NZ615855B2 - Dose setting mechanism and injection device - Google Patents

Abstract

Disclosed is a dose setting mechanism (1) for a resettable drug delivery device and an injection device. The present dose setting mechanism (1) allows a user to change or replace a cartridge containing medicament and to reset the dose setting mechanism (1) to an initial state. The dose setting mechanism (1) comprises a dose setting member (3); a drive member (4); a first clutch; spring means (7) and engaging means. The drive member (4) drives a piston rod in a distal direction during dose dispensing. The drive member (4) comprises a proximal drive member and a distal drive member (4’). The first clutch releasably couples the proximal and distal (4’) drive members. The spring means (7) biases the proximal and distal (4’) drive members in the coupled state during dose setting and dispensing. The engaging means are associated with the proximal drive member and the dose setting member (3). The engaging means comprises hooks provide on fingers protruding from the proximal end of the proximal drive member and a corresponding inwardly protruding flange on the proximal end of the dose setting member (3). The proximal drive member entrains the dose setting member (3) in the distal direction during dose dispensing but allows relative axial movement of the proximal drive member with respect to the dose setting member (3) in the proximal direction. nism (1) comprises a dose setting member (3); a drive member (4); a first clutch; spring means (7) and engaging means. The drive member (4) drives a piston rod in a distal direction during dose dispensing. The drive member (4) comprises a proximal drive member and a distal drive member (4’). The first clutch releasably couples the proximal and distal (4’) drive members. The spring means (7) biases the proximal and distal (4’) drive members in the coupled state during dose setting and dispensing. The engaging means are associated with the proximal drive member and the dose setting member (3). The engaging means comprises hooks provide on fingers protruding from the proximal end of the proximal drive member and a corresponding inwardly protruding flange on the proximal end of the dose setting member (3). The proximal drive member entrains the dose setting member (3) in the distal direction during dose dispensing but allows relative axial movement of the proximal drive member with respect to the dose setting member (3) in the proximal direction.

Description

Dose Setting Mechanism and Injection Device The present invention is ed to a dose setting mechanism for a drug delivery device, like a pe or, that provides for administration by injection of me- dicinal products from a multidose cartridge and where the user can select a variable dose of medicament in incremental steps or units from a given range of doses per- mitted by the device mechanism. The dose setting mechanism comprises a dose g member (e.g. a number sleeve) and a drive member (e.g. a drive sleeve). 1O Further components may be provided, for example a housing, a clutch and a clicker. r, the invention refers to an injection device with such a dose setting mecha- nism.

In more detail, the invention is directed to a dose setting mechanism for a resettable drug delivery device which uses a two part drive sleeve that should remain coupled during both dialing and se and which only les when the user presses on the piston rod to reset the device. A resettable drug delivery device allows the user to change or to replace a cartridge containing a medicament and to reset the dose setting mechanism to an initial state allowing dose setting and dose dispensing using the new cartridge.

In a reusable pen having a two piece drive sleeve, the two halves of the drive sleeve are d during both dialing and dispense but are decoupled to enable the piston rod to reset when a new dge is fitted. A potential failure mode of such a design is that if the attached needle is blocked, or if the user s to attach a needle, and the user attempts to dispense a dose by pressing a dose button, then the dose button will begin to advance, the number sleeve will begin to rotate (counting down- wards from the “set” dose) and the piston rod will begin to advance distally (in the direction of the cartridge), causing the deformable elements of the cartridge, for 3O example a rubber bung and/or a rubber septum closing the needle end of the car- tridge, to compress or deform until such time as the pressure from the cartridge bung against the piston rod becomes sufficient to resist the applied user force and the dispensing mechanism will then jam. This will typically occur within a few mm movement of the piston rod (i.e. within a few ” of the number sleeve display). The increased resistance to movement of the dose button, and the jamming of the dispense mechanism, alerts the user to the fact that the mechanism is not working correctly (i.e. the medicament is not being dispensed), even though the number sleeve will now be displaying a number less than the “set” dose (i.e. the number sleeve appears to display a “partially dispensed” dose). If the user then releases pressure on the dose button, the deformable elements of the cartridge will tend to return to their original state, causing pressure on the piston rod which will cause it to move proximally (in the direction of the dose setting ism) which will in turn cause the device to go into a reset mode which will relieve the pressure in the system and will enable the dispensing mechanism to operate again, with the user force required to start the dose button moving again, having returned to the normal operating value, i.e. before the jam occurred. During reset the number sleeve, which is not affected by the ing of the piston rod, will ue to display the “partially sed” dose. If the needle remains d, and, in an attempt to complete this undelivered or apparently partially delivered dose, the user repeats this cycle of pressing and releasing the dose button, whilst the device repeatedly jams and self-resets, the number sleeve will appear to be display that the device is dispensing medicament in stages of several units, with the number sleeve eventually returning to y zero units, i.e. the number sleeve appears to display a “completed dose”, when in fact no medicament is dispensed.

It is therefore an object of this invention to provide an improved and yet compact dose setting mechanism for a resettable pen device that removes this potential failure mode, or to at least e the public with a useful choice.

A first aspect of the present invention provides a dose setting mechanism for a drug delivery device, the mechanism comprising: a dose setting member, a drive member, for driving a piston rod in a distal direction during dose sing, the drive member sing a proximal drive member and a distal drive member, a first clutch for releasably coupling the proximal drive member and the distal drive member, spring means for g the proximal drive member and the distal drive member in the coupled state during dose setting and dose dispensing, and engaging means associated to the proximal drive member and to the dose setting member, characterized in that the engaging means se hooks ed on fingers protruding from the proximal end of the proximal drive member and a corresponding inwardly protruding flange on the proximal end of the dose setting member such that the proximal drive member entrains the dose setting member in the distal direction during dose dispensing but allows a relative axial movement of the al drive member with respect to the dose setting member in the proximal direction.

