Patent Publication Number: US-2018050161-A1

Title: Drug Delivery Device

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is the national stage entry of International Patent Application No. PCT/EP2016/055218, filed on Mar. 11, 2016, and claims priority to Application No. EP 15305379.8, filed in on Mar. 12, 2015, the disclosures of which are expressly incorporated herein in entirety by reference thereto. 
    
    
     TECHNICAL FIELD 
     The disclosure is generally directed to a drug delivery device for selecting and dispensing a number of user variable doses of a medicament. 
     BACKGROUND 
     Pen type 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 invention 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. 
     There are basically two types of drug delivery devices: resettable devices (i.e., reusable) and non-resettable (i.e., disposable). For example, disposable pen 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. 
     These types of pen delivery devices (so named because they often resemble an enlarged fountain pen) 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. 
     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. 
     The dosing section or dose setting mechanism is typically the portion of the pen device that is used to set (select) a dose. During an injection, a spindle 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. 
     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. 
     Especially for visually impaired users it is helpful to have a non-visual feedback during operation of the device. This may include a feedback generated during dose setting, a feedback generated during dose correction, a feedback generated during dose dispensing and/or a feedback generated at the end of dose dispensing. A non-visual feedback signal may be an audible and/or tactile feedback signal. 
     A drug delivery device with a clicker mechanism active during dose dispensing is described in the unpublished European patent application “Drug Delivery Device”, filed on Jul. 1, 2014 by the same applicant, currently pending as EP 14 306 065.5. The drug delivery device comprises a clutch mechanism for rotationally coupling and decoupling a dose setting member and a driver. Further, an additional clutch mechanism is provided for rotationally coupling and decoupling the driver and the housing. Both clutch mechanisms are biased into a dose setting state by a clutch spring interposed between the housing and the driver. 
     SUMMARY 
     In certain aspects, a torsion spring may be used in addition to the function of a drive spring as an axially acting spring, e.g. for biasing component parts of the device into a dose setting position and/or a dose dispensing position. In other words, a helical torsion spring may be used to define a state of the device, especially the dose setting state or the dose dispensing state. For example, the drive spring may push (bias) clutch components into engagement and/or disengage component parts. In addition or as an alternative, the drive spring may pull clutch components into engagement and/or disengage component parts. Thus, the use of a torsion spring as a drive spring for driving component parts during dose dispensing and as a clutch spring for coupling and/or decoupling component parts is an important aspect of some embodiments. This avoids additional costly metal parts, such as an additional clutch spring, and may facilitate assembly of a device due to a reduced number of component parts. 
     Some embodiments described herein are applicable for both types of devices, i.e. for disposable devices as well as for reusable devices. 
     In certain aspects, a drug delivery device for selecting and dispensing a number of user variable doses of a medicament comprises a housing having a proximal end and an opposite distal end, a dose setting member rotatable relative to the housing during dose setting and during dose dispensing, a driver axially displaceable relative to the housing between a proximal dose setting position and a distal dose dispensing position, and an axially compressible torsion spring which is rotationally and axially constrained with a first end to the housing, wherein the torsion spring is rotationally constrained with a second, opposite end to the dose setting member, and wherein the torsion spring biases the drive sleeve into its dose setting position. The device may further comprise a spring collar which is rotationally constrained to the dose setting member and axially displaceable thereto between a proximal dose setting position and a distal dose dispensing position, wherein the torsion spring is rotationally constrained to the dose setting member via the spring collar, and wherein the torsion spring biases the spring collar into its dose setting position. 
     In a preferred embodiment, the drive spring may be prestrained and/or may be strained (charged) during dose setting. The drive spring may be attached at one end to the housing component and/or an additional housing component and at the other end to a component part coupled to a dose setting member, e.g. the number sleeve. The torsion spring may be pre-wound upon assembly of a drug delivery device, such that it applies a torque to the mechanism when the mechanism is at zero units dialled. 
     Providing a resilient drive member, such as a torsion spring, generating the force or torque required for dose dispensing, reduces the user applied forces for dose dispensing. This is especially helpful for users with impaired dexterity. In addition, the dial extension of manually driven devices, which is a result of the required dispensing stroke, may be omitted by providing the resilient member because a small triggering stroke may be necessary for releasing the resilient member. 
     The torsion spring may be formed from a helical wire with at least two different pitches. Preferably, both ends are formed from ‘closed’ coils, i.e. the pitch equals the wire diameter and each coil contacts the adjacent coil, while the central portion has ‘open’ coils, i.e. the coils do not contact each other. 
     Having both open and closed coils in the spring has the following advantages: When a dose is set, the torsion spring is usually charged. If all the coils were closed, winding up the spring would increase the length of the spring by one wire diameter for each turn, and so hook ends of the spring would no longer be aligned with their anchor points, which are e.g. on the number sleeve and the housing. The open coils allow the spring to compress to accommodate the additional turns of wire, without increasing the total length of the spring. Further, the open coils allow the spring to be compressed during assembly. For example, the spring is manufactured longer than the space available in the device. It is then compressed during assembly, ensuring that the axial positions of the hook ends are better aligned with their anchor points on the housing and the number sleeve. In addition, it is easier to manufacture the spring to a specified length if most of the coils are closed, as the length of these coils is only a function of the wire diameter. Including at least one open coil allows the spring to be compressed during assembly, which biases the number sleeve axially relative to the housing in a consistent direction, reducing the effects of geometric tolerances. In addition, this allows providing an axial force biasing one or more component parts, e.g. for coupling and/or decoupling and/or to hold or bring the device in a state or mode. The addition of closed coils at each end makes the springs less prone to tangling with each other when they are stored together between manufacture and assembly. Closed coils at the ends provide a flat surface for contact with the housing and number sleeve which is preferred. 
