Patent Publication Number: US-2016228651-A1

Title: Drug Delivery Device with Improved Dose Reset Mechanism

Description:
The present invention generally relates to drug delivery devices adapted to expel a user settable dose of drug from a cartridge. In a specific aspect the invention relates to a spring-driven device of the wind-up type. 
     BACKGROUND OF THE INVENTION 
     In the disclosure of the present invention reference is mostly made to the treatment of diabetes, however, this is only an exemplary use of the present invention. 
     A general type of drug delivery devices suitable for delivery of a user set amount of drug comprises a spring which is strained during dose setting, the stored energy subsequently being used to expel the set dose of drug from a cartridge arranged in the device. The user usually strains a torsion spring by rotating a rotatable dose setting member, the force thereby applied by the user being stored in the torsion spring for later release. 
     An example of a known “wind-up” device having a pen-formed configuration and applying a torsion spring is disclosed in U.S. Pat. No. 5,104,380. In this wind-up device the dose setting member is located at the proximal end and works such that when the user rotates the dose setting member the spring is strained and maintained in this strained position until the user releases the set dose by activating the latch provided on the side of the housing. The wind-up pen disclosed in U.S. Pat. No. 5,104,380 has the disadvantage that if a user sets a dose too large it is not possible to decrease the set dose. The user then has to release the latch mechanism thereby expelling the entire set dose before a new correct dose can be set and delivered. 
     Addressing this problem, wind-up pens in which the user can actually decrease the set dose prior to dosing has been proposed, see e.g. WO 2006/045526 and WO 2010/089418. 
     These “automatic” delivery devices are based on a torsion spring which is tightened during dose setting and thereafter released to inject the set dose. If a user erroneously sets a dose higher than needed these injection devices has the possibility of lowering the set dose by rotating the dose setting member in an opposite rotational direction. Such dial-down mechanisms can therefore save the user from expelling expensive drug due to an erroneous dose setting. 
     In WO 2006/045526, the dial-up/dial-down mechanism is based on a flexible ratchet arm which is locked in a one-way engagement with a toothed ring. When the user sets a dose the dose setting button provided at the proximal end of the delivery device is rotated. This dose setting button is connected to the ratchet element via a longitudinal stretching tubular sleeve. The ratchet element is provided with a ratchet arm in a toothed engagement with the toothed ring such that the ratchet arm when the dose setting button is rotated locks against the force of the torsion spring in the subsequent teeth of the toothed ring thereby straining the torsion spring in incremental steps. In order to reduce the set size, the ratchet arm is actively pulled out of engagement with the toothed ring whereby the force accumulated in the torsion spring rotates the ratchet element rapidly backwards such that the ratchet arm engages the previous tooth in the toothed ring thereby lowering the set dose with one increment. Due to the presence of the longitudinal tube, it is possible to locate the ratchet mechanism away from the dose setting button e.g. in the proximity of the drive mechanism which is preferred when the side mounted latch mechanism engages directly on the drive mechanism. The Flex-Touch® and FlexPro® drug delivery devices provided by Novo Nordisk, Bagsvæd, Denmark comprise a ratchet mechanism of the type disclosed in WO 2006/045526. WO 2011/025448 discloses a further drug delivery device comprising a ratchet mechanism of this type. 
     Due to the design of a ratchet mechanism of the type disclosed in WO 2006/045526 and WO 2011/025448 a certain rotational slack or play is allowed between certain elements, which may result in an overall design in which the rotational increments between set doses are not the same. Specifically, the rotational increment between the initial zero position and the first set position, e.g. corresponding to 1 IU of insulin, may be smaller than for the subsequent increments. For example, in the FlexTouch® drug delivery device the rotational increment between 0 and 1 IU of insulin is approximately 9 degrees whereas the rotational increment between each IU up to 80 IU of insulin is 15 degrees. On the scale drum this is reflected in a shorter distance between 0 and 1 as between e.g. 1 and 2, which may be a problem to users with impaired vision. Further, due to tolerances in the device mechanism, the initial smaller rotational increment makes it more difficult to implement an electronic dose logging feature based on detection of rotational increments. 
     The dial-down arrangement known from WO 2006/045526 could be referred to as being an “active” dial-down arrangement as the ratchet arm needs to be radially and actively moved free of its toothed engagement in order to dial down the set dose size. An example of a “passive” dial-down arrangement is known from e.g. WO 2008/031235 disclosing a dose setting mechanism with a two-way ratchet. 
     A dial-down mechanism which is not active is known from WO 2007/063342. In this arrangement as best seen in  FIG. 12 , a plurality of flexible arms engages the inside toothing of a drive gear thereby retaining the torsion spring in its strained position. These arms are flexible and can deflect radially inwardly when the user dials down the set dose without an additional element to release the arms. 
     Having regard to the above, it is an object of the present invention to provide a drug delivery device of the above “active” type having the same rotational increment between each user settable dose increment. The incorporated dose setting mechanism should be accurate, reliable and cost-effective. 
     DISCLOSURE OF THE INVENTION 
     In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objects or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments. 
     Thus, in a first aspect of the invention a dial up/dial down spring-driven drug delivery device is provided comprising a rotatable driver assembly allowing a user to set a dose amount to be expelled and strain a drive spring correspondingly. A rotatable ratchet member is coupled to the driver assembly with a rotational play, the play allowing the driver assembly to release the ratchet member and thereby decrease a set dose. A helically moving scale drum is coupled to the driver assembly and comprises a stop surface preventing the driver assembly from being rotated below an initial position, whereby the driver assembly in the initial position is prevented from being rotated in the resetting direction relative to the ratchet member corresponding to the rotational play. 
     In a more specific aspect a drug delivery device is provided having an expelling assembly comprising a piston rod, a drive spring, a driver assembly, a ratchet and a scale drum. The piston rod is adapted to engage and axially displace a piston in a loaded cartridge in a distal direction to thereby expel a dose of drug from the cartridge. The rotatable driver assembly allows a user to set a dose amount to be expelled and strain the drive spring correspondingly. The ratchet allows the driver assembly to be rotated from an initial position in a first direction “dial up” and to be held in a rotational position corresponding to a set dose. The ratchet comprises a toothing structure and a rotatable ratchet member coupled to the driver assembly and rotating therewith, the ratchet member comprising a ratchet arm (i.e. at least one) adapted to uni-directionally engage the toothing structure. The scale drum is coupled rotationally locked but axially displaceable to the driver assembly, and is arranged to helically rotate relative to a housing during dose setting. The driver assembly comprises a reset portion adapted to engage the ratchet arm to release it from engagement with the toothing, thereby allowing the ratchet member and the driver assembly to be rotated in a second “dial down” direction opposite the first direction corresponding to an adjusted dose position. The ratchet member is coupled to the driver assembly with a rotational play, the play allowing the driver assembly with the reset portion to rotate in the second direction relative to the ratchet member (i.e. from a given position in which it is rotationally held corresponding to a set dose) to thereby release the ratchet arm from engagement with the toothing. The scale drum comprises a first stop surface adapted to engage a corresponding first stop surface associated with the housing, the first stop surfaces engaging each other corresponding to the initial position. By this arrangement it is prevented that the driver assembly in the initial position can be rotated in the second direction relative to the ratchet member corresponding to the rotational play. 
     In other words, by the above design of an “active” dial down mechanism the play needed to operate the active ratchet reset structure is positioned such that it is blocked with the driver assembly is in an initial position, the design allowing a dial up/dial down drug delivery having the same rotational increment between each user settable dose increment. 
     The driver assembly may comprise the dose setting portion adapted to be gripped and rotated by a user during dose setting and dose adjusting, e.g. in the form of a proximally arranged dose knob or ring as used on most known pen-formed drug delivery devices. 
     Biasing means may be arranged between the ratchet member and the driver assembly (e.g. a flexible portion of the ratchet member or of the driver assembly) to ensure that the rotational play is provided when the driver assembly with the reset portion is rotated, against the bias, in the second direction relative to the ratchet member to reset a set dose. Indeed, in the initial position resetting is blocked by the above-described stop surfaces. 
     The drive spring may comprise a proximal end connected directly or indirectly to the housing and a distal end connected directly or indirectly to the ratchet member. The drive spring may be in the form of a helically wound torque spring. 
     A clutch may be arranged between the dose setting portion and the remaining portion of the driver assembly. The clutch provides a non-rotational coupling between the dose setting portion and the remaining portion of the driver assembly during normal dose setting and dose adjusting operation, and allows the dose setting portion to be rotated in the second direction when a given torque is exceeded with the driver assembly in the initial zero position, thereby protecting the dose setting mechanism from being over-strained and thus damaged. 
