A crimped annular metal band is typically used to hold the rubber seal in place. While the cartridge housing may be typically made of plastic, cartridge reservoirs have historically been made of glass. 
         [0007]    The needle assembly is typically a replaceable double-ended needle assembly. Before an injection, a replaceable double-ended needle assembly is attached to one end of the cartridge assembly, a dose is set, and then the set dose is administered. Such removable needle assemblies may be threaded onto, or pushed (i.e., snapped) onto the pierceable seal end of the cartridge assembly. 
         [0008]    The dosing section or dose setting mechanism is typically the portion of the device that is used to set (select) a dose. During an injection, a plunger or piston rod contained within the dose setting mechanism presses against the bung or stopper of the cartridge. This force causes the medication contained within the cartridge to be injected through an attached needle assembly. After an injection, as generally recommended by most drug delivery device and/or needle assembly manufacturers and suppliers, the needle assembly is removed and discarded. 
         [0009]    A disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament according to the present disclosure typically comprises a housing, a cartridge holder for receiving a cartridge, a plunger and means for driving the plunger during dose dispensing. Such a disposable drug delivery device is known from WO 2004/078241 A1, wherein the cartridge holder is rigidly attached to the device housing. The plunger is a piston rod, which acts on a cartridge bung, and advances by a driver during dose dispensing. This known device is a manually driven device, where the component parts are in general disposed concentrically around a common longitudinal axis. During dose setting some component parts wind out of the housing and are pushed back into the housing during dose dispensing. This known device is a so called pen type device because it has the outer shape of an enlarged fountain pen. 
         [0010]    Alternative designs of the housing are known. For example, EP 1 250 167 B1 shows a drug delivery device with a bended piston rod with a cogging which meshes with teeth of a drive gear. A dose setting element is provided as a toothed wheel which is rotatable about an axis which is perpendicular to the longitudinal axis of the cartridge. 
         [0011]    An injection button is provided which is lifted from an end of the housing when a dose is set which makes the device bulky especially if a large dose is set. When the injection button is pressed to inject a set dose engagement between a toothed wheel on the dose setting member and a cogging of the injection button causes the dose setting member to rotate. A ratchet coupling between the dose setting member and a driver is active to rotate the driver with the dose setting member and to drive the piston rod into the cartridge. Thus, this known device is of the fully manually driven type, too. The bended piston rod may be detrimental especially for transmitting higher axial loads. 
         [0012]    US 2005/1957625 A1 and GB 624 958 A disclose a dispensing mechanism with a plunger which is in contact with a compression spring and attached to a belt which is wound on a spool. The spool is allowed to rotate, thereby releasing the belt, by means of mechanical features, e.g. an anchor escape lever in US 2005/1957625 A1 or a rotatable cap member in GB 624 958 A. 
         [0013]    A different concept is shown in WO 99/20327 A2 which refers to a spring actuated infusion syringe. A plunger acting on the bung of the syringe is permanently exerted to pressure of a spring and dispensing is controlled by opening the outflow of the syringe by removing an obstruction from the conduit. The axial movement of the plunger by the compression spring is limited by a belt which does not control the movement of the plunger during dispensing but prevents the plunger from being pushed out of the device. 
         [0014]    WO 2014/036239 A2, WO 2010/112377 A1 and WO 2008/142394 A1 each disclose a drug delivery device comprising a spring loaded piston which is attached to a belt or tether retaining the piston against the force of the spring. One end of the belt is attached to a spool on a gear wheel which is in engagement with a worm gear driven by an electric motor. Actuation of the motor allows unwinding of the belt which in turn allows displacement of the piston by the spring. In addition, WO 2014/036239 A2 mentions a control unit with a sensor detecting slack in the belt or tether. Further a sensor and an encoder may be used to provide positional feedback, end-of-dose signal and error indication. 
         [0015]    The present disclosure provides an improved alternative to the above solutions. Especially, the present disclosure provides a drive mechanism and a drug delivery device which require lower forces during dose setting and/or dose dispensing and which are compact irrespective of the size of the set dose. 
         [0016]    This object is solved by a drive mechanism with the features of claim  1 . 
