WO2014029725A1

WO2014029725A1 - Drive mechanism for a drug delivery device with pivotable lever

Info

Publication number: WO2014029725A1
Application number: PCT/EP2013/067223
Authority: WO
Inventors: Axel Teucher; Michael Jugl
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2012-08-20
Filing date: 2013-08-19
Publication date: 2014-02-27

Abstract

The present invention relates to drug delivery and to a drive mechanism for such drug delivery device for dispensing of a dose of a medicament. The drive mechanism comprises: an elongated body (12; 102) extending in an axial direction (1, 2), a piston rod (36; 136) to engage with a piston (114) of a cartridge (112) containing the medicament and being movably disposed in axial direction (1, 2) with respect to the body (12, 102), at least one lever (16; 126) pivotally arranged relative to the body (12; 102), and at least one lever linkage (20; 120) operably engaged with the piston rod (36; 136) and pivotally connected to the lever (16; 126) for transferring a pivoting displacement of the lever (16; 126) into an axial displacement of the piston rod (36; 136).

Description

Drive mechanism for a drug delivery device with pivotable lever Description The present invention relates to a drive mechanism of a drug delivery device, in particular of an injection device, such like a pen-type injector. The drive mechanism has at least one pivotable or pivot-mounted lever for setting and/or dispensing of a dose of a medicament typically provided in a cartridge. Background and Prior Art

Drug delivery devices allowing for multiple dosing of a required dosage of a liquid medicament, such as liquid drugs, and further providing administration of the medicament to a patient, are as such well-known in the art. Generally, such devices have substantially the same purpose as that of an ordinary syringe. They may be designed as an injection device, e.g. as a pen-type injector.

Drug delivery devices of this kind have to meet a number of user specific requirements. For instance in case of those with diabetes, many users will be physically infirm and may also have impaired vision. Therefore, these devices need to be robust in construction, yet easy to use, both in terms of the manipulation of the parts and understanding by a user of its operation. Further, the dose setting must be easy and unambiguous and where the device is to be disposable rather than reusable, the device should be inexpensive to manufacture and easy to dispose. In order to meet these requirements, the number of parts and steps required to assemble the device and an overall number of material types the device is made from have to be kept to a minimum.

Typically, the medicament to be administered is provided in a cartridge that has a moveable piston or bung mechanically interacting with a piston rod of a drive mechanism of the drug delivery device. By applying thrust to the piston in a distal direction, a predefined amount of the medicament can be expelled from the cartridge.

Drug delivery devices of e.g. pen-injector type typically comprise a distal housing component that serves as a cartridge holder and further comprise a proximal housing component or body to engage with the distal housing component and being further adapted to accommodate a drive mechanism to operably engage with the cartridge for dispensing a predefined amount of the medicament provided therein. With drug delivery devices, such like pen-type injectors of disposable or reusable type a needle assembly comprising a needle hub and a double-tipped injection needle is to be removably arranged on a distal dispensing end of the housing of the drug delivery device. Typically, the distal end of the device may serve as a cartridge holder comprising an access opening to receive a proximally extending portion of the needle. The cartridge located in the distal housing portion or cartridge holder typically comprises a pierceable seal, such like a septum being penetrable by the injection needle. With many drug delivery devices of pen-injector type, a user has to depress a dose button, typically located at a proximal end section of the pen housing, in an axial distal direction. In practical use, the dose button is to be depressed by a user's thumb while the residual fingers of the same hand grip the housing of the drug delivery device. Furthermore, where an injection force is exclusively to be derived from a user-applied driving force, the handling of a proximal dose button can become problematic, in particular for users suffering side effects or being otherwise handicapped to appropriately depress the dose button.

Therefore, there is a need for alternative drive mechanisms for manually operated drug delivery devices, such like pen-type injectors.

Document DE 10 2005 026 129 A1 discloses an injection pen having a pivot mounted lever with a driving member near a pivot axis thereof. The driving member comprises a somewhat circular shaped toothed profile that meshes with a correspondingly toothed profile of a linearly displaceable driven member. The driven member is threadedly engaged with a piston rod. A lever-induced distally directed displacement of the driven member therefore transfers to a combined rotational and distally directed displacement of the piston rod. The mutual engagement of toothed surfaces requires a very accurate and precise design and/or assembly of the respective interacting components of the drive mechanism.

Geometric tolerances of the inter-engaging components as well as tolerances in the process of assembly may eventually lead to malfunction or to an operational heaviness when operating the lever. Moreover, a meshed engagement of mutually corresponding geared or toothed surfaces in close proximity to a pivot axis comes along with comparatively high mechanical loads that are due to by the leverage-effect of the pivoting lever. Objects of the Invention

It is therefore an object of the present invention to provide an alternative drive mechanism, wherein a dose- or injection-inducing component can be depressed also by other fingers than a thumb. It would be desirable to provide a drive mechanism which is operable by several fingers and/or by the palm of a user's hand. Here, it is a further aim to improve the general handling of a drug delivery device, especially of a pen-type injector, which should be easy to use and which should be intuitive in understanding and handling.

Additionally, the drive mechanism should be robust and reliable even in a long-term use. Furthermore, the drive mechanism and/or the respective drug delivery device should comprise a comparatively simple and low-maintenance structure. Moreover, the drive mechanism and the device should be cost-efficient to manufacture and to assemble.

