Abstract:
The present disclosure is generally directed to a drive mechanism for use in a drug delivery device having a cylindrical cartridge, i.e. a handheld injection device for selecting and dispensing a number of user variable doses of a medicament. The drive mechanism includes a base element, a toothed piston rod, which is guided within and movable relative to the base portion, and a drive gear having a pinion, which is rotatably held in the base element and in meshed engagement with the toothed piston rod. The toothed piston rod includes multiple rigid rod pieces which are connected by hinges. The rigid rod pieces comprise a flat plate provided with a straight toothed rack.

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/EP2015/078903, filed on Dec. 8, 2015, which claims priority to European Patent Application No. 14306962.3, 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 for use in a drug delivery device, i.e. a handheld injection device for selecting and dispensing a number of user variable doses of a medicament. 
       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. The present disclosure is not directed to so called fixed dose devices which only allow dispensing of a predefined dose without 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 of 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]    The dosing section of drug delivery devices for selecting and dispensing a number of user variable doses of a medicament often comprises a display for indicating the selected dose to a user. This is especially important where a user may select a different dose each time depending on the state of health. There are mechanical displays, e.g. a drum with printed numbers on its outer surface, wherein the number corresponding to the actually selected dose is visible through a window or opening in the device. Although such mechanical displays are simple and reliable, they usually require a relatively large construction space which makes the devices bulky. In addition, the size of the numbers is in some cases too small for visually impaired users. Further, electronic displays are known, e.g. LCD displays, which have the benefit of a relatively large number size without requiring too much construction space. However, a downside of electronic displays is that they require an energy source and that such electronic components may be too expensive, especially in a disposable drug delivery device. 
         [0010]    A disposable drug delivery device is known from WO 2004/078241 A1, wherein the display comprises a number sleeve with numbers printed on its outer surface. The device further comprises a housing, a cartridge holder for retaining a cartridge containing a medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a dose setting knob coupled to the driver and fixed to the number sleeve, and an injection button. The number sleeve is in threaded engagement with the housing, such that the number sleeve rotates along a helical path in a first direction during dose selecting and rotates back into the housing in a second, opposite direction during dose dispensing. 
         [0011]    An alternative design of the display is known for example from EP 1 250 167 B1, which shows a drug delivery device with a display similar to an egg-timer. A dose setting element is provided rotatable about an axis which is perpendicular to the longitudinal axis of the cartridge. The number display is arranged as a ring having respective markings with a pointer tip on the dose setting element pointing at the set dose marking. A downside of this display is that only every five number is indicated as a figure with dashes for every single unit. This makes it difficult to read the exact dose. Further, it may be difficult to identify the exact position of the pointer tip, which again raises the risk of a misreading. 
         [0012]    U.S. Pat. No. 5,947,934 mentions the use of a flexible piston rod in an injection syringe without indicating details regarding the design of the piston rod or its interaction with other component parts. 
         [0013]    U.S. Pat. No. 6,074,372 refers to an injection syringe with an elongate straight piston rod having a toothed part which engages barbs of a dose administration wheel. A further example of a flexible piston rod with a cogging engaging a pinion is given in U.S. Pat. No. 6,582,404. 
         [0014]    WO 98/01173 A1 refers to a flexible piston rod and a rack and pinion drive mechanism. A first embodiment of WO 98/01173 A1 discloses a piston rod formed by a tape-like flexible rack. A second embodiment comprises multiple rigid rod pieces connected by hinges. The rigid rod pieces are each provided with curved racks. Supporters provided on the opposite side of the racks fit into the cartridge interior to guide the piston rod within the cartridge. It is proposed to drive such a piston rod either by a force applied to the rod end opposite to the cartridge, which requires guiding the rod over its entire length or by a pinion with the piston rod looping around the pinion. Both alternatives result in constraints regarding the design and location of a drive mechanism within a drug delivery device. In addition, the flexural stiffness may require improvement depending on the application of the device. 
         [0015]    Further flexible piston rods with rigid toothed rod pieces connected to each other by hinges are known from WO 01/83008 A1 and WO 2012/089445 A1. 
       SUMMARY 
       [0016]    The present disclosure is not directed to so called fixed dose devices which only allow dispensing of a predefined dose without the possibility to increase or decrease the set dose. 
         [0017]    The present disclosure provides an improved drive mechanism and drug delivery device with reduced frictional forces allowing a wider freedom of design choices. 
         [0018]    A drive mechanism according to the disclosure is suitable for use in a drug delivery device with a cylindrical cartridge and comprises a base element or chassis, a toothed piston rod, which is guided within and movable relative to the base portion or chassis, and a drive gear having a pinion, which is rotatably held in the base element or chassis and in meshed engagement with the toothed piston rod. The toothed piston rod comprises multiple rigid rod pieces which are connected by hinges, for example integral hinges, such that the rigid rod pieces are arranged in a swivelling manner one behind the other. The rigid rod pieces each comprise a flat plate provided with a straight toothed rack. In other words, neither the rigid rod pieces nor the toothed racks are curved or cambered. This increases the flexural stiffness of the rod and allows use of the rod in a rack and pinion application not requiring that the rod loops around a pinion. Thus, there are more design options for the location and arrangement of the rod and the pinion within a drive mechanism and/or within a drug delivery device. In addition, the pinion may be relatively small, which is not possible when the rod is intended to loop around the pinion. 
         [0019]    Typically, the flexible piston rod is located within the base element or chassis and engages, via a rack and pinion interface, the drive gear so that rotation of the drive gear advances the piston rod. When used in a drug delivery device with a cartridge having a bung, the distal end of the piston rod acts on the bung within the liquid medicament cartridge, which expels medicament from the cartridge during dose dispensing by the advancement of the piston rod. 
         [0020]    The flexible piston rod is a single component with discrete segments (rigid rod pieces) connected together by thin sections of material which form flexible hinges. The flexibility in bending permits a significantly shorter device format whilst using a conventional glass medicament cartridge. 
         [0021]    In a preferred embodiment of the disclosure, the end faces of the segments are planar and, when the flexible piston rod is straightened, the adjacent segment faces abut each other, allowing the component to withstand a compressive load. Together with the design of the segments as flat plates, this contributes to the flexural stiffness of the rod. The flexible piston rod may be restrained within the base element or chassis to maintain the flexed state and prevent the rack gear teeth from disengaging from the pinion of the drive gear. As the piston rod is advanced, via the rack and pinion engagement with the drive gear, the trailing segments of piston rod are drawn into engagement with the drive gear pinion. The subsequent segments drive the preceding segments, loading them in compression, and apply a force to the bung. As the flexible piston rod advances, the first segment may move out of the support provided by the base element or chassis. Without additional support it is likely that the piston rod would buckle under this compressive loading. The additional support to prevent buckling is created by the inner wall of the cartridge providing constraint to the outer surfaces of the flexible piston rod. 