         [0017]    According to a first aspect, a drive mechanism for an injection device is provided, the mechanism comprising: a housing having a longitudinal axis defined by a compartment for receiving a cartridge, a plunger suitable for acting on a bung of a cartridge retained in the housing, a strained spring arranged between the housing and the plunger, a retaining member coupled to the plunger, and a release member operable between a first state, in which the release member constrains the retaining member to the housing, thus preventing movement of the plunger, and a second state, in which the release member is movable relative to the housing, thus allowing movement of the plunger by means of the spring. 
         [0018]    The present disclosure is based on the idea to provide a power reservoir applying an axial load on a plunger which acts on the cartridge bung. To avoid uncontrolled dispensing from the cartridge, a retaining member is provided which is coupled to the plunger to hold the plunger against the force of the power reservoir. A release member which is coupled to the retaining member allows movement of the retaining member and, thus, the plunger for a desired distance corresponding to the dose to be dispensed. In other words, a tensile load acts on the retaining member under the action of the power reservoir and the retaining member is released during dose dispensing. An example of a power reservoir is a compression spring. 
         [0019]    Preferably, the drive mechanism comprises a housing, the plunger, the power reservoir, the retaining member and the release member. The housing may have a longitudinal axis defined by a compartment for receiving a cartridge. The plunger which is coupled to the retaining member is suitable for acting on a bung of the cartridge if retained in the housing. The power reservoir, preferably a pre-strained (e.g. pressure) spring, is arranged between the housing and the plunger, for example coaxially with the longitudinal axis defined by the cartridge or its compartment. The release member is preferably operable between a first state and a second state. In its first state the release member constrains the retaining member to the housing, thus preventing movement of the plunger under the action of the power reservoir. In its second state the release member is movable relative to the housing, thus allowing movement of the plunger by means of the power reservoir. 
         [0020]    The use of a spring or the like has the benefit of reducing the user force required to expel the contents of the cartridge. A pre-strained spring has the further advantage to reduce the force required during dose setting. As an alternative to a pre-strained spring, a spring or other suitable power reservoir may be used which is charged or strained during dose setting. Another benefit of devices where the force required to expel the contents of the cartridge is provided by a power reservoir instead of the user is that a dial extension of the device may be avoided, which means that the size of the device remains the same irrespective of whether a dose is set or the amount of the set dose. This makes the device more compact and user-friendly. 
         [0021]    The retaining member is preferably a flexible element with high tensile modulus and strength, like glass or aramid fibre reinforced poly-urethane. The retaining member may have the form of a belt or cable. As the load acting on the retaining member is a tensile force, the drive mechanism may be further reduced in size by winding the retaining member on a spool or the like which is not possible with pressure loaded piston rods. In addition, the retaining member may be compact in size compared to a piston rod which requires a compressive stiffness for transmitting axial pressure loads. 
         [0022]    The plunger may be constrained to one end of the retaining member. Preferably, it is axially, i.e. in the longitudinal direction of cartridge, fixed to the retaining member. As an alternative, the plunger may be a unitary part of the retaining member, for example a widened end thereof. 
         [0023]    According to a preferred embodiment, the release member is in its second state rotatable relative to the housing. For example, the retaining member is attached to and wound on a drum or spool which is in gear engagement with the release member. Thus, rotation of the release member allows the retaining member to unwind from the drum or spool a desired distance corresponding to the distance the plunger is pushed into the cartridge under the action of the spring or the like. As an alternative, the retaining member may be directly attached to and wound on the release member. 
         [0024]    The present disclosure also features a drug delivery device including a drive mechanism as defined above and a dose setting member which is rotatable relative to the release member during dose setting and which rotates together with the release member during dose dispensing. 
         [0025]    Preferably, the dose setting member and the release member are arranged rotatably within the housing with their respective axis of rotation being perpendicular to the longitudinal axis of the housing. This arrangement of the component parts has advantages regarding size and ease of use of the device. The dose setting member and the release member may be arranged coaxially. This common axis may however be offset from the axis of a drum or spool to which the retaining member may be attached. 