Summary of the Invention

In a first aspect, a drive mechanism for a drug delivery device is provided, which is adaptable and operable for dispensing of a dose of a medicament. The drive mechanism comprises an elongated body extending in an axial direction. The body may be of arbitrary shape but preferably comprises a substantially cylindrical or tubular geometry. The body serves as a housing to accommodate various components of the drive mechanism which interact in such a way, that a well-defined dose or amount of a medicament can be set and subsequently dispensed from a container or cartridge at least partially filled with the medicament. The drive mechanism further comprises a piston rod, substantially extending in axial direction that serves to engage with a piston of a cartridge containing the medicament. The piston rod is movably disposed in the elongated body in axial direction with respect to said body. In particular, the piston rod is movably disposed in an axial and distal direction, hence to a dispensing end of the drive mechanism to exert a respective distally directed pressure to the piston of the cartridge. This way, the piston, which is movably arranged in a barrel of the cartridge, can be accordingly displaced in distal direction, thereby expelling a pre-defined amount or dose of the medicament therefrom. Accordingly, the proximal direction relates to the direction opposite the distal direction and faces away from the dispensing end of the drive mechanism of the drug delivery device, respectively.

The drive mechanism further comprises at least one lever pivotally arranged relative to the body. By means of the lever, a dispensing or injection force provided by a user of the device can be received and transferred into the drive mechanism as a driving force, which, at the end, is transferred into a distally directed displacement of the piston rod for expelling a dose of the medicament from the cartridge. The interconnection between the at least one lever and the piston rod is provided by at least one lever linkage which is operably engaged with the piston rod and which is pivotally connected to the lever. By means of the lever linkage, a pivoting displacement of the lever can be effectively transferred to a desired axial displacement of the piston rod.

Preferably, the axial displacement of the piston rod is a pure sliding motion induced by an inwardly directed pivoting of the at least one lever.

By means of the lever linkage, an axially directed component of the pivoting movement of the lever can be extracted and can be selectively transferred to a respective displacement of the piston rod in a rather direct and unaltered way. By means of the lever linkage, a direct control and feedback between the pivotally arranged lever and the piston rod can be provided. Moreover, by way of the lever linkage, mechanical forces and point loads inside the drive mechanism can be substantially reduced, thus allowing to implement rather filigree and delicate components of the drive mechanism. In effect, by means of the lever linkage between piston rod and lever, a down-sizing of the drive mechanism may be achieved.

In a preferred embodiment, the pivot axis of the at least one lever extends in a plane substantially perpendicular to the axial direction. Given that the body is of tubular or cylindrical shape, the pivot axis may extend in tangential direction with respect to the tubular-shaped body. Moreover, the pivot axis of the lever may coincide with the body and may be directly arranged at or in the outer circumference of the body. Here, it is also conceivable, that the body comprises a radially inwardly extending recess or a

comparative receptacle to receive the pivot-mounted lever. Additionally or alternatively, the pivot axis or the mounting point of the lever may be provided on or at an outwardly, e.g. radially outwardly extending protruding portion of the body. The at least one lever, which is preferably attached to the body may be pivoted between an initial state, in which the lever substantially co-aligns with the outer circumference of the body and an activated position or orientation, in which the lever is pivoted outwardly and at least partially protrudes from the body.

In a further preferred embodiment, the at least one lever linkage is pivotally connected to the at least one lever at a pre-defined distance from the pivot axis. By varying the distance of the connection point of the lever linkage from the pivot axis of the lever, a leverage effect of the lever-induced operation of the drive mechanism can be modified and controlled accordingly. By connecting the at least one lever linkage at a predefined distance from the pivot axis of the at least one lever, the ratio of the force exerted by a user to the axially directed driving force of the piston rod, which is derived therefrom, can be appropriately modified and optimized to provide a smooth operation of the drive mechanism, especially during dose dispensing.

In another embodiment, a proximal end of the lever linkage is pivotally connected with the at least one lever while an oppositely located distal end of the lever linkage is pivotally connected with a drive member. The drive member in turn is operably engaged with the piston rod to transfer a distally directed axial displacement of the lever linkage to the piston rod.

The lever linkage may comprise a single rod of rather straight and elongated shape.

However, in other embodiments, the lever linkage may also comprise a bended shape or may comprise a plurality of mutually connected and/or pivot-mounted links.

Here, it is of particular benefit, when the drive member is at least unidirectionally axially engageable with the piston rod in order to transfer a distally directed sliding displacement of the drive member into a corresponding distally directed sliding displacement of the piston rod. Preferably, the drive member and/or the at least one lever linkage is axially engaged with the piston rod in such a way, that at least a distally directed component of a movement of the lever linkage can be effectively and unalteredly transferred into a corresponding distally directed displacement of the piston rod.

This way, a rather direct control and feedback of the piston rod's movement can be provided. In a further preferred embodiment, the drive member axially abuts with the piston rod to transfer a lever-induced, distally directed displacement of the drive member directly and unaltered into a corresponding, distally directed displacement of the piston rod. Mutual axial abutment of the drive member and the piston rod may either take place at a single of at a plurality of pre-defined axial positions of the piston rod.