Comprises/comprising and grammatical ions f when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

A second aspect of the present invention provides an injection device comprising a dose setting mechanism according to the first aspect and a medicament which is preferably contained in a dge.

The dose setting mechanism of the present invention can be used in devices which use a two part drive sleeve that remains coupled during both dose dialing and dose dispensing and which only decouples when the user presses on the piston rod to reset the device e.g. replacing a cartridge. A dose setting mechanism according to the pre- sent invention comprises a dose setting , e.g. a number sleeve, a dose button, a drive member, e.g. a drive , for g a piston rod in a distal direc- tion during dose sing, a first clutch and spring means.

Typically, the drive member comprises a proximal drive member and a distal drive member which are releasably coupled via the first clutch. The spring means are designed for biasing the proximal drive member and the distal drive member in the coupled state such that during dose setting and dose sing relative rotation of the two parts of the drive member is not allowed. Preferably, the first clutch rotation- ally couples the proximal drive member and the distal drive member during dose setting and dose dispensing and rotationally decouples the proximal drive member and the distal drive member during resetting of the mechanism. The operation of the dose button by the user, e.g. during dispense, increases the compression of the spring means, and therefore ts decoupling of the clutch during dispense when a force is applied to the piston rod.

Further, engaging means are provided which are ated to the al drive member and to the dose setting member, respectively. Said engaging means are designed and arranged such that the proximal drive member entrains the dose setting member in the distal ion during dose dispensing but allows a relative axial movement of the proximal drive member with respect to the dose setting mem- ber in the proximal direction at all other times. If the mechanism is a resettable mechanism it is preferred that the engaging means, if applicable together with fur- ther means, allow a relative axial movement of the proximal drive member with respect to the dose setting member in the al direction only when a close but- ton for transmitting a dispensing force applied by a user to the mechanism is pressed during or following dose dispense, and resists relative axial movement when the dose button is not depressed during reset. In normal, non-dispensing, operation the proximal drive member and the dose setting member will be biased into contact at the engaging means by the force applied by the spring means. Ac- cording to a red embodiment of the invention, the engaging means may com- prise hooks provided on fingers protruding from the proximal end of the proximal drive member and a corresponding inwardly protruding flange on the proximal end of the dose setting member.

The above mentioned design of the dose setting mechanism allows the al half of the drive sleeve to move proximally with the distal half of the drive sleeve in the event that the close button is released with residual bung compression, e.g. during the potential failure mode of the user attempting to dispense medicament with a blocked needle. If both halves move together axially then they do not decouple and the device does not enter the reset mode thus avoiding the potential failure mode. In this case if a new, unblocked, needle is , then the spring means, which will have been further compressed by the proximal movement of both halves of the drive member, will cause the whole drive member to be driven distally again, dispensing medicament from the needle and relieving the compression in the cartridge, and restoring the correlation between the displayed dose on the number sleeve and the set dose in the mechanism.

Typically, the engaging means comprise a flange or protrusion provided on the proximal drive member and a corresponding flange or protrusion provided on the dose setting . Thus, the engaging means are integrally formed on the proxi- mal drive member and the dose setting , respectively. As an alternative, the engaging means may se separate components which are attached to the proximal drive member and/or to the dose setting member.

According to a preferred embodiment of the invention the dose setting mechanism further comprises a second clutch for releasably ng the drive member, pref- erably the proximal drive member, and the dose setting . Said second clutch may comprise a tubular t having at least one axial groove engaging a spline provided on proximal drive member. Thus, the second Clutch is rotationally fixed to the, e.g. proximal, drive member such that the drive member rotates during dose setting if the second clutch is rotated via the dose g member. The keyed engagement of the drive member and the clutch may be realized by more than a single pair of corresponding spline and groove.

By permitting relative axial movement of the proximal drive member with respect to the dose g member in the proximal direction, the device resetting ing an attempted dispense with a blocked needle is prevented. However, if both proximal and distal halves of the drive member were to move proximally during reset this would also prevent the device from being able to enter the reset mode when a new cartridge is fitted. This is because ng the reset mode requires that the proximal half of the drive sleeve is prevented from proximal axial nt whilst the drive sleeve distal end is decoupled by being driven proximally. Thus, according to a further aspect of the present invention, means are provided for restraining relative axial movement of the proximal drive member with respect to the dose setting mem— ber in the al direction during resetting of the . It is preferred to provide the at least one axial groove with a step which is located at a tion from a first portion of the groove having a smaller width to a second portion of the groove hav- ing a larger width, wherein the width of the spline is chosen to allow the spline to slide within both portions of the groove. The proximal half of the drive member and the second clutch are rotationally biased such that the spline is in contact with the side of the groove containing the step, i.e. the spline, and hence the proximal half of the drive member, is free to travel in the proximal or distal direction guided in the groove but resists further proximal movement when the end of the spline contacts the step. Thus, the step in the axial groove may prevent proximal movement of the proximal drive member during resetting. Resistance to al nt of the proximal half of the drive member is also provided by the frictional forces between the proximal half of the drive member and the second clutch. Under the action of normal resetting forces the resistance to proximal movement of the distal end of the drive member only needs to be sufficient to me the friction in the first clutch coupling the distal and proximal halves of the drive member.

