Abstract:
The invention relates to a reusable drug delivery device for selecting and dispensing a number of user variable doses of a medicament. The device comprises a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/EP2013/067860 filed Aug. 29, 2013, which claims priority to European Patent Application No. 12182564.0 filed Aug. 31, 2012, and U.S. Provisional Patent Application No. 61/696,496, filed Sep. 4, 2012. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
     TECHNICAL FIELD 
     The present invention is generally directed to drug delivery devices. More particularly, the present invention is directed to reusable drug delivery devices. 
     BACKGROUND 
     Pen type drug delivery devices have application where regular injection by persons without formal medical training occurs. This may be increasingly common among patients having diabetes where self-treatment enables such patients to conduct effective management of their disease. In practice, such a drug delivery device allows a user to individually select and dispense a number of user variable doses of a medicament. The present invention is not directed to so called fixed dose devices which only allow dispensing of a predefined dose without the possibility to increase or decrease the set dose. 
     There are basically two types of drug delivery devices: resettable devices (i.e., reusable) and non-resettable (i.e., disposable). For example, disposable pen delivery devices are supplied as self-contained devices. Such self-contained devices do not have removable pre-filled cartridges. Rather, the pre-filled cartridges may not be removed and replaced from these devices without destroying the device itself. Consequently, such disposable devices need not have a resettable dose setting mechanism. 
     These types of pen delivery devices (so named because they often resemble an enlarged fountain pen) are generally comprised of three primary elements: a cartridge section that includes a cartridge often contained within a housing or holder; a needle assembly connected to one end of the cartridge section; and a dosing section connected to the other end of the cartridge section. A cartridge (often referred to as an ampoule) typically includes a reservoir that is filled with a medication (e.g., insulin), a movable rubber type bung or stopper located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often necked-down, end. A crimped annular metal band is typically used to hold the rubber seal in place. While the cartridge housing may be typically made of plastic, cartridge reservoirs have historically been made of glass. 
     The needle assembly is typically a replaceable double-ended needle assembly. Before an injection, a replaceable double-ended needle assembly is attached to one end of the cartridge assembly, a dose is set, and then the set dose is administered. Such removable needle assemblies may be threaded onto, or pushed (i.e., snapped) onto the pierceable seal end of the cartridge assembly. 
     The dosing section or dose setting mechanism is typically the portion of the pen device that is used to set a dose. During an injection, a spindle or piston rod contained within the dose setting mechanism presses against the bung or stopper of the cartridge. This force causes the medication contained within the cartridge to be injected through an attached needle assembly. After an injection, as generally recommended by most drug delivery device and/or needle assembly manufacturers and suppliers, the needle assembly is removed and discarded. 
     For reusable drug delivery devices it is necessary to allow the piston rod or lead screw to be reset, i.e. pushed and/or wound back into the device, during the step of replacing an empty cartridge by a new (full) cartridge. In addition, many drug delivery devices comprise a dose limiter for preventing the setting of a dose, which exceeds the amount of liquid left in a cartridge of the drug delivery device. If such a dose limiter is provided, this dose limiter mechanism has to be reset, too. 
     In the following resetting of the device is to be understood the act of replacing or exchanging a cartridge involves a retraction of the piston rod or lead screw and, if present, bringing the dose limiter (last dose protection mechanism) back into an initial configuration allowing dose setting. 
     It is an object of the present invention to provide an improved reusable drug delivery device. 
     SUMMARY 
     According to a first embodiment of the present invention, this object is solved by a drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, a clutch for rotationally coupling the driver to the housing or the display member and a button rotationally coupled to the display member and to the driver, wherein the driver is in threaded engagement with the piston rod, permanently rotationally locked to the button, axially displaceable relative to the button and comprises at least two separate components which are rotationally coupled during dose setting and during dose dispensing and which are rotationally decoupled during resetting of the device. Decoupling of the two driver components during resetting has the benefit that both, the piston rod, which is in threaded engagement with the driver, and a dose limiter mechanism, which usually acts on the driver, can be reset together by spinning one of the driver components whereas the other remains stationary in the device. The driver may comprise a third component for coupling the first and second components during dose setting and dose dispensing. 