     In some embodiments, the device comprises a housing having a proximal end which may have a trigger or dispensing button and an opposite distal end which is facing towards the injection site. A dose setting member may be guided within the housing to be rotatable relative to the housing during dose setting and during dose dispensing. The dose setting member may be a number sleeve which is at least in one mode or state of the device rotationally constrained to a dial grip which may be operated by a user to set (or cancel) a dose. Further, an axially compressible torsion spring is provided rotationally and axially constrained with a first end to the housing. This torsion spring may be used as a drive spring during dose dispensing and as a clutch spring if the device further comprises a spring collar which is rotationally constrained to the dose setting member and axially displaceable thereto between an, e.g. proximal, dose setting position and an, e.g. distal, dose dispensing position. The torsion spring is preferably rotationally constrained with a second, opposite end to the dose setting member via the spring collar, and the torsion spring biases the spring collar into its dose setting position. In other words, the torsion spring has the additional function of holding or biasing the spring collar into a position which defines a state or mode of the device, preferably the dose setting mode. The spring collar may in turn push, pull or hold one or more additional component parts in a state or mode allowing e.g. dose setting, dose dispensing or resetting of the device. On the other hand, it is possible to displace the spring collar relative to the dose setting member to which it is rotationally constrained against the bias of the torsion spring if a force is exerted on the spring collar, e.g. by pushing an actuation button to start dispensing or by operating a trigger. 
     The spring collar may be a ring-shaped element interposed between the spring and the dose setting member and located e.g. within the tubular dose setting member. The dose setting member may comprise at least one axially extending spline engaging at least one corresponding spline of the spring collar to allow relative axial movement while preventing relative rotation. Preferably, the spring collar comprises means for interacting with other component parts, e.g. a driver. 
     In a further detailed embodiment, the drug delivery device comprises a driver which is axially displaceable relative to the housing between an, e.g. proximal, dose setting position and an, e.g. distal, dose dispensing position, wherein the torsion spring biases the driver for example into its dose setting position via the spring collar. The driver may be a tubular component part engaging a piston rod or spindle such that upon operation of the driver during dose dispensing the piston rod or spindle is moved distally to expel medicament from the cartridge. This movement of the driver and/or the piston rod or spindle may be an axial displacement, a rotation or a combination thereof, e.g. a movement along a helical path. In some embodiments the driver and the piston rod or spindle may perform a relative movement with respect to each other during dose setting and/or during dose dispensing. 
     With the spring collar interposed between the helical drive spring and the dose setting member (e.g. number sleeve), the coupling is split into several component parts allowing relative axial movement between the dose setting member and one end of the drive spring. This allows using the helical drive spring to exert axial forces and a torque for driving the device during dispensing. 
     The spring collar may have a first axial contact surface and the driver may have a second axial contact surface abutting the first axial contact surface. This allows exerting a force in the axial direction from the spring collar to the driver and vice versa. For example, the driver comprises a radial flange having a distal face which is the second axial contact surface, and the spring collar comprises a proximal end face which is the first axial contact surface. In addition, the spring collar may have a third axial contact surface and the dose setting member may have a fourth axial contact surface abutting the third axial contact surface. For example, the spring collar comprises a radial flange having a proximal face which is the third axial contact surface, and the dose setting member may have an internal stepped portion with a distal face which is the fourth axial contact surface. 
     In other words, important aspects of some embodiments include that the helical drive spring (torsion spring) is attached to an annular engagement piece, namely the spring collar, which is arranged coaxially with the spring and the dose setting member, that the engagement piece is rotationally coupled and axially displaceable relative to the dose setting member (number sleeve), that the engagement piece has a collar section configured for sliding contact to the drive sleeve, and/or that the engagement piece is configured to abut against the number sleeve in a rest position, e.g. when the device is in the dose setting mode. 
     To avoid increasing the length of the device during operation, the dose setting member may be axially constrained to the housing. In other words, relative axial movement of component parts, e.g. the spring collar and/or the driver, with respect to the housing is also a relative movement with respect to the dose setting member. 
     Dose setting and dose dispensing typically involves a relative movement between the dose setting member and the driver in one of the dose setting mode or the dose dispensing mode and a combined movement in the other of the dose setting mode or the dose dispensing mode. Thus, a clutch may be provided between the dose setting member and the driver for allowing or preventing relative movement depending on the mode or state of the device. For example, the dose setting member is coupled to the driver via at least one clutch such that during one of dose setting and dose dispensing relative rotation between the dose setting member and the driver is allowed, while during the other of dose setting and dose dispensing relative rotation between the dose setting member and the driver is prevented. For example, during dose setting relative rotation between the dose setting member and the driver is allowed, while during dose dispensing relative rotation between the dose setting member and the driver is prevented. The at least one clutch may comprise a ring of teeth on a proximal face of the driver and corresponding teeth on a distal face of a separate clutch plate which is rotationally constrained to the dose setting member. In some embodiments, the torsion spring has the function of a clutch spring which axially biases the driver towards the clutch plate. 
     The driver may be axially displaceable relative to the housing with the positions of the driver defining the dose setting mode and the dose dispensing mode of the device, wherein the position of the driver may be defined by the position of the spring collar. In its dose setting position, the driver may be rotationally constrained to the housing and, in its dose dispensing position, may be rotatable relative to the housing. In this dose dispensing position the torsion spring acts as a drive spring for driving the dose setting member and/or the driver. 
     The drug delivery device may further comprise a button located at the proximal end of the housing and coupled to the driver such that an axial movement of the button in the distal direction displaces the driver and the spring collar against the axial bias of the torsion spring, and such that an axial movement of the driver and the spring collar in the proximal direction displaces the button. In other words, the spring has the additional function of biasing the button, e.g. into its at rest or dose setting position. 
     According to a preferred embodiment the button is axially displaceable between a dose setting position and a dose dispensing position, wherein the button is rotatable relative to the housing in its dose setting position and rotationally locked to the housing in its dose dispensing position. A dispense clicker may be provided by ratchet features of the button and a clicker arm of the clutch plate. Thus, the clicker feedback signal is not generated during dose setting (or dose correction) but only during dose dispensing, when relative rotation between the (fixed) button and the (rotating) clutch element occurs. Rotationally constraining the button to the housing during dose dispensing has the additional advantage that there is no friction due to relative rotation between a user&#39;s finger and the button. Further, this prevents unintended manipulation of the set dose during dispensing. 
     If the button is rotatable relative to the number sleeve in its dose dispensing position and rotationally locked to the number sleeve in its dose setting position, relative rotation between the button and the clutch element which is constrained to the number sleeve occurs during dose dispensing but not during dose setting. This allows generating different feedback signals during dose setting and dose dispensing. 