         [0022]    The base element or chassis is a rigid component part, which is typically fixed within a device housing or is a part thereof. The base element or chassis is the (immovable) reference for relative movements of the piston rod, the drive gear or further component parts of the drive mechanism or the drug delivery device. 
         [0023]    According to an embodiment of the disclosure, the base element or chassis comprises a first curved guiding section and a second straight guiding section with the drive gear and/or its pinion being arranged protruding into or adjacent to the second straight guiding section. In other words, the meshing engagement between the pinion and the rod segments occurs in the straight guiding section. Thus, the design of the curved guiding section has not to be adapted to allow engagement of the pinion and the rod but may have a form suitable to optimize the available space for storing the flexible piston rod. This drive mechanism allows the design of a relatively compact drug delivery device. 
         [0024]    In addition, the base element or chassis may comprise a receiving section for retaining the cartridge. Typically, the receiving section is arranged adjacent to the second straight guiding section such that the rod enters the cartridge shortly after the pinion. The second straight guiding section may lead into or merge into the receiving section. 
         [0025]    To further increase the flexural stiffness of the rod, the flat plate of each segment or rod piece may comprise a flange located on the opposite side of the straight toothed rack. The end faces of the flanges are preferably planar and, when the flexible piston rod is straightened, the adjacent flange faces abut each other, allowing the component to withstand a compressive load. The length of the flanges is preferably adapted to the dimensions of the cartridge such that the flanges (in addition to the plates) guide the rod within the cartridge. 
         [0026]    In a preferred embodiment the base element or chassis has a generally circular configuration with the pinion being located at the center of the base element wherein the first curved guiding section and the second straight guiding section are located offset from the center of the base element. This may contribute in reducing the overall dimensions of the drug delivery device using this drive mechanism. 
         [0027]    Further, the drive mechanism may comprise a clutch provided by a splined portion of the drive gear and a corresponding splined portion of the base element. Preferably, the drive gear is axially movable along its rotational axis between a first position, typically a dose setting or dose correcting position, in which the drive gear is rotationally constrained to the base element by engagement of the clutch and a second position, typically a dose dispensing position, in which the clutch is disengaged and relative rotation between the base element and the drive gear is allowed. This prevents unintended movement of the piston rod during dose setting or dose correction. In addition, this constraint may be used to react a force or torque of an optional drive spring. 
         [0028]    According to a further development of this idea, the drive mechanism may comprise a compression spring interposed between the base element and the drive gear. Preferably, the spring biases the drive gear into its first position relative to the base element. In other words, the drive gear and the base element or chassis are decoupled by relative movement of the drive gear and the base element or chassis against the force of the spring. 
         [0029]    In a preferred embodiment of the disclosure the drive mechanism further comprises a drive spring. This may be a spring which is charged during dose setting, i.e. a spring storing energy applied by a user, or a spring pre-strained during manufacture or assembly of the mechanism or a combination thereof. Preferably, the drive spring is fixed to the base element or chassis (or any other housing component) with one end and, at least when the drive gear is allowed to rotate relative to the base element, exerts a force or torque to the drive gear for rotating the drive gear relative to the base element, which rotation results in a movement of the toothed piston rod. The spring may be directly attached to the drive gear, e.g. if the spring is charged for the whole intended life of the mechanism during manufacture or assembly. As an alternative, the spring may be attached to a component part which is (directly or indirectly) coupled to the drive gear for dose dispensing. 
         [0030]    The use of a drive spring or the like energy storage 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. 
         [0031]    A drug delivery device according to the disclosure comprises a drive mechanism as defined above. The device may further comprise a dose setting member for setting user variable doses of a medicament, a display for indicating the dose set by the dose setting member and at least one coupling member interposed between the drive gear and the dose setting member and/or the display. Typically, the coupling member is arranged such that relative rotation between the drive gear and the dose setting member is allowed during dose setting. For example, the coupling member may rotate together with the dose setting member and/or the display during dose setting while the drive gear is rotationally constrained to the base element. During dose dispensing the coupling member, the dose setting member and/or the display may be rotationally constrained to the drive gear. 
         [0032]    In addition, the drug delivery device may comprise a housing, which is rigidly fixed with the base element or chassis, e.g. by permanent attachment or as an integral part thereof. The housing may have a longitudinal axis defined by a compartment for receiving the cartridge, e.g. the cartridge receiving section of the drive mechanism, wherein the dose setting member is arranged rotatable within the housing with its axis of rotation being perpendicular to the longitudinal axis of the housing. This allows an ergonomic design of the drug delivery device. 
         [0033]    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. The rotation of the dose setting member, the coupling element and/or the display or number wheel may be limited by rotational stops defining a minimum dose position and a maximum dose position. The minimum dose position and the maximum dose position may be defined by rotational hard stops provided on the housing and e.g. the number wheel of the display. Preferably, the same protrusions define a minimum dose position and a maximum dose position, i.e. the relative rotation between the minimum and maximum dose stop is limited to nearly 360°. 
         [0034]    The drug delivery device may further comprise a trigger being axially movable in the direction of the axis of rotation of the dose setting member, i.e. perpendicular to the longitudinal axis of the housing. Actuation of the trigger typically results in an axial movement of the drive gear for rotationally decoupling the drive gear and the base element. 
         [0035]    According to a further embodiment of the present disclosure the 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 by a ratchet provided between the coupling element and the drive gear wherein re-engagement of ratchet teeth generates a feedback signal. A dose dispensing feedback may be generated between the base element or chassis and the drive gear. For example, a clicker arm in the form of a compliant cantilever beam integrated in the chassis interfaces axially with ratchet features on the drive gear. 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 may be provided by the chassis and the coupling member which is 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, is distinct from the further feedback(s). For example, a different sound may be generated. Preferably, the end of dose dispensing feedback mechanism comprises a ramp feature on one of the base element and the coupling member and a flexible clicker arm on the other of the base element and the coupling member. The coupling member may be axially movable along the axis of rotation of the dose setting member between a dose setting and dose correcting position and a dose dispensing position. This prevents the ramp and the clicker arm from interacting during dose correction (reducing a set dose). In this context, end of dose dispensing shall mean the moment, when the piston rod has completed its advancement corresponding to the set dose. Thus, due to the elasticity of the cartridge bung, liquid may still be expelled shortly after the end of dose dispensing. 
         [0036]    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. A preferred embodiment of the disclosure is based on the idea to provide a series of markings on the outer circumference of a number wheel of the display and to deviate the image of the markings of the number wheel, preferably by 90°, by means of a prism. The outer circumference of a wheel is an area having enough space to arrange the series of markings with every single figure illustrated, or with every second figure illustrated and a line to mark intermediate positions. On the other hand, as the outer circumference of a wheel might not be the most convenient position of the markings to be readable by a user during dose setting and during dispensing, deviation is provided to increase ease of use. 