     According to a second embodiment of the present invention, this object is solved by a drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, a clutch for rotationally coupling the driver to the housing or the display member and a button rotationally coupled to the display member and to the driver, wherein the display member has a distal end provided with an inwardly protruding thread and a proximal end provided with an inwardly protruding flange, wherein the display member comprises two separate components with a first component comprising the thread and the other component comprising the flange. The display member has to be coupled to the housing and to the driver. The construction of the display member with two inwardly directed engaging features avoids a bulky design of the device which would be the result if one engagement feature would be on the outside and the other would be on the inside of the display member. In addition, the inwardly directed engagement features make it possible to provide further functions on the outer surface of the display member, e.g. limiting stop elements. Providing two separate components, which are preferably axially and rotationally constrained, makes production of the display member more efficient and easier. Preferably, the display member has a series of numbers or the like symbols arranged on its outer surface for indicating a set dose. If the display member is in threaded engagement with the housing, the numbers or the like may be arranged on a helical path. 
     According to a third embodiment of the present invention, this object is solved by a drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, a clutch for rotationally coupling the driver to the housing or the display member and a button rotationally coupled to the display member and to the driver, wherein the button comprises fingers which engage corresponding slots of the driver for rotationally coupling the button to the driver and which comprise snap features engaging corresponding snap features of the clutch for axially coupling the button to the clutch. In other words, the driver and the button are rotationally coupled by a dog clutch or claw coupling with the fingers of the button having the additional function of axially constraining the button to the clutch member. This additional function in one component reduces the number of component parts of the device and assembling complexity. 
     According to a fourth embodiment of the present invention, this object is solved by a drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, a clutch for rotationally coupling the driver to the housing or the display member and a button rotationally coupled to the display member and to the driver, wherein the driver comprises fingers which engage corresponding slots of the button for rotationally coupling the button to the driver and which comprise hook features engaging corresponding contact features of the display member for axially coupling the driver to the display member. In other words, the driver and the button are rotationally coupled by a dog clutch or claw coupling with the fingers of the driver having the additional function of axially engaging the display member, e.g. for entraining the display member during dose dispensing. This additional function in one component reduces the number of component parts of the device and assembling complexity. 
     According to a fifth embodiment of the present invention, this object is solved by a drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, a clutch for rotationally coupling the driver to the housing or the display member and a button rotationally coupled to the display member and to the driver, wherein the button comprises a ring of clicker teeth engaging a corresponding clicker feature of the display member at least during dose dispensing. The clicker produces a tactile and/or audible feedback during use of the device and is usually provided with at least one separate component. In the present embodiment of the invention, these functions of the device are realized without adding component parts. Preferably, the display member comprises an elastically deformable finger having a protrusion for engaging the clicker teeth. An additional clicker may be provided, which is active during dose setting. 
     Preferably, the piston rod is a double threaded piston rod having a first outer thread engaging an internal thread of the housing and a second outer thread engaging an internal thread of the driver, wherein the first and second outer threads may overlap each other at least partially. This allows providing a mechanical advantage, i.e. a transmission (gear) ratio, in the device. Typically, the dial extension of the button, i.e. the distance the button winds out of the housing during dose setting, will be larger than the distance the piston rod is displaced relative to the cartridge holder and thus the cartridge. This allows dispensing even small amounts of a medicament with a maximum of dispensing control by the user. The first and second outer threads may have a different pitch. However, it is preferred if the first and second outer threads have the same pitch but are oppositely directed. 
     One of the outer threads of the piston rod may be in engagement with a corresponding inner thread of the housing, preferably an inner housing body. Thus, the piston rod rotates both, during dose dispensing and during resetting of the device, .i.e. when the piston rod is pushed (wound) back. 
     A further reduction of the number of component parts may be achieved if the piston rod comprises a bearing attached to the piston rod by at least one predefined breakage point. The bearing is axially constrained but rotatable with respect to the piston rod after detachment of the bearing by destroying the at least one predefined breakage point during or after assembly. Thus, only one single component has to be handled during assembly which in use fulfils the function of two separate components. 