     In some embodiments the clutch element is axially biased in abutment with the button by the drive spring such that the button axially displaces the clutch element when displaced into its dose dispensing position and that the clutch element axially displaces the button into its dose setting position. Thus, the drive spring holds the button in its dose setting position if no external force is exerted on the button. Preferably, the drive sleeve is axially movable together with the button and the clutch element between a dose setting position and a dose dispensing position. 
     The drive sleeve may be coupled to the button via the clutch element such that upon actuation of the button the drive sleeve and the clutch element are translated against the bias of the drive spring from a proximal position in which the drive sleeve is rotationally locked to the housing into a distal position in which the drive sleeve is rotationally un-locked from the housing, and wherein upon release of the button the drive spring translates the drive sleeve, the clutch element and the button into the proximal position. 
     The drive spring may bias clutch features of the clutch element and the drive sleeve into engagement. Preferably, the clutch features together form a releasable ratchet clutch suitable to couple and de-couple the drive sleeve and the clutch element. For example the clutch features may be rotationally constrained when engaged and free to rotate relative to each other when disengaged. The disengaged state of the corresponding clutch features may include a condition where the clutch features contact each other, but are allowed to overhaul each other, i.e. the corresponding clutch features slip. Further, this ratchet clutch interface may be designed, e.g. by providing meshing ratchet teeth on the drive sleeve and on the clutch element, such that relative rotation of the drive sleeve and the number sleeve requires relatively low force or torque in one direction, preferably the dose setting direction, and requires a significantly higher force or torque in the opposite direction, preferably the dose correction direction. For example, in the dose setting direction, a shallow ramp reduces the torque but winding up the spring increases the torque, while in the dose correction direction, a steep ramp increases the torque but unwinding the spring reduces the torque. Thus, the torque for dose correction and dose dialling may therefore be equal, but one may be larger than the other. As an alternative, the ratchet features may be designed to allow relative rotation of the drive sleeve and the number sleeve only in one direction, typically the dose setting direction, while fully preventing relative rotation of the drive sleeve and the number sleeve only in the opposite direction. 
     In a preferred embodiment the number sleeve and the drive sleeve are allowed to rotate relative to each other when the drive sleeve is in its first axial position and are rotationally constrained when the drive sleeve is in its second axial position. In the drug delivery device, the first axial position may be a dose setting position and the second axial position may be dose dispensing position. 
     In addition to the dispense clicker, a feedback signal may be provided during dose setting and/or dose correction. Preferably, the ratchet clutch formed by teeth on the drive sleeve and the clutch element generate an audible and/or tactile feedback signal upon relative rotation of the clutch element with respect to the drive sleeve during dose setting and/or dose correction. This feedback signal may be distinct from the dispense clicker signal. 
     The clutch features may be in a releasable engagement allowing the clutch features to be overhauled against the bias of the drive spring at least in one rotational direction when the drive sleeve is in the proximal position and that the clutch features are rotationally constrained when the drive sleeve is in the distal position. For example, the clutch features may each comprise a series of teeth, preferably saw-teeth, which are allowed to slip over each other if not pressed against each other too firmly. In other words, the clutch features may be overhauled against the bias of the drive spring by allowing the drive sleeve and/or the clutch element to translate axially against the force of the drive spring. This may result in an oscillating axial movement of the drive sleeve and/or the clutch element due to continued disengagement and following re-engagement into the next detented position. An audible click may be generated by this re-engagement, and tactile feedback may be given by the change in torque input required. 
     In addition, the clutch features preferably comprise teeth having a ramp angle allowing overhauling of the ratchet, e.g. for dose correction. In other words, relative rotation of the drive sleeve and the clutch element is allowed in both directions when the clutch arrangement is in the state or condition where the clutch features and the corresponding clutch features are not rotationally fixed. 
     Preferably, the clutch features provides a detented position between the drive sleeve and the clutch element corresponding to each dose unit, and engage different ramped tooth angles during clockwise and anti-clockwise relative rotation. This is especially useful if the device further comprises a drive spring having a force or torque which is reacted via the clutch features from the clutch element and the drive sleeve to the housing. The drive spring may be directly or indirectly coupled to the clutch element. 
     A further feedback signal may be provided as an end of dose dispensing indication. Preferably, the drug delivery device further comprises a clicker arrangement having a clicker arm on the number sleeve, a ramp on the drive sleeve and a cam on a further element, e.g. a gauge element, wherein upon relative rotation of the number sleeve and the gauge element the clicker arm is elastically deflectable by the cam and relaxable upon disengagement with the cam thereby generating an audible and/or tactile feedback signal. When the drive sleeve is in a first axial position, the ramp preferably does not interact with the clicker arm which in turn prevents the clicker arm from contacting the cam, and when the drive sleeve is in a second axial position, the ramp deflects the clicker arm such that the clicker arm contacts the cam. The number sleeve and the gauge element may be in threaded engagement. Thus, the gauge element is axially displaced upon relative rotation of the number sleeve. This allows engagement and dis-engagement of the cam and the clicker arm depending on the relative axial position of the cam and the clicker arm. 
     With respect to the feedback signal generated at the end of dose dispensing, it is an important aspect some embodiments that the clicker arrangement comprises a first, rotatable element and a second, non-rotatable element with one of the first element and the second element comprising a clicker arm, which is elastically deformable, and the other of the first element and the second element comprising a cam. Upon relative rotation of the first element and the second element the clicker arm is elastically deflected by the cam and relaxes upon disengagement with the cam thereby generating an audible and/or tactile feedback signal. Certain aspects include the idea of further providing a third, axially movable element having a ramp which interacts with the clicker arm at least in a defined position of the third element. In more detail, the ramp does not interact with the clicker arm which in turn prevents the clicker arm from contacting the cam when the third element is in a first axial position. However, when the third element is in a second axial position, the ramp deflects the clicker arm such that the clicker arm contacts the cam. In other words, the clicker arrangement may be activated to generate the feedback signal by bringing the third element in its second position and may be de-activated preventing generation of a signal by bringing the third element in its first position. This allows the feedback signal to be produced only in a defined mode, typically during dose dispensing when used in a drug delivery device. The feedback signal generated by the clicker arrangement is preferably distinct from other signals which may be generated in a drug delivery device, for example a visual indication and/or an audible and/or tactile feedback signal generated during dose setting, dose correction and/or dose dispensing. Dose correction is understood to be reducing an already set dose without dispensing medicament. 