         [0026]    According to a preferred embodiment, the drug delivery device comprises a limiter mechanism defining a maximum settable dose and a minimum settable dose. Typically, the minimum settable dose is zero (0 IU of insulin formulation), such that the limiter stops the device at the end of dose dispensing. The maximum settable dose, for example 60, 80 or 120 IU of insulin formulation, may be limited to reduce the risk of overdosage and to avoid the additional spring force needed for dispensing very high doses, while still being suitable for a wide range of patients needing different dose sizes. Preferably, the limits for the minimum dose and the maximum dose are provided by hard stop features. For example, the rotation of the dose setting member relative to the housing is limited by rotational stops defining a minimum dose position and a maximum dose position. The minimum dose stop has to be robust enough to withstand the load exerted by the power reservoir via the retaining member. 
         [0027]    The drug delivery device may further comprise a trigger which is axially movable in the direction of the axis of rotation of the dose setting member. Actuation of the trigger switches the release member between its first and second state. For example, the trigger may act on a clutch which constrains the release member to the housing in its first state, i.e. when the trigger is not actuated, and which allows rotation of the release member for dose dispensing as soon as the trigger is actuated. 
         [0028]    A dial gear may be provided in the drug delivery device which is rotationally coupled to the release member during dose dispensing. Thus, decelerating the dial gear may be used to control dispensing speed. In general, there are different ways to create the friction decelerating a dial gear or the like component of the device. For example a component part may be pressed against for the dial gear. As an alternative, a ratchet may be provided which may be brought into and out of engagement with the dial gear. Further, a flexible element may be used which acts on the dial gear. According to a preferred embodiment the friction means comprises a multi-plate clutch system acting between a stationary component part and the (rotating) dial gear. The multi-plate clutch system may comprise a spring, at least one first clutch plate, which is rotationally constrained to the dial gear, and at least one second clutch plate, which is rotationally constrained to the housing at least during dose dispensing. The spring may press the clutch plates against each other, thus creating friction between a rotating and a non-rotating plate, which thus decelerates the dial gear. 
         [0029]    Preferably, the multi-plate clutch system further comprises a cage which is rotationally constrained to the housing at least during dose dispensing and which is rotationally constrained to the second clutch plate(s), wherein the spring biases the cage towards at least one component part of the dial gear. Amending the axial position of the spring, the cage and/or the dial gear results in a variation of the friction decelerating the dial gear during dose dispensing. 
         [0030]    According to a further embodiment a dispensing speed control mechanism is provided for use in an injection device having a release button or trigger, which is displaceable to initiate dispensing of a set dose, a first component part, which is driven by a power reservoir during dose dispensing, and a second component part, which is stationary during dose dispensing. The speed control mechanism comprises friction means for decelerating the first component part during dose dispensing depending on the position of the release button. In other words, the user is able to control the dispensing speed by increasing or decreasing friction within the device and thus use either the full dispensing speed provided by the power reservoir or a speed reduced due to the internal friction. 
         [0031]    Preferably, the release button or trigger has to be depressed a first distance to initiate dose dispensing, e.g. by releasing a clutch, and may then be depressed further a second distance to control and amend dispensing speed. This may include examples where due to the position of the release button there is either friction decelerating the driver or not. As an alternative, the magnitude of the friction decelerating the driver may be individually and preferably steplessly amended or adjusted by varying the position of the release button or trigger. 
         [0032]    In a preferred embodiment, the friction is at a high level just after the button or trigger is depressed the first distance and decreases as the button or trigger is pressed further for the full amount or fractions of the second distance. Typically, the release button or trigger is pressed in an axial direction of the housing and relative to the housing. 
         [0033]    According to a further embodiment the handheld injection device comprises clicker components. Different clicker mechanisms may be active during dose setting and dose dispensing. For example, a dose setting feedback may be generated between the housing and a dial member. A dose dispensing feedback may be generated between a chassis fixed to the housing and the release member. To provide an additional non-visual, i.e. an audible and/or tactile, feedback to a user only at the end of dispensing of a set dose, a clicker between the chassis and the dial gear may be active as the device returns to its minimum dose stop. To differentiate between these feedback signals, the end of dose dispensing feedback, which is generated only at the end of dispensing of a set dose dose, is distinct from the further feedback(s). For example, a different sound may be generated. 
         [0034]    In addition to the non-visual feedbacks, drug delivery devices usually have a display indicating the actually set dose. For example, a number wheel may be arranged coaxially with and rotationally coupled to the dose setting member with a series of markings being provided on the outer circumference of the number wheel. 