     According to a preferred embodiment, the driver is a tubular element having a distal portion engaging a nut interposed between the housing and the driver, and a proximal portion which at least partly surrounds a tubular portion of the button. Preferably, one of the housing and the driver comprises at least one spline and the other of the housing and the driver comprises a threaded portion with the nut interposed between the housing and the driver, wherein the nut comprises at least one protrusion engaging the at least one spline and a thread engaging the threaded portion, and wherein the threaded portion of the housing or the driver comprises a rotational end stop. If the nut abuts the rotational end stop, further movement of the nut in the thread is prevented which thus prevents further rotation of the driver relative to the housing which is required during dose setting. Thus, the nut may be used to limit the settable dose. This is e.g. required to prevent setting a dose exceeding the amount of medicament in the cartridge. 
     Preferably, the housing comprises an outer body and an inner body with the cartridge holder being releasably coupled to the inner body. The inner body may be rotationally and axially constrained within the outer body such that a cylindrical gap exists between the inner body and the outer body. Preferably, the inner body comprises an outer thread engaging an inner thread of the display member and comprises at least one inner spline engaging a protrusion of a clicker and/or a dose limiter nut. 
     In a standard embodiment, the splines of the inner body are axially aligned with the pen device. In an alternative embodiment, it is possible to reduce dispense force, increase the velocity ratio and to increase the thread pitch of the display member (i.e. increase of friction coefficient asymptote), by providing the inner body with at least one inner spline which is helically twisted. In other words, the splines are not axially aligned, which results in the driver and the button traveling helically during dose dispensing. This may require adding an over-cap for the button as an additional component preventing relative rotation with respect to a user&#39;s hand, typically the thumb, during dose dispensing. 
     If the driver comprises a first component which is in threaded engagement with a nut and a second component, the first and the second components may be operatively coupled together in a releasable manner. It is preferred that when a user sets a dose by rotating the button, both the first component and the second component of the driver rotate together. Further, when a user resets the device, the first component of the driver is preferably decoupled from the second component of the driver and the first component is allowed to rotate with respect to the housing and with respect to the second component. The nut may be part of a dose limiter for preventing the setting of a dose, which exceeds the amount of liquid left in a cartridge of the drug delivery device. Thus, a simple and yet reliable resetting mechanism is provided by splitting the driver into two components. 
     The precision of a last dose protection mechanism, i.e. a dose limiter for preventing the setting of a dose, which exceeds the amount of liquid left in a cartridge of the drug delivery device, may be increased by the driver being in threaded engagement with a nut, and the threaded engagement comprises a helical groove having a first pitch provided along a first portion of the driver, a second pitch provided along a second portion of the driver wherein the first pitch is smaller than the second pitch, and, optionally, a third pitch provided along a third portion of the driver wherein the third pitch is smaller than the second pitch. Preferably, the second and third portions are located close to a rotational hard stop limiting further movement of the nut for preventing the setting of a dose, which exceeds the amount of liquid left in a cartridge of the drug delivery device. The pitch of the first portion may be selected small to reduce the axial length of the device. The increased pitch of the second portion results in a higher axial displacement of the nut relative to the driver such that the nut may pass a relatively large and thus robust rotational hard stop. 
     The drug delivery device may further comprise a clicker producing a tactile and/or audible feedback during dose setting, i.e. increasing or reducing the dose. This additional clicker may include a first toothed element rotationally constrained to the housing, a second toothed element rotationally constrained to the driver and a spring biasing the first toothed element and the second toothed element into engagement. 
     A transparent window may be provided within the housing for allowing a user to view the numbers or the like on the display member indicating the set dose. Preferably, the housing comprises an inner body and an outer body with the window being attached to the housing by first retaining means of the inner body and second retaining means of the outer body. 
     The basic function of the drug delivery device according to the present invention may include that a dose is selected by rotating a button component, which travels helically during dose setting. A dose may be delivered by pressing on the same button component, which now moves axially during dispensing. Preferably, any dose size can be selected, in predefined increments, between zero and a predefined maximum dose, e.g. 80 units. It is a further advantage if the mechanism permits cancelling of a dose without medicament being dispensed, e.g. by rotation of the button component in the opposite direction to when selecting a dose. 
     It is preferred if during dose setting the button is rotated which entrains the driver and the display member such that the button, the driver and the display member are moved on a helical path with respect to the housing and the piston rod. Further, during dose dispensing the button is axially displaced which entrains the driver and the display member such that the button, the driver and the display member are axially moved with respect to the housing and the piston rod, with the display member and the piston rod rotating with respect to the housing, the button and the driver. 