Hence, the additional feature of the step overcomes a potential drawback of the device because axial movement of the proximal half of the drive member is pre- vented during normal device reset when the second clutch is coupled to the dose setting member, whereas, following an attempted dispense with a blocked needle, the second clutch, which is fixed to the close button, will have been moved distally during dispense, decoupling it from the dose setting member, and so the end of the spline will already be beyond the step of the groove. In the second instance the frictional forces between the proximal half of the drive member and the second clutch will actually assist, rather than resist, proximal movement of the proximal half of the drive . Further, in the second instance, the friction in the first clutch between the proximal and distal halves of the drive sleeve will be many times higher than in the normal reset case (because the force acting on the piston rod, and hence, via its threaded connection to the drive sleeve distal end, attempting to rotate the drive sleeve distal end resisted by the features of the first clutch, is much higher in the case of the cartridge with blocked needle compared to the normal reset force).

Therefore, the friction force in the first clutch is sufficient to ensure the proximal movement of the al half of the drive member without the first clutch becoming led.

In normal operation, when the user presses the dose , the step of the groove in the second clutch must pass the end of the spline on the proximal end of the drive sleeve. At this point the engaging means between the proximal half of the drive member and the dose setting member will prevent the distal movement of the proxi- mal half of the drive sleeve. The resisting force of the step in the second clutch groove and the friction of the second clutch on the proximal half of the drive sleeve will be small relative to the available user force on the close . The user may experience a small detent force on the dose button as the step passes over the end of the spline (which may also be an advantageous as it helps to provide ve tactile feedback to the close button and therefore helps to prevent accidental dis- pense).

The s in the second clutch and spline on the proximal drive member may be swapped over to achieve the same function.

Preferably, the dose setting mechanism according to the present invention r comprises means for biasing and/or holding the spline of the drive member in a defined angular position with respect to the groove of the clutch. This ensures that the steps in the clutch grooves engage with the ends of the drive sleeve proximal end splines so as to prevent the drive sleeve sliding proximally during reset.

According to a further development of this idea, the means for biasing and/or holding the spline comprise a clicker mechanism. Preferably, the clicker mechanism com— prises two clicker parts, each provided with corresponding toothed rings on ng end faces of the two clicker parts. r corresponding toothed rings may be pro- vided on the other end face of one of the clicker parts and on the ng face of the second clutch for releasably g the second clutch to the clicker. According to one embodiment, the first clicker part has two toothed ring on its end faces as biasing es ng the second clutch to the first clicker part and clicker fea— tures ably coupling the first clicker part to the second clicker part. The first clicker part is onally coupled to a housing component by means of external axial splines on the first clicker and internal axial grooves in the housing. Further, the second clicker part has an axial groove engaging an axial spline on the drive sleeve al end to rotationally couple these two components.

A potential ck of the above described design where the whole mechanism can move proximally relative to the dose setting member and the housing when the dose button is released after dispense with a blocked needle is that the user is subsequently unable to dial up or down, i.e. to amend the set dose. This is because in this condition the proximal drive member is proximally displaced relative to the second clutch and hence the spring means is compressed and therefore the first clicker part and second clicker part are rotationally locked together (as in the dis- pense condition), which in turn rotationally locks the proximal drive member to the housing. If in this situation the user applies excessive torsion to the dose setting member then, due to the small size of and limited engagement between the splines on the al drive member rotationally coupling it to the first clicker part (this limited engagement is due to the limited dose button travel), these splines could fail by plastic deformation, leading to subsequent device failure or dose errors.

A solution to this potential drawback is to form the splines and grooves engaging the proximal drive member and the first clicker part when the dose button is pressed as rounded splines / grooves. In this case, after dispensing with a d needle, if the user tries to rotate the dose setting member, the round splines and grooves will resist the on and the dialling torque will be significantly higher than the normal torque required to overcome the clicker teeth, and this should provide clear feed— back to the user that something is wrong and therefore not to continue to apply greater dialling torque. If the user nevertheless continues to try and dial, applying even greater torque, then, rather than deforming plastically, the rounded s will bump underneath the rounded grooves in the first clicker part and will not cause permanent damage to the .

In the needle blocked failure condition, and in the event that the user applies an excessive dialling torsion to the jammed mechanism such that the rounded splines and groove bump over as described, then the second clutch and hence close button will be engaged with the number sleeve and the device will dial up or down ly except for the very high dialling .

As mentioned above, the correct way to overcome this failure mode (i.e. attempting to dispense with a blocked needle) is to replace the blocked needle with a onal needle, allowing medicament to escape through the needle and relieving the com- pressive loads on the internal mechanism. If the user then proceeds to dispense by pressing on the dose button they will receive the dialled dose.

According to preferred embodiment of the present ion, the dose setting mem- ber comprises a dose dial sleeve (or number sleeve) which is rotatable relative to the housing to set a dose. r, the drive member may comprise a drive sleeve which is movable in a first axial direction relative to the housing member during dose setting and which is movable in a second axial direction relative to the housing member during dose dispensing, which second axial direction is te to said first axial direction. Preferably, the movement of the drive sleeve during dose setting includes a translational component and a rotational component, e.g. a movement along a helical path. During dose dispensing it is preferred that the drive sleeve moves only y, i.e. without any rotational components of the movement.