     The cam preferably does not contact the clicker arm when the third element is in its first axial position, which is when used in a drug delivery device preferably if a trigger or actuation button is in a not depressed ‘at rest’ condition. Thus, during storage or dialling the clicker arm is not deflected and will not suffer creep deformation. In addition the clicker arrangement does not cause friction losses during dialling or dose correction which contributes to a user-friendly device requiring only low dialling force or torque. 
     During dialling (dose setting), the second element may translate, e.g. in the proximal direction, so the cam is no longer aligned axially with the clicker arm. Preferably, at the start of dose delivery when the third element translates in the distal direction, the ramp on the third element pushes the clicker arm for example radially outwards. During dose delivery, the second element may translate back in the distal direction, and towards the end of dose delivery, the clicker arm contacts the cam. Only in this position is generation of the feedback signal possible. For small doses, the cam and the clicker arm may be in contact at the start of dose dispensing. After dose delivery, the trigger or button is typically released and the clicker arrangement returns to its ‘at rest’ position. 
     Preferably, the element comprising the clicker arm is a tubular element with the clicker arm being deflectable radially inwards and outwards. The third element comprising the ramp is preferably arranged radially inwards of the element comprising the clicker arm such that the ramp is able to push the clicker arm radially outwards. The element comprising the cam may be arranged radially outwards of the element comprising the clicker arm such that the cam is able to push the clicker arm radially inwards. 
     There are various ways of generating the audible and/or tactile feedback signal by any of the clicker arrangements. For example, the audible and/or tactile feedback signal may be generated by disengagement of a clicker arm and a tooth or a cam. In other words, the signal is caused e.g. by the pre-tensioned clicker arm falling off an edge of the tooth or cam. As an alternative, the audible and/or tactile feedback signal may be generated by contact of a first portion of the clicker arm with the tooth or cam after disengagement of a second portion of the clicker arm with the tooth or cam. For example, the second portion of the clicker arm, e.g. a lever portion, may hit the tooth or cam after the first portion of the clicker arm, e.g. a projecting tip of the arm, disengages or loses contact with the tooth or cam. In an embodiment comprising a cam it is preferred if the element with the cam further comprises a recess for receiving the second portion, e.g. the tip, of the clicker arm after disengagement of the second portion of the clicker arm with the cam. 
     The clutch element comprises the corresponding clutch features and may have the form of a plate or disk. As an alternative, the clutch element may have the form of a sleeve. The clutch element is axially interposed between the sleeve and the button such that axial movement of the button in a first direction, preferably in the distal direction, is transferred to the sleeve via the clutch element and axial movement in the opposite, preferably proximal, direction is transferred to the button via the clutch element. As an alternative, the clutch element may be a unitary part of the button. In a preferred embodiment the clutch element is permanently or releasably coupled to further component parts of a drug delivery device, for example a number sleeve and/or a dose setting member. The clutch element may be a multi-functional element having in addition to the interface with the sleeve and the interface with the button e.g. a clicker feature and/or at least one further interface. 
     The button is preferably a user operable element located proximally from the sleeve and the clutch element. When used in a drug delivery device, the button may extend from the proximal end of the device and, preferably, does not change its axial position during dose setting. The button is preferably coupled to a user operable dose setting member and may be releasably coupled to a number sleeve component and/or a stationary housing component. In an alternative embodiment, the button may be part of a dose setting arrangement or may be the dose setting member. The button is a multi-functional element having in addition to the above features the clicker feature. 
     The stationary housing component is a fixed basis for relative movements of the axially movable sleeve, the clutch element and the button. It may be part of a multi-component housing or may be the only housing component of a drug delivery device. In a preferred embodiment, the stationary housing component comprises an axial support or bearing for the drive spring and means for releasably engaging the sleeve. Preferably, the housing component comprises one or more teeth, for example a ring of teeth, engaging one or more corresponding teeth, preferably also a ring of teeth, of the sleeve depending on the relative axial position of the sleeve with respect to the housing component. In other words, the engagement means or teeth mesh and interlock in a first, e.g. proximal, position of the sleeve relative to the housing component and are disengaged, thus allowing relative rotation, in a second, e.g. distal, position of the sleeve relative to the housing component. The housing component may be a multi-functional element having in addition to the above features e.g. a clicker feature and/or an interface to a piston rod. 
     The axially movable drive sleeve is a tubular element which has, preferably at its distal end, an interface for releasable engagement with the housing component and, preferably at its proximal end, an interface for releasable engagement with the clutch element, namely the clutch features. Preferably, the drive sleeve is rotationally constrained to the piston rod which is in threaded engagement with the stationary housing part. In other words, rotation of the drive sleeve relative to the housing component causes rotation of the piston rod and, thus, axial displacement of the piston rod relative to the housing component. This may be used in a drug delivery device during dose dispensing to advance a piston in a cartridge to expel medication from the cartridge. The drive sleeve may be a multi-functional element having in addition to the above features e.g. a clicker feature and/or an activation interface for a clicker. 
     In a drug delivery device at least one dose setting member may be provided operable to set a dose, wherein actuation of the button causes dispensing of the set dose. Preferably, the operation of the at least one dose setting member strains the drive spring and actuation of the button allows the drive spring to relax and thereby rotate the clutch element, the drive sleeve and the piston rod relative to the housing component which causes the piston rod to advance in the distal direction relative to the housing component. 
     The drug delivery device may comprise the housing, having the first aperture, the number sleeve positioned within the housing and rotatable with respect to the housing during dose setting and during dose dispensing, and the gauge element, which is interposed between the housing and the number sleeve. Preferably, the gauge element has a second aperture, which is positioned with respect to the first aperture of the housing such that at least a part of the number sleeve is visible through the first and second apertures. The gauge element may be axially guided within the housing and in threaded engagement with the number sleeve such that rotation of the number sleeve causes an axial displacement of the gauge element. 
     The position of the gauge element may thus be used to identify the actually set and/or dispensed dose. Different colours of sections of the gauge member may facilitate identifying the set and/or dispensed dose without reading numbers, symbols or the like on a display. As the gauge element is in threaded engagement with the number sleeve, rotation of the number sleeve causes an axial displacement of the gauge element relative to the number sleeve and relative to the housing. The gauge element may have the form of a shield or strip extending in the longitudinal direction of the device. As an alternative, the gauge element may be a sleeve. In some embodiments, the number sleeve is marked with a sequence of numbers or symbols and the gauge element comprises an aperture or window. With the number sleeve located radially inwards of the gauge element, this allows that at least one of the numbers or symbols on the number sleeve is visible through the aperture or window. In other words, the gauge element may be used to shield or cover a portion of the number sleeve and to allow viewing only on a limited portion of the number sleeve. This function may be in addition to the gauge element itself being suitable for identifying or indicating the actually set and/or dispensed dose. 