     To prevent malfunction or misuse of the device, the dose setting mechanism may be provided with stops preventing dialling of a dose below zero units or dialling of a dose above a maximum dose. Preferably, rotational hard stops are provided, e.g. between the display member and the housing as a zero unit stop and/or as a maximum units stop. If the housing comprises an inner body and an outer body, a first rotational stop may be provided between the inner body and the display member and a second rotational stop may be provided between the outer body and the display member for limiting the rotational movement of the display member relative to the housing. The minimum dose, usually zero units, may be defined by the first rotational stop and the maximum dose, e.g. 60, 80 or 120 units, may be defined by the second rotational stop. 
     The drug delivery device may comprise a cartridge containing a medicament. The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
     wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a 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-LysB28ProB29human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
     Exendin-4 derivatives are for example selected from the following list of compounds:
     H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   des Pro36 Exendin-4(1-39),   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),   wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;   or an Exendin-4 derivative of the sequence   des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;   or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.   

     Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
     A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
     Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. 
     The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
     There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. 
     Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
     In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. 
     Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three 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. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
     Pharmaceutically acceptable solvates are for example hydrates. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       A non-limiting, exemplary embodiment of the invention will now be described with reference to the accompanying drawings, in which: 
         FIG. 1  shows a drug delivery device with a cap attached in accordance with the present invention; 
         FIG. 2  shows the drug delivery device of  FIG. 1  with the cap removed and a dose of 79 units dialed; 
         FIG. 3  shows in an exploded view the components of the drug delivery device of  FIG. 1 ; 
         FIG. 4  shows the outer body of the drug delivery device of  FIG. 1 ; 
         FIG. 5 a    shows the inner body of the drug delivery device of  FIG. 1 ; 
         FIG. 5 b    shows a detail of the inner body of  FIG. 5   a;    
         FIG. 6  shows the cartridge holder of the drug delivery device of  FIG. 1 ; 
         FIG. 7 a    shows a first display member component of the drug delivery device of  FIG. 1 ; 
         FIG. 7 b    shows a detail of the first display member of  FIG. 7   a;    
         FIG. 8  shows a second display member component of the drug delivery device of  FIG. 1 ; 
         FIG. 9  shows a first driver component of the drug delivery device of  FIG. 1 ; 
         FIG. 10  shows a second driver component of the drug delivery device of  FIG. 1 ; 
         FIG. 11  shows a third driver component of the drug delivery device of  FIG. 1 ; 
         FIG. 12  shows the last dose nut of the drug delivery device of  FIG. 1 ; 
         FIG. 13  shows a clutch component of the drug delivery device of  FIG. 1 ; 
         FIG. 14  shows a first clicker component of the drug delivery device of  FIG. 1 ; 
         FIG. 15  shows a second clicker component of the drug delivery device of  FIG. 1 ; 
         FIG. 16  shows the button of the drug delivery device of  FIG. 1 ; 
         FIG. 17  shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a zero unit position with the button released; 
         FIG. 18  shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a position with some units dialed; and 
         FIG. 19  shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a zero unit position with the button pressed. 
     
    
    
     DETAILED DESCRIPTION 
       FIGS. 1 and 2  show a drug delivery device  1  in the form of an injection pen. The device has a distal end (lower end in  FIG. 1 ) and a proximal end (upper end in  FIG. 1 ). The component parts of the drug delivery device  1  are shown in  FIG. 3  in more detail. The drug delivery device  1  comprises an outer housing part  10 , an inner body  20 , a piston rod  30 , a driver  40 , a nut  50 , a display member  60 , a button  70 , a cartridge holder  80  for receiving a cartridge  81 , a clutch  90 , a clicker  100 , a spring  110 , a cap  120  and a window insert  130 . A needle arrangement (not shown) comprising a needle hub and a needle cover may be provided as additional components, which can be exchanged as explained above. The piston rod  30  comprises a bearing  31 . The driver comprises a distal driver part  41 , a proximal driver part  42  and a coupler  43 . The display member  60  comprises a number sleeve  61  and a dial sleeve  62 . The clicker comprises a distal clicker part  101 , a proximal clicker part  102  and a spring  103 . 