If the second clutch rotationally couples the dose setting member and the drive member during dose setting and rotationally decouples the dose g member and the drive member during dose dispensing, the drive member follows a move— ment of the dose setting member along a l path during dose setting while the dose setting member is allowed to rotate relative to the drive member during dose dispensing. It is an advantage that the dose setting mechanism requires less force during dose dispensing.

In the following, the invention will be described by a way of an example and with reference to the schematic drawings in which: Figure 1 shows a partial section of a dose g mechanism with a dose dialled and with the dose button pressed in (is in the dose dispensing mode), Figure 2 shows a partial section of the dose setting mechanism of Figure 1 after releasing the close button following an attempted close with a blocked needle (a dose is still dialled), Figure 3 shows an ed detail of the dose setting mechanism of Figure 1 (still with a dose dialled and with the dose button pressed in), Figure 4 shows a further enlarged detail of the dose setting mechanism of Figure 1 with a dose dialled and with the dose button ed (i.e. in the dose dialling mode), Figure 5 shows a further enlarged detail of the dose setting mechanism of Figure 4 Figure 6 shows a further enlarged detail of the dose setting mechanism of Figures 1, 2 or 3, Figure 7 shows as a sectional view an enlarged detail of the proximal drive mem- ber of the dose setting mechanism of Figures 1, 2 or 3, Figure 8 shows as a perspective view an enlarged detail of the proximal drive member of the dose setting mechanism of Figures 1, 2 or 3, Figure 9 shows a perspective view of the distal drive member of the dose g ism of Figure 1, Figure 10 shows a perspective view of a coupler of the dose setting mechanism of Figure 1, Figure 11 shows a perspective view of the proximal drive member of the dose setting mechanism of Figure 1, Figure 12 shows a perspective view of the second r component of the dose setting mechanism of Figure 1, Figure 13 shows a perspective view of the first r component of the dose setting mechanism of Figure 1, Figure 14 shows a perspective view of the second clutch element of the dose setting mechanism of Figure 1, and Figure 15 shows an exploded view of the components of an injection device.

Figure 1 shows a typical dose setting mechanism 1 of an injection device with a r mechanism. The dose setting mechanism comprises an (internal) housing member 2, a dose setting member 3 comprising a dose dial sleeve or number sleeve, a drive member 4 in the form of a drive sleeve, a tubular second clutch element 5 and a r 6. The second clutch element 5 is located n the dose setting member 3 and the drive member 4 and is rotationally coupled to the drive member 4 by means of at least one groove and corresponding spline. r, the second clutch element 5 is axially e relative to the dose setting member 3 for rotationally coupling and decoupling the dose setting member 3 and the drive mem— ber 4. As shown in Figures 1 and 14, the second clutch element 5 uses two sets of matching face teeth 5a, 5b which are provided on an inner end face of the close setting member 3 and a corresponding end face of the tubular second clutch ele- ment 5.

In the Figures, a dose setting mechanism is shown where the clicker 6 is split into two parts, first clicker component 6' and second clicker component 6" which are depicted in more detail in Figures 12 and 13. The first clicker component 6' is splined to the housing member 2 and therefore must be free to rotate ve to the drive member 4 and second clutch element 5 during dialing.

Clicker teeth 6a, 6b are provided in a similar manner as described above with re- spect to second clutch element 5, however the teeth 6a, 6b have a much wer angle compared to teeth 5a, 5b. These clicker teeth in conjunction with the coil spring 7, provide the detents for the dialed dose and the clicks for tactile and audible ck. In other words, clicker teeth 6a, 6b which are provided on first and second clicker element, respectively, are allowed to ride one over the other during dose setting. First clicker component 6' moves axially by only very small amounts (equal to the height of teeth 6d between the first r 6’ and second clutch 5) during dialing and therefore it can be rotationally locked to the drive member 4 after only a very small relative axial displacement and well within the axial engagement of the clutch teeth 5a, 5b.

The second clicker component 6" component is always rotationally coupled to the drive member 4 and shuttles axially, alternately compressing and uncompressing the clicker spring 7, as the clicker teeth 6a, 6b ride over one another during dialing.

The spring 7 further serves to provide the necessary axial force to engage clutch teeth 5a on second clutch element 5 (which is splined to the drive member 4 as explained below) with clutch features 5b on the number sleeve 3 at the end of a delivered dose and during subsequent dialing of the next dose. In this way the one spring 7 serves two functions.

The drive member comprises two components, a distal drive member 4’ and a proximal drive member 4”. As shown in Figure 9 the distal drive member 4’ may be provided with an internal thread engaging a threaded piston rod 8. The proximal drive member 4” which is shown in Figure 11 is a tubular element (drive sleeve) surrounded by the second clutch element 5 and the clicker mechanism 6. A coupler 4'" as shown in Figure 10 may be provided attached to distal half 4’ of the drive member providing a first clutch to rotationally couple the two drive sleeve halves 4’, 4” together during dialing and dose dispensing. The r and distal half 4’ are provided as separate components for manufacturing reasons only and, once fixed together during device assembly, on as one single component. The coupler 4'" is provided with teeth engaging corresponding teeth on the proximal half 4” of the drive member in the coupled state of the drive member 4, Le. during dose setting and dose dispensing, this defining the first clutch. During g the clicker spring 7 biases the two halves of the drive member into their coupled condition. r, the two halves of the drive member 4 may be decoupled for ing the device allowing the distal drive member 4’, which is threaded to the piston rod 8, to move ally under the action of the piston rod while the proximal drive member 4” remains fixed within the g 2 via its splined connection to the clicker mechanism and second clutch.