     In a preferred embodiment, the number sleeve, during dose setting, is adapted to undergo a mere rotational movement within the housing and relative to the housing. In other words, the number sleeve does not perform a translational movement during dose setting. This prevents the need for the number sleeve to be wound out of the housing or for the housing to be prolonged for covering the number sleeve within the housing. 
     It is preferred if the device is suitable for dispensing variable, user-selectable, doses of medicament. The device may be a disposable device, i.e. a device which does not provide for an exchange of an empty cartridge. 
     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 torque 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. The limiter mechanism may comprise a first rotational stop on the number sleeve and a first counter stop on the gauge element, which abut in the minimum dose (zero) position, and a second rotational stop on the number sleeve and a second counter stop on the gauge element, which abut in the maximum dose position. As the number sleeve rotates relative to the gauge element during dose setting and during dose dispensing, these two components are suitable to form a reliable and robust limiter mechanism. 
     The drug delivery device may further comprise a last dose protection mechanism for preventing the setting of a dose, which exceeds the amount of liquid left in a cartridge. This has the advantage that the user knows how much will be delivered before starting the dose delivery. It also ensures that dose delivery stops in a controlled manner without the bung entering the neck portion of the cartridge where the diameter is smaller which may result in an underdose. In a preferred embodiment, this last dose protection mechanism only detects the medicament remaining in the cartridge when the cartridge contains less than the maximum dose (e.g. 120 IU). For example, the last dose protection mechanism comprises a nut member interposed between the drive member and a component which rotates during dose setting and dose dispensing. The component which rotates during dose setting and dose dispensing may be the number sleeve or a dial sleeve rotationally constrained to the number sleeve. In a preferred embodiment, the number sleeve and/or a dial sleeve rotate during dose setting and during dose dispensing, whereas the drive member only rotates during dose dispensing together with the number sleeve and/or the dial sleeve. Thus, in this embodiment, the nut member will only move axially during dose setting and will remain stationary with respect to these components during dose dispensing. Preferably, the nut member is threaded to the drive member and splined to the number sleeve and/or the dial sleeve. As an alternative, the nut member may be threaded to the number sleeve and/or the dial sleeve and may be splined to the drive member. The nut member may be a full nut or a part thereof, e.g. a half nut. 
     A further aspect of some embodiments, is the provision of several interfaces on the axially movable drive sleeve. Preferably, the drive sleeve has a first interface for permanently rotationally constraining the drive sleeve and the lead screw. A second interface may be provided between the drive sleeve and the housing (or a housing component) for rotationally constraining the drive sleeve and the housing depending on the axial position of the drive sleeve. A third interface may be provided between the drive sleeve and the number sleeve (or a dose setting component) for rotationally constraining the drive sleeve and the number sleeve depending on the axial position of the drive sleeve. A fourth interface may be provided between the drive sleeve and the clutch element for rotationally constraining the drive sleeve and the clutch element depending on the axial position of the drive sleeve and/or the bias of the drive spring. A fifth interface may be provided between the drive sleeve and the number sleeve or the gauge element for generating a feedback signal upon rotation of the drive sleeve, preferably only at the end of dose dispensing, and depending on the axial position of the drive sleeve. A sixth interface is provided between the drive sleeve and the spring collar. 
     Further, the drug delivery device may comprise a second clutch rotationally coupling the actuation button to the number sleeve when the actuation button and the drive sleeve are in the first dose setting position and de-coupling the actuation button from the number sleeve when the actuation button and the drive sleeve are in the second dose dispensing position. In a preferred embodiment a releasable interface between the housing and the button is provided by e.g. splines engaging with the housing to prevent rotation of the button and hence the dose selector during dispense. 
     Preferably, the piston rod (lead screw) advances by a fixed displacement for each revolution of the movable (drive) sleeve. In other embodiments, the rate of displacement may vary. For example, the piston rod may advance a large displacement per revolution to dispense a first amount of medicament from the cartridge and then a smaller displacement per revolution to dispense the rest of the cartridge. This is advantageous, as it can compensate for the fact that the first dose dispensed from the cartridge often has a lower volume than other doses, for a given displacement of the mechanism. If the pitch is equal on the threads of the housing and the piston rod, the piston rod advances a fixed amount for every revolution of the movable sleeve. However, if in an alternative embodiment the first turn of the thread on the piston rod has a large pitch and the other turns have a small pitch, during the first revolution the piston rod displacement depends on the large pitch of the first turn of thread on the piston rod, so it displaces a large amount per revolution. For subsequent revolutions the piston rod displacement depends on the smaller pitch of the piston rod thread, so it displaces a smaller amount. If, in a further embodiment, the housing thread has a larger pitch than the piston rod, during the first revolution, the piston rod displacement depends on the pitch of the housing thread, so it displaces a large amount per revolution. For subsequent revolutions the piston rod displacement depends on the pitch of the piston rod thread, so it displaces a smaller amount. 
     The aperture in the housing and/or the aperture in the gauge element may be a simple opening. However, it is preferred if at least one aperture is closed by a window or lens which prevents intrusion of dirt and/or may increase legibility of e.g. numbers on the number sleeve, for example due to a magnification. 
     According to a preferred embodiment, the number sleeve is clipped to the housing at the distal end. This reduces the geometric tolerances for the gauge position. In other words, the number sleeve is preferably axially fixed relative to the housing but allowed to rotate relative thereto. 
     Preferably, the drive sleeve is clipped inside the number sleeve to retain it during subsequent assembly steps. In an alternative embodiment, the drive sleeve is clipped to the housing instead to retain it during subsequent assembly steps. In both embodiments, the drive sleeve is free to move beyond its assembled position when the button is pressed. The clips prevent movement in the disassembly direction, but do not prevent further movement, e.g. for dispense. 
     The lens and the window in the gauge may be incorporated into the housing using a ‘twin-shot’ moulding technology. For example, they are moulded during a ‘first shot’ in a translucent material, and the outer cover of the housing is moulded during a ‘second shot’ in an opaque material. 
     If there is only one threaded portion on the gauge element this reduces the length of this component. 
     Preferably, the tooth geometry on the clutch plate and the drive sleeve is chosen such that the dialling torque is low. Further, the clutch plate may comprise a dispense clicker which interferes with clicker teeth on the button. 
     The drug delivery device may comprise a cartridge containing 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.
 
     Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
     Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-S er-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
     Exendin-4 derivatives are for example selected from the following list of compounds: 
     H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
     H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
     des Pro36 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(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. 
     Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
     A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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 on 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. 
     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). 
     Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
     Pharmaceutically acceptable solvates are for example hydrates. 
     Especially in disposable devices it is desirable to reduce the use of relatively cost intensive metal parts, like springs. Further, it is desirable to reduce the number of component parts to facilitate assembly of such devices. An advantage of certain aspects may be to provide a drug delivery device as defined above which requires fewer component parts and especially reduces the number of expensive metal parts. 
     Non-limiting, exemplary embodiments will now be described with reference to the accompanying drawings, in which: 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  shows a top view of the drug delivery device in the minimum dose position; 
         FIG. 2  shows an exploded view of the components of a known device similar to that of  FIG. 1 ; 
         FIG. 3  shows a sectional view of the device of  FIG. 2 ; 
         FIG. 4  shows a spring collar of the drug delivery device; 
         FIG. 5  shows an interface between the dose setting member and the spring collar of  FIG. 4 ; 
         FIG. 6 a    shows an enlarged sectional view of a detail of the device of  FIG. 1  in the dose setting mode; and 
         FIG. 6 b    shows an enlarged sectional view of a detail of the device of  FIG. 1  in the dose dispensing mode. 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 1  shows a drug delivery device in the form of an injection pen. The device has a distal end (left end in  FIG. 1 ) and a proximal end (right end in  FIG. 1 ). The component parts of the drug delivery device are shown in  FIG. 2 . The drug delivery device comprises a body or housing  10 , a cartridge holder  20 , a lead screw (piston rod)  30 , a drive sleeve  40 , a nut  50 , a dose indicator (number sleeve)  60 , a trigger element in the form of a button  70 , a dial grip or dose selector  80 , a torsion spring  90 , a cartridge  100 , a gauge element  110 , a clutch plate  120 , a clutch spring (not present in the embodiments) and a bearing  140 . A needle arrangement (not shown) with a needle hub and a needle cover may be provided as additional components, which can be exchanged as explained above. All components are located concentrically about a common principal axis I of the mechanism, which is shown in  FIG. 3 . As can be seen in  FIGS. 4, 6   a  and  6   b , the device further comprises a spring collar  130  interposed between the dose setting member  60  and the spring  90 . The annular spring collar has outer splines  131  or the like, a proximal end face  132  and means for engaging the drive spring  90 . 
     The housing  10  or body is a generally tubular element having a proximal end with an enlarged diameter. The housing  10  provides location for the liquid medication cartridge  100  and cartridge holder  20 , windows  11   a ,  11   b  for viewing the dose number on the number sleeve  60  and the gauge element  110 , and a feature on its external surface, e.g. a circumferential groove, to axially retain the dose selector  80 . A flange-like or cylindrical inner wall comprises an inner thread engaging the piston rod  30 . The housing  10  further has at least one internal, axially orientated slot or the like for axially guiding the gauge element  110 . In the embodiment shown in the Figures, the distal end is provided with an axially extending strip partly overlapping cartridge holder  20 . The Figures depict the housing  10  as a single housing component. However, the housing  10  could comprise two or more housing components which may be permanently attached to each other during assembly of the device. 
     The cartridge holder  20  is located at the distal side of housing  10  and permanently attached thereto. The cartridge holder may be a transparent or translucent component which is tubular to receive cartridge  100 . The distal end of cartridge holder  20  may be provided with means for attaching a needle arrangement. A removable cap (not shown) may be provided to fit over the cartridge holder  20  and may be retained via clip features on the housing  10 . 
     The piston rod  30  is rotationally constrained to the drive sleeve  40  via a splined interface. When rotated, the piston rod  30  is forced to move axially relative to the drive sleeve  40 , through its threaded interface with the inner wall of housing  10 . The lead screw  30  is an elongate member with an outer thread ( FIG. 3 ) engaging the corresponding thread of the inner wall of housing  10 . The leadscrew thread may have a large lead-in, for example a wedge shape form, at its distal end to engage a corresponding housing thread form on the first rotation. The interface comprises at least one longitudinal groove or track and a corresponding protrusion or spline of the driver  40 . At its distal end, the lead screw  30  is provided with an interface for clip attachment of the bearing  140 . 
     The drive sleeve  40  is a hollow member surrounding the lead screw  30  and arranged within number sleeve  60 . It extends from an interface with the clutch plate  120  to an interface with the housing  10 . The drive sleeve  40  is axially movable relative to the housing  10 , the piston rod  30  and the number sleeve  60  in the distal direction against the axial bias of drive spring  90  and in the opposite proximal direction under the axial bias of drive spring  90 . 
     A splined tooth interface with the housing  10  prevents rotation of the drive sleeve  40  during dose setting. This interface comprises for example a ring of radially extending outer teeth at the distal end of drive sleeve  40  and corresponding radially extending inner teeth of the housing component  10 . When the button  70  is pressed, these drive sleeve  40  to housing  10  spline teeth are disengaged allowing the drive sleeve  40  to rotate relative to housing  10 . 
     A further splined tooth interface with the number sleeve  60  is not engaged during dialling, but engages when the button  70  is pressed, preventing relative rotation between the drive sleeve  40  and number sleeve  60  during dispense. This interface may comprise inwardly directed splines on a flange on the inner surface of the number sleeve  60  and a ring of radially extending outer splines of drive sleeve  40 . The corresponding splines are located on the number sleeve  60  and the drive sleeve  40 , respectively, such that axial movement of the drive sleeve  40  relative to the (axially fixed) number sleeve  60  engages or disengages the splines to rotationally couple or decouple the drive sleeve  40  and the number sleeve  60 . Preferably, the splines are arranged such that they are decoupled when teeth of drive sleeve  40  and inner teeth of housing component  10  mesh and engage when teeth and inner teeth disengage. 
     A further interface of the drive sleeve  40  comprises a ring of ratchet teeth located at the proximal end face of drive sleeve  40  and a ring of corresponding ratchet teeth of clutch plate  120 . 
     The driver  40  has a threaded section providing a helical track for the nut  50 . In addition, a last dose abutment or stop is provided which may be the end of the thread track or preferably a rotational hard stop for interaction with a corresponding last dose stop of nut  50 , thus limiting movement of the nut  50  on the driver thread. At least one longitudinal spline engages a corresponding track of the lead screw  30 . Further, the drive sleeve is provided with a ramp interacting with a clicker arm when the drive sleeve  40  is in its distal position during dose dispensing, i.e. when button  70  is depressed. 
     The driver  40  comprises a flange  41  extending radially outwards ( FIGS. 6 a , 6 b   ). The distal face of this flange  41  is designed to abut the proximal end face  132  of spring collar  130  under the bias of spring  90 . 
     The last dose nut  50  is located between the number sleeve  60  and the drive sleeve  40 . It is rotationally constrained to the number sleeve  60 , via a splined interface. It moves along a helical path relative to the drive sleeve  40 , via a threaded interface, when relative rotation occurs between the number sleeve  60  and drive sleeve  40  which is during dialling only. As an alternative, the nut  50  may be splined to the driver  40  and threaded to the number sleeve  60 . A last dose stop is provided engaging a stop of drive sleeve  40  when a dose is set corresponding to the remaining dispensable amount of medicament in the cartridge  100 . 
     The dose setting member or number sleeve  60  is a tubular element as shown in  FIGS. 2 and 3 . The number sleeve  60  is rotated during dose setting (via dose selector  80 ) and dose correction and during dose dispensing by torsion spring  90 . Together with gauge element  110  the number sleeve  60  defines a zero position (‘at rest’) and a maximum dose position. Thus, the number sleeve  60  may be seen as a dose setting member. 