     The outer housing part  10 , which is shown in  FIG. 4 , is a generally tubular element having a distal part  11  for attaching the inner body  20  and a proximal part, which is provided with a rotational hard stop  12  on its inner surface (not shown) which contact mating faces of the display member  60  when the maximum units (in this example 80 U ) stop is engaged. The end face also serves as the end of dose dispense stop for the button  70 , and the bore in the end face centers the display member  60  during both dialing and dispense. An aperture  13  is provided for receiving window insert  130 . The outer body  10  provides the user with a surface to grip and react against during dispense. 
     The inner body  20  is a generally tubular element having different diameter regions. As can be seen in  FIGS. 17 to 19 , the inner body  20  is received in the outer body  10  and permanently fixed therein to prevent any relative movement of the inner body  20  with respect to the outer body  10 . The inner body has the functions to house the drive mechanism within, guiding the clickers and the last dose nut  50  via internal splines, to provide an internal thread through which the piston rod  30  (lead screw) is driven, to support and guide the number sleeve  61  and the dial sleeve  62  on an external thread form, to secure the cartridge holder  80  and to secure the outer body  10  and the window insert  130 . 
     The outermost diameter of the inner body  20  also forms part of the visual design and remains visible when the cap  120  is secured to the cartridge holder  80  as a ring separating the cap  120  from the outer body  10 . This visible ring also has depressions which align with the cap snap features on the cartridge holder  80  to indicate that the cartridge holder has been correctly fitted. 
     An external thread  21  is provided on the outer surface of the inner body  20 . Further, splines  22  ( FIG. 5 b   ) are provided on the inner surface of the inner body  20 . These internal splines  22  guide the proximal part of the clicker  102  axially during both dialing and dispense and also prevent the last dose nut  50  from rotating. Some of the splines may be wider to ensure correct rotational assembly of the internal components, and these wider splines may have a stepped entry to encourage the last dose nut  50  which has mating chamfered external ribs to rotate up against the stop face on the distal drive sleeve  41  during assembly. At the open end shown in  FIG. 5 b    there are additional short splines which together with the alternating long splines  22  are used to rotationally lock the button  70  (dose dial grip) at the end of dispense and serve to increase the strength of the 0 U dial stop when the button  70  is depressed. This is achieved by engagement with male spline features  94  on the clutch component  90 . 
     Bayonet features  23  guide the cartridge holder  80  into the mechanism during cartridge replacement, compressing the cartridge bias spring  110 , and then back off the cartridge holder  80  a small distance in order to reduce axial play in the mechanism. Snap features inside the inner body  20  lock the cartridge holder  80  rotationally when it has been correctly fitted. The profile of these snaps aims to prevent the user from partially fitting the cartridge holder  80 , the cartridge bias spring  110  ejecting the cartridge holder  80  if the snaps have not at least started to engage. A window retention nose  24  retains the window insert  130  when the outer body  10  and window insert  130  assembly is axially inserted onto the inner body  20 . Two diametrically opposite stop faces  25  define the rotational end position for the number sleeve  61 . This end position is the end of dose detent position for the minimum dose (0 U). 
     The piston rod  30  is an elongate element having two external threads  32 ,  33  with opposite hand which overlap each other. One of these threads  32  engages the inner thread of the inner body  20 . A disk-like bearing  31  is provided at the distal end of the piston rod  30 . The bearing  31  may be a separate component as shown in  FIG. 3  or may be attached to the piston rod  30  as a one-piece component via a predetermined breaking point. 
     The piston rod  30  transfers the dispense load from the driver  40  to the bearing  31 , creating a mechanical advantage greater than 1:1 by converting the torque generated on the piston rod  30  by the driver  40  thread interface into additional axial load as the piston rod passes through the thread in the inner body  20 . The piston rod  30  is reset by pressing on the bearing  31  and this in turn rotates the piston rod back into the inner body  20 . This disengages and then rotates the distal drive sleeve  41 , resetting the last dose nut  50  back to its starting position on the distal drive sleeve  41 . 
     The driver  40  is a generally tubular element having in the embodiment shown in the Figures three components which are depicted in  FIGS. 9 to 11  in more detail. 