         [0037]    Regarding the direction of the deviation, it is convenient for some users if the display faces in the direction in which actuation is required during dose setting and/or dose dispensing. For example, if rotation in a plane is required for dose setting and pushing a trigger perpendicular to said plane is required for dose dispensing the display may be arranged next to this plane. Preferably, the number wheel is rotatable about an axis, wherein the prism is arranged such that the image of the markings of the number wheel is deviated in a direction parallel to said axis. According to a preferred embodiment, the at least one prism is a triangular prism, and the series of markings is provided reversed (mirrored) on the outer circumference of the number wheel to be readable through the prism. As an alternative, a penta-prism may be used instead of a simple (triangular) prism allowing the transmission of an image through a right angle without inverting it, that is, without changing the image&#39;s handedness. Thus, the series of markings is provided non-mirrored on the outer circumference of the number wheel. 
         [0038]    Preferably, the surface of the prism is designed to provide a magnification of the markings on the number wheel. This allows it even with limited space available on the outer circumferential surface of the number wheel to provide an individual figure for every unit (or every second unit) of dose to be set which still is conveniently readable by a user. 
         [0039]    According to a further aspect of the present disclosure, the drive mechanism further comprises a nut which is guided axially displaceable and non-rotatable with respect to one of the drive gear and the coupling member. For example, the nut is rotationally coupled to the drive gear, via a splined interface. It moves along a helical path relative to the coupling member, via a threaded interface, when relative rotation occurs between the coupling member and drive gear (i.e. during dialing). The nut moves towards an end stop, wherein 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. 
         [0040]    The coupling member of the drug delivery device may be a single component part in the form of a dial gear which is rotationally coupled to the display (e.g. the number wheel) via a splined interface that permits relative axial movement between the dial gear and number wheel. In a preferred embodiment, the drive gear is axially constrained between the chassis and dial gear and biased away from the chassis by the compression spring, which is also the trigger spring. The drive gear is rotationally coupled to the dial gear via a detent and clutch interface, which occurs on an axial abutment. It is preferably possible to overhaul this ratchet, which provides a detented position between the dial gear and the drive gear corresponding to each dose unit, and engages different ramped tooth angles during clockwise (CW) and counter clockwise (CCW) relative rotation. A dose setting member or dial may be rotationally constrained via a splined interface to the dial gear, at least during dose setting and dose correction. In the at rest condition, the dial gear splines are engaged with the dial. 
         [0041]    As an alternative, the coupling member may comprise two or more component parts, e.g. a cam ring and a dial gear. Preferably, the cam ring is rotationally constrained to the dial gear, e.g. by splines, and has a one-way ratchet interface with the dose setting member or dial. Thus, during dose setting a rotation in a first (e.g. CW) direction is transmitted from the dose setting member via the cam ring to the dial gear, which is allowed to rotate relative to the drive gear. During dose correction (CCW rotation), the one-way ratchet interface between the cam ring and the dose setting member causes axial displacement of the dial gear. Preferably, this axial displacement is used to disengage the ratchet between the drive gear and the dial gear, thus allowing the dial gear to rotate under the action of the drive spring, for example for one dose increment. In this alternative embodiment the dial gear to drive gear detent and clutch interface maximizes the security of the interface by increasing the feature size. 
         [0042]    The device may comprise a dose setting mechanism with several interfaces. This mechanism preferably comprises the dose setting member which is rotatable relative to the housing in a first direction for dose setting and in an opposite second direction for dose correcting, a first set of ratchet teeth forming a one-way-ratchet interface provided between a drive member and a coupling member allowing rotation of the coupling member relative to the drive member in the first direction and preventing relative rotation in the opposite second direction, a cam ring which is rotationally constrained to the coupling member and axially displaceable to the coupling member, and which is in axial contact with the drive member, a second set of ratchet teeth forming a ramped interface between the dose setting member and the cam ring preventing relative rotation of the dose setting member and the cam ring in the first direction and allowing rotation of the dose setting member relative to the cam ring in the opposite second direction, wherein the rotation of the dose setting member relative to the cam ring in the opposite second direction causes an axial displacement of the cam ring relative to the dose setting member, and a drive spring biasing the coupling member in the second direction. 
         [0043]    If the height of the first set of teeth is smaller than the height of the second set of teeth and the spacing of the first set of teeth is smaller than the spacing of the second set of teeth, a stepwise dose correction caused by the drive spring and rotation of the dose setting member may occur. For example, rotation of the dose setting member in the second direction is not transmitted to the cam ring due to the saw teeth profile. As the drive gear is held unrotatably within the chassis and is rotationally coupled via the coupling member (dial gear) to the cam ring, relative rotation occurs between dose setting member and cam ring. Due to the ramped tooth profile of the interface between cam ring and dose setting member, this causes an axial displacement of the cam ring, which acts on the drive gear, thus disengaging the interface between the drive gear and the coupling member. Now the coupling member is free to rotate together with the cam ring under the bias of the drive spring, which reduces (corrects) the set dose. As the cam ring rotates together with the coupling member, its ramped teeth slide back on the ramped teeth of the dose setting member to the fully engaged previous position, which allows the cam ring to shift back axially which re-engages the interface between the drive gear and the coupling member. In other words, the rotational movement allowed is only the spacing of two adjacent teeth of the drive gear to coupling member interface, which is typically one single dose increment (1 IU). This process may be repeated until the desired (reduced) dose is set. 
         [0044]    According to a further aspect of the present disclosure, a spring driven drug delivery device has the mechanism axis about which the component parts rotate orientated perpendicular to the cartridge axis. This results in a compact spring driven device. For example, a drug delivery device may comprise a housing having a longitudinal axis defined by a compartment for receiving the cartridge, and a dose setting and drive mechanism for driving an, e.g. toothed, piston rod with component parts rotating about a second axis during dose setting and/or dose dispensing, wherein the second axis is perpendicular to the longitudinal axis of the housing. Preferably, the dose setting and drive mechanism further comprises a drive spring which exerts a force or torque for driving the piston rod during dose dispensing. In a preferred embodiment, the dose setting and drive mechanism comprises at least a dose setting element, e.g. a dial member, a dial gear and/or a number wheel, and a drive element, e.g. a drive gear, which are both rotatable about the second axis. 
         [0045]    The cartridge of the drug delivery device typically contains a medicament. 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, wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4. 
         [0046]    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. 
         [0047]    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-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
         [0048]    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. 
         [0049]    Exendin-4 derivatives are for example selected from the following list of compounds: 
         [0000]                    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
 