         [0035]    Preferably, the drug delivery device further comprises a prism arranged relative to the number wheel such that the series of markings on the number wheel is visible in the direction of the axis of rotation of the dose setting member. The use of a simple prism requires that the markings on the number wheel are arranged reversed (mirrored) to be readable through the prism. As an alternative, a penta-prism may be used instead of a simple prism. The surface of the prism may be designed to provide a magnification of the markings on the number wheel. As an alternative to the use of a prism, the housing may have a lateral opening or window through which the markings on the number wheel are visible. 
         [0036]    The drug delivery device may comprise a dose dial grip for dose setting and clutch means (which may comprise one or more clutches) coupling the dose dial grip rotationally to the dose setting member during dose setting and rotationally de-coupling the dose dial grip from the dose setting member and coupling the dose setting member rotationally to the release member during dose dispensing. Preferably, this clutch is actuated by the trigger. This arrangement of the clutch has the benefit that the dose dial grip is free to spin during dose dispensing without interfering with the components moving during dispensing. As an alternative, the dose dial grip may be constrained to the housing during dispensing. 
         [0037]    According to a further aspect, the drive mechanism further comprises a nut which is guided axially displaceable and non-rotatable with respect to one of the dose setting member and the release member. For example, the nut and the dose setting member or the release member are provided with corresponding splines and notches. The nut further has a thread engaging a thread of the other of the dose setting member and the release member such that relative rotation between the dose setting member and the release member during dose setting causes the nut to move towards an end stop. 
         [0038]    In certain aspects, an injection device may comprise a cartridge containing a medicament and a drive mechanism as mentioned above. The nut and the end stop may be provided in the drive mechanism of the injection device such that the nut prevents setting of a dose exceeding the (dispensable) amount of a medicament in the injection device. In other words, the end stop preferably defines the length of a track on which the nut travels during dose setting, wherein the length of the track corresponds to the total (dispensable) amount of medicament in the cartridge. 
         [0039]    The device according to the present disclosure is preferably a disposable injection device. It has low torque requirements to set a dose, low force requirements to trigger dispense of medicament and permits any dose to be selected within a range of zero to a pre-defined maximum. It has relatively low part count, very compact size and is particularly attractive for cost sensitive device applications. 
         [0040]    The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, 
         [0041]    wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, 
         [0042]    wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, 
         [0043]    wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4. 
         [0044]    Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
         [0045]    Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyhepta-decanoyl) human insulin. 
         [0046]    Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
         [0047]    Exendin-4 derivatives are for example selected from the following list of compounds:
   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   des Pro36 Exendin-4(1-39),   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
 
wherein the group-Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
 
or an Exendin-4 derivative of the sequence
   des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,   des Met(0)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-N H2;
 
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
   
 
         [0096]    Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
         [0097]    A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
         [0098]    Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. 
         [0099]    The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
         [0100]    There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in 
         [0101]    IgA, IgD, IgE, IgG, and IgM antibodies, respectively. 
         [0102]    Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
         [0103]    In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. 
         [0104]    Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity. 
         [0105]    An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H-H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv). 