     The distal drive sleeve  41  engages with the piston rod thread  33  to drive the piston rod  30  through the inner body  20  during dose delivery. The distal drive sleeve  41  is also permanently connected to the coupler  43  which in turn is releasably engaged through reset clutch features to the proximal drive sleeve  42 . The two halves of the drive sleeve are rotationally and axially connected during dialing and dispense, but are de-coupled rotationally during device reset so that they can rotate relative to each other. 
     The external thread  44  engages with the last dose nut  50 . The thread form has three stages, a shallow first stage (left hand side in  FIG. 9 ) over which the nut  50  travels to count the majority of the units dialed, a fast stage over which the last dose nut moves rapidly axially prior to engaging the stop faces, and a final shallow section which ensures that when the stop faces have engaged, the axial restraint on the nut  50  extends over a reasonable length of thread form. Four equi-spaced stop faces  45  engage with mating stop faces  51  on the last dose nut  50  to limit the number of units that can be dialed. Splines  46  are provided at the proximal end of distal drive sleeve  41  to transfer torque from or to the coupler  43 , which may be snapped on the distal drive sleeve  41 . 
     The proximal drive sleeve  42  shown in  FIG. 10  supports the clicker components  100  and the clutch  90  and transfers rotational movement from the dose button  90  to the coupler  42  and distal drive sleeve  41 . 
     Teeth features  47  located at the distal end of proximal drive sleeve  42  engage with the reset clutch features on the coupler  43  to connect both halves of the drive sleeve during dialing and dispense. During reset these teeth  47  disengage. 
     Several splines are provided on the outer surface of proximal drive sleeve  42  engaging with distal clicker part  101 , preventing relative rotation during dialing and dispense. Further splines, which are located in the middle region of proximal drive sleeve  42 , engage with the clutch  90  component. They may be arranged to be non-rotationally symmetric so that the various clicker components cannot be assembled accidentally upside down. 
     The proximal portion of proximal drive sleeve  42  has four arms or fingers  48 . A hook-like bearing surface  49  exists on the underside (as seen in  FIG. 10 ) of flange segments on the end of the flexible fingers  48 . The flexible fingers  48  are separated with gaps or slots that make space for the button  70  to snap to the clutch  90  and also enable these fingers to flex inwards during assembly of the proximal drive sleeve  42  to the dial sleeve  62 . After assembly the hooks  49  retain the proximal drive sleeve  42  relative to the dial sleeve  62  under the reaction force from the spring  103 . During dispense the button  70  depresses the spring  103  via the clutch  90  and the clicker components and this spring  103  is reacted through the coupler  43  to the proximal drive sleeve  42  which then through these bearing surfaces applies axial load to the dial sleeve  62 . This axial load drives the dial sleeve  62  and hence number sleeve  61  along the helical thread of the inner body  20 , back into the body of the device, until the 0 U stop faces on the number sleeve  61  contact the inner body  20 . 
     The coupler  43  shown in  FIG. 11  rotationally couples the two halves of the drive sleeve together during dialing and dispense, whilst allowing them to de-couple during reset. The coupler  43  has to also transfer the last dose protection stop load from the proximal drive sleeve  42  to the distal drive sleeve  41 . Two sets of teeth are provided in the coupler  43  for engaging teeth  46  and teeth  47 , respectively. The coupler  43  is snapped onto distal drive sleeve  41  allowing limited relative axial movement with respect to the proximal drive sleeve  42 . 
     The nut  50  is provided between the inner body  20  and the distal drive sleeve  41  of driver  40 . Stop faces  51  are located on the proximal face of last dose nut  50  to limit the number of units that can be dialed if the stop faces  51  contact stops  45  of distal drive sleeve  41 . The function of the last dose nut  50  is to prevent the user from dialing beyond a finite amount. This limit is based on the dispensable volume of the cartridge  81  and when reached, the user must replace the cartridge  81  and reset the device. 
     External ribs  52  of the nut  50  engage splines  22  of inner body  20 . An internal thread  53  of the nut engages the external thread  44  of distal drive sleeve  41 . As an alternative, splines and ribs could be provided on the interface between the nut  50  and the driver  40  and threads could be provided on the interface between the nut  50  and the inner body  20 . As a further alternative, the nut  50  may be designed as e.g. a half nut. 
     The display member  60  is a generally tubular element which is composed of number sleeve  61  and dial sleeve  62  which are snapped together during assembly to axially and rotationally constrain these two components, which thus act as a single part. 