         [0000]                    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(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4       (1-39)-NH2,               H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]       Exendin-4(1-39)-NH2,               H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14,       Asp28] Exendin-4(1-39)-NH2,               des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-       4(1-39)-(Lys)6-NH2,               H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]       Exendin-4(1-39)-(Lys)6-NH2,               H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14,       Asp28] Exendin-4(1-39)-(Lys)6-NH2,               H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]       Exendin-4(1-39)-Lys6-NH2,               H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)       25] Exendin-4(1-39)-NH2,               H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]       Exendin-4(1-39)-NH2,               H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14,       Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,               des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25,       Asp28] Exendin-4(1-39)-(Lys)6-NH2,               H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14,       Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,               H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14,       Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;            
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
 
         [0050]    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. 
         [0051]    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. 
         [0052]    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. 
         [0053]    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. 
         [0054]    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 IgA, IgD, IgE, IgG, and IgM antibodies, respectively. 
         [0055]    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. 
         [0056]    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). 
         [0057]    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. 
         [0058]    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. 
         [0059]    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). 
         [0060]    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. 
         [0061]    Pharmaceutically acceptable solvates are for example hydrates. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0062]    The present disclosure will now be described in further detail with reference to the accompanying schematic drawings, wherein 
           [0063]      FIG. 1  shows an exploded view of an injection device comprising a drive mechanism, 
           [0064]      FIG. 2  shows a perspective view of the device of  FIG. 1 , 
           [0065]      FIG. 3  shows cut-away view of the device of  FIG. 2 , 
           [0066]      FIG. 4  shows a detail of the device of  FIG. 2 , 
           [0067]      FIG. 5  shows a detail of the device of  FIG. 2 , 
           [0068]      FIG. 6  shows a detail of the device of  FIG. 2 , 
           [0069]      FIGS. 7 a    &amp;  b  show the piston rod of the device of  FIG. 1  in a flexed position and in a straight position, 
           [0070]      FIG. 8  shows components of the drive mechanism of the device of  FIG. 2 , 
           [0071]      FIG. 9  shows a partial sectional view of a detail of the device of  FIG. 2  in the dose setting condition, 
           [0072]      FIG. 10  shows a partial sectional view of a detail of the device of  FIG. 2  in the dose dispensing condition, 
           [0073]      FIG. 11  shows the detail of  FIG. 5  in the dose dispensing condition, 
           [0074]      FIG. 12  shows a detail of the device of  FIG. 2 , 
           [0075]      FIG. 13  shows a detail of the device of  FIG. 2 , 
           [0076]      FIG. 14 a    shows a detail of a ratchet of the device of  FIG. 2   
           [0077]      FIG. 14 b    shows an alternative embodiment of a ratchet, 
           [0078]      FIG. 15  shows a detail of the ratchet of  FIG. 14   b,    
           [0079]      FIG. 16  shows a detail of the ratchet of  FIG. 14   b,    
           [0080]      FIG. 17  shows a detail of the ratchet of  FIG. 14   b,    
           [0081]      FIGS. 18 a  to 18 d    show a sequence of movements in the ratchet of  FIG. 14   b,    
           [0082]      FIG. 19  shows a detail of the device of  FIG. 2 , 
           [0083]      FIGS. 20 a  to 20 d    show an end of dose click sequence of the device of  FIG. 2 , 
           [0084]      FIGS. 21 a - b    show the mechanism of  FIGS. 20 a  to 20 d    in the dose setting condition and in the dose dispensing condition, 
           [0085]      FIG. 22  shows the application of a tool during assembly of the device of  FIG. 2 , and 
           [0086]      FIG. 23  shows in a sectional view the use of the tool of  FIG. 22 . 
       
    
    