         [0106]    Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
         [0107]    Pharmaceutically acceptable solvates are for example hydrates. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0108]    The present disclosure will now be described in further detail with reference to the accompanying schematic drawings, wherein 
           [0109]      FIG. 1  shows an exploded view of an injection device comprising a drive mechanism 
           [0110]      FIG. 2  shows a perspective view of the device of  FIG. 1 , 
           [0111]      FIG. 3  shows a top view of components of the drive mechanism of Figure 
           [0112]      FIG. 4  shows a bottom view of components of the drive mechanism of  FIG. 1 , 
           [0113]      FIG. 5  shows a perspective view of components of the drive mechanism of  FIG. 1 , 
           [0114]      FIGS. 6   a,    6   b  show sectional views of components of the device of  FIG. 1 , 
           [0115]      FIGS. 7   a,    7   b  show details of the device of  FIG. 1  in the minimum dose position and in the maximum dose position, 
           [0116]      FIG. 8  shows a detail of the device of  FIG. 1 , 
           [0117]      FIG. 9  shows a detail of the device of  FIG. 1  in the dose setting condition, 
           [0118]      FIG. 10  shows a detail of the device of  FIG. 1  in the dose dispensing condition, 
           [0119]      FIG. 11  shows a detail of the device of  FIG. 1 , 
           [0120]      FIG. 12  shows a sectional view of a detail of the device of  FIG. 1 , 
           [0121]      FIG. 13  shows the device of  FIG. 1  with an empty cartridge, 
           [0122]      FIG. 14  shows the device of  FIG. 1  with an empty cartridge, 
           [0123]      FIG. 15  shows the device of  FIG. 1  with a full cartridge prior to dose setting, 
           [0124]      FIG. 16  shows the device of  FIG. 1  with a full cartridge prior to dose setting, 
           [0125]      FIG. 17  shows the device of  FIG. 1  with a full cartridge with maximum dose set, 
           [0126]      FIG. 18  shows the device of  FIG. 1  with a full cartridge with maximum dose set, 
           [0127]      FIGS. 19 a  to 19 c    show a trigger actuation sequence of the device of  FIG. 1 , 
           [0128]      FIGS. 20   a,    20   b  show details of the device of  FIG. 1 , 
           [0129]      FIGS. 21 a  to 21 c    show an end of dose click sequence of the device of  FIG. 1 , and 
           [0130]      FIGS. 22 a  to 22 c    sectional views of a detail of a drug delivery device. 
       
    
    
     DETAILED DESCRIPTION 
       [0131]      FIGS. 1 and 2  show views of the drug delivery device.  FIG. 1  illustrates the component parts incorporated into the injection device which are a body  10 , a cartridge holder  20 , a trigger  40 , a dial member  50  comprising a dial  51  and a dial cover  52  a medicament cartridge  30 , a last dose nut  60 , a dial gear  70 , a trigger spring  80 , a prism  90 , a number wheel  100 , a release gear  110 , a belt assembly  120 , a belt gear  130 , a main spring  140  and a chassis  150 . 
         [0132]    The body  10 , the cartridge holder  20  and chassis  150  form a housing which has a distal end at the side receiving the cartridge  30  (right hand side in  FIG. 2 ) and an opposite proximal end. The cartridge holder defines a longitudinal axis of the housing. A rotational axis is provided perpendicular to this longitudinal axis with the trigger  40 , the dial member  50 , the last dose nut  60 , the dial gear  70 , the trigger spring  80 , the number wheel  100  and the release gear  110  are arranged concentrically about this rotational axis. 
         [0133]    The medicament cartridge  30  is housed within the cartridge holder  20 . The cartridge holder  20  is rigidly constrained in the body  10 . The cartridge holder  20  provides location and containment of the medicament cartridge and prism  90 . 
         [0134]    The belt assembly  120  comprises a belt  121  and a plunger  122 . The belt  121  is a flexible element with high tensile modulus and strength. Suitable materials include glass or aramid fibre reinforced poly-urethane. Features at each end of the belt  121  provide axial constraint and allow it to carry a tensile load. The distal end of the belt  121  is connected to the plunger  122  via spline features as shown in  FIG. 3 . The opposite end of the belt  121  is restrained by the belt gear  130  and partially wound onto it.  FIG. 3  shows the belt  121  assembled to the belt gear  130  in the “as delivered” condition (prior to any doses being delivered). 
         [0135]    The distal face of the plunger  122  abuts a bung of the medicament cartridge  30  and the main spring  140  acts directly on the proximal surface of the plunger  122 . It is the main spring  140  acting on the plunger  122  that drives the bung axially in order to deliver medicament. Tension in the belt  121  prevents the main spring  140  releasing and, therefore, by controlling the release of the belt  121 , accurate control of the medicament delivery can be achieved.  FIG. 4  shows the main spring  140  in its fully compressed state, i.e. the state prior to dispensing the first dose, interposed between the plunger  122  and a bearing face of the chassis  150 . The belt  121  is held in tension by the main spring  140  and follows a curved path in the device defined by a belt guide feature  151  on the chassis  150 . 
         [0136]    The main spring  140  is supplied to the user in the fully charged state (near “coil bound”). It acts between the proximal face of the plunger  122  and an abutment on the chassis  150 . Tension in the belt  121  prevents the energy stored in the main spring  140  from being released until a dose is dispensed. 