In a preferred embodiment the piston rod at least in sections comprises a toothed outer profile with a plurality of consecutively arranged teeth. Preferably, the toothed profile comprises a saw-toothed shape, such that a mutual relative displacement of drive member and piston rod is allowed in one direction but is blocked or locked in the opposite direction. A mutually engaging or interlocking configuration is provided when the drive member is displaced in distal direction relative to the body. Due to an interlock feature, said distal displacement of the drive member can be unalteredly transferred to a corresponding distal displacement of the piston rod.

In a further preferred embodiment, the drive member comprises at least one radially inwardly extending portion to engage with at least one tooth of the piston rod. The inwardly extending portion of the drive member preferably extends at a pre-defined angle inwardly and in distal direction so as to get in axial abutment configuration with a stop face of a tooth of the piston rod, which may extend in radial direction with regard to the axial elongation of the piston rod. The various consecutive teeth of the toothed profile of the piston rod may each comprise a bevelled surface extending from a radial inwardly directed position towards a radially outwardly protruding position in proximal direction, thereby forming the radial stop surface between a proximal outer portion of a first tooth and a radially inwardly located portion of a consecutive second tooth located proximally from the first tooth.

Preferably, the drive member acts as a ratchet, which is displaceable in proximal direction relative to the piston rod. Such proximally directed displacement is typically accompanied by a flexible deformation of the inwardly extending portion of the drive member.

Preferably, the drive member comprises a ring or an annular shape extending in a plane perpendicular to the axial direction. In such a configuration, the drive member preferably comprises a plurality of inwardly extending portions engaging with the teeth of the piston rod. In a further embodiment, the drive mechanism also comprises a stop element to limit a proximally directed displacement of the drive member relative to the body. By limiting the distally directed displacement of the drive member, the maximum angle, the lever can be lifted from its initial position can be modified. Accordingly, the position of the stop element has a direct impact on the activated position of the lever. Depending on the axial position of the stop element, the activated or pivoted orientation of the at least one lever may vary accordingly. By modifying and controlling the axial position of the stop element, the number of teeth along which the drive member can be proximally moved when displacing the lever from its initial into its activated position may vary. Preferably, the stop element is fixable to the body in well-defined discrete axial positions, which correspond with the size and the number of teeth of the piston rod.

In particular embodiments, there may be provided means to individually vary the axial position of the stop element in order to modify the size of the dose of the medicament while with other embodiments, the stop element is axially fixed to the body in a predefined position. This way, a drug delivery device with a fixed dose size can be provided.

Here, only a customer support of the drug delivery device or other authorized persons, like medical staff, may be enabled to modify the position and hence the dose size if required. Additionally, it is conceivable, that the particular drive mechanism is limited to only one pre-defined dose size. Varying the size of a dose to be dispensed may then require to make use of a differently configured drug delivery device.

In still another embodiment, the drive mechanism further comprises a blocking element axially fixed to the body and having at least one radially inwardly extending portion to engage with the piston rod and to impede a proximally directed displacement of the piston rod relative to the body. The blocking element may comprise a similar shape and geometry compared to the drive member. It may comprise a ring-like or annular shape and may entirely surround the toothed piston rod. The blocking element may also comprise inwardly extending slanted portions to engage with a stop face of consecutive teeth of the piston rod. However and in contrast to the drive member the blocking element is axially fixed to the body.

The mutual engagement of the blocking element and the piston rod is such, that a distally directed displacement of the piston rod relative to the body and/or relative to the blocking element is supported and allowed whereas the blocking element impedes and blocks a potential proximally directed displacement of the piston rod relative to the body and/or relative to the blocking element. This way, withdrawal of the piston rod into an initial configuration can be effectively prevented. Hence, the blocking element is particularly suitable for disposable drug delivery devices, when a reset of the drive mechanism, i.e. a proximally directed returning of the piston rod into an initial position should be effectively disabled.

Consequently, once a last dose configuration of a cartridge has been reached, a reset of the drive mechanism for replacing the empty cartridge by a filled one can be effectively prevented. In this way, the drive mechanism provides an effective means to antagonize product-counter fighting.

The above-described embodiment refers to a uni-directional engagement and mechanical coupling of the drive member and the piston rod to provide a ratchet-like drive mechanism. However, the lever-operated drive mechanism and the lever linkage may also support a bidirectional and permanent coupling of at least the lever linkage with the piston rod. Here, the piston rod, typically comprising a radially widened pressure foot at a distal end abuts with a piston of a cartridge positioned in a cartridge holder. A cartridge holder of the drive mechanism comprises an outer threaded shaft portion which is threadedly engaged with a distally located receptacle of the body. This way, the cartridge holder as a whole can be threadedly inserted in proximal direction into the body during setting of a dose of the medicament.

Also here, in an initial configuration or after dispensing of a previous dose, the piston rod with its pressure foot is in direct axial abutment with the piston of the cartridge. By displacing the cartridge holder in proximal direction further into the receptacle and into the body, the cartridge with its piston and the piston rod operably engaged therewith experiences a correspondingly directed proximal displacement relative to the body. This proximally directed displacement of the piston rod then induces an outwardly directed pivoting motion to the at least one lever linkage and the pivoting lever connected therewith. Here, the pivoting angle is directly correlated to the magnitude of the relative axial displacement between the cartridge holder and the body of the drive mechanism.