     The scale drum may be provided with a second stop surface adapted to engage a corresponding second stop surface associated with the housing, the two second stop surfaces engaging each other corresponding to a maximum dose position in which the driver assembly can be set. 
     The drug delivery device may further comprise user actuated release means for releasing the driver assembly and the drive spring, the rotating driver assembly thereby driving, directly or indirectly, the piston rod in the distal direction corresponding to the set dose. The release means may comprise an axially displaceable clutch member coupled to the ratchet member, the clutch member comprising the toothing structure. Alternatively, the toothing structure may be arranged on e.g. an inner surface of the housing. 
     The expelling assembly may comprise a drive element in engagement with the piston rod and being adapted to be rotated by the driver assembly and spring to thereby drive the piston rod distally. For example, the piston rod may be connected rotationally locked but axially displaceable to the drive element, the drive element thereby rotating the piston rod distally via a threaded engagement with a non-rotational nut portion connected to the housing or formed integrally therewith. Alternatively, the driver may be arranged in threaded connection with the piston rod, the piston rod being arranged non-rotational but axially moveable through a nut bore. 
     The scale drum may be provided with an outer surface with a plurality of dose numerals arranged helically in a row, whereby a dose numeral corresponding to the set dose is shown in a housing window as the scale drum rotates helically relative to the housing during dose setting. The scale drum may be in threaded engagement with the housing, the housing inner surface comprising a helical thread, the scale drum outer surface comprising thread means adapted to engage the housing helical thread. 
     As used herein, the term “insulin” is meant to encompass any drug-containing flowable medicine capable of being passed through a delivery means such as a cannula or hollow needle in a controlled manner, such as a liquid, solution, gel or fine suspension, and which has a blood glucose controlling effect, e.g. human insulin and analogues thereof as well as non-insulins such as GLP-1 and analogues thereof. In the description of exemplary embodiments reference will be made to the use of insulin. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the following the invention will be further described with reference to the drawings, wherein 
         FIGS. 1A and 1B  show a front-loaded drug delivery device with respectively without a drug cartridge mounted, 
         FIGS. 2A and 2B  show detail views of the cartridge holder of  FIG. 1A  in an open respectively closed state, 
         FIG. 3  shows in an exploded view components of a pen device of the type shown in  FIG. 1A , 
         FIG. 4  shows in an exploded view a part of the components shown in  FIG. 3 , 
         FIG. 5A  shows in a sectional view a control track assembly, 
         FIG. 5B  shows in a perspective view the control track assembly, 
         FIGS. 6A-6C  show in perspective views a cartridge holder assembly in different operational states, 
         FIGS. 7A-7C  show in perspective views a coupling assembly in operational states corresponding to  FIGS. 6A-6C , 
         FIG. 8  corresponds to  FIG. 7A  with some structures removed, 
         FIGS. 9A and 9B  show in perspective views an alternative coupling assembly in different operational states, 
         FIGS. 10A and 10B  show components for a rotational brake for an expelling mechanism, 
         FIGS. 11A and 11B  show components for a further rotational brake for an expelling mechanism, 
         FIGS. 12A and 12B  show an alternative configuration for a front-loaded cartridge holder with and without a cartridge and needle assembly mounted, 
         FIGS. 13A and 13B  show control tracks for the cartridge holder of  FIG. 12B , 
         FIG. 14A  shows in detail slightly modified versions of the components shown in  FIG. 4 , and 
         FIG. 14B  shows the components of  FIG. 14A  in an assembled state. 
     
    
    
     In the figures like structures are mainly identified by like reference numerals. 
     DESCRIPTION OF EXEMPLARY EMBODIMENTS 
     When in the following terms such as “upper” and “lower”, “right” and “left”, “horizontal” and “vertical” or similar relative expressions are used, these only refer to the appended figures and not necessarily to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only. When the term member or element is used for a given component it generally indicates that in the described embodiment the component is a unitary component, however, the same member or element may alternatively comprise a number of sub-components just as two or more of the described components could be provided as unitary components, e.g. manufactured as a single injection moulded part. When it is defined that members are mounted axially free to each other it generally indicates that they can be moved relative to each other, typically between defined stop positions whereas when it is defined that members are mounted rotationally free to each other it generally indicates that they can be rotated relative to each other either freely or between defined stop positions. The terms “assembly” and “subassembly” do not imply that the described components necessarily can be assembled to provide a unitary or functional assembly or subassembly during a given assembly procedure but is merely used to describe components grouped together as being functionally more closely related. 
     Referring to  FIGS. 1A and 1B  a pen-formed drug delivery device  1  will be described. More specifically, the pen device comprises a cap part (not shown) and a main part having a proximal body or drive assembly portion  2  with a housing  40  in which a drug expelling mechanism is arranged or integrated, and a distal cartridge holder portion in which a drug-filled transparent cartridge  90  with a distal needle-penetrable septum  92  is arranged and retained in place by a cartridge holder assembly  3  mounted to the proximal portion. The cartridge may for example contain an insulin, a GLP-1 or a growth hormone formulation. The device is designed to be loaded by the user with a new cartridge through a distal receiving opening in the cartridge holder assembly, the cartridge being provided with a piston driven by a piston rod  80  forming part of the expelling mechanism. A proximal-most rotatable dose setting member  70  serves to manually set a desired dose of drug shown in display window  50  and which can then be expelled when the release button  81  is actuated. In the shown drug delivery device the expelling mechanism comprises a spring which is strained during dose setting and then released to drive the piston rod when the release button is actuated. Alternatively the expelling mechanism may be fully manual in which case the dose setting member and the release button moves proximally during dose setting corresponding to the set dose size, and then moved distally by the user to expel the set dose. The cartridge is provided with distal coupling means in the form of a needle hub mount  95  having, in the shown example, an external thread adapted to engage an inner thread of a corresponding hub of a needle assembly. In alternative embodiments the thread may be combined with or replaced by other connection means, e.g. a bayonet coupling. The shown exemplary hub mount further comprises a circumferential flange with a number of distally facing pointed projections serving as a coupling means for the cartridge holder assembly as will be described in more detail below. A hub mount of the shown type is described in U.S. Pat. No. 5,693,027. Alternatively the needle hub mount may be formed as part of the cartridge holder, e.g. in the form of a “split” hub mount having two parts arranged on each of the gripping shoulders, see below. 
     As shown, the cartridge holder assembly  3  has the same general appearance as a traditional cartridge holder which is detachably coupled to the housing by e.g. a threaded coupling or a bayonet coupling and into which a new cartridge can be received as well as removed through a proximal opening, i.e. it comprises no additional user operated release or locking means. Instead, what appears merely to be the cartridge holder per se is in fact user operated coupling means in the form of an outer rotatable tube member  10  operated by the user to control movement of cartridge holding means in the form of an inner cartridge holder member  30  (see  FIG. 2A ) to thereby open and close gripping shoulders  35  configured to grip and hold a cartridge. More specifically, the gripping shoulder  35  is provided with a plurality of gripping teeth  38  spaced circumferentially to provide a plurality of gaps, each tooth having a triangular configuration with a proximally oriented pointed end, thereby creating a plurality of gaps having a distally oriented pointed configuration, this allowing the above-described distally facing pointed projections on the cartridge to be received between the teeth  38  to thereby serve as a gripping means when the cartridge holding means has been moved into engagement with the cartridge. In this way an easy-to-use front loaded drug delivery device is provided which appears as a traditional rear loaded device and which is also actuated by rotational movement to mount and remove a cartridge, the resemblance providing for ease of acceptance and adaptation among users accustomed to traditional types of rear loaded drug delivery devices. 
     When it is time to mount a new cartridge the outer tube member is rotated e.g. 90 degrees by which action the gripping shoulders  35  are moved distally and slightly outwards, this allowing the mounted cartridge to be removed. For ease of operation the cartridge may be moved distally a certain distance as the shoulders are moved, e.g. by engagement with arms forming the gripping shoulders and/or by additional spring means providing a biasing distally directed force.  FIG. 1B  shows the device with the cartridge removed and the gripping shoulders in their un-locked “open” position in which a cartridge can be removed and a new inserted. Depending on the design of the locking and actuation mechanism the gripping shoulders may be able to be left in the open position or they may be retracted automatically as the outer tube member is rotated backwards by return spring means. Whether or not a spring is provided the cartridge holder may be provided with locking means allowing the outer tube member to be securely parked in either the open or closed position, e.g. by a rotational snap lock. When a new cartridge is inserted the drive expelling means has to be in a state allowing the piston rod to be pushed proximally by the piston of the new cartridge. An exemplary embodiment of a coupling mechanism providing this functionality will be described below. 