         [0137]    The belt gear  130  controls release of the belt  121  through a geared interface with a pinion  111  of the release gear  110 . It is radially constrained by the chassis  150  via a combination of abutments. The combined effect of these abutments ensure that the resultant force acting on the belt gear  130  from the belt  121  biases the geared interface with pinion  111  of the release gear  110  into engagement as shown in  FIG. 5 . This acts to minimize backlash between the gears and also reduce the risk of disengagement in the event of shock loading. 
         [0138]    The chassis  150  locates the mechanism within the body  10  and is rigidly fixed into the body  10  via spline and spring clip features. It provides location for the belt gear  130  and belt  121 . Flexible features within the chassis  150  (chassis locking arms  152 ) fix the release gear  110  rotationally during dialing ( FIG. 6 a   ) but disengage to allow rotation during triggering ( FIG. 6 b   ). Abutments adjacent to these chassis locking arms  152  provide tangential support and prevent excessive deflection when loaded by the release gear  110 . 
         [0139]    The number wheel  100  incorporates stop features  101 ,  102  which engage with abutments  153 ,  154  on the chassis  150  and correspond with the minimum ( FIG. 7 a   ) and maximum ( FIG. 7 b   ) dose set. This restricts the maximum dose that may be set and creates the end of dose stop when the mechanism returns to the zero unit position. The number wheel  100  is printed with a series of numbers on the external surface which create the dose display when viewed through the prism  90 . The number wheel  100  is rotationally coupled to the dial gear  70  as shown in  FIG. 8 . Further, the number wheel is axially located between the chassis  150  and the body  10  and radially constrained by the body  10 . 
         [0140]    The dose set is displayed on the outer surface of the device to provide feedback to the user. In this embodiment, the prism  90  reflects the display from the number wheel  100  so that the dose is displayed on the front face of the device (upper side in  FIG. 2 ). The prism  90  is retained within the cartridge holder  20  and body  10  once assembled as shown in  FIG. 10 . The prism  90  uses the phenomenon of “Total Internal Reflection” to achieve reflection of the number without any special treatment to the surfaces (such as metal coating). The nature of this prism is that the display is mirrored. To account for this, the printing on the number wheel  100  is reversed so the net effect provides a conventional dose number display. An additional function of the prism  90  is that the surfaces can be designed to also provide magnification, in addition to the primary function of reflection. 
         [0141]    Alternative prism arrangements (for example a penta-prism) could perform the same function without mirroring the display if required. An alternative embodiment negates the requirement for the prism  90  component and displays the dose on the side of the device. The number wheel  100  is then printed with conventional, non-mirrored, text and a small window is formed in the side of the body  10 . 
         [0142]    The dial gear  70  is rotationally coupled to the dial member  50  during dialing ( FIG. 9 ) and rotationally coupled to the release gear  110  during dispense ( FIG. 10 ). The dial gear  70  may translate axially between abutments provided by the release gear  110  and the dial member  50  and is biased into contact with the dial member  50  via the trigger spring  80  when the trigger  40  is not depressed. The trigger spring  80  acts between the dial gear  70  and release gear  110 . The chassis locking arms  152  are axially coupled to the dial gear  70  with snap clips which permit relative rotation. 
         [0143]    The dial member  50  comprises the dial  51  and the dial cover  52  which are permanently and rigidly fixed together. The dial member  50  is axially and radially located in the body  10  via snap clips and the rotational position is detented via a flexible cantilever arm  53  locating in radial ratchet teeth  11  within the body  10  ( FIG. 11 ). These detent features provide positive feedback to the user during dialing and align the dial member  50  and number wheel  100  with the body  10  so the units of the dose display accurately align with the prism  90 . 
         [0144]    The trigger  40  is snap fitted into the dial member  50  and axially constrained between abutments on the dial member  50  and dial gear  70 . The user may axially translate the trigger  40  between these abutments by overcoming the force of the trigger spring  80  which is transferred through the dial gear  70  ( FIG. 12 ). 
         [0145]    During dose setting, the release gear  110  is in toothed engagement with the belt gear  130  and rotationally fixed by the chassis locking arms  152 . When the trigger  40  is depressed, the release gear  110  is rotationally coupled to the dial gear  70  and is released from the chassis locking arms  152 . It is axially constrained between the dial gear  70  and chassis  150  and is biased toward the chassis  150  abutment by the trigger spring  80 . 