     DETAILED DESCRIPTION 
       [0087]      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 casework or body  10 , a cartridge holder  20 , a base element or chassis  30 , a trigger or dose button  40 , a dial member  50  with a dial cover  51 , a last dose nut  60 , a dial gear  70 , a trigger spring  80 , a prism  90 , a number wheel  100 , a drive gear  110 , a flexible piston rod  120 , a drive spring  130  and a medicament cartridge  140 . 
         [0088]    The casework or body  10  forms together with cartridge holder  20  the housing of the device. It is the basis for relative movements of other component parts during use of the device. Body  10  and cartridge holder  20  may be permanently attached to each other by snap hooks  21 . Cartridge holder  20  has an opening into which prism  90  is inserted and permanently fixed. Further, the base element or chassis  30  is permanently attached to the body  10  and cartridge holder  20  such that these component parts behave in use as a single part. The liquid medicament cartridge  140  contains a movable bung  141  and is housed within the cartridge holder  20 . Body  10  comprises a protrusion ( FIG. 6 ) interacting with a corresponding protrusion of the number wheel  100 . The upper right side (in  FIG. 6 ) of the body protrusion forms a zero unit stop  11  and the opposite lower left side forms a maximum dose stop  12 . The upper right side (in  FIG. 6 ) of the number wheel protrusion forms a maximum dose counter stop  101  and the opposite lower left side forms a zero unit counter stop  102 . 
         [0089]    Chassis  30  is a disc-like component with a generally circular configuration. Splines  31  are provided at an inner side for releasably engaging drive gear  110  ( FIGS. 5 and 11 ). Chassis  30  comprises a bearing  32 , which may have the form of a cut open cylinder located at the center of chassis  30 , for receiving a pinion of the drive gear ( FIG. 8 ). Further, a first curved guiding section  33  a second straight guiding section  34  and a receiving section  35  for retaining the cartridge  140  are provided. A clicker arm  36  is located within the disc-shaped chassis  30  ( FIGS. 8 and 13 ). 
         [0090]    The trigger or dose button  40  is axially constrained between the dial  50  and dial gear  70 . It may be fixed to the dial gear  70  by snap hooks  41 . Dose button  40  is axially displaceable relative to the body  10  and to the dial  50 . 
         [0091]    The dial  50  is axially constrained to the body  10  via clip features (not shown in  FIG. 1 ). It is rotationally constrained, via a splined interface, to the dial gear  70 . This splined interface is disconnected when the dose button  40  is pressed. The dial  50  may have the form of a disc or ring with a serrated outer surface as indicated in  FIG. 1 . The dial cover  51  is rigidly fixed into the dial  50 . 
         [0092]    The last dose nut  60  is located between the dial gear  70  and drive gear  110 . It is rotationally coupled to the drive gear  110 , via a splined interface (grooves  61  and splines  111 ). It moves along a helical path relative to the dial gear  70 , via a threaded interface (outer thread  62  and inner thread  71 ), when relative rotation occurs between the dial gear  70  and drive gear  110  (i.e. during dialing). A rotational end stop  63  is provided on the nut  60  for engagement with a last dose stop  72  on dial gear  70  ( FIG. 12 ). 
         [0093]    Dial gear  70  is a cup shaped member with an annular recess in its upper surface (in  FIG. 1 ) for receiving a skirt of dial  50  and dose button  40 . Dial gear  70  has an interface (inner thread  71 , last dose stop  72 ) with the last dose nut  60 . Its upper surface is provided with a ring of axially extending teeth  73  engaging corresponding spline teeth on the lower side of dial  50 . The opposite lower skirt face comprises ratchet teeth  74  interacting with corresponding ratchet teeth  112  of drive gear  110  ( FIG. 4 ). Splines  75  engage a corresponding interface of number wheel  100 . Slots  76  may engage splines of a cam ring provided in an alternative embodiment. A clicker arm  77  interacts with a ramp  37  of chassis  30  at the end of dose dispensing. Cut-outs  78  may be provided to allow access to drive gear  110  during the assembly process. 
         [0094]    The trigger spring  80  applies a force between the chassis  30  and drive gear  110  to separate them. In the “at rest” condition, this ensures that the drive gear  110  is rotationally coupled to the chassis  30  and that the spline teeth  73  of dial gear  70  are engaged with the dial  50  ( FIGS. 5 and 11 ). 
         [0095]    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 ( FIG. 6 ). The prism  90  is retained within the cartridge holder  20  and body  10  once assembled. 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 displayed. 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. Alternative prism arrangements (for example a Penta-prism) could perform the same function without mirroring the display if required. 
         [0096]    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 . 
         [0097]    The number wheel  100  is axially constrained between the chassis  30  and body  10 . It is rotationally coupled to the dial gear  70 , via a splined interface (splines  75 ), that permits relative axial movement between the dial gear  70  and number wheel  100 . The number wheel  100  is free to rotate, relative to the body  10 , between two fixed, rotational stops formed by abutments on the number wheel  100  and body  10 . A sequence of numbers, markings or symbols is provided on the outer circumference of the number wheel  100 . 
         [0098]    The drive gear  110  is axially constrained between the chassis  30  and dial gear  70  and biased away from the chassis  30  by the trigger spring  80 . It is rotationally coupled to the dial gear  70  via a detent and clutch interface ( FIG. 4 ), which occurs on an axial abutment. The detent and clutch interface  74 ,  112  provides a detented position between the dial gear  70  and drive gear  110  corresponding to each dose unit, and engages different ramped tooth angles during CW (clockwise) and CCW (counter-clockwise) relative rotation. The drive gear  110  is rotationally coupled to the chassis  30 , via a splined interface  31 ,  113  ( FIG. 5 ). When the dose button  40  is pressed, this spline interface  31 ,  113  is disengaged and ratchet features  115  interact with clicker arm  36  ( FIG. 13 ), providing audible feedback during dose delivery. Further, the drive gear  110  comprises a pinion  114  engaging the flexible piston rod  120 . Location features  116 , e.g. in the form of openings, may be provided for engagement with a tool during the assembly process. 
         [0099]    The flexible piston rod  120  is located within the chassis  30  and engages, via a rack and pinion interface, the drive gear  110  so that CCW rotation of the drive gear  110  advances the piston rod  120 . The distal end of the piston rod  120  acts on the bung  141  within the liquid medicament cartridge  140 . As shown in  FIGS. 7 a  and 7 b   , the piston rod  120  is a single component with discrete rigid rod pieces or segments  121  connected together by thin sections of material which form flexible hinges  122 . The end faces of the segments  121  are planar and, when the piston rod  120  is straightened ( FIG. 7 b   ) the adjacent segment faces abut each other, allowing the component to withstand a compressive load. Segments  121  are shaped as a flat plate provided with rack teeth  123  on one side and a flange  124  on the opposite side. The segment facing towards the cartridge (lower segment in  FIG. 7 b   ) comprises a pressure foot  125  for contacting the cartridge bung. The piston rod  120  is restrained within the chassis  30  to maintain the flexed state and prevent the rack gear teeth from disengaging from the drive gear  110  ( FIG. 8 ). As the piston rod  120  is advanced, via the rack  123  and pinion  114  engagement with the drive gear  110 , the trailing segments  121  of piston rod  120  are drawn into engagement with the drive gear pinion  114 . The subsequent segments  121  drive the preceding segments, loading them in compression, and apply a force to the bung. As the piston rod  120  advances, the first segment moves out of the support  34  provided by the chassis  30 . Without additional support it is likely that the piston rod  120  would buckle under this compressive loading. The additional support to prevent buckling is created by the inner side wall of the cartridge  140  providing constraint to the outer surfaces of the piston rod  120 . 
         [0100]    The drive spring  130  is attached at one end to the chassis  30  and at the other end to the number wheel  100 . The drive spring  130  is pre-wound upon assembly, such that it applies a torque to the number wheel  100  when the mechanism is at zero units dialed. The action of rotating the dial  50 , to set a dose, rotates the dial gear  70  and number wheel  100  relative to the chassis  30 , and (further) winds up the spring. As shown in  FIG. 3 , drive spring  130  is located radially interposed between chassis  30  and number wheel  100 . The mechanism contains the helical drive spring  130  to store energy, which is charged during setting of the dose, by the action of the user rotating the dial  50 . The spring energy is stored until the mechanism is triggered for dispense at which point the energy stored is used to deliver the medicament from the cartridge to the user. 
         [0101]    The drug delivery device can be operated to deliver a number of user variable doses of medicament from the cartridge  140 , via a needle (not shown). The device is disposable and is delivered to the user in a fully assembled condition ready for use. The mechanism provides separate user interfaces for setting and delivery of a dose. In short, a dose is set by rotating dial  50  located on the face of the device. Delivery of a dose is initiated by pressing dose button  40 , positioned in the center of the dial  50 , and dose delivery will continue while the dose button  40  remains depressed, until the complete set dose has been delivered. The mechanism provides audible, visual and tactile feedback both on the setting and delivery of each dose. Any dose size can be selected between zero and a pre-defined maximum, in increments to suit the medicament and user profile. The mechanism permits cancelling of a dose without any medicament being dispensed by rotation of the dial  50  in the opposing direction to when selecting a dose. 