     The mechanical arrangement providing the above-described user-interface, i.e. rotation of an outer tubular sleeve member moves gripping shoulders in and out, can be provided in numerous ways. As shown in  FIGS. 2A and 2B  the cartridge holder  30  comprises two opposed flexible arms  31  extending from a proximal ring portion arranged in axially guided sliding and thus non-rotational engagement with the outer tubular sleeve member, each arm being provided with a gripping shoulder  35 . By this arrangement the gripping shoulders will rotate together with the outer tubular sleeve member and thus relative to the housing  40  as they are moved axially. In shown embodiment two opposed windows  32  are formed in the gripping member, one in each arm, each window being aligned with a corresponding window  12  formed in the outer tubular sleeve member, the two pairs of windows moving together in rotational alignment. Alternatively the gripping member and/or the outer tubular sleeve member may be manufactured fully or partly from a transparent material. Each gripping shoulder comprises an outer inclined and curved surface  37  adapted to engage a correspondingly curved distal actuation edge  17  of the outer tubular sleeve member  10 , as well as a pair of inclined edge portions  36  adapted to engage a pair of corresponding inclined actuation surfaces  16  arranged on the inner surface of the actuation sleeve. By this arrangement the inclined actuation surfaces  36  will force the gripping shoulders outwardly to their open position as the actuation surfaces  36  are moved distally and into sliding contact with the sleeve actuation surfaces  16 . Correspondingly, when the arms are moved proximally the outer curved surfaces  37  engage the actuation edges  17  and are thereby forced inwardly into their gripping position. 
     In alternative embodiments the gripping members may be arranged non-rotationally relative to the body portion  2 , just as the actuation sleeve may be arranged to be moved axially only or by a combination of axial and rotational movement. 
       FIG. 3  shows an exploded view of a pen-formed drug delivery device  101  of the type shown in  FIGS. 2A and 2B . As aspects of the invention relate to the working principles of such a pen, an exemplary embodiment of a complete pen mechanism and its features will be described, most of which are merely illustrative examples of features and designs adapted to work with and support the aspects of the present invention. The pen will be described as comprising three assemblies, a dose setting assembly  100 , a dose expelling and coupling assembly  200 , and a cartridge holder and housing assembly  300 .  FIG. 4  corresponds to  FIG. 3 , however, to provide a better detail view some of the components are not shown and the remaining components have been rearranged. 
     More specifically, the dose setting assembly  100  comprises a ratchet member  110 , a ratchet tube  120 , a reset tube  130 , a helical torque spring  139 , a scale drum  140  with an outer helically arranged row of dose numerals (not shown), a spring base member  150 , a button module  160 , a user-operated dial member  170  for setting a dose of drug to be expelled, and a release button subassembly comprising a button ring  181 , a button top window  182  and a button spring  180 . The button module may be in the form a simple mechanical member adapted to be incorporated in the described mechanical design, or it may be in the form of an electronic module adapted to detect relative movement between different members in order to provide an electronic dose logging feature, however, the latter module version is incorporated in the same way as the simple version. The button window is adapted to be used when the button module is in the form of a logging module having a proximally facing display. Otherwise the button ring and top may be manufactured as a single button member. The proximal end of the reset tube member  130  is adapted to be connected rotationally and axially locked to the distal tube portion of the button module  160 , however, this arrangement is mainly to allow the button part to be provided as a separate module, e.g. with or without electronic features. 
     Functionally, in an assembled state, the button module distal tube portion  161  is mounted axially and rotationally locked to the reset tube  130  which is mounted concentrically inside the ratchet tube  120 , the two tubes being axially and rotationally locked at their distal ends, the latter arrangement being mainly for the purpose of moulding and subsequent assembly of the two components. However, the split design also allows the two members to be connected similar to a universal joint via projections  134  on the reset tube received in openings  124  on the ratchet tube (see  FIG. 14A ), this providing a mechanism with improved kinematic mobility being less over-constrained. Thus, during dose setting the dial member  170 , the ratchet tube  120 , the reset tube  130  and the button module  160  are rotationally locked forming a driver assembly. 
     The ratchet member  110  is mounted axially locked on the reset tube but is allowed to rotate a few degrees (see below) by means of axial snap connection means  135  on the reset tube, this “play” being controlled by the control projection  113  arranged in a ratchet tube cut-out  123 . In this way a rotationally flexible connection is provided between the ratchet member and the reset tube, and thereby also between the ratchet member and the ratchet tube. More specifically, axially extending flexible arms  136  on the reset tube (see  FIG. 14A ) are received in the ratchet member, the flexible arms positioning the control projection  113  in the cut-out  123  such that there is no rotational play between the ratchet tube and the ratchet member during dose setting, however, during dose re-setting the ratchet member is allowed to move against the bias and corresponding to the rotational play provided between the projection  113  and the ratchet tube cut-out  123 . 
     The reset tube comprises on its inner surface two opposed longitudinal grooves  131  adapted to engage radial projections  286  of the EOC member (see below), whereby the EOC can be rotated by the reset tube but is allowed to move axially. A clutch member  290  with outer spline elements is mounted axially locked on the ratchet member; this providing that the ratchet tube via the ratchet member can be moved axially in and out of rotational engagement with the housing via the clutch member. The dial member  170  is mounted axially locked but rotationally free on the inner housing proximal end. During dose setting the dial member is rotationally locked to the reset tube via toothed engagement with the button module (see below), rotation of the dial member thereby resulting in a corresponding rotation of the reset tube and thereby the ratchet tube and ratchet member. The release button  181  is axially locked to the reset tube via the button module but is free to rotate. The return spring  180  provides a proximally directed force on the button and the thereto mounted reset tube. The scale drum  140  is arranged in the circumferential space between the ratchet tube and the inner housing, the drum being rotationally locked to the ratchet tube via cooperating longitudinal splines  121 ,  141  and being in rotational threaded engagement with the inner surface of the inner housing via cooperating thread structures  142 ,  202 , whereby the row of numerals passes window openings  203 ,  343  in the inner respectively outer housing (see below) when the drum is rotated relative to the housing by the ratchet tube. The proximal end of the scale drum comprises a stop surface  144  adapted to engage a corresponding stop surface  151  on the spring base member  150  to thereby provide a rotational stop for an initial (or end) rotational position, and the distal end of the scale drum comprises a further stop surface  143  adapted to engage a corresponding stop surface  205  on the proximal housing inner surface when the maximum dose has been reached during dose setting, e.g. 100 units of insulin (IU). The torque spring  139  is arranged in the circumferential space between the ratchet tube and the reset tube and is at its proximal end secured to the spring base member  150  and thus the housing and at its distal end to the ratchet member  110 , whereby the spring is strained when the ratchet member is rotated relative to the housing by rotation of the dial member. A ratchet mechanism with a flexible ratchet arm  111  is provided between the ratchet member and the clutch member, the latter being provided with an inner circumferential teeth structure  291  (or toothing), each tooth providing a ratchet stop such that the ratchet tube is held in the position to which it is rotated by a user via the reset tube when a dose is set. In order to allow a set dose to be reduced a ratchet release mechanism in the form of a release member  122  is provided on the ratchet tube and acting on the ratchet member to move it inwards and thereby out of engagement with the teeth structure, this allowing a set dose to be reduced by one or more ratchet increments by turning the dial member in the opposite second direction, the release mechanism being actuated when the ratchet tube is rotated the above-described few degrees of play relative to the ratchet member. Alternatively the release mechanism could be arranged on the reset tube. 
     The dose expelling and coupling assembly  200  comprises a fork member (or “slider”)  210 , a distal housing  220 , a ring member  230 , a compression spring  235 , a nut housing  240  comprising a central portion with a threaded nut bore  245 , a drive assembly comprising an outer drive member  250 , a coupling member  260  and an inner drive member  270 , a threaded piston rod  280  having an external thread  284  and two opposed longitudinal planar surfaces  283 , an end-of-content (EOC) member  285 , a piston rod washer  289 , a clutch member  290  and a proximal housing  201 . 