         [0146]    The mechanism incorporates a last dose nut  60  to prevent setting of a dose greater than that which remains within the medicament cartridge. This is positioned between the dial gear  70  and release gear  110  since the dial gear  70  rotates relative to the release gear  110  during dose set and not during dispense. The last dose nut  60  is splined to the inner surface of the dial gear  70  and threaded to the release gear  110  such that clockwise rotation of the dial member  50  rotates the last dose nut  60  and translates it towards the last dose stop on the release gear  110 . 
         [0147]    The last dose nut  60  is successively translated towards the stop as doses are set until the cartridge dose limit is reached. At this point the last dose nut  60  contacts the abutment  112  on the release gear  110  which prevents further clockwise rotation of the last dose nut  60  and, therefore, rotation of the dial gear  70  and dial member  50 .  FIGS. 13 and 14  show the device shortly before the nut contacts abutment  112 . The number of permissible rotations of the last dose nut  60  is determined by the capacity of the cartridge  30 . 
         [0148]    The dial member  50  is rotated by the user in a clockwise direction to set a dose starting from the position shown in  FIGS. 15 and 16 . The dose can be cancelled by rotating the dial member  50  in a counter-clockwise direction either before any dispense or, alternatively, if the trigger  40  is released mid-dispense, the remaining dose may be cancelled. 
         [0149]    The selected dose is displayed through the body  10  via the number wheel  100  and prism  90  as described previously. Irrespective of whether the dial member  50  is rotated clockwise or counter-clockwise the dose displayed will always indicate the dose to be dispensed. In addition, the dose display also decrements as the dose is dispensed and thus displays the dose remaining to be dispensed. As the dose is dialed up the number wheel  100  is driven away from the zero unit stop  153  on the chassis  150  and towards the maximum unit stop  154 . The dial member  50  can be rotated by the user in both clockwise and counter-clockwise directions when the number wheel  100  is not in contact with the zero dose stop abutment  153  or maximum dose stop abutment  154  of the chassis  150 . The zero unit abutment  153  prevents counter-clockwise rotation of the dial member  50  below the zero unit position. The maximum dose abutment  154  prevents setting of a dose greater than the mechanism maximum which is depicted in  FIGS. 17 and 18 . 
         [0150]    The detent features  11 ,  53  between dial member  50  and body  10  controls the position of the dial member  50  to ensure that discrete units are selected and that the spline features between dial member  50  and release gear  110  are correctly aligned to permit spline meshing when the device is triggered. 
         [0151]    During dose setting, the release gear  110  is biased by the trigger spring  80  into engagement with the locking arms  152 , which then couple the release gear  110  to the chassis  150 . The release gear  110  is therefore fixed rotationally during dose set. This in turn prevents rotation of the belt gear  130  and, therefore, release of the belt  121 . 
         [0152]    The device may be triggered by the user through application of an axial force on the trigger  40  ( FIG. 19 a   ). The trigger  40  acts on the dial gear  70 , translating the dial gear  70  and chassis locking arms  152 , compressing the trigger spring  80 . As the dial gear  70  translates it first decouples from the dial member  50  as the face teeth disengage. At this stage (mid trigger position,  FIG. 19 b   ) the dial member  50  can no longer be rotated in either direction since the dial member  50  detent arm  53  is prevented from deflecting by an annular abutment on the dial gear  70 . Further translation of the trigger  40  couples the dial gear  70  to release gear  110  via splines and finally decouples the release gear  110  from the chassis  150  ( FIG. 19 c   ). 
         [0153]    On triggering, the release gear  110  rotates, controlled by the dial gear  70  and number wheel  100 . The belt gear  130  rotates, due to the torque generated by the main spring  140  acting through the belt  121 . As the main spring  140  extends, the plunger  122  is driven against the bung, creating a distal translation and causing medicament to be dispensed. Since the release gear  110 , dial gear  70  and number wheel  100  are rotationally coupled, the number wheel  100  also rotates during dispense in a counter-clockwise direction, returning towards the zero unit stop  101 ,  153 . At the zero unit position the number wheel  100  contacts the abutment  153  on the chassis  150 , preventing further rotation of the dial gear  70 , release gear  110  and belt gear  130 , stopping release of the belt  121  and any further dispense of medicament. 