In this way, the pivoting lever is pivoted in an activated or outwardly pointing position, in which it can be gripped by a plurality of fingers or a palm of the hand of a user. By compressing the fingers and/or the palm in a fist-like configuration, the at least one lever is pivoted back into its initial configuration, thereby inducing an opposite, distally directed displacement of the piston rod relative to the body. Since the cartridge holder and the body and/or its receptacle remain axially fixed during such a dose dispending action, the piston of the cartridge then receives a corresponding distally directed displacement, thereby expelling a pre-defined amount of the medicament from the cartridge.

In a preferred embodiment, the threaded engagement of the cartridge holder and the receptacle of the body is of self-locking type. Hence, axially directed forces between cartridge holder and body do not lead to a rotation of the cartridge holder relative to the receptacle of the body. This way, it can be ensured, that cartridge holder and body remain mutually fixed during such a lever-induced dose dispensing.

In another aspect, the piston rod which is in axial abutment with the piston of the cartridge is displaced in proximal direction in response to a further or repeated proximally directed displacement of the cartridge holder relative to the body. During such a dose setting procedure, the proximally displaced piston rod induces an outwardly directed pivoting motion to the at least one lever linkage and hence to the at least one lever. Since axial relative displacement of cartridge holder and body is achieved by a threaded engagement, cartridge holder and body can be axially displaced in a rather continuous and stepless way.

Moreover, in the event that a set dose is too large, the dose size can be reduced even prior to an injection procedure by screwing the cartridge holder and body in an opposite sense of rotation. This way, the size of a set dose can be arbitrarily corrected prior to a dose dispensing or injection procedure.

According to another embodiment, the cartridge holder further comprises a radially widened socket near its distal end. The socket comprises a stop face which is intended to axially abut with a rim of the body's receptacle in a final dose position. When the proximally positioned stop face of the socket of the cartridge holder abuts with the receptacle or a surrounding rim of the body, a further relative rotation of screwing of the cartridge holder into the body is effectively impeded. Preferably, mutual abutment of the stop face with the receptacle coincides with a configuration of the cartridge, wherein the cartridge's piston approaches a distal or outlet end of the cartridge, i.e. when the medicament contained in the cartridge is typically used up.

With all embodiments as described above not only a single lever with a single lever linkage but a plurality of levers and lever linkages may be used. Preferably, two diametrically or oppositely disposed levers and respective lever linkages may be implemented and used in order to transfer lever-pivoting induced forces in a rather homogeneous and smooth way into an axial displacement of the piston rod. Also in terms of handling of the drive mechanism, a two-fold lever- and lever linkage-arrangement might be beneficial. However, in principle, the drive mechanism may work and may be

implemented with one lever and one lever linkage only.

In another independent aspect, a drug delivery device, such like a pen-type injector is provided which comprises a drive mechanism as described above. Moreover, the drug delivery device also comprises a cartridge being filled with a medicament. The cartridge typically comprises a tubular barrel made from a vitreous or plastic material and having a pierceable seal at a distal end thereof. At an opposite end, an axially displaceable piston, which seals the inner volume of the cartridge, is provided, by way of which the

medicament contained therein can be expelled via the distally provided seal when pierced or penetrated by an injection needle or when otherwise connected with a fluid transferring structure.

The term "drug" or "medicament", as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a 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 compound, wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP- 1 ) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.

Insulin analogues are for example Gly(A21 ), Arg(B31 ), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin;

human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28- B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N- palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-

ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; Β29-Ν-(ω- carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(oo-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1 -39), a peptide of the sequence H-His-Gly-Glu- Gly-Thr-Phe-Thr-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 Pro36, des Pro37 Exendin-4(1 -39)-N H2,

H-(Lys)5-des Pro36, des Pro37 Exendin-4(1 -39)-N H2,

des Pro36 Exendin-4(1 -39),

des Pro36 [Asp28] Exendin-4(1 -39),

des Pro36 [lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, lsoAsp28] Exendin-4(1 -39); or des Pro36 [Asp28] Exendin-4(1 -39),

des Pro36 [lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, lsoAsp28] Exendin-4(1 -39),

wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; or an Exendin-4 derivative of the sequence

des Pro36 Exendin-4(1 -39)-Lys6-NH2 (AVE0010),

H-(Lys)6-des Pro36 [Asp28] Exendin-4(1 -39)-Lys6-NH2,

des Asp28 Pro36, Pro37, Pro38Exendin-4(1 -39)-N H2,

H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1 -39)-NH2,

H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1 -39)-N H2,

des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1 -39)-(Lys)6-N H2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1 -39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1 -39)-(Lys)6-NH2,

H-(Lys)6-des Pro36 [Trp(02)25, Asp28] Exendin-4(1 -39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Trp(02)25] Exendin-4(1 -39)-N H2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-N H2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-N H2, des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Met(0)14, Asp28] Exendin-4(1 -39)-Lys6-NH2,

des Met(0)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1 -39)-N H2,

H-(Lys)6-desPro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-NH2, des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Lys6-des Pro36 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)-Lys6-N H2,

H-des Asp28 Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25] Exendin-4(1 -39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-N H2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)- NH2,

des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25, Asp28] Exendin-4(S1 -39)- (Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)- (Lys)6-NH2; or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned

Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (~150kDa) that are also known as

immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-1 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 immunoglobulin fold in which two β sheets create a "sandwich" shape, held together by interactions between conserved cysteines and other charged amino acids. There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.