     Functionally, in an assembled state, the inner drive member  270  comprising a central bore with two opposed planar surfaces is mounted axially locked but rotationally free on the central portion of the nut housing  240  by means of a circumferential flange  244  (see  FIG. 8 ) surrounding the proximal opening of the nut bore and a pair of opposed gripping flanges  274  arranged on the distal end of the inner drive member. The central nut portion is carried in the nut housing by arm structures  246  (see  FIG. 8 ) providing openings through which the proximal-most part  214  of the fork element is arranged. The piston rod is arranged through the two aligned bores with the threaded bore  245  receiving the piston rod thread  284  and with the two opposed planar surfaces  273  of the inner drive member in engagement with the opposed planar surfaces  283  on the piston rod, whereby rotation of the inner drive member results in rotation and thereby distal axial movement of the piston rod due to the threaded engagement between the piston rod and the nut bore. On the piston rod the end-of-content (EOC) member  285  is threadedly mounted and on the distal end the washer  289  is axially mounted but rotationally free. The washer can be considered the part of the piston rod which is adapted to directly engage a cartridge piston. The EOC member comprises a pair of opposed radial projections  286  for engagement with the reset tube (see above). 
     The ring-formed outer drive member  250 , which is mounted axially locked but rotationally free in the nut housing, is in permanent rotational engagement with the ring-formed clutch member  290  by means of cooperating coupling structures, such that the engagement allows axial movement of the clutch member relative to the outer drive member. The outer drive member further comprises a pair of opposed circumferentially extending flexible ratchet arms  251  adapted to uni-directionally engage corresponding ratchet teeth  241  (see  FIG. 7A ) arranged on the nut housing inner surface. In the embodiment of  FIG. 4  the outer drive member is provided with a proximal supporting ring structure  256 . The clutch member is provided with outer spline elements  292  adapted to engage corresponding spline elements  204  on the proximal housing inner surface, this allowing the clutch member to be moved between a rotationally locked proximal position, in which the splines are in engagement with the inner housing, and a rotationally free distal position in which the splines are out of engagement with the inner housing. 
     Between the outer and inner drive members the ring-formed coupling member  260  is arranged, this providing that the drive assembly can be actuated between a resetting state (see below) in which the inner drive member and thereby the piston rod can be rotated relative to the outer drive member and thereby the nut housing, and an operational state in which the inner and outer drive members are rotationally locked to each other. The coupling member is mounted axially locked but rotationally free on the proximal end portion  214  of the fork member  210 , as well as rotationally locked but axially free on the inner drive member via cooperating spline structures  261 ,  271 . The coupling member comprises circumferentially arranged outer coupling teeth  262  adapted to be moved axially in and out of engagement with corresponding coupling teeth  252  arranged circumferentially on the inner surface of the outer drive member. By this arrangement the coupling member can be actuated via axial movement of the fork member between a proximal position in which the coupling member and outer drive member are rotationally disengaged, this corresponding to the resetting state, and a distal position in which the coupling member and outer drive member are rotationally engaged, this corresponding to the operational state. As will be described below, the fork member is actuated during user-operated cartridge change. 
     By providing a drive assembly with an “internal” coupling member as the axially actuated coupling component, it is possible to mount both the outer and inner drive members axially fixed as described above, this allowing e.g. the inner drive member in cooperation with the EOC member to serve as part of a safety system, this as described in WO 2007/017053. 
     The ring member  230  is mounted rotationally locked but axially free to the nut housing  240  and is biased distally by the compression spring  235 , the ring thereby providing a distally directed force on an inserted cartridge. The functionality of the ring member as well as the distal housing  220  will be described together with components of the cartridge holder and housing assembly. 
     The cartridge holder and housing assembly  300  comprises a cap member  360 , a user operated generally tubular actuation sleeve  310 , a ring-formed sleeve mount  320 , a cartridge holder  330 , and an outer housing assembly comprising a tubular housing member  340 , a magnifier lens  350 , and a clip member  355  also serving as a lens mount. The cartridge holder is adapted to receive and hold a generally cylindrical drug-filled cartridge  380  provided with distal coupling means in the form of a needle hub mount  385  having, in the shown example, an external thread adapted to engage an inner thread of a corresponding hub of a needle assembly. In alternative embodiments the thread may be combined with or replaced by other connection means, e.g. a bayonet coupling. The hub mount further comprises a circumferential flange with a number of distally facing pointed projections  388  serving as a coupling means for the cartridge holder assembly as will be described in more detail below. A hub mount of the shown type is described in U.S. Pat. No. 5,693,027. 
     Functionally, in an assembled state, the cartridge holder  330  is mounted rotationally locked but axially free inside the actuation sleeve  310  which is mounted axially locked but rotationally moveable to the sleeve mount  320  which again is mounted axially and rotationally locked to the distal housing. The fork member  210  is mounted rotationally locked but axially free to the cartridge holder by means of the two fork legs  219  being received in opposed slots  339  formed in the cartridge holder. As will be described in detail below the combined sleeve mount and distal housing provide an inner circumferential control track in which pairs of opposed lateral control protrusions  333 ,  213  of respectively the cartridge holder and the fork member are received, the track providing controlled axial movement of respectively the cartridge holder and the fork member when the two components are rotated relative to the track by means of the user rotating the actuation sleeve. The sleeve mount is further provided with two pairs of stop surfaces  329  (see  FIG. 5A ) adapted to engage corresponding lateral stop surfaces provided on a pair of control extensions  319  arranged on the proximal end of the actuation sleeve, the stop surfaces providing rotational stops for the actuation sleeve. 
     The cartridge holder comprises a pair of opposed flexible arms  331  extending from a proximal ring portion, each arm being provided with a distal gripping portion, or “jaw”,  335  having a plurality of proximal facing gripping teeth  338  spaced circumferentially to engage the above-described distally facing pointed projections  388  on the cartridge. A pair of longitudinally oriented opposed slots is formed between the arms, the slots each receiving a longitudinally oriented spline  314  formed on the inner surface of the actuation sleeve, this providing axially guided non-rotational engagement with the sleeve. Two opposed windows  332  are formed in the cartridge holder, one in each arm, each window being aligned with a corresponding window  312  formed in the outer tubular sleeve, the two pairs of windows moving together in rotational alignment. Corresponding to the embodiment of  FIG. 2B  each gripping portion  335  comprises an outer proximally-facing inclined and curved surface  337  adapted to engage a correspondingly curved distal circumferential edge  317  of the sleeve member  310 , as well as a pair of inclined distally-facing edge portions  336  adapted to engage a pair of corresponding inclined proximally facing actuation surfaces  316  arranged on the inner surface of the actuation sleeve. By this arrangement the inclined actuation surfaces  336  will force the gripping shoulders outwardly to their open position as the actuation surfaces  336  are moved distally and into sliding contact with the sleeve actuation surfaces  316 . Correspondingly, when the arms are moved proximally the outer curved surfaces  337  engage the actuation edges  317  and are thereby forced inwardly into their gripping position. As indicated above, axial movement of the cartridge holder is controlled by the cartridge holder control protrusions  333  being rotated in the control track by means of rotating the actuation sleeve. 
     As described above, the fork member is rotationally coupled to the cartridge holder via fork legs  219  and correspondingly rotates together therewith when the actuation sleeve is rotated, axial movement being controlled by the fork control protrusions  213  being received in the control track. To ensure that the piston rod is free to be pushed proximally during cartridge insertion, actuation of the cartridge holder between its receiving and gripping state and actuation of the drive coupling via the fork member take place in sequence. More specifically, in the shown embodiment full actuation of the cartridge holder takes place during a 60 degrees rotation of the actuation sleeve during which the fork member is not moved axially. When the cartridge thus has been properly locked in place and the piston rod correspondingly has been pushed to a corresponding proximal position, a subsequent 30 degrees further rotation of the actuation sleeve results in the drive coupling being actuated between the resetting state and the operational state by means of the fork member being moved distally during which the cartridge holder is not moved axially. In this way it is ensured to a high degree that the piston rod washer is positioned just in contact with the cartridge piston without build-up of tension in the system or creation of an air gap between the piston rod washer and the cartridge piston. 