         [0154]    The trigger  40  is subsequently released, re-engaging the chassis locking arms  152  to lock the rotational position of the release gear  110 , belt gear  130 , belt  121 , plunger  122  and main spring  140  independently from the zero unit stop between chassis  150  and number wheel  100 . This allows the next dose to be set without immediate release of the main spring  140 . Aside from the last dose nut  60 , release gear  110 , belt gear  130 , belt  121 , plunger  122  and main spring  140  all other components in the device return to their original positions once the entire dose has completed dispense. 
         [0155]    The release gear  110  splines that engage with the chassis locking arms  152  are angled so the release gear  110  is turned against the torque induced by the main spring  140  as they re-engage when the trigger  40  is released ( FIGS. 20   a,    20   b ). Back-winding the release gear  110  ensures that the chassis locking arms  152  react the main spring  140  force in place of the zero unit stop as the trigger  40  is released. This prevents the release gear  110  rotating to take up clearance at this interface when the subsequent dose is dialed (and the zero unit stop is disengaged), which could lead to the dispense of some fluid. 
         [0156]    Feedback is provided to the user during dose setting by the interaction between the dial member  50  detent arm  53  and the body  10  ratchet features  11 . Dispense feedback is created through interaction between the chassis  150  and ratchet features on the release gear  110 . A cantilever arm on the chassis  150  rides over the ratchet features on the release gear  110 . 
         [0157]    A single, distinctive click is created as the device returns to the zero unit stop. This provides clear feedback to the user that the dose has been completed in addition to the dispense clicker ceasing. A cantilever arm  155  in the chassis  150  engages with the dial gear  70  when in the dispense condition. This arm is deflected as the dial gear  70  approaches the zero unit stop and rapidly released as the dial gear  70  engages the zero unit stop ( FIGS. 21 a  to 21 c   ). 
         [0158]    It is possible to incorporate a mechanism that allows the user to control the speed of dispense by the distance that they move the trigger  40 . In this second embodiment the features and functions are identical to the first embodiment as described above. However, an additional system  160  is included as shown in  FIGS. 22 a    to  22   c.    
         [0159]    The embodiment shows a multiplate clutch system  160  integrated into the device acting between the dial member  50  (which is locked during dispense) and dial gear  70 . The system comprises a carrier  161  which is splined to the dial member  50 , a clutch spring  162  and a clutch pack comprising rotating plates  163  which are splined to the dial gear  70  and static plates  164  which are splined to the dial member  50  via carrier  161 . 
         [0160]    For the embodiment shown in  FIGS. 22 a    to  22   c,  force applied to the clutch pack  163 ,  164  from the clutch spring  162  reduces as the trigger  40  is depressed. Multiple clutch plates  163 ,  164  increase the torque capacity of the clutch for a given clutch spring force. In this embodiment, the overall trigger  40  travel is increased by the addition of the user variable speed control. 
         [0161]    The facility for removing the need for a user to prime the device when first used can also be incorporated. This involves removing the variable distance (dependent on component and cartridge tolerances) between the cartridge bung  31  and the plunger  122  during manufacture such that the plunger  122  is in contact (and applies a small force) to the bung  31  when assembled. This “prime elimination” is achieved using the following method: The cartridge holder  20  must be divided into two separate components (cartridge holder  20  and rear body) and the device assembled omitting the rear body. A small dose of approximately  10  units is dialed by rotating the dial member  50  as the user would. The belt gear  130  is rotationally coupled to an assembly tool with torque measurement capability. The trigger  40  is depressed to release the mechanism and the torque generated in the belt gear  130  is measured as it is rotated clockwise via the assembly tool, thus releasing belt  121 . As the belt  121  is released, the plunger  122  approaches the bung  31  under the main spring  140  force. When the plunger  122  contacts the bung  31 , the bung will begin to react a proportion of the main spring  140  force, thus reducing the belt gear  130  torque. Measurement of this change in torque as the belt  121  is released allows a specific force to be applied to the bung  31  by the main spring  140 . Release of the trigger  40  subsequently locks the mechanism and any set doses remaining are then dialed to zero. Finally the rear body is clipped into position to complete the assembly.