         [0102]    The force required to actuate the dose button  40  and the distance which it has to move are small, providing a significant ergonomic advantage, particularly for those users with impaired dexterity. The mechanism requires consistent user input forces to set a dose and initiate the delivery of a dose, which are insensitive to variations in the force required to displace the bung  141  within the cartridge  140 . The dial  50  is disengaged during dose delivery so that it does not rotate which improves handling of the device during use. The device has relatively low part count, very compact size and is particularly attractive for cost sensitive device applications. 
         [0103]    In the following use and function of the device will be described in more detail. 
         [0104]    With the device in the at rest condition, dose marking ‘0’ on the number wheel  100  is visible through the prism  90  in the Body ( FIGS. 2 and 3 ). The drive spring  130 , which has a number of pre-wound turns applied to it during assembly of the device, applies a torque to the dial gear  70  via the spline interface with the number wheel  100 . The dial gear  70  is prevented from rotating, under the action of this torque, by its detent and clutch interface  74 ,  112  with the drive gear  110 . The drive gear  110  is prevented from rotating by the interlock provided by the engagement of splined teeth  113 ,  31  on the drive gear  110  and chassis  30 . 
         [0105]    The user selects a variable dose of liquid medicament by rotating the dial  50  CW, which generates an identical rotation in the dial gear  70 . Rotation of the dial gear  70  causes rotation of the number wheel  100 , which in turn causes wind up of the drive spring  130 , increasing the energy stored within it. The drive gear  110  is still prevented from rotating, due to the engagement of its splined teeth  113  with the chassis  30 . Relative rotation must therefore occur between the dial gear  70  and drive gear  110 , via the detent and clutch interface  74 ,  112 . 
         [0106]    The user torque required to rotate the dial  50  is a sum of the torque required to wind up the drive spring  130 , and the torque required to overhaul the ratchet feature  74 ,  112 . The trigger spring  80  acts to provide an axial force to engage the ratchet feature  74 ,  112  and to bias the components (drive gear  110 , dial gear  70  and dose button  40 ) away from the chassis  30  and towards the dial  50 . The axial load acts to maintain the ratchet teeth  74 ,  112  engagement of the dial gear  70  and drive gear  110 . The torque required to overhaul the ratchet  74 ,  112  is resultant from the axial load applied by the trigger spring  80 , the CW ramp angle of the ratchet  74 ,  112 , the friction coefficient between the mating surfaces and the mean radius of the ratchet features. 
         [0107]    As the user rotates the dial  50  sufficiently to increment the mechanism by 1 unit, the dial gear  70  rotates relative to the drive gear  110  by one ratchet tooth  74 ,  112 . At this point the ratchet teeth re-engage into the next detented position. An audible click is generated by the ratchet re-engagement, and tactile feedback is given by the change in torque input required. 
         [0108]    Relative rotation of the dial gear  70  and the drive gear  110  causes the last dose nut  60  to travel axially, via the threaded engagement with the dial gear  70 , towards the last dose abutment  72  on the dial gear  70  ( FIG. 12 ). 
         [0109]    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  50  is rotated CW or CCW, 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. 
         [0110]    CW rotation of the dial gear  70  rotates the number wheel  100  away from the zero unit stop  11  on the body  10  ( FIG. 6 ) and towards the maximum unit stop  12 . The dial  50  can be rotated by the user in both CW and CCW directions when the number wheel  100  is not in contact with the zero dose abutments  11 ,  102  or the maximum dose stop abutments  12 ,  101 . The zero unit abutment prevents CCW rotation of the dial  50  below the zero unit position. The maximum dose abutment prevents setting of a dose greater than the mechanism maximum. 
         [0111]    With no user torque applied to the dial  50 , the dial gear  70  is now prevented from rotating under the action of the torque applied by the drive spring  130 , solely by the ratchet engagement  74 ,  112  between the dial gear  70  and the drive gear  110 . The torque necessary to overhaul the ratchet in the CCW direction is resultant from the axial load applied by the trigger spring  80 , the CCW ramp angle of the ratchet  74 ,  112 , the friction coefficient between the mating surfaces and the mean radius of the ratchet features. The torque necessary to overhaul the ratchet must be greater than the torque applied to the number wheel  100  (and hence dial gear  70 ) by the drive spring  130 . The ratchet ramp angle is therefore increased in the CCW direction to ensure this is the case. The user may now choose to increase the selected dose by continuing to rotate the dial  50  in the CW direction. The process of overhauling the detent and clutch interface  74 ,  112  between the dial gear  70  and drive gear  110  is repeated for each dose unit. Additional energy is stored within the drive spring  130  for each dose unit and audible and tactile feedback is provided for each unit dialled by the re-engagement of the teeth  74 ,  112 . The torque required to rotate the dial  50  increases as the torque required to wind up the drive spring  130  increases. The torque required to overhaul the ratchet in the CCW direction must therefore be greater than the torque applied to the dial gear  70  by the drive spring  130  when the maximum dose has been reached. 
         [0112]    If the user continues to increase the selected dose until the maximum dose limit  12 ,  101  is reached, the number wheel  100  engages with its maximum dose abutment on the body  10 , which prevents further rotation of the number wheel  100 , dial gear  70  and dial  50 . At this point the maximum dose marking on the number wheel  100  is aligned to the prism  90  and shown on the front of the device. 
         [0113]    Depending on how many units have already been delivered by the mechanism, during selection of a dose, end stop  63  of the last dose nut  60  may contact its last dose abutment  72  with the dial gear  70  ( FIG. 12 ). The abutment  72  prevents further relative rotation of the dial gear  70  and the drive gear  110 , and therefore limits the dose that can be selected. The position of the last dose nut  60  is determined by the total number of relative rotations between the dial gear  70  and drive gear  110 , which have occurred each time the user sets a dose. 
         [0114]    With the mechanism in a state in which a dose has been selected, the user is able to deselect any number of units from this dose. Deselecting a dose is achieved by the user rotating the dial  50  CCW. The torque applied to the dial  50  by the user is sufficient, when combined with the torque applied by the drive spring  130 , to overhaul the ratchet  74 ,  112  between the dial gear  70  and drive gear  110  in the CCW direction. When the ratchet is overhauled, CCW rotation occurs in the number wheel  100  (via the dial gear  70 ), which returns the number wheel  100  towards the zero dose position, and unwinds the drive spring  130 . The relative rotation between the dial gear  70  and drive gear  110  causes the last dose nut  60  to return axially, away from the last dose abutment. 
         [0115]    An alternative embodiment of the dial gear  70  to drive gear  110  interface depicted in  FIG. 18 a    maximizes the security of the interface by increasing the feature size. The ratchet teeth profile is altered such that the ratchet teeth  74 ′,  112 ′ are saw-tooth shaped ( FIG. 18 b   ). The effect of this is that the engagement height is increased but it is no longer possible to overhaul the interface when rotating the dial  50  CCW. In order to allow decrement of a set dose the dial gear  70  and dial  50  are modified and an additional component, the cam ring  150 , is required which is depicted in  FIGS. 16 and 18   a  to  18   d .  FIG. 15  shows the underside of dial  50  alternative spline features to engage with cam ring  150  and  FIG. 17  shows the design of dial gear  70  of the alternative embodiment. 
         [0116]    Cam ring  150  comprises four splines  151  which engage with slots  76  dial gear  70 . On its upper side facing towards the dial  50 , the cam ring  150  is provided with ramp-like saw teeth  152  engaging corresponding ramp-like saw teeth  52  of the dial. In addition, straight spline features  53  and  153  are provided on the dial  50  and the cam ring  150  ( FIGS. 15 and 16 ). 
         [0117]    During dose set (CW dial rotation) the vertical abutments of ramp-like saw teeth  52  of dial  50  engage with vertical abutments of ramp-like saw teeth  152  of the cam ring  150  to directly transmit torque to the dial gear  70  via the spline engagement (splines  151  and slots  76 ) between the cam ring  150  and dial gear  70 . Rotation of the dial gear  70  causes wind up of the drive spring  130 , increasing the energy stored within it. The drive gear  110  is still prevented from rotating, due to the engagement of its splined teeth  113  with the chassis  30 . Relative rotation must therefore occur between the dial gear  70  and drive gear  110 , via the detent and clutch interface  74 ′,  112 ′. The at rest position is shown in  FIG. 18   a.    