Figure 1 shows the device with a button 9 depressed during dose dispensing. This les the clutch teeth 5a, 5b between the second clutch element 5 and the number sleeve 3 and compresses the clicker spring 7. Whether or not the clicker spring 7 is compressed to a solid state, the load compressing this spring is sufficient to prevent the clicker face teeth 6a, 6b from disengaging under any dispense loads applied by the user to the button during dispense. These clicker face teeth 6a, 6b therefore rotationally lock the two clicker ts 6’, 6”. Since the dispense force is erred directly from spring 7 to the distal drive sleeve 4’, with the distal drive sleeve 4’ effectively pulling the distal drive sleeve 4” in the distal direction, there is no tendency for the first clutch to le the distal and proximal drive sleeve halves 4’, 4” during dispense. Further, as the first clicker 6’ is splined to the housing member 2 and the second r 6” is splined to the distal drive sleeve 4’, this effectively locks the entire drive sleeve 4 to the g member 2 in rotation.

The al drive member 4” has at its proximal end a flange 4a or collar engaging a corresponding flange or protrusion 3a of the number sleeve 3 to entrain same under the distal movement of the drive member 4” during dose dispensing. As de- picted in Figures 7 and 8 in more detail, the engaging means may comprise hooks 4a provided on fingers protruding from the proximal end of the al drive mem- ber 4" and a corresponding inwardly protruding flange 3a on the proximal end of the dose setting member 3.

Figure 2 shows what happens if the dose button is released whilst there is still a proximal axial force acting on the distal drive member due to compression of the cartridge bung, e.g. resulting from attempting to dispense with a blocked needle. In contrast to the distal direction, where flange 4a of the proximal drive member 4” entrains number sleeve 3, the proximal drive member 4” is free to move in the proximal direction relative to the number sleeve 3. In other words, the proximal drive member 4” is allowed to move proximally together with the distal drive member 4’ when the dose button is released with residual compression in the cartridge (eg. of the cartridge bung and septum). If both halves move together axially then they do not decouple and the device does not enter the reset mode. In this case if a new needle is fitted then the spring 7 will drive the drive sleeve in the distal direction, dispensing ment until the compressive forces in the cartridge have fully re- laxed.

It is preferred to provide an additional feature that allows the resetting of the device 1 when a new cartridge is , i.e. it is preferred to provide an additional feature which does not prevent axial movement of the proximal drive member 4” following dispense with a blocked needle but does block or limit this same nt during normal device reset (and also permits the distal movement of the second clutch 5 relative to the distal drive sleeve 4” during pressing of the dose button to initiate a normal dispense). In the first instance the second clutch 5 is decoupled from the number sleeve 3 and in the second case it is coupled, resulting in different relative axial positions of the second clutch 5 to the proximal drive member 4”. Therefore a feature placed between these two parts can be added to allow relative axial move- ment in the first instance but block or limit this nt in the second instance.

Such a e is shown in Figures 3 to 5 where the second clutch element 5 is keyed to the proximal drive member 4” by means of longitudinally directed splines 4b formed on the al drive member 4” engaging corresponding grooves 50 of the second clutch 5 to prevent relative rotation between the clutch member 5 and the drive member 4, while allowing relative longitudinal movement there between. In the grooves 50 steps 5d are ed so as to prevent proximal movement of the proximal drive member 4” only during normal reset. In other words, grooves 50 have a distal portion of larger width and a proximal portion of smaller width with the step 5d located at the tion between these two portions. Thus, depending on the axial arrangement of the spline 4b within the groove 50 proximal movement of the spline 4b is either stopped by step 5d or allowed guiding the spline 4b in the portion of the groove 50 with the smaller width. As an alternative the spline(s) 4b may be provided on the tubular t of the second clutch and the groove(s) 50 may be provided on the al drive member.

In order to ensure the step 5d in the second clutch groove 5c engages with the spline 4b of the drive sleeve al end 4” so as to prevent the drive sleeve slid- ing proximally during reset, the spline 4b on the drive sleeve must be biased into the step 5d in the second clutch. This is achieved through the angled faces of the toothed engagement of the second clutch 5 (teeth 5e) and the first clicker 6’ (teeth 6d), the toothed ment of the first and second clicker components 6’, 6” and the splined engagement of the second clicker 6” and the proximal drive member 4“.

In other words, the angled teeth (5e, 6d) between the first clicker 6’ will tend to intro- duce relative on between the second clutch 5 and proximal drive member 4”, within the limits of the fits of the other toothed or splined engagements, such that the spline 4b is biased towards the step 5d during resetting of the device, or whenever the user has released the close button.

To increase robustness of the clicker mechanism against user abuse, it is preferred to form the splines 40 of the proximal drive member 4” and/or the corresponding grooves 6c of the first clicker ent 6’, respectively, such that at least one of the splines 40 and the grooves (So has a rounded form or contour. ore when the parts are in the positions shown in Figure 2 after releasing the close button fol- lowing attempting to dispense with a blocked needle, if the user tries to rotate the dose g member 3, the dialling torque will be significantly higher than the normal torque required to overcome the clicker teeth 6a, 6b, and it should therefore be obvious to the user that something is wrong, eg. the needle is blocked and the mechanism is jammed. However, if the user continues to try and dial, the rounded splines are allowed to bump underneath the grooves in the first clicker part and will not be plastically deformed and ore will not cause permanent damage to the device.

As mentioned above, the correct way to overcome this 'misuse' failure mode is to e the blocked needle, which will relieve the cartridge pressure by releasing medicament through the needle. The user can then prime the device and deliver the required dose.