Distinct heavy chains differ in size and composition; a and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (C_H) and the variable region (V_H). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, a and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 1 10 amino acids long and is composed of a single Ig domain.

In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 21 1 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.

Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.

An "antibody fragment" contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab')2 fragment containing both Fab pieces and the hinge region, including the H-H interchain disulfide bond. F(ab')2 is divalent for antigen binding. The disulfide bond of F(ab')2 may be cleaved in order to obtain Fab'. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. 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: hydrogen, an optionally substituted C1 -C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10- heteroaryl group. Further examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences" 17. ed. Alfonso R. Gennaro (Ed.), Mark

Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

It will be further apparent to those skilled in the pertinent art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. Further, it is to be noted, that any reference signs used in the appended claims are not to be construed as limiting the scope of the present invention.

Brief Description of the Drawings

In the following, preferred embodiments of the invention will be described by making reference to the drawings, in which:

Fig. 1 shows a first embodiment of a drive mechanism for a drug delivery device in cross section with lifted or activated levers, Fig. 2 illustrates the drive mechanism according to claim 1 with the levers in an initial configuration after a dose dispensing procedure,

Fig. 3 perspectively illustrates another embodiment of a drive mechanism,

Fig. 4 shows the embodiment according to Fig. 3 in an exploded view,

Fig. 5 illustrates a perspective view of the drive mechanism with a partially removed body,

Fig. 6 shows the device according to Fig. 5 in longitudinal cross section,

Fig. 7 perspectively illustrates the drive mechanism during a dose setting procedure,

Fig. 8 shows the device according to Fig. 7 in longitudinal cross section,

Fig. 9 shows a longitudinal cross section of the device according to Fig. 8 after dose dispensing,

Fig. 10 shows the configuration of the device with a cartridge holder in a last dose position,

Fig. 1 1 shows the device configuration according to Fig. 10 in a longitudinal cross

section and

Fig. 12 is illustrative of a final configuration of the drive mechanism after dispensing of a last or final dose from a cartridge.

Detailed Description

Fig. 1 is illustrative of a drive mechanism of a drug delivery device 10 comprising a tubular shaped body 12. Inside the elongated body, which extends in an axial direction, which is characterized by a distal direction 1 and an opposite proximal direction 2, a piston rod 36 is disposed. The piston rod 36 is adapted to engage with a piston 1 14 of a cartridge 1 12 filled with a medicament to be dispensed. Apparently, such a cartridge 1 12 is only disclosed in the embodiment according to Figs. 4 to 12. With the embodiment according to Figs. 1 and 2, a cartridge 1 12 is to be axially secured relative to the body 12. The drive mechanism as shown in Figs. 1 and 2 comprises two oppositely located levers 16 being pivotally arranged at the outer circumference of the body 12. A comparison of the configurations according to Figs. 1 and 2 reveals, that the levers 16 can be pivoted with respect to a pivot axis 14, which substantially extends in a plane perpendicular to the axial direction 1 , 2. Hence, the levers 16 may be pivoted outwardly from a configuration as shown in Fig. 2 to reach an activated configuration with a slanted orientation as shown in Fig. 1 . The two levers 16 are substantially symmetrically shaped and comprise a stopper 18, preferably of polymeric or elastic material, by way of which a defined abutment with the outer circumference of the body 12 can be realized, as shown in Fig. 2. The levers 16 comprise a substantially straight and elongated shape but may also comprise a bended or curved shape, which might be advantageous from an ergonomic point of view.

At a particular distance from the pivot axis 14 a lever linkage 20 is pivotally arranged and connected to the respective lever 16. Here, a respective pivot axis 22 extends

substantially parallel to the pivot axis 14 of the lever 16. With its opposite end, the lever linkage 20 is pivot mounted and pivotally connected with a drive member 48. Also there, the pivot axis 24 by way of which the lever linkage 20 and the drive member 48 are pivotally interconnected may extend substantially parallel to the pivot axis 14 and/or to the pivot axis 22.

The drive member 48, which may either comprise a plurality of separate elements or which may comprise a ring substantially surrounding the piston rod 36 is axially displaceable with respect to the body 12. Such axial displacement of the drive member 48 in either distal direction 1 or proximal direction 2 can be governed and is typically accompanied by a respective pivoting of the lever and/or of the lever linkage.

As illustrated in Figs. 1 and 2, the body 12 comprises a recessed portion or a through opening 26, e.g. in form of a longitudinal slit, through which the lever linkage 20 extends from the outside located lever 16 into the body 12.