     The ring member  230  comprises a ring portion, a pair of opposed radial guide protrusions  232  adapted to engage corresponding openings  242  in the nut housing, and a pair of opposed proximal protrusions  231 . The latter each has a distal surface  233  adapted to engage the proximal edge of an inserted cartridge, as well as a proximal stop surface adapted to engage a corresponding distal stop surface on the fork member. For that purpose the fork member comprises a pair of circumferential arms  212  each providing a distal stop surface. As appears, the ring portion which encircles the cartridge holder merely serves as a carrier for the different protrusions. To prevent a user inserting a cartridge too deep into the cartridge holder, the ring member is actuated between a receiving and an operational state. More specifically, when the cartridge holder is in the initial receiving state with the gripping portions  335  fully apart, the user will insert the cartridge against the biasing force provided by the ring member. However, to prevent the cartridge from being pushed too deeply into the cartridge holder, the fork member provides via the above-described stop surfaces a proximal stop for the ring member, the stop position corresponding to a position somewhat distally of the fully inserted position. As the user then starts to rotate the actuation sleeve and the gripping portions are moved proximally the fork member stop surfaces  212  are rotated out of engagement with the ring member which is then allowed to be moved to its operational position as the cartridge is moved proximally by means of the gripping portions. In a front-loaded drug delivery device such an arrangement helps ensure that a cartridge is not inserted too deeply during initial loading of a cartridge, i.e. it can be prevented that the user pushes the piston rod too far proximally when the cartridge is inserted and thereby creates an air gap between the piston rod and the cartridge piston in the operational state in which the cartridge is mounted in the cartridge holder and the piston rod is locked in its operational state. As appears, depending on the actual design of the control track, the locking arms may start move proximally before the stop surfaces are rotated out of engagement with the ring member, however, to avoid tension in the system, the ring member should be free to move proximally when the gripping arms engage the cartridge and start pulling it proximally towards the biasing force from the ring member. 
     To prevent the user from releasing the expelling mechanism before the actuation sleeve has been fully rotated to its operational position, the fork member also serves to prevent a set and strained expelling mechanism from being released. More specifically, until the drive coupling is in the operational state the proximal-most surface of coupling member mounted on the fork element serves as a stop for the ratchet assembly thereby preventing the clutch member from being moved distally out of engagement with the housing and thus released. A further mechanism preventing a user from releasing the expelling mechanism before a cartridge has been mounted will be described below with reference to  FIGS. 9A and 9B . 
     The outer housing  340  mainly serves to protect the interior components and to provide stiffness and an attractive outer appearance. Especially, the outer housing covers all the joints of the different inner housing parts. 
     Having described the individual components as well as the structural and functional relationship with reference to the exploded views of  FIGS. 3 and 4 , the functionality of certain subsystems will be described in greater detail with reference to  FIGS. 5-9  illustrating the structural and functional interaction between individual components. 
     More specifically,  FIG. 5A  shows in a sectional view a full 180 degrees half portion of the control track  221  responsible for axial movement of one cartridge holder control protrusion and one fork member control protrusion, the opposed other half of the control track being into engagement with the other two control protrusions. The control track is formed by the sleeve mount  320  and the distal housing  220  in combination.  FIG. 5B  shows in a perspective view a portion of the control track. The shown track portions comprise (reference numerals refer to the sleeve part of the track) a cartridge holder slope portion  321  on the sleeve mount, an intermediate axially equidistant portion  323 , and a fork member slope portion  324 . 
       FIGS. 6A-6C  illustrate in different operational states a cartridge holder assembly comprising the above-described cartridge holder  330 , fork member  210 , actuation sleeve  310 , sleeve mount  320 , and coupling member  260 . As described above, the actuation sleeve is rotatable mounted in the sleeve mount which is mounted to the distal housing  220  to thereby form the control track, the cartridge holder is axially displaceable mounted in the actuation sleeve with the control protrusions  333  arranged in the control track, the fork member is axially displaceable mounted in the cartridge holder with the control protrusions  213  arranged in the control track, and the coupling member  260  is rotatable mounted on the fork member distal end. When the actuation sleeve is rotated the cartridge holder and therewith the fork member are rotated as well as moved axially via engagement with the control track. As the coupling member is rotationally locked to the inner drive member  270  it does not rotate relative to the piston rod, however, as the piston rod is pushed proximally during cartridge loading the piston rod and thereby the coupling member will rotate relative to the housing. 
     During cartridge loading for the shown embodiment the following operations take place. With the cartridge holder in its receiving state with the gripping portions  335  fully apart and in their distal-most position a used cartridge can be removed and a new cartridge can be inserted, this at the same time providing that the piston rod, which initially is positioned corresponding to the position of the piston in the used cartridge, is pushed proximally. As shown in  FIG. 6A  the cartridge holder control protrusions  333  are positioned in the distal end of the cartridge holder slope portions, and the fork member control protrusions  213  are positioned in the intermediate track portions just next to the cartridge holder slope portions. 
     Actuation of the cartridge holder then takes place during a 60 degrees rotation of the actuation sleeve during which the gripping portions are moved inwards and retracted to their proximal-most holding position. In this intermediate state the cartridge has been properly locked in place and the piston rod correspondingly has been pushed to a corresponding proximal position. The fork member is not moved axially during this operation but merely rotates. More specifically as shown in  FIG. 6B , during the initial 60 degrees rotation of the actuation sleeve  310  the cartridge holder control protrusions  333  are moved proximally in the cartridge holder slope portions  321  and into the intermediate track portions  323  just next to the cartridge holder slope portions, and the fork member control protrusions  213  are moved in the intermediate track portions from just next to the cartridge holder slope portions to just next to the fork member slope portions  324 . 
     Actuation of the drive coupling then takes place during a further 30 degrees rotation of the actuation sleeve during which the fork member is moved to its distal-most position with the coupling member in engagement with the outer drive member  250 . The cartridge holder  330  is not moved axially during this operation but merely rotates. More specifically as shown in  FIG. 6C , during the further 30 degrees rotation of the actuation sleeve the fork member  210  control protrusions  213  are moved distally in the fork member slope portions  324 , and the cartridge holder control protrusions  333  are moved in the intermediate track portions  324  from just next to the cartridge holder slope portions  321  to the middle portion of the intermediate track portions  323 . In this way it is ensured to a high degree that the piston rod washer is positioned just in contact with the cartridge piston without build-up of tension in the system. 
     When a loaded cartridge is to be replaced the above-described operations are performed in the reverse order by rotating the actuation sleeve a full 90 degrees in the opposite direction, whereby first the drive coupling disengages and then the cartridge holder is moved from its proximal holding position to its distal receiving position. 
     Although  FIGS. 6A-6C  for illustrative purposes do not show the ring member  230 , it can be seen how the circumferential arms  212  of the fork member  210  is rotated during the initial cartridge holder actuation, thereby rotationally retracting the stop surfaces for the ring member, this allowing the biased ring member to be moved proximally by the cartridge. 
     With reference to  FIGS. 6A-6C  the combined actuation mechanism for the cartridge holder and the drive coupling was described. Next with reference to  FIGS. 7A-7C  the same operational states will be described focusing on the actual coupling elements per se. 
     More specifically,  FIG. 7C  (providing the best view of the components) illustrates a coupling assembly comprising the above-described fork member  210 , nut housing  240 , the drive assembly comprising the outer drive member  250 , the coupling member  260  and the inner drive member  270 , the threaded piston rod  280 , the EOC member  285  and the piston rod washer  289 . 
     As described above, the inner drive member  270  is mounted axially locked but rotationally free on the central portion of the nut housing  240  by means of the circumferential flange  244  (see  FIG. 8 ) surrounding the proximal opening of the nut bore and the pair of opposed gripping flanges  274  arranged on the distal end of the inner drive member. The piston rod is arranged through the two aligned bores with the threaded bore receiving the piston rod thread and with the two opposed planar surfaces  273  (see  FIG. 4 ) of the inner drive member in engagement with the opposed planar surfaces  283  on the piston rod. On the piston rod the EOC member  285  and the washer  289  are mounted. The outer drive member  250  is mounted axially locked but rotationally free in the nut housing with the flexible ratchet arms  251  uni-directionally engaging the ratchet teeth  241  arranged on the nut housing inner surface. 
     The coupling member  260  is mounted axially locked but rotationally free on the proximal end portion  214  of the fork member  210 , as well as rotationally locked but axially free on the inner drive member  270  via the cooperating spline structures  261 ,  271 . The coupling member comprises circumferentially arranged outer coupling teeth  262  adapted to be moved axially in and out of engagement with the corresponding coupling teeth  252  arranged circumferentially on the inner surface of the outer drive member. By this arrangement the coupling member can be actuated via axial movement of the fork member (as described above with reference to  FIGS. 6A-6C ) from a proximal position in which the coupling member and outer drive member are rotationally disengaged (see  FIG. 7A ), this corresponding to the resetting state, via the intermediate state in which the fork member has been rotated but not moved axially (see  FIG. 7B ), to a distal position in which the coupling member and outer drive member are rotationally engaged, this corresponding to the operational state as shown in  FIG. 7C . 
       FIG. 8  corresponds to  FIG. 7A , however, to better illustrate the mounting of the inner drive member  260  on the central nut portion via the above-described bearing structures  244 ,  274  the coupling member has been removed and the fork member  210  partially cut away. 