Summarizing, the proximal movement of the drive sleeve 4 (including the proximal portion 4", possibly a coupler and distal portion 4') is a safety feature designed to overcome a failure mode where the user applies a se force to the device without no needle (or a blocked needle) fitted. This creates very high forces in the device (eg. if the user s 8ON then a 2:1 gear ratio of a mechanism will deliver imately 160N to the dges rubber stopper). These high forces are sufficient to cause the rubber parts of the cartridge (stopper and septum) to deform elastically (like a giant spring). This deformation creates space for the spindle to advance by a couple of units (~approx 5-10 units) which in turn allows the number sleeve 3 to rotate back (so that the number sleeve now displays 5-10 units less than the ‘set’ close t any insulin having been dispensed).

When the user releases the force on the dose dial grip (not shown) the elastic forces in the cartridge press back against the bearing, which can cause the spindle to reset. However, the number sleeve 3 retains in now decreased number (approx. 5- units below the set dose). When the spindle moves back, resetting the device, the pressure in the cartridge is released. Therefore the entire process can be re- peated. With every ‘dose’ the number displayed in the close window by the number sleeve 3 will decrease by 5-10 units. Eventually the number sleeve 3 will return to 0 t any insulin having been dispensed.

The solution to the problem is to allow the entire drive sleeve 4 to move proximally (i.e. towards the close dial grip) when very high loads are applied to the spindle.

However, under normal resetting loads this is not desirable because if the entire drive sleeve 4 moves together proximally then the distal and proximal drive sleeves 4', 4" do not have relative axial movement and therefore do not disengage to allow reset. Under normal resetting loads (typically 2-4N) the proximal drive sleeve portion 4" must be prevented from moving proximally. To ensure that this happens the grooves 50 on the clutch 5, that engage ribs es 4b) on the proximal portion 4" of the drive sleeve 4, each have a small step 5d to provide a on force to resist nt of the proximal drive sleeve 4". The g force of the spring 7 and the shallow biasing teeth on the end of the first clicker component 6' ensure that the splines 4b of the proximal drive sleeve 4" are always rotated (biased) against the side of the clutch grooves 50 that contains this step 5d.

Under normal reset loads (2-4N) the only force tending to move the proximal drive sleeve 4" in the proximal direction is friction between the distal drive sleeve 4' (or its coupler) and proximal drive sleeve 4". In this instance al movement of the proximal drive sleeve 4" is also resisted by friction between the proximal drive sleeve 4" and the clutch 5, first and second clicker parts 6', 6", and the dose dial grip. Therefore the small steps 5d are advantageous.

When the user has attempted to dispense a dose with no needle fitted the dose dial grip has already been pressed in and therefore the clutch 5 and hence step 5d on the side of the clutch splines has already moved distally relative to the end of the proximal drive sleeve splines. Therefore when the user lets go of the dose dial grip, the drive s 4', 4" and clutch 5 plus dose dial grip can all move proximally together and will do so under the compressive force from the bung on the piston rod and hence distal drive sleeve 4'. So in this case the step 5d in the clutch is not rele- vant as there is no relative movement between the proximal drive sleeve and clutch.

The dose setting mechanism may be part of an injection device further sing a cartridge containing a medicament. The cartridge may be held in a cartridge holder which can be ently or releasably attached to the dose g mechanism.

The term ,,medicament“, as used herein, means a ceutical formulation con— taining at least one ceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, 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 com- pound, 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 ment the pharmaceutically active nd comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications ated 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 n-4 or an analogue or derivative of exendin-S or exendin-4.

Insulin analogues are for example Gly(A21), Arg(BSt), Arg(832) human insulin; Lys(B3), G|u(829) human insulin; Lys(828), Pro(829) human insulin; Asp(828) human insulin; human insulin, wherein proline in on B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position 829 Lys may be replaced by Pro; 6) human insulin; B-BBO) human insulin; Des(B27) human insulin and 0) human insulin.