By comparing the configurations of Figs. 1 and 2 it is apparent, that a distally directed displacement of the drive member 48 can be induced by lifting the outer levers 16 from their initial configuration as shown in Fig. 2 into a lifted or activated configuration according to Fig. 1 . Since the pivot axis 14 of the lever 16 is arranged proximal compared to a distal free end of the lever 16, lifting of the lever 16 is accompanied by a respective outwardly and proximally directed displacement, hence a combined rotational and longitudinal displacement of the lever linkage 20. Since the drive member 48 is somewhat restrained-guided inside the body, only the proximally directed component of the movement of the lever linkage 20 is transferred into a linear movement of the drive member 48. The drive member 48, which may resemble a ratchet disc, further comprises radially inwardly and distally pointing protrusions 50, which engage with consecutive teeth 38 of the piston rod 36.

Moreover, there is provided a blocking element 28 at a distal end section of the body 12. The blocking element 28 may comprise a similar or even identical shape and geometry compared to the drive member 48. However, in contrast to the drive member 48, the blocking element 28 is axially fixed to the body 12. In effect, both components, the blocking element 28 and the drive member 48 may be designed and may comprise a kind of a ratchet nut. The various teeth 38 of the piston rod 36 comprise a saw-toothed profile. Hence, each tooth 38 comprises a bevelled or slanted side face 40 or shank, which extends from distal 1 to proximal direction 2 radially outwardly. At the end of each tooth 38 there is provided a socket portion having a radially inwardly extended stop face 42.

As illustrated in Figs. 1 and 2, a distal and radially inwardly extended portion of the protrusions 30, 50 of the blocking element 28 and the drive member 48 engage with the stop face 42 of a particular tooth 38. Since the blocking element 28 is axially fixed to the body 12, a proximally directed displacement of the piston rod 36 relative to the body 12 is substantially blocked and impeded. The drive member 48 however may be displaced in proximal direction 2 with regard to both, the body 12 and the uni-directionally fixed piston rod 36. Such proximally directed displacement of the drive member 48 can be achieved by lifting the outer levers 16 from their initial configuration according to Fig. 2 to their lifted configuration according to Fig. 1 .

During a proximally directed displacement of the drive member 48, the radially inwardly and distally extending protrusions 50 thereof mesh with consecutive teeth 38 of the piston rod 36, which cannot move in proximal direction 2 due to the engagement with the blocking element 28. Once arrived in the activated configuration of Fig. 1 , a user may apply radially inwardly directed pressure to at least one or to both radially protruding levers 16. This way, the drive member 48 being uni-directionally engaged with the piston rod 36 induces a correspondingly directed distal displacement of the piston rod 36 relative to the body 12. Since the mutual engagement of the blocking element 28 and the piston rod 36 allows for a distally directed displacement of piston rod 36 relative to the blocking element 28 and/or relative to the body 12, the piston rod 36 can be driven in distal direction 1 , thereby exerting a respective distally directed pressure to a piston 1 14 of a cartridge 1 12 for expelling the medicament therefrom.

The ratchet-like mutual engagement of the piston rod 36 with the drive member 48 and/or with the blocking element 28 allows to dispense discrete amounts of the medicament wherein the various discrete steps correlate with the axial size of the teeth 38 of the piston rod 36.

The drive mechanism according to Figs. 1 and 2 also comprises a stop element 44, which may comprise a sleeve-like or tubular shape. The stop element 44 is disposed proximal to the drive member 48 and serves as a limiting element for the axiall displacement of the drive member 48. As shown in Fig. 2, the stop element 44 comprises a distally located stop face 46, which, in the configuration according to Fig. 1 abuts with a proximal stop face 52 of the drive member 48. By axially fixing the stop element 44 inside the body 12, a proximally directed displacement of the drive member 48 can be limited during a dose setting procedure. The stop element 44 may therefore serve as a maximum dose limiting feature.

In preferred embodiments, the stop element 44 may be displaceably arranged at various axial positions in the body 12. This way, the maximum dose to be set with the present drive mechanism can be varied. However, such axial variations of the stop element should only be conducted by authorized staff or by trained customer service but not by the patient or user of the device himself.

The drive mechanism and the device 10 as indicated by Figs. 1 and 2 is particularly adaptable for repeatedly or regularly dispensing doses of equal size. Hence, this embodiment is suitable for a fixed dose drug delivery device, such like a fixed-dose pen- type injector. The embodiment according to Figs. 3 to 12 differs from the drive mechanism according to Figs. 1 and 2 in that oppositely located levers 1 16 are permanently and non-releasably connected to a piston rod 136. The device 100 or its drive mechanism as illustrated in Fig. 3 comprises a body 102, a distally located grip 1 10 as well as a cartridge holder 104 mounted at a distal end of the body 102.

As illustrated in Fig. 4, the cartridge holder 104 serves to receive a tubular shaped cartridge 1 12 having a piston 1 14 slidably disposed therein and sealing the interior volume of the cartridge 1 12. A cartridge, which may comprise a vial or a carpule further comprises a pierceable seal or a septum 1 13 as indicated in Fig. 6. As further illustrated there, the distally located head of the cartridge 1 12 is located inside a stepped down and threaded neck portion or socket 108 of the cartridge holder 104. The outer thread of the socket 108 is adapted to threadedly receive a correspondingly shaped needle assembly having a needle hub with a corresponding and mating inner thread and further having a double- tipped needle, which by assembly of the needle assembly onto the threaded socket 108 penetrates the septum 1 13, thereby gaining access to the inner volume of the cartridge 1 12.