     For manufacturing reasons the number sleeve  60  of the embodiment shown in the Figures comprises a number sleeve lower  60   a  which is rigidly fixed to a number sleeve upper  60   b  during assembly to form the number sleeve  60 . Number sleeve lower  60   a  and number sleeve upper  60   b  are separate components only to simplify number sleeve  60  mould tooling and assembly. As an alternative, the number sleeve  60  may be a unitary component. The number sleeve  60  is constrained to the housing  10  by features towards the distal end to allow rotation but not translation. The number sleeve lower  60   a  is marked with a sequence of numbers, which are visible through the gauge element  110  and the openings  11   a ,  11   b  in the housing  10 , to denote the dialled dose of medicament. 
     Further, the number sleeve lower  60   a  has a portion with an outer thread engaging the gauge element  110 . End stops are provided at the opposite ends of this thread to limit relative movement with respect to the gauge element  110 . 
     An inner surface of the number sleeve lower  60   a  is provided with a step or internal flange  61  defining an axial abutment surface. This portion receives the spring collar  130  which has outer splines  131  engaging internal splines  62  of the number sleeve lower  60   a  such that the spring collar  130  is permanently rotationally constrained to the number sleeve lower  60   a . In the embodiment depicted in  FIGS. 4 and 5 , the number sleeve is provided with protrusions  62  guided in recesses  131  of the spring collar. However, other splined interfaces between number sleeve  60  and spring collar  130  are possible. The proximal end face  132  of the spring collar is designed to contact the axial abutment surface of the number sleeve lower  60   a  defined by the step or flange  61 , thus limiting axial movement of the spring collar  130  in the proximal direction. As an alternative (or in addition) the length of the spline grooves of the number sleeve lower  60   a  may limit the axial movement of the spring collar  130  in the proximal direction. As an alternative, flange  41  of the drive sleeve  40  contacts proximal end face  132  of the spring collar  130 . This pushes proximal end face  132  out of contact with flange  61  and biases the drive sleeve  40  in the proximal direction. 
     The dose selector  80  is axially constrained to the housing  10 . It is rotationally constrained, via the splined interface, to the button  70 . This splined interface which includes grooves interacting with spline features formed by the annular skirt of button  70  remains engaged irrespective of the dose button  70  axial positions. The dose selector  80  or dose dial grip is a sleeve-like component with a serrated outer skirt. 
     The torsion spring  90  is attached at its distal end to the housing  10  and at the other end to the spring collar  130 . The torsion spring  90  is located inside the number sleeve  60  and surrounds a distal portion of the drive sleeve  40 . The torsion spring  90  may be pre-wound upon assembly, such that it applies a torque to the number sleeve  60  when the mechanism is at zero units dialled. The action of rotating the dose selector  80 , to set a dose, rotates the number sleeve  60  relative to the housing  10 , and charges the torsion spring  90  further. 
     The torsion spring  90  is formed from a helical wire with at least two different pitches. Both ends are formed from ‘closed’ coils, i.e. the pitch equals the wire diameter and each coil contacts the adjacent coil. The central portion has ‘open’ coils, i.e. the coils do not contact each other. This allows the spring  90  to exert an axial force in addition to a torque. 
     The cartridge  100  is received in cartridge holder  20  ( FIG. 3 ). The cartridge  100  may be a glass ampoule having a moveable rubber bung  101  at its proximal end. The distal end of cartridge  100  is provided with a pierceable rubber seal which is held in place by a crimped annular metal band. In the embodiment depicted in the Figures, the cartridge  100  is a standard 1.5 ml cartridge. The device is designed to be disposable in that the cartridge  100  cannot be replaced by the user or health care professional. However, a reusable variant of the device could be provided by making the cartridge holder  20  removable and allowing backwinding of the lead screw  30  and the resetting of nut  50 . 
     The gauge element  110  is constrained to prevent rotation but allow translation relative to the housing  10  via a splined interface. The gauge element  110  has a helical feature on its inner surface which engages with the helical thread cut in the number sleeve  60  such that rotation of the number sleeve  60  causes axial translation of the gauge element  110 . This helical feature on the gauge element  110  also creates stop abutments against the end of the helical cut in the number sleeve  60  to limit the minimum and maximum dose that can be set. 
     The gauge element  110  has a generally plate or band like component having a central aperture or window and two flanges extending on either side of the aperture. The flanges are preferably not transparent and thus shield or cover the number sleeve  60 , whereas the aperture or window allows viewing a portion of the number sleeve lower  60   a . Further, gauge element  110  has a cam and a recess interacting with the clicker arm of the number sleeve  60  at the end of dose dispensing. 
     The clutch plate  120  is a ring-like component. The clutch plate  120  is splined to the number sleeve  60 . It is also coupled to the drive sleeve  40  via a ratchet interface. The ratchet provides a detented position between the number sleeve  60  and drive sleeve  40  corresponding to each dose unit, and engages different ramped tooth angles during clockwise and anti-clockwise relative rotation. A clicker arm is provided on the clutch plate  120  for interaction with ratchet features of the button  70 . 
     The drive spring  90  acts as a torsion spring and as a compression spring. The axial position of the drive sleeve  40 , clutch plate  120  and button  70  is defined by the action of the drive spring  90 , which applies a force on the drive sleeve  40  (via spring collar  130 ) in the proximal direction. This spring force is reacted via the drive sleeve  40 , clutch plate  120 , and button  70 , and when ‘at rest’ it is further reacted through the dose selector  80  to the housing  10 . The spring force ensures that the ratchet interface between driver and clutch plate is always engaged. In the ‘at rest’ position, it also ensures that the button splines are engaged with the number sleeve splines, and the drive sleeve teeth are engaged with teeth of the housing  10 . In addition, the force of the drive spring  90  is sufficient to push button  70  back in the proximal direction after dose dispensing. 
     The spring collar  130  is shown in  FIG. 4  in detail. In addition to its splines  131  and the proximal contact face  132  it comprises anchor features  133  for retaining the proximal hook end of spring  90 . The spring is thereby axially and rotationally constrained to spring collar  130 . In other words, the spring collar  130  is a ring with a guide surface that guides the end of spring  90  during assembly and an anchor point to locate the hook end form of the spring  90 . 
     The bearing  140  is axially constrained to the piston rod  30  and acts on the bung  101  within the liquid medicament cartridge. It is axially clipped to the lead screw  30 , but free to rotate. 
     With the device in the ‘at rest’ condition as shown in  FIG. 6 a   , the number sleeve  60  is positioned against its zero dose abutment with the gauge element  110  and the button  70  is not depressed. Dose marking ‘0’ on the number sleeve  60  is visible through the windows of the housing  10  and gauge element  110 , respectively. The torsion spring  90 , which has a number of pre-wound turns applied to it during assembly of the device, applies a torque to the number sleeve  60  and is prevented from rotating by the zero dose abutment. Further, the spring  90  applies an axial force on the spring collar  130 , the drive sleeve  40  (via abutment faces  41 ,  132 ), the clutch plate  120  and the button  70  biasing these component parts in the proximal direction (right hand side in  FIG. 6 a   ). This force is reacted through the dial grip  80  to the housing  10 . As an alternative, it may be reacted by the spring collar  130  abutting with its face  132  the flange  61  of the lower part  60   a  of number sleeve  60 . 
     The user selects a variable dose of liquid medicament by rotating the dose selector  80  clockwise, which generates an identical rotation in the number sleeve  60 . Rotation of the number sleeve  60  causes charging of the torsion spring  90 , increasing the energy stored within it. As the number sleeve  60  rotates, the gauge element  110  translates axially due to its threaded engagement thereby showing the value of the dialled dose. The gauge element  110  has flanges either side of its window area which cover the numbers printed on the number sleeve  60  adjacent to the dialled dose to ensure only the set dose number is made visible to the user. 
     A specific feature of some embodiments is the inclusion of a visual feedback feature in addition to the discrete dose number display typical on devices of this type. The distal end (flange) of the gauge element  110  creates a sliding scale through the small window  11   a  in the housing  10 . As an alternative, the sliding scale could be formed using a separate component engaged with the number sleeve  60  on a different helical track. 
     As a dose is set by the user, the gauge element  110  translates axially, the distance moved proportional to the magnitude of the dose set. This feature gives clear feedback to the user regarding the approximate size of the dose set. The dispense speed of an auto-injector mechanism may be higher than for a manual injector device, so it may not be possible to read the numerical dose display during dispense. The gauge feature provides feedback to the user during dispense regarding dispense progress without the need to read the dose number itself. For example, the gauge display may be formed by an opaque element on the gauge element  110  revealing a contrasting coloured component underneath. Alternatively, the revealable element may be printed with coarse dose numbers or other indices to provide more precise resolution. In addition, the gauge display simulates a syringe action during dose set and dispense. 