         [0118]    When the dial  50  is rotated CCW the dial gear  70  and cam ring  150  are not carried by it due to the profile of the detent and clutch interface ( 74 ′,  112 ′) between the dial gear  70  and drive gear  110  (which is rotationally coupled to the chassis  30  throughout the dose select or deselect action). CCW rotation of the dial  50 , therefore, results in relative rotation between the cam ring  150  and dial  50 . The ramp features of saw teeth  52 , 152  between dial  50  and cam ring  150  cause the cam ring  150  to displace axially as a result of the relative rotation ( FIG. 18 b   ). The cam ring  150  applies an axial force to the drive gear  110 , displacing it against the trigger spring  80  force, separating the drive gear  110  and dial gear  70  and disengaging the detent and clutch interface  74 ′ and  112 ′. 
         [0119]    When the dial  50  has rotated sufficiently to disengage detent and clutch interface  74 ′,  112 ′, splines  53  on the dial  50  contact splines  153  on the cam ring  150  and prevent further relative rotation between the dial  50  and cam ring  150 . Clearance between the splines  53 ,  153  allows enough relative rotation of the dial  50  and cam ring  150  to disengage detent and clutch interface  74 ′,  112 ′, but not enough for the saw-teeth  52 ,  152  to override each other and cause the dial  50  to become de-synchronised with the cam ring  150  and dial gear  70 . 
         [0120]    Detent and clutch interface ( 74 ′,  112 ) reacts the drive spring  130  torque, applied to the dial gear  70  via the number wheel  100 . When the detent and clutch interface is disengaged, the drive spring  130  torque rotates the dial gear  70  CCW by one unit increment via the number wheel  100  ( FIG. 18 c   ). Rotation of the dial gear  70  may also be assisted by the user torque applied to the dial  50  and transferred to the cam ring  150  via splines  53 ,  153  and further to the dial gear  70  via splines  76 ,  151 . 
         [0121]    The cam ring  150  is then driven rotationally by the dial gear  70 , relative to the dial  50 , returning along the helical path and to its original axial position. The trigger spring  80  returns the drive gear  110  axially and re-engages the detent and clutch interface  74 ′ and  112 ′ between dial gear  70  and drive gear  110  ( FIG. 18 d   ). At this stage the dial  50  may be rotated in either a CW direction to select a higher dose or a CCW to further reduce the dose set. 
         [0122]    With any of the above mentioned alternative mechanisms in a state in which a dose has been selected, the user is able to activate the mechanism to commence delivery of a dose. Delivery of a dose is initiated by the user depressing the dose button  40  in the center of the dial  50 .  FIG. 9  shows the device with dose button  40  released as during dose setting and dose correction, while  FIG. 10  shows the device with dose button  40  depressed for dose dispensing. 
         [0123]    When the dose button  40  is depressed, it moves axially, acting on the dial gear  70 , which in turn acts on the drive gear  110 . The dial gear  70  disengages its spline teeth  73  from the dial  50  and then the drive gear  110  disengages its spline teeth  113  from the corresponding teeth  31  of the chassis  30  ( FIG. 11 ). When the splined interface  31 ,  113  between the chassis  30  and the drive gear  110  disengage, the interface which prevents rotation of the drive gear  110  during selection of a dose is removed. Thus, the order of disengagement is important to prevent unintended discharging of the drive spring  130 . 
         [0124]    The torque applied to the dial gear  70 , via the number wheel  100 , from the drive spring  130  is transmitted, via the detent and clutch interface, into the drive gear  110 . This torque causes rotation of the drive gear  110  and hence, due to its geared engagement with the piston rod  120 , advancement of the piston rod  120 . Axial displacement of the piston rod  120  forces liquid medicament to be delivered from the mechanism, as the distal end of the piston rod  120  contacts and displaces the bung  141  within the cartridge  140 . The rotation of the dial gear  70  also causes the number wheel  100  to rotate CCW, towards the zero dose abutment and decrementing the dose displayed. 
         [0125]    The clicker arm  36  is a compliant cantilever beam integrated into the chassis  30 , which interfaces axially with ratchet features  115  on the drive gear  110 . The ratchet teeth spacing corresponds to the drive gear  110  rotation required to deliver a single dose unit. During dispense, as the drive gear  110  rotates, the ratchet features  115  engage with the clicker arm  36  to produce an audible click with each dose unit delivered ( FIG. 13 ). The torque required to overhaul the clicker arm  36  is resultant from the profile of ratchet teeth  115 , the stiffness of the cantilever beam and the nominal interference between clicker arm  36  and ratchet  115 . The clicker arm interface is designed such that the torque required to overhaul is significantly less than the torque provided by the drive spring  130 . 
         [0126]    Delivery of a dose continues via the mechanical interactions described above while the user continues to depress the dose button  40 . If the user releases the dose button  40 , the trigger spring  80  returns the dose button  40  to its at rest position via the drive gear  110  and dial gear  70 , the drive gear  110  becomes rotationally constrained and delivery of a dose is halted. 
         [0127]    With the dose button  40  depressed, delivery of a dose continues until the number wheel  100  reaches the zero dose abutment  102  with the body  10 . The torque applied to the number wheel  100  by the drive spring  130  is reacted by the abutment of the number wheel  100  to the body  10  and the number wheel  100 , dial gear  70  and drive gear  110  are prevented from rotating further. During delivery of a dose, the drive gear  110  and dial gear  70  rotate together, so that no relative motion in the last dose nut  60  occurs. The last dose nut  60  therefore travels towards its abutment on the dial gear  70  during dialing only. 
         [0128]    Once the delivery of a dose is stopped, by the number wheel  100  returning to the zero dose abutment  11 , the user may release the dose button  40 , which will re-engage the chassis  30  spline teeth  31  with teeth  113  of the drive gear  110 . The mechanism is now returned to the at rest condition. 
         [0129]    It is possible to angle either the spline teeth  113  on the drive gear  110  or the spline teeth  31  on chassis  30  so that when the dose button  40  is released the re-engagement of the spline teeth  31 ,  113  fractionally ‘backwind’ the drive gear  110  thereby removing the engagement of the number wheel  100  to the chassis  30  zero dose stop abutment ( FIG. 19 ). This removes the effect of clearances in the mechanism (for example due to tolerances) which could otherwise lead to slight advancement of the piston rod  120  and medicament dispense when the device is dialed dialled for the subsequent dose (due to the number wheel  100  zero dose stop no longer restraining the mechanism and instead the restraint returning to the splines between the drive gear  110  and chassis  30 ). 
         [0130]    An audible click occurs at the end of dose when the mechanism reaches its zero position  11 ,  102 . The click is created by interaction between ramp  37  of the chassis  30  and a flexible clicker arm  77  on the dial gear  70  when the dial gear  70  is in the dispensing axial position. The advantage with this design is that the click feedback only occurs during dose delivery ( FIG. 21 b   ), i.e. when button  40  and dial gear  70  are depressed, and not during dialing or cancelling of a dose, when clicker arm  77  and ramp  37  are axially spaced as shown in  FIG. 21   a.    
         [0131]    The sequence of generating the click is shown in  FIGS. 20 a  to 20 d   , with  FIG. 20 a    depicting the situation that e.g. 6 units are remaining and clicker arm  77  approaches ramp  37 . In  FIG. 20 b    there are 2 units remaining and clicker arm  77  contacts ramp  37  of chassis  30 .  FIG. 20 c    shows the interface just prior to the click with 0.5 units remaining. The clicker arm  77  is deflected against ramp  37 . The end of dose is shown in  FIG. 20 d   , when the audible click is generated as clicker arm  77  passes off ramp  37  of chassis  30 . 
         [0132]    A further aspect of the present disclosure pertains to the facility for removing the need for a user to prime the device when first used. This involves removing the variable distance (dependent on component and cartridge tolerances) between the bung  141  of cartridge  140  and the distal face (foot  125 ) of the piston rod  120  during manufacture such that the piston rod  120  is in contact with the bung  141  when assembled. For this prime elimination the device is assembled completely, however omitting the dose button  40 . An assembly tool  160  engages with location features  116  in the drive gear  110 , through cut-outs  78  in the dial gear  70  ( FIG. 22 ). The detent and clutch interface  74 ,  112  between the dial gear  70  and drive gear  110  is disengaged by axially translating the drive gear  110  towards the chassis  30 , compressing the trigger spring  80  ( FIG. 23 ). In this state of the device the drive gear  110  is rotated CCW by the assembly tool  160  until the torque required to rotate the drive gear  110  reaches a pre-determined value, corresponding to the required axial force applied to the bung  141  by the piston rod  120 . The assembly tool  160  is then retracted, allowing the trigger spring  80  to return the drive gear  110  to the at rest position where it is rotationally constrained by the spline engagement to the chassis  30 . Finally, the dose button  40  is fitted into the dial  50  via snap clip features  41 . 
         [0133]    As an alternative to the embodiments depicted in the Figures which comprise a prism, a window or opening may be provided in the body, for example in the cylindrical side surface, through which markings of the number wheel  100  are visible. 
         [0000]    
       