As becomes apparent from the sequence of Figs. 5 to 12, the cartridge holder 104 comprises a threaded shaft 106 which is threadedly engaged with a receptacle 134 of the body 102. This way, the entire cartridge holder 104 with the cartridge 1 12 assembled therein can be screwed into the body 102 as becomes apparent from a comparison of e.g. Fig. 5 and Fig. 10. This way, the piston rod 136 having a distally located pressure foot 139 and being in direct abutment with the proximal end face of the piston 1 14 of the cartridge 1 12 experiences a proximally directed displacement as illustrated in Fig. 7 when the cartridge holder 104 is screwed into the body 102 in proximal direction 2.

The piston rod 136 comprises an axially extending pin or head at its proximal end as illustrated in Fig. 4. By way of this pin, the piston rod can be axially engaged with a drive member 122, such that the piston rod 136 during a dose setting and during a screwing motion of the cartridge holder 104 relative to the body 102 may freely rotate with respect to its longitudinal axis in the drive member 122. The drive member 122 further comprises radially extending lobes 132 that form a hinge-like interconnection with a lever linkage 120. Hence, as shown in Figs. 4 to 12, the lever linkage 120 is pivot mounted to the drive member 122 with a distal end portion. With its opposite proximally extending end portion, the lever linkage 120 is pivotally connected with a proximal end portion of the lever 1 16. For this purpose, the oppositely located levers 1 16 comprise radially inwardly extending support structures 146 that form a hinge-joint with the proximal end of the two lever linkages 120.

Moreover, the outer levers 1 16 are pivotally connected to the receptacle 134 which comprises an annular structure with diametrically oppositely disposed radially outwardly extending protruding portions 132. The levers 16 comprise a correspondingly shaped bracket 130 at their distal end to mate and to receive these protrusions 132. By making use of a pivot pin 128, the levers 1 16 are hinge-joint with the receptacle structure 134. Moreover, as becomes apparent from Fig. 4, the body 102 comprises an upper cover 1 18 and a lower cover 1 19. The two covers 1 18, 1 19 comprise a number of through openings 140 at their distally located edge, by way of which the two covers 1 18, 1 19 can be assembled with correspondingly shaped protruding pins 138 provided around the outer circumference of the receptacle structure 134.

Moreover, as further illustrated in Figs. 5 and 7, the oppositely disposed support structures 146 are directly mutually interconnected via a tension spring element 142, which in the event of a dose setting procedure provides a radially inwardly directed counter force to keep the oppositely disposed levers 1 16 in a well-defined configuration.

Since in an initial configuration as shown in Figs. 6 and 9 the lever linkages 120 are slightly tilted or slanted and extend somewhat radially outwardly in proximal direction, a proximally directed displacement of the piston rod 136 will lead to a respective spreading of the lever linkages 120, thereby pivoting the outer levers 1 16 from their initial

configuration, as for instance illustrated in Fig. 6 into an activated and radially outwardly extending configuration as for instance shown in Fig. 7.

This displacement of the piston rod 136 acts against the tension of the spring element 142. Moreover, since the proximally directed displacement of the piston rod 136 is induced by a proximally directed displacement of the cartridge holder 104 with the cartridge 1 12 disposed therein, it is beneficial, that the friction forces between the cartridge's 1 12 side walls and the piston 1 14 are larger than the mechanical resistance required to push the piston rod 136 and the levers 1 16 into the activated configuration as shown in Fig. 8. As soon as the activated configuration according to Fig. 8 has been reached, a user may apply radially inwardly directed forces or pressure to the oppositely disposed levers 1 16, thereby inducing a distally directed displacement of the piston rod 136 relative to the receptacle 134 and relative to the cartridge holder 104. In this context it is to be mentioned, that the threaded engagement of the threaded shaft 106 of the cartridge holder 104 and the receptacle 134 of the body 102 is of self-locking type. Hence, applying a distally directed force to the piston 1 14, cartridge 1 12 and consequently onto the cartridge holder 104 does not lead to a rotative counter-directional displacement of cartridge holder 104 and body 102, respectively.

This way, it can be ensured, that a distally directed and a pivot-induced displacement of the piston rod 136 is unalteredly transferred to the piston 1 14 of the cartridge 1 12.

By comparing the configurations according to Figs. 6 and 9 it is apparent, that after a first dose dispensing as illustrated in Fig. 9, a proximally located edge 105 of the threaded shaft 106 of the cartridge holder 104 has been displaced in proximal direction 2 when compared to the configuration of Fig. 6. Since the configuration of the drive mechanism, in particular of the piston rod 136, the lever linkages 120 and the outer levers 1 16 is identical in Figs. 6 and 9 the piston 1 14 of the cartridge 1 12 has moved in distal direction relative to the cartridge 1 12 in Fig. 9.

Furthermore, it is to be mentioned, that the threaded shaft 106 of the cartridge holder 104 terminates at a proximally facing stop face 144 adjacent a gripping structure of the cartridge holder 104. The stop face 144 is adapted to engage with the outer rim of the receptacle 134 when a last dose configuration, as illustrated in Fig. 10, is reached. Once the stop face 144 abuts with the receptacle structure 134 and/or with the body 102, a further proximally directed displacement of the cartridge holder 104 relative to the body 102 and/or relative to the receptacle 134 is no longer given.