     The openings  11   a ,  11   b  in the housing  10  allow the user to view the gauge feature and number display. To reduce dust ingress and prevent the user from touching moving parts, these openings  11   a ,  11   b  are covered by translucent windows. These windows may be separate components, but in this embodiment they are incorporated into the housing  10  using ‘twin-shot’ moulding technology. 
     The mechanism utilises a dose selector  80  with an increased diameter relative to the housing  10  which aids dialling although this is not a requirement of the mechanism. This feature is particularly useful (but not essential) for an auto-injector mechanism where a power supply is charged during dose setting and the torque required to turn the dose selector  80  may be higher than for a non-auto injector device. 
     The drive sleeve  40  is prevented from rotating as the dose is set and the number sleeve  60  rotated, due to the engagement of its splined teeth with teeth of the housing  10 . Relative rotation must therefore occur between the clutch plate  120  and drive sleeve  40  via the ratchet interface. 
     The user torque required to rotate the dose selector  80  is a sum of the torque required to wind up the torsion spring  90 , and the torque required to overhaul the ratchet interface. The torsion spring  90  is designed to provide an axial force to the ratchet interface and to bias the clutch plate  120  onto the drive sleeve  40 . As the user rotates the dose selector  80  sufficiently to increment the mechanism by one increment, the number sleeve  60  rotates relative to the drive sleeve  40  by one ratchet tooth. 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. 
     Relative rotation of the number sleeve  60  and the drive sleeve  40  is allowed as splines are disengaged during dose setting. This relative rotation also causes the last dose nut  50  to travel along its threaded path, towards its last dose abutment on the drive sleeve  40 . With no user torque applied to the dose selector  80 , the number sleeve  60  is now prevented from rotating back under the torque applied by the torsion spring  90 , solely by the ratchet interface between the clutch plate  120  and the drive sleeve  40 . The user may now choose to increase the selected dose by continuing to rotate the dose selector  80  in the clockwise direction. If the user continues to increase the selected dose until the maximum dose limit is reached, the number sleeve  60  engages with its maximum dose abutment on the maximum dose abutment of gauge element  110 . This prevents further rotation of the number sleeve  60 , clutch plate  120  and dose selector  80 . 
     Depending on how many increments have already been delivered by the mechanism, during selection of a dose, the last dose nut  50  may contact its last dose abutment with stop face of the drive sleeve  40 . The abutment prevents further relative rotation between the number sleeve  60  and the drive sleeve  40 , and therefore limits the dose that can be selected. The position of the last dose nut  50  is determined by the total number of relative rotations between the number sleeve  60  and drive sleeve  40 , which have occurred each time the user sets a dose. 
     With the mechanism in a state in which a dose has been selected, the user is able to deselect any number of increments from this dose. Deselecting a dose is achieved by the user rotating the dose selector  80  anti-clockwise. The torque applied to the dose selector  80  by the user is sufficient, when combined with the torque applied by the torsion spring  90 , to overhaul the ratchet interface between the clutch plate  120  and drive sleeve  40  in the anti-clockwise direction. When the ratchet is overhauled, anti-clockwise rotation occurs in the number sleeve  60  (via the clutch plate  120 ), which returns the number sleeve  60  towards the zero dose position, and unwinds the torsion spring  90 . The relative rotation between the number sleeve  60  and drive sleeve  40  causes the last dose nut  50  to return along its helical path, away from the last dose abutment. 
     With the mechanism 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 button  70  axially in the distal direction. When the button  70  is depressed, splines between the button  70  and number sleeve  60  are disengaged, rotationally disconnecting the button  70  and dose selector  80  from the delivery mechanism, i.e. from number sleeve  60 , gauge element  110  and torsion spring  90 . Splines on the button  70  engage with splines on the housing  10 , preventing rotation of the button  70  (and hence the dose selector  80 ) during dispense. As the button  70  is stationary during dispense, it can be used in the dispense clicker mechanism. A stop feature in the housing  10  limits axial travel of the button  70  and reacts any axial abuse loads applied by the user, reducing the risk of damaging internal components. 
     The clutch plate  120  and drive sleeve  40  travel axially with the button  70 . This engages the splined tooth interface between the drive sleeve  40  and number sleeve  60  preventing relative rotation between the drive sleeve  40  and number sleeve  60  during dispense. The splined tooth interface between the drive sleeve  40  and the housing  10  disengages, so the drive sleeve  40  can now rotate and is driven by the torsion spring  90  via the number sleeve  60 , and clutch plate  120 . Further, the distal movement of drive sleeve  40  compresses the spring  90  as the spring collar  130  is moved distally together with the drive sleeve  40  (via abutment faces  41 ,  132 ). Compression of spring  90  is possible due to the open coils in the middle portion of the spring  90 . 
     Rotation of the drive sleeve  40  causes the piston rod  30  to rotate due to their splined engagement, and the piston rod  30  then advances due to its threaded engagement to the housing  10 . The number sleeve  60  rotation also causes the gauge element  110  to traverse axially back to its zero position whereby the zero dose abutment stops the mechanism. 
     Delivery of a dose continues via the mechanical interactions described above while the user continues to depress the button  70 . If the user releases the button  70 , the torsion spring  90  returns the drive sleeve  40  to its ‘at rest’ position (together with the spring collar  130 , the clutch plate  120  and button  70 ), engaging the splines between the drive sleeve  40  and housing  10 , preventing further rotation and stopping dose delivery. 
     During delivery of a dose, the drive sleeve  40  and number sleeve  60  rotate together, so that no relative motion in the last dose nut  50  occurs. The last dose nut  50  therefore travels axially relative to the drive sleeve  40  during dialling only. 
     At the end of dose dispensing, additional audible feedback is provided in the form of a ‘click’, distinct from the ‘clicks’ provided during dispense, to inform the user that the device has returned to its zero position via the interaction of the clicker arm on the number sleeve  60  with the ramp on the drive sleeve  40  and the cam and the recess on the gauge element  110 . This embodiment allows feedback to only be created at the end of dose delivery and not created if the device is dialled back to, or away from, the zero position. 
     
       
         
           
               
             
               
                   
               
               
                 Reference Numerals: 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 10 
                 housing 
               
               
                  11a 
                 opening (window) 
               
               
                  11b 
                 opening (window) 
               
               
                 20 
                 cartridge holder 
               
               
                 30 
                 lead screw (piston rod) 
               
               
                 40 
                 driver (axially movable drive sleeve) 
               
               
                 41 
                 flange 
               
               
                 50 
                 nut 
               
               
                 60 
                 dose indicator (number sleeve) 
               
               
                  60a 
                 number sleeve lower 
               
               
                  60b 
                 number sleeve upper 
               
               
                 61 
                 flange 
               
               
                 62 
                 spline 
               
               
                 70 
                 button 
               
               
                 80 
                 dose selector 
               
               
                 90 
                 torsion spring 
               
               
                 100  
                 cartridge 
               
               
                 101  
                 bung 
               
               
                 110  
                 gauge element 
               
               
                 120  
                 clutch plate 
               
               
                 130  
                 spring collar 
               
               
                 131  
                 spline 
               
               
                 132  
                 proximal contact face 
               
               
                 133  
                 anchor feature 
               
               
                 140  
                 bearing 
               
               
                 I 
                 longitudinal axis