Insulin derivates are for example BZQ-N—myristoyl—des(B30) human insulin; BZQ-N- palmitoyl-des(BBO) human insulin; BZQ-N-myristoyl human insulin; BZQ-N-palmitoyl human insulin; BZ8—N-myristoyl Pr0829 human insulin; B28-N-palmitoyl- LysBZBProB29 human insulin; BSO-N-myristoyl-ThrBZQLysBSO human insulin; B30- N-palmitoyl- ThrBZQLysBso human insulin; BZQ-N-(N-palmitoyl-Y-glutamyl)— des(BSO) human n; BZQ-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; BZQ-N-(w—carboxyheptadecanoyl)-des(BSO) human insulin and BZQ-N—(wcarboxyheptadecanoyl ) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the ce H-His- Gly-Glu-Gly-Thr—Phe-Thr-Ser-Asp-Leu-Ser—Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg- Leu-Phe-lle-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 Pr036, des Pr037 Exendin-4(1-39)-NH2, H-(Lys)5-des Pr036, des Pr037 Exendin-4(1-39)-NH2, des Pr036 Exendin—4(1—39), des Pr036 [Asp28] Exendin-4(1-39), des Pr036 [lsoAsp28] Exendin-4(1-39), des Pr036 [Met(O)14, Asp28] Exendin-4(1-39), des Pr036 [Met(O)14, IsoAsp28] Exendin-4(1-39), des Pr036 [Trp(02)25, Asp28] Exendin-4(1-39), des Pro36 [Trp(02)25, lsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14 Trp(02)25, Asp28] Exendin-4(1-39), des Pr036 [Met(O)14 )25, lsoAsp28] Exendin—4(1-39); or des Pr036 [Asp28] Exendin-4(1-39), des Pr036 p28] Exendin-4(1-39), des Pr036 [Met(O)14, Asp28] Exendin-4(1-39), des Pro36 [Met(O)14, lsoAsp28] Exendin-4(1-39), des Pr036 2)25, Asp28] Exendin-4(1-39), des Pr036 [Trp(02)25, IsoAsp28] Exendin-4(1-39), des Pr036 [Met(O)14 Trp(02)25, Asp28] Exendin-4(1-39), des Pr036 [Met(O)14 Trp(02)25, lsoAsp28] Exendin-4(1-39), wherein the group -Lys6—NH2 may be bound to the inus of the n-4 derivative; or an n-4 derivative of the sequence des Pro36 Exendin-4(1-39)-Lys6—NH2 (AVEOO10), H-(Lys)6-des Pr036 [Asp28] Exendin-4(1-39)-Lys6-NH2, des Asp28 Pr036, Pr037, Pr038Exendin-4(1-39)-NH2, )6-des Pr036, Pr038 [Asp28] Exendin-4(1-39)-NH2, H-Asn-(Glu)5des Pr036, ProS7, Pr038 [Asp28] Exendin-4(1-39)-NH2, des Pr036, Pr037, Pr038 [Asp28] Exendin-4(1-39)—(Lys)6—NH2, H-(Lys)6-des Pr036, Pr037, Pr038 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, (Glu)5—des Pr036, Pr037, Pr038 [Asp28] Exendin-4(1-39)-(Lys)6—NH2, )6-des Pr036 [Trp(02)25, Asp28] Exendin-4(1-39)-Lys6-NH2, H-des Asp28 Pr036, Pr037, Pr038 [Trp(02)25] Exendin—4(1-39)-NH2, H—(Lys)6—des Pro36, Pr037, Pr038 [Trp(02)25, Asp28] Exendin—4(1—39)—NH2, H—Asn-(Glu)5—des Pr036, Pr037, Pr038 [Trp(02)25, Asp28] Exendin—4(1—39)—NH2, des Pr036, Pr037, Pr038 [Trp(02)25, Asp28] n-4(1-39)-(Lys)6-NH2, H-(Lys)6—des Pr036, Pr037, Pr038 [Trp(02)25, Asp28] Exendin-4(1—39)-(Lys)6—NH2, H-Asn-(GIu)5-des Pr036, Pr037, Pr038 [Trp(02)25, Asp28] Exendin—4(1-39)-(Lys)6- NH2, H-(Lys)6—des Pr036 [Met(O)14, Asp28] Exendin—4(1-39)—Lys6—NH2, des Met(O)14 Asp28 Pr036, Pr037, Pr038 Exendin-4(1-39)-NH2, H—(Lys)6-desPr036, Pr037, Pr038 [Met(O)14, Asp28] Exendin-4(1-39)—NH2, H-Asn-(GIu)5-des Pr036, Pr037, Pr038 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, des Pr036, Pr037, Pr038 [Met(O)14, Asp28] Exendin-4(1-39)—(Lys)6—NH2, H-(Lys)6-des Pr036, Pro37, Pr038 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5 des Pr036, Pr037, Pr038 [Met(O)14, Asp28] n-4(1-39)-(Lys)6— NH2, H-LysB-des Pr036 [Met(O)14, Trp(02)25, Asp28] Exendin-4(1-39)-Ly56-NH2, H-des Asp28 Pr036, Pro37, Pr038 [Met(O)14, Trp(02)25] Exendin-4(1-39)-NH2, H—(Lys)6-des Pr036, Pr037, Pr038 [Met(O)14, Asp28] Exendin-4(’|-39)-NH2, H-Asn—(GIu)5—des Pr036, Pr037, Pr038 )14, )25, Asp28] Exendin—4(1— des Pro36, Pr037, Pr038 [Met(O)14, Trp(02)25, Asp28] Exendin-4(1-39)-(Lys)6- NH2, H-(Lys)6—des Pr036, Pro37, Pr038 [Met(O)14, Trp(02)25, Asp28] Exendin-4(S1-39)- (Lys)6-NH2, H-Asn-(GIu)5-des Pr036, Pr037, Pr038 [Met(O)14, Trp(02)25, Asp28] Exendin-4(1— 39)-(Lys)6-NH2; or a pharmaceutically acceptable salt or e of any one of the afore-mentioned Exendin-4 derivative. es are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, r 50, such as Gonadotropine tropin, 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 n or a deriva- tive thereof, or a sulphated, eg. a ulphated 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. dies are globular plasma proteins (~15O kDa) that are also known as immu- noglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each anti— body is an immunoglobulin (lg) monomer (containing only one lg unit); secreted antibodies can also be dimeric with two lg units as with lgA, tetrameric with four lg units like teleost fish lgM, or pentameric with five lg units, like mammalian lgM.

The lg monomer is a aped molecule that consists of four polypeptide chains; two cal 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 hain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called lg domains. These domains contain about 70-1 10 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 im— munoglobulin fold in which two [3 sheets create a “sandwich” shape, held together by interactions between conserved nes and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by or, 6, a, y, and u. The type of heavy chain present defines the isotype of antibody; these chains are found in lgA, lgD, lgE, IgG, and lgM antibodies, respectively.