As shown in Fig. 1 1 , this last dose configuration coincides with a position of the piston 1 14 close to a distal head- or outlet portion of the cartridge 1 12. When the stop face 144 gets in axial abutment with the body 102, the levers 1 16 cannot be pivoted any further radially outwardly. After applying a radially inwardly directed force or pressure to the levers 1 16, as shown in Fig. 1 1 , a final or terminal configuration of the drug delivery device 100 can be attained in Fig. 12. As indicated there, the piston 1 14 is near a distal outlet of the cartridge 1 12 and the medicament disposed in the cartridge 1 12 may have been almost completely dispensed from the cartridge 1 12. List of Reference Numerals

1 distal direction

2 proximal direction 10 drug delivery device

12 body

14 pivot axis

16 lever

18 stopper

20 lever linkage

22 pivot axis

24 pivot axis

26 through opening

28 blocking element 30 protrusion

36 piston rod

38 tooth

40 bevelled face

42 stop face

44 stop element

46 stop face

48 drive member

50 protrusion

52 stop face

100 drug delivery device

102 body

104 cartridge holder

105 edge

106 threaded shaft 108 socket

1 10 grip

1 12 cartridge

1 13 septum

1 14 piston

1 16 lever

1 18 cover

1 19 cover lever linkage driving member pivot pin pivot pin pivot pin bracket protrusion receptacle piston rod pin

pressure foot spring element stop face support structure

Claims

aims

A drive mechanism for a drug delivery device for dispensing of a dose of a

medicament, the drive mechanism comprising: an elongated body (12; 102) extending in an axial direction (1 , 2),

- a piston rod (36; 136) to engage with a piston (1 14) of a cartridge (1 12) containing the medicament and being movably disposed in axial direction (1 , 2) with respect to the body (12, 102),

- at least one lever (16; 126) pivotally arranged relative to the body (12; 102), and at least one lever linkage (20; 120) operably engaged with the piston rod (36; 136) and pivotally connected to the lever (16; 126) for transferring a pivoting displacement of the lever (16; 126) into an axial displacement of the piston rod (36; 136).

The drive mechanism according to claim 1 , wherein a pivot axis (14; 128) of the at least one lever (16; 126) extends in a plane substantially perpendicular to the axial direction (1 , 2) and wherein the at least one lever linkage (20; 120) is pivotally connected to the at least one lever (16, 126) at a predefined distance from the pivot axis (14; 128).

The drive mechanism according to any one of the preceding claims, wherein a proximal end of the lever linkage (20; 120) is pivotally connected with the at least one lever (16; 126) and wherein an opposite distal end of the lever linkage (20; 120) is pivotally connected with a drive member (48; 122) being operably engaged with the piston rod (36; 136).

The drive mechanism according to claim 3, wherein the drive member (48; 122) axially abuts with the piston rod (36; 136) to transfer a lever-induced, distally directed displacement of the drive member (48; 122) to the piston rod (36; 136).

The drive mechanism according to any one of the preceding claims, wherein the piston rod (36) at least in sections comprises a toothed outer profile with a plurality of consecutively arranged teeth (38).

6. The drive mechanism according to claim 5, wherein the drive member (48) comprises at least one inwardly extending portion (50) to engage with a tooth (38) of the piston rod (36). 7. The drive mechanism according to claim 5 or 6, wherein the drive member (48) is displaceable in proximal direction (2) relative to the piston rod (36).

8. The drive mechanism according to any one of the preceding claims 3 to 7, further comprising a stop element (44) to limit a proximally directed displacement of the drive member (48) relative to the body (12), wherein the stop element (44) is fixable to the body (12) in at least two different axial positions.

9. The drive mechanism according to any one of the preceding claims, further comprising a blocking element (28) axially fixed to the body (12) and having at least one radially inwardly extending portion (30) to engage with the piston rod (36) and to impede a proximally directed displacement of the piston rod (36) relative to the body (12).

10. The drive mechanism according to any one of the preceding claims 1 to 4 or 5, further comprising a cartridge holder (104) to receive the cartridge (1 12), wherein the cartridge holder (104) comprises an outer threaded shaft portion (106) threadedly engaged with a receptacle (134) of the body (102) for threadedly inserting the cartridge holder (104) in proximal direction (2) into the body (12) during setting of a dose of the medicament. 1 1 . The drive mechanism according to claim 10, wherein the threaded engagement of the cartridge holder (104) and the receptacle (134) of the body (102) is of self-locking type.

12. The drive mechanism according to claim 10 or 1 1 , wherein in response to a further or repeated proximally directed displacement of the cartridge holder (104) relative to the body (12) the piston rod (136) being in axial abutment with the piston (1 14) of the cartridge (1 12) is displaced in proximal direction (2) accordingly, thereby inducing an outwardly directed pivoting motion onto the at least one lever linkage (120) and/or the at least one lever (1 16).

13. The drive mechanism according to any one of the preceding claims 10 to 12, wherein the cartridge holder (104) comprises a radially widened socket with a stop face (144) to axially abut with a rim of the receptacle (134) in a final dose position. 14. A drug delivery device comprising a drive mechanism according to any one of the preceding claims and further comprising a cartridge filled with the medicament.