     With reference to  FIGS. 9A and 9B  an alternative configuration of the ring member  230  and the outer drive member  250  of  FIG. 4  will be described, the members having been modified to provide a lock against release of a set and strained expelling mechanism unless a cartridge has been loaded in the cartridge holder, irrespective of the state of the cartridge holding assembly. 
     More specifically, the ring member  430  comprises as the above-described ring member  230  a pair of opposed radial guide protrusions  432  adapted to engage openings in the nut housing, and a pair of opposed proximal protrusions  431 . A control arm  433  extends proximally from one of the lateral guide protrusion as is provided with an inner control protrusion  434 . The control arm is guided in a corresponding longitudinal slot in a modified nut housing (not shown). The outer drive member  450  comprises as the above-described outer drive member  250  a pair of opposed ratchet arms  451 , a plurality of coupling teeth  452  as well as a proximal supporting ring portion  456 , however, in addition a plurality of teeth structures  454  are arranged circumferentially on the outer distal surface, the equidistantly arranged teeth providing a plurality of gaps  455  each configured to accommodate the control protrusion  434 . When no cartridge is inserted in the cartridge holder the ring member and thereby also the control protrusion  434  is biased to its distal-most position by spring  235 , whereby as shown in  FIG. 9A  the control protrusion is seated between two teeth structures  454  thereby preventing rotation of the outer drive member. When a cartridge has been loaded in the cartridge holder the ring member and thereby also the control protrusion  434  has been moved proximally and out of engagement with the outer drive member. When the cartridge is removed the spring  235  will return the ring member to its initial position and thereby move the control protrusion into blocking engagement with the outer drive member as shown in  FIG. 9B . To facilitate seating of the control protrusion between the teeth both structures are provided with pointed surfaces on their facing ends. 
     With reference to  FIGS. 10A and 10B  an alternative configuration of the nut housing  240  and the outer drive member  250  of  FIG. 4  will be described, the modifications in combination with a further brake member  575  arranged between the two members providing a rotational brake for the expelling mechanism. 
     More specifically, the modified nut housing  540  comprises as the  FIG. 4  embodiment a central nut portion with a threaded bore  545  being carried in the nut housing by supporting arm structures  546 , circumferentially arranged ratchet teeth  541  on the nut housing inner surface and distal guide openings  542 . The main additional features of the modified nut housing is a circumferential flange with a proximal sliding surface  547  for the brake member  575  as well as a pair of opposed radial guide grooves  548  formed in the flange proximal surface and arranged generally corresponding to the location of the support arms  546 . The modified outer drive member  550  comprises as the  FIG. 4  embodiment a pair of ratchet arms  551  and a plurality of circumferentially arranged coupling teeth  552 , whereas the support ring portion  256  has been removed. The main additional feature of the modified outer drive member is an uneven number of circumferentially arranged brake teeth structures  558  arranged on the distally facing circumferential surface  557 . Each brake tooth has a general triangular configuration with an inner axially facing point, two neighbouring inclined surfaces (one of which serves as a brake surface  559 ), an outwardly facing base and a distally facing surface, the latter in combination forming a distal sliding surface for the brake member  575 . In combination the brake teeth form a radially oriented inwardly directed serrated surface structure. 
     The brake member  575  is in the form of a generally oval metal ring with a proximal (upper in  FIG. 10B ) sliding surface and an opposed distal sliding surface. On the distal surface is arranged a pair of radially oriented opposed guide portions  576  adapted to be arranged in the radial grooves  547  of the but housing. As the width of the brake member corresponding to the opposed guide portions is smaller than the inner diameter of the nut housing, the mounted brake member can slide back and forth corresponding to the guide grooves but cannot rotate. On the proximal surface and corresponding to the guide portions are arranged a pair of opposed brake protrusions  577  each having a general triangular configuration with an outwardly facing point, neighbouring first and second inclined surfaces (one of which serves as a brake surface  578 ) and an inwardly facing base. The brake protrusions are adapted to be received in the spaces between the teeth structures on the outer drive member. The brake member is further provided with a second set of proximally-facing opposed protrusions being offset 90 degrees relative to the brake protrusions and located corresponding to the inner edge of the oval ring, these protrusions merely adding stiffness and weight to the brake member. 
     In an assembled state the brake member  575  is mounted between the nut housing  540  and the outer drive member  550  with a slight axial play providing that mainly gravity will result in sliding contact between distal and proximal surfaces of the members, i.e. with the performed drug delivery device positioned vertically either the distal sliding surface of the brake member will slide on the flange proximal surface  547  or the proximal sliding surface of the brake member will slide on the distal sliding surfaces of the sliding surface of the brake member will slide on the flange proximal surface  558 . The distal surfaces of the brake member guide portions and the proximal surfaces of the brake protrusions are not in sliding contact with the guide grooves respectively the outer drive member distal surface. 
     The braking mechanism of  FIGS. 10A and 10B  works as follows: When the drive mechanism rotates driven by the released spring the outer drive member with the circumferentially arranged brake teeth rotates as well being part of the mechanism. For a brake protrusion positioned next to a brake tooth the contacting surface of the “leading” brake tooth will generate a tangential force on the brake member&#39;s contacting brake surface, and the nut housing will generate a corresponding reaction force on the opposite surface of the opposed guide portion. As the brake surface on the rotating part of the drive mechanism is inclined relative to a radial line towards the axis of revolution of the rotating part, and the contacting surface of the guide groove on the nut housing is parallel with a radial line towards the axis of revolution of the rotating part, the tangential force on the brake protrusion will result in radial movement of the brake member towards the centre axis corresponding to the guide grooves. 
     At some time the sliding brake surface on the brake member will lose contact with the brake surface on the rotating part because the tooth on the rotating part has limited length. However, after a short movement with no contact between the brake member  575  and the rotating part the opposed brake projection on the brake member will hit an inclined surface on a brake tooth on the opposite side of the rotating drive member  550 . Subsequently the rotating part will force the brake member to change direction and slide back in the opposite direction. This movement of the brake member back and forth will continue until the drive mechanism has stopped. 
     Because the brake member has a finite mass, it requires a certain force to make it accelerate and change direction of velocity. During normal operation of the device, when the drive mechanism rotates slowly, i.e. due to flow resistance of the drug being expelled through a narrow needle, the acceleration of the brake member is small and requires only little force. But when the drive mechanism rotates fast the braking effect is high due to brake member inertia as well as friction and impact generated heating of the components. 
     With no contact between the cartridge piston and piston rod, and with no other elements preventing the motion, the drive mechanism will continue to spin up until the force required to accelerate the brake member back and forth equals the force from the spring. The kinetic energy from the spring is lost in the brake due to acceleration of the brake member, sliding friction when the brake member slides between the rotating outer drive member and the nut housing, and to internal friction in the material when the brake member impacts on an opposing sliding surface and stops/changes direction of motion. 
     The amount of energy that is used to perform the linear movement of the brake member depends on the speed and the weight of the brake member (kinetic energy=½ mv 2 ). In the described embodiment the brake member  575  is formed from a polymer but could alternatively be formed from metal. Since the speed of the brake member is defined by the rotational speed of the drive mechanism and the angles of the inclined sliding surfaces, the amount of energy used for moving the brake member will increase when the rotational speed of the drive mechanism increases. 
     As described above the brake member generates a braking effect due to its inertia and due to friction and impact generated heating of the components. All these braking effects increase when the speed of the drive mechanism is high. Therefore the braking effect from the braking element will be much higher when there is no contact between the piston rod washer and the cartridge piston. 
     With reference to  FIGS. 11A and 11B  an alternative configuration of the brake assembly of  FIGS. 10A and 10B  will be described, the main difference being the incorporation of a plurality of relatively small metal brake members  675  instead of a single relatively large brake member. 
     More specifically, the nut housing  640  comprises as the  FIG. 10A  embodiment a central nut portion with a threaded bore  645  being carried in the nut housing by supporting arm structures  646 , circumferentially arranged ratchet teeth  641  on the nut housing inner surface, a circumferential flange with a proximal surface  647  and distal guide openings  642 . However, instead of only two guide grooves in the  FIG. 10A  nut housing a plurality of radial guide grooves  648  are formed in the flange proximal surface, each guide groove comprising opposed radial surfaces, one serving as a brake surface. The outer drive member  650  comprises as the  FIG. 10A  embodiment a pair of ratchet arms  651 , a plurality of circumferentially arranged coupling teeth  652  and a distally facing circumferential sliding surface  657  with a plurality of peripherally arranged outer brake teeth structures  658 . Further, a plurality of circumferentially arranged inner brake teeth structures  659  is provided, each brake tooth having a general triangular configuration corresponding to the outer brake teeth but with an outwards facing point, the inner teeth being arranged off-set relative to the outer teeth corresponding to the spacing between the latter. In combination the outer brake teeth form a radially oriented inwardly directed serrated surface structure and the inner brake teeth form a radially oriented outwardly directed serrated surface structure. 