Distinct heavy chains differ in size and composition; or and y contain approximately 450 amino acids and 6 approximately 500 amino acids, while u and s have approxi- mately 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 e, but differs in antibodies of different isotypes. Heavy chains y, d and 6 have a constant region composed of three tandem lg domains, and a hinge region for added flexibility; heavy chains u and a have a nt region ed 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 lg .

In mammals, there are two types of immunoglobulin light chain denoted by A and K.

A light chain has two successive domains: one constant domain (CL) and one vari- able domain (VL). The approximate length of a light chain is 211 to 217 amino acids.

Each antibody ns two light chains that are always identical; only one type of light chain, K or A, is present per antibody in mammals.

Although the general structure of all antibodies is very r, the unique property of a given antibody is determined by the variable (V) s, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Be- cause 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 de- termines the final antigen specificity.

An “antibody fragment” contains at least one antigen binding nt 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 ning one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but ning 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 ion yields a single 2 fragment containing both Fab pieces and the hinge region, including the H-H inter- chain 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'. er, the variable regions of the heavy and light chains can be fused together to form a single chain variable frag- ment (scFv).

Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCI 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: hy— drogen, an optionally tuted Cl-CB-alkyl group, an ally substituted C2- CB-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically accept- able salts are described in "Remington's Pharmaceutical Sciences" 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., USA, 1985 and in Encyclopedia of Pharmaceutical logy.

Pharmaceutically acceptable es are for example hydrates.

Reference numerals: dose setting mechanism housing member number sleeve (dose setting member) 3a protrusion drive sleeve (drive member) 4. distal drive member 4.. proximal drive member 4... coupler 4a flange 4b spline 40 spline (second) clutch member 5a, 5b clutch teeth 5c groove 5d step 5e angled teeth clicker 6a, 6b clicker teeth 6c groove 6d angled teeth 6' first r component 6" second clicker component clicker spring piston rod button

Claims (17)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. Dose setting mechanism for a drug delivery device, the ism comprising: a dose setting , a drive member, for driving a piston rod in a distal direction during dose dispensing, the drive member comprising a proximal drive member and a distal drive member, a first clutch for ably coupling the proximal drive member and the distal drive member, spring means for biasing the proximal drive member and the distal drive member in the coupled state during dose setting and dose dispensing, and engaging means ated to the al drive member and to the dose setting , wherein the engaging means comprise hooks provided on fingers protruding from the proximal end of the proximal drive member and a corresponding inwardly protruding flange on the proximal end of the dose setting member such that the proximal drive member entrains the dose setting member in the distal direction during dose dispensing but allows a relative axial nt of the proximal drive member with respect to the dose setting member in the proximal direction.

2. Dose setting mechanism according to claim 1, characterized in that the mechanism is a resettable mechanism further comprising a dose button for transmitting a dispensing force applied by a user to the mechanism, wherein the engaging means allow a relative axial movement of the al drive member with respect to the dose setting member in the proximal direction only when the dose button is pressed during or following dose dispense, and resists relative axial movement when the dose button is not depressed during reset.

3. Dose setting mechanism according to any one of the preceding , characterized in that the first clutch rotationally couples the proximal drive member and the distal drive member during dose setting and dose dispensing and rotationally decouples the proximal drive member and the distal drive member during resetting of the mechanism.

4. Dose setting mechanism according to any one of the ing claims, characterized in that, when the proximal drive member is not moved in the proximal direction with t to the dose setting member then the first clutch will rotationally decouple ting reset of the piston rod.

5. Dose g mechanism according to any one of the preceding claims r comprising a second clutch for releasably coupling the proximal drive member and the dose setting member, characterized in that the second clutch comprises a tubular element having at least one axial groove engaging a spline provided on proximal drive member.

6. Dose setting mechanism according to claim 5, characterized in that the at least one axial groove is ed with a step which is located at a transition from a first portion of the groove having a smaller width to a second n of the groove having a larger width, wherein the width of the spline is chosen to allow the spline to slide within both portions of the groove.

7. Dose setting mechanism according to claim 6, characterized in that the step in the axial groove prevents proximal movement of the proximal drive member during resetting.

8. Dose setting mechanism according to claim 5 or 6, further comprising means for biasing and/or holding the spline in an angular position with respect to the groove.

9. Dose setting mechanism according to claim 8, characterized in that the means for biasing and/or g the spline comprise a clicker mechanism for releasably coupling the second clutch and the proximal drive member during resetting of the mechanism.

10. Dose g mechanism according to claim 9, characterized in that the clicker mechanism ses two clicker parts, a first clicker part being rotationally releasably coupled to the clutch, a second r part being rotationally fixed to the proximal drive member and the two clicker parts being rotationally releasably coupled to each other.

11. Dose setting mechanism according to any of claims 9 or 10, characterized in that the first clicker part is rotationally fixed to the proximal drive member by a clicker spline engaging a ponding clicker , wherein the clicker spline and/or the clicker groove has a rounded e.

12. Dose setting mechanism according to any one of the preceding claims, characterized in that the second clutch rotationally s the dose setting member and the drive member during dose setting and rotationally decouples the dose setting member and the drive member during dose dispensing.

13. Dose g ism according to any one of the preceding claims, wherein the drug delivery device is a resettable drug delivery device.

14. Injection device comprising a dose setting mechanism according to any one of the preceding claims and a medicament.

15. Injection device according to claim 14, wherein the medicament is contained in a cartridge.

16. Dose setting mechanism for a drug delivery device, the dose setting mechanism substantially as herein described with reference to any embodiment shown in the accompanying drawings.

17. Injection device substantially as herein described with reference to any embodiment shown in the accompanying drawings.