         
               
             
               
               
             
           
               
                   
               
               
                 Reference numerals 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 10 
                 body (casework) 
               
               
                 11 
                 minimum stop 
               
               
                 12 
                 maximum stop 
               
               
                 20 
                 cartridge holder 
               
               
                 21 
                 snap hook 
               
               
                 30 
                 chassis (base element) 
               
               
                 31 
                 spline teeth 
               
               
                 32 
                 bearing 
               
               
                 33 
                 first curved guiding section 
               
               
                 34 
                 second straight guiding section 
               
               
                 35 
                 receiving section 
               
               
                 36 
                 clicker arm 
               
               
                 37 
                 ramp 
               
               
                 40 
                 dose button 
               
               
                 41 
                 snap hook 
               
               
                 50 
                 dial (dose setting member) 
               
               
                 51 
                 dial cover 
               
               
                 52 
                 saw teeth 
               
               
                 53 
                 spline 
               
               
                 60 
                 last dose nut 
               
               
                 61 
                 groove 
               
               
                 62 
                 outer thread 
               
               
                 63 
                 end stop 
               
               
                 70 
                 dial gear (coupling element) 
               
               
                 71 
                 thread 
               
               
                 72 
                 stop 
               
               
                 73 
                 teeth 
               
               
                 74, 74′ 
                 teeth 
               
               
                 75 
                 spline 
               
               
                 76 
                 slot 
               
               
                 77 
                 clicker arm 
               
               
                 78 
                 cut-out 
               
               
                 80 
                 trigger spring 
               
               
                 90 
                 prism 
               
               
                 100 
                 number wheel (display) 
               
               
                 101 
                 maximum stop 
               
               
                 102 
                 minimum stop 
               
               
                 110 
                 drive gear 
               
               
                 111 
                 spline 
               
               
                 112, 112′ 
                 teeth 
               
               
                 113 
                 spline teeth 
               
               
                 114 
                 pinion 
               
               
                 115 
                 ratchet 
               
               
                 116 
                 location feature 
               
               
                 120 
                 flexible piston rod 
               
               
                 121 
                 segment (rigid rod piece) 
               
               
                 122 
                 hinge 
               
               
                 123 
                 rack teeth 
               
               
                 124 
                 flange 
               
               
                 125 
                 foot 
               
               
                 130 
                 drive spring 
               
               
                 140 
                 cartridge 
               
               
                 141 
                 bung 
               
               
                 150 
                 cam ring 
               
               
                 151 
                 spline 
               
               
                 152 
                 saw teeth 
               
               
                 153 
                 spline 
               
               
                 160 
                 assembly tool