     Each brake member  675  has a general cube form with four side surfaces, one of which serves as a brake surface  578 , a proximal (upper in  FIG. 11B ) sliding surface  676  and an opposed distal sliding surface. The four “corners” arranged perpendicular to the sliding surfaces are in the form of four inclined chamfers, two of which serve as brake chamfers  677  adapted to engage the brake surfaces of a brake teeth. 
     In an assembled state the brake members  675  are mounted between the nut housing  640  and the outer drive member  650 , each brake member being arranged in a corresponding guide groove  648  with a slight axial play providing that mainly gravity will result in sliding contact between distal and proximal surfaces of the members, i.e. with the pen-formed drug delivery device positioned vertically either the distal sliding surface of the brake member will slide on the proximal guide groove bottom surface or the proximal sliding surface  676  of the brake member will slide on the distal sliding surface  657  of the outer drive member. In the shown embodiment the opposed flange surfaces  657 ,  647  are arranged perpendicularly to the axis of rotation, however, alternatively they could be inclined, i.e. having a generally concave or convex configuration. Correspondingly, the orientation of the guide grooves could deviate from the shown strict radial orientation. 
     The braking mechanism of  FIGS. 11A and 11B  works as follows: When the drive mechanism rotates driven by the released spring the outer drive member will generate tangential forces on the brake chamfers on a number of the brake members, and the nut housing guide grooves will generate corresponding reaction forces on the opposed brake surface on the brake member. As the sliding brake surfaces on the outer drive member are inclined relative to radial lines towards the axis of revolution of the outer drive member, and the guide groove brake surfaces on the nut housing are parallel with radial lines towards the axis of revolution of the outer drive member, the tangential forces on the brake members will result in radial movement of the brake members (some of the brake members will move towards the centre axis and some will move away from the centre axis). Hereby the brake members slide on their brake chamfers  677  towards the outer drive member and on their brake surfaces  678  towards the nut housing. 
     At some time the brake chamfer on a given brake member will lose contact to the sliding surface (e.g. on the set of teeth on the outer circumference on the outer drive member), because the tooth brake surface on the outer drive member has limited length. However, after a short movement with no contact between the brake member and the outer drive member, the other side on the brake member will hit the sliding surface on the tooth on the opposite set of teeth of the outer drive member (e.g. on the set of teeth on the inner circumference on the outer drive member). Subsequently the outer drive member will force the brake members to change direction and slide in the opposed direction. This movement of the brake members will continue until the drive mechanism is stopped. 
     During the above-described operation of the braking mechanism as shown in  FIGS. 11A and 11B  essentially the same braking effects as was described above in respect of the braking mechanism as shown in  FIGS. 10A and 10B  will take place, the main difference being that a plurality of smaller brake elements are moved radially back and forth instead of a single larger brake element. 
     In the embodiments of  FIGS. 10A and 10B  the one or more brake elements are arranged non-rotational relative to the housing, however, alternatively the brake element(s) may rotate with the rotating component, the serrated surface structure being arranged on the housing and the guide structures being arranged on the rotating component. 
     As described above the scale drum  140  is in rotational threaded engagement with the inner surface of the inner proximal housing  201  via cooperating thread structures  142 ,  202 . 
     Whereas the proximal housing in the shown embodiment comprises a female thread in the form of an essentially complete helical groove  220 , the scale drum is merely provided with a male thread in the form of a thread structure arranged corresponding to the proximal end portion of the scale drum. The scale drum thread structure could be in the form of a single flange structure spanning e.g. 360 degrees or be divided into a number of discrete flange portions or projections, i.e. “groove guides”, engaging the helical groove. By arranging the scale drum outer thread structure at the end(s) only instead of circumferentially along the entire length of the drum it is possible to print the helically arranged rows of dose numerals closer to each other thereby allowing a shorter drum length for a given number of numerals. 
     Having described the different components of the expelling mechanism and their functional relationship as well as the operation of the cartridge holder and coupling, operation of the pen expelling mechanism will be described next with reference mainly to  FIGS. 3 and 4 . 
     The pen mechanism can be considered as two interacting systems, a dose system and a dial system. During dose setting the dial mechanism rotates and the torsion spring is loaded. The dose mechanism is locked to the housing and cannot move. When the push button is pushed down, the dose mechanism is released from the housing and due to the engagement to the dial system, the torsion spring will now rotate back the dial system to the starting point and rotate the dose system along with it. 
     The central part of the dose mechanism is the piston rod  280 , the actual displacement of the piston being performed by the piston rod. During dose delivery, the piston rod is rotated by the inner drive member  270  and due to the threaded interaction with the threaded nut bore  245  which is fixed to the housing, the piston rod moves forward in the distal direction. Between the rubber piston and the piston rod, the piston washer  289  is placed which serves as a bearing for the rotating piston rod and evens out the pressure on the rubber piston. As the piston rod has a non-circular cross section where the piston rod drive member engages with the piston rod, the inner drive member is locked rotationally to the piston rod, but free to move along the piston rod axis. Consequently, rotation of the inner drive member results in a linear forwards (i.e. distal) movement of the piston. The outer drive member  250  is provided with a pair of ratchet arms  251  which, via the coupling member  260 , prevent the inner drive member from rotating clockwise (seen from the push button end). Due to the engagement with the inner drive member, the piston rod can thus only move forwards. During dose delivery, the inner drive member rotates anti-clockwise and the ratchet arms  251  provide the user with small clicks due to the engagement with the ratchet teeth on the nut housing inner surface, e.g. one click per unit of insulin expelled. 
     Turning to the dial system, the dose is set and reset by turning the dial member  170 . When turning the dial member, the reset tube  130 , the EOC member  285 , the ratchet tube  120 , the ratchet member  110  and the scale drum  140  all turn with it. As the ratchet tube is connected to the distal end of the torque spring  139  via the ratchet member, the spring is loaded. During dose setting, the arm  111  of the ratchet performs a dial click for each unit dialled due to the interaction with the inner teeth structure  291  of the clutch member  290 . In the shown embodiment the clutch member is provided with  24  ratchet stops providing  24  clicks (increments) for a full 360 degrees rotation relative to the housing. The spring is preloaded during assembly which enables the mechanism to deliver both small and large doses within an acceptable speed interval. As the scale drum is rotationally engaged with the ratchet tube, but movable in the axial direction and the scale drum is in threaded engagement with the housing, the scale drum will move in a helical pattern when the dial system is turned, the number corresponding to the set dose being shown in the housing window  343 . 
     The ratchet  110 ,  291  between the ratchet tube  120  and the clutch member  290  prevents the spring from turning back the parts. During resetting, the reset tube moves the ratchet arm  111 , thereby releasing the ratchet click by click, one click corresponding to one unit IU of insulin in the described embodiment. More specifically, when the dial member is turned clockwise, the reset tube simply rotates the ratchet tube allowing the arm of the ratchet to freely interact with the teeth structures  291  in the clutch element. When the dial member is turned counter-clockwise, the reset tube interacts directly with the ratchet click arm forcing the click arm towards the centre of the pen away from the teeth in the clutch, thus allowing the click arm on the ratchet to move “one click” backwards due to torque caused by the loaded spring. 
     To deliver a set dose, the push button  181  is pushed in the distal direction by the user. The reset tube  130  decouples from the dial member as the toothed engagement  162 ,  172  between the dial member and the button module is moved axially apart (see below) and subsequently the clutch member  290  disengages the housing splines  204  and starts to rotate together with the outer drive member  270 . Now the dial mechanism returns to “zero” together with the clutch member, the drive members  250 ,  270  and the coupling member  260 , this leading to a dose of drug being expelled. It is possible to stop and start a dose at any time by releasing or pushing the push button at any time during drug delivery. A dose of less than 5 IU normally cannot be paused, since the rubber piston is compressed very quickly leading to a compression of the rubber piston and subsequently delivery of insulin when the piston returns to the original dimensions. 
     The EOC feature prevents the user from setting a larger dose than left in the cartridge. The EOC member  285  is rotationally locked to the reset tube, which makes the EOC member rotate during dose setting, resetting and dose delivery, during which it can be moved axially back and forth following the thread of the piston rod. When it reaches the proximal end of the piston rod a stop is provided, this preventing all the connected parts, including the dial member, from being rotated further in the dose setting direction by the spring, i.e. the now set dose corresponds to the remaining drug content in the cartridge. 
     The scale drum  140  is provided with a distal stop surface adapted to engage a corresponding stop surface on the housing inner surface, this providing a maximum dose stop for the scale drum preventing all the connected parts, including the dial member, from being rotated further in the dose setting direction. In the shown embodiment the maximum dose is set to 100 IU. Correspondingly, the scale drum is provided with a proximal stop surface adapted to engage a corresponding stop surface on the spring base member, this preventing all the connected parts, including the dial member, from being rotated further in the dose expelling direction, thereby providing a “zero” stop for the entire expelling mechanism. This said, the dial member may be provided with a torque limiter allowing it to be dialled past its normal stop position, see below. 
     To prevent accidental over-dosage in case something should fail in the dialling mechanism allowing the scale drum or the ratchet tube to move beyond their zero-position, the EOC member serves to provide a security system. More specifically, in an initial state with a full cartridge the EOC member is positioned in a distal-most axial position almost in contact with the inner drive element. After a given dose has been expelled the EOC member will again be positioned almost in contact with the inner drive element. Correspondingly, the EOC member will lock against the inner drive element in case the mechanism tries to deliver a dose beyond the zero-position. Due to tolerances and flexibility of the different parts of the mechanism the EOC will travel a short distance allowing a small “over dose” of drug to be expelled, e.g. 3-5 IU of insulin. 
     The expelling mechanism further comprises an end-of-dose (EOD) click feature providing a distinct feedback at the end of an expelled dose informing the user that the full amount of drug has been expelled. More specifically, the EOD function is made by the interaction between the spring base and the scale drum. When the scale drum returns to zero, a small click arm on the spring base is forced backwards by the progressing scale drum. Just before “zero” the arm is released and the arm hits a surface on the scale drum. 
     The shown mechanism is further provided with a torque limiter in order to protect the mechanism from overload applied by the user via the dial member. This feature is provided by the interface between the dial member  170  and the button module  160  which as described above are rotationally locked to each other during dose setting. More specifically, in the shown embodiment the dial member is provided with a circumferential inner teeth structure  172  engaging a number of corresponding teeth arranged on a flexible carrier portion  162  of the button module. The button module teeth are designed to transmit a torque of a given specified maximum size, e.g. 150-300 Nmm, above which the flexible carrier portion and the teeth will bend inwards and make the dial member turn without rotating the rest of the dial mechanism. Thus, the mechanism inside the pen cannot be stressed at a higher load than the torque limiter transmits through the teeth, this being the case for rotation in both directions. 
     With reference to  FIGS. 4-6  the combined actuation mechanism for the cartridge holder and the drive coupling was described. Next with reference to  FIGS. 12 and 13  an alternative cartridge holder mechanism will be described, the mechanism comprising blocking means configured to prevent the cartridge holder from being actuated between the closed and the open state when a cartridge  780  with a mounted needle assembly  790  is held in a mounted position as shown in  FIG. 12A . 
     With reference to  FIG. 4  a unitary cartridge holder  330  was described, comprising a pair of opposed lateral control protrusions  333  guided in a control track providing controlled axial movement of the cartridge holder when rotated relative to the track by means of the user rotating the actuation sleeve. Indeed, each control protrusion and the associated portion of the control track provide the same movement. 
     In contrast, in the embodiment of  FIGS. 12A and 12B  the cartridge holder has been divided lengthwise providing first and second cartridge holder members  730 ,  731 , the axial movement of each member being controlled independently by a control protrusion arranged in an associated portion of a control track formed by the sleeve mount  720  and the distal housing  721  in combination, the latter mounted to nut housing  740 . 
     Whereas the control protrusions on the two cartridge holder members may be identical, the corresponding two control track portions are different providing that the two cartridge holder parts can move axially independently of each other as the actuation sleeve  710  is rotated, this as shown in  FIG. 12B  in which only the gripping jaw  735  of the first cartridge holder member has been moved distally. 
     Turning to  FIG. 13A  the first control track portion  725  that controls the first cartridge holder member is designed with a first slope arranged to ensure that the first cartridge holder member moves relatively far distally during the first part of the rotation from the operational state towards the loading state. 
     Turning to  FIG. 13B  the second control track portion  726  that controls the second cartridge holder member is designed with a second slope arranged to ensure that the second cartridge holder member does not move distally during the first part of the rotation of the actuation sleeve from the operational state towards the loading state. This second cartridge holder member with its gripping jaw will therefore hold a loaded cartridge in the operational position during the first part of the rotation, this corresponding to the above-described embodiment. In  FIG. 13B  it can also be seen that the second slope on the guiding track starts “later” as compared to the first slope when the control protrusions on the two cartridge holder members (in the figures) are moved from left to right. 
     In a situation of use and with a loaded cartridge, both of the cartridge holder members are in their proximal-most position corresponding to an operational state, see  FIG. 1A  showing a cartridge held in a loaded position. When a needle assembly is mounted on the needle hub mount  95  of the cartridge, the proximal portion of the needle hub is positioned in close proximity to the distal-most portion of the gripping jaws. Turning to  FIG. 12B  showing a cartridge holder with no cartridge inserted, the actuation sleeve  710  has been rotated an amount resulting in the second cartridge holder member having been moved distally whereas the first cartridge holder member essentially has not been moved axially. Further rotation would then result in also the first cartridge holder member being moved distally, i.e. corresponding to  FIG. 1B . However, in case a needle assembly had been mounted on the cartridge hub mount the gripping jaw of the second cartridge holder member would engage the proximal-most edge of the needle hub, this preventing further rotation of the actuation sleeve due to the control protrusion of the second cartridge holder member arranged in the second control track portion blocking further rotation. By this arrangement the second cartridge holder member serves as a blocking member preventing the cartridge holding means from being actuated between the closed and the open state. 
     In an alternative embodiment (not shown), the blocking means could comprise a blocking member adapted to be moved to a blocking position when a needle assembly is mounted on a mounted cartridge, e.g. a rod member guided axially inside the actuation sleeve and serving to block the actuation sleeve when pushed proximally. This type of blocking means actuated when a needle assembly is attached could be considered as “active” in contrast to “passive” where the blocking means is prevented from moving due to a mounted needle assembly as in the embodiment shown in  FIGS. 12A and 12B . 
     With reference to  FIGS. 10 and 11  two versions of a brake assembly was described. As an alternative to a brake mechanism in a spring-driven drug delivery device in which the problem of undesired high speeds of components is an issue, an energy absorbing end-of-dose stop may be provided adapted to absorb and dissipate energy from an impact. 
     An end of dose stop made by polymers will normally be elastic up to a certain threshold level of impact force. If the impact force is lower than the threshold level the end of dose stop will deform elastically, i.e. no yield. However if the energy at impact is high due to high speed, the end of dose stop will deform plastically, with a reaction force substantially equal to the threshold force level. Since the reaction force from the end of dose stop is limited to the threshold level it limits the forces on the other components in the device, i.e. parts of the housing and parts of the drive mechanism and possibly parts of a sensor system. However the end of dose stop has been damaged due to the plastic yielding and may break. 
     Alternatively, an end of dose stop made by elastic metals will normally be able to withstand the energy at impact from the drive mechanism, even if it hits the end of dose stop at high speed. However the energy from the drive mechanism will lead to high forces, which will be counteracted with an identical reaction force. This reaction force will be transmitted to other components in the device, i.e. parts of the housing and parts of the drive mechanism and possibly parts of a sensor system. Therefore such an end of dose stop with elastic metal may result in other components being damaged. 
     However, with an end of dose stop made by a pseudo elastic material, e.g. shape memory alloys such as nickel-titanium, it is possible to combine the benefits without having the drawbacks from the two solutions described above. Springs made by pseudo elastic metals are known to have a normal elastic behaviour up to a certain threshold force level. If the impact force is lower than the threshold level the end of dose stop will deform elastically like the polymer end of dose stop described above. However, if the energy at impact is high due to high speed, the end of dose stop will deform with a reaction force substantially equal to the threshold force level. However since the end of dose stop is pseudo elastic it will be able to spring back without damage, even after a large deformation of the stop, i.e. with no yield. Since the reaction force from the end of dose stop is limited to the threshold level it limits the forces on the other components in the device. 
     In the above description of exemplary embodiments, the different structures and means providing the described functionality for the different components have been described to a degree to which the concept of the present invention will be apparent to the skilled reader. The detailed construction and specification for the different components are considered the object of a normal design procedure performed by the skilled person along the lines set out in the present specification.