     The main functions of the number sleeve  61  depicted in  FIG. 8  are to provide a surface onto which dose numbers can be printed to display the dialed dose, to guide the helical path of the internal mechanism during dialing to follow the helical thread form on the piston rod  30  when threaded to the inner body  20  and to attach to the dial sleeve  62 .The number sleeve  61  is designed to be fully enclosed in the outer body  10  during dialing and dispense and therefore only the dialed dose is visible to the user through the window aperture. The number sleeve has a 0 U (minimum dose) stop face  63  to limit its travel when dialed in but the 80 U (maximum dose) stop faces that limit the dialed out condition are located on the dial sleeve  62 . At the end of each dispense stroke, this stop face  63  engages with mating surface  25  on the inner body  20  to limit the rotational position of the number sleeve  61 . 
     A helical drive face  64  forms a thread that guides the number sleeve  61  during dialing and dispense to follow the helical path  21  on the inner body. 
     The dial sleeve  62  is assembled to the number sleeve  61  such that once assembled, no relative movement is allowed. The parts are made as separate components to enable both molding and assembly. Also, whereas the number sleeve  61  is preferably white to give contrast for the e.g. black dose numbers, the dial sleeve  62  color can be chosen to suit the aesthetics or perhaps to distinguish the drug type. 
     At the proximal end, the dial sleeve  62  has internal clutch features  65  that engage with the clutch component  90  during dialing and disengage from the clutch during dispense. These clutch features  65  rotationally lock the dial sleeve  62  to the clutch  90  during dialing and when the 0 U and 80 U stops are engaged. When the button  70  is depressed these clutch features disengage to allow the clutch  90  and drive mechanism to move axially whilst the dial sleeve  62  and number sleeve  61  spin back to the 0 U start position. 
     The dial sleeve  62  rotates out during dialing through its engagement with the clutch  90  and number sleeve  61 , and rotates back in during dispense under the axial force applied by the proximal drive sleeve  42  to a flange-like bearing face  66  on the end of the dial sleeve. This bearing face  66  engages with the flexible arms  48  of the proximal drive sleeve  42  during dispense. Two diametrically opposite faces  67  engage with the outer body  10  when the maximum dose (e.g. 80 U ) has been dialed, forming the maximum dose stop faces. 
     A ratchet arm  68  engages with ratchet features on the button  70  (dose dial grip) to provide audible feedback during dispense, giving one click per unit delivered. Further, this prevents the user from gripping and rotating the number sleeve  61  outwards from a partially dialed out position whilst holding the button  70  pressed in. This would back wind the piston rod  30  which would result in an under dose on the subsequent dialed dose. It may further strengthen the 0 U stop. 
     The button  70  which is shown in  FIG. 16  serves as a dose dial grip and is retained by the clutch  90  to transfer the actions of the user to the clutch. It also carries ratchet teeth  71  that engage the ratchet arm  68  on the dial sleeve  62 , which serves as the dispensing clicker giving audible feedback (ratchet clicks), and an end face  72  which serves as the dose completion stop face with the outer body  10 . This end face  72  thus serves to define the end position during dispense when it contacts the outer body  10  to provide a very positive stop improving dose accuracy. 
     A central sleeve-like portion of button  70  is provided with four arms  73  having hook-like snap features  74  at their respective distal ends. The arms  73  form splined surfaces engaging with the clutch  90  to transfer torque from the button  70  through the clutch to the dial sleeve  62  and proximal drive sleeve  42 . The snap features  74  engage apertures in the clutch  90  and are designed with angled undercut faces to maintain engagement when an axial load is applied to pull the button  70  out of the pen body  10 . The space between arms  73  defines pockets giving clearance for the flexible arms  48  of proximal drive sleeve  42  to slide freely relative to the button  70  and clutch  90  when the button  70  is depressed and released during dose dispense. 
     The cartridge holder  80  attaches to the inner body  20  with a bayonet connection  82  and houses the glass ampoule or cartridge  81  containing the medication to be dispensed. The cartridge holder  80  includes an aperture  83  in the rear face (as seen in  FIG. 6 ) which if gripped by the user prevents the ampoule from falling out when the cartridge holder is removed from the inner body  20 . The front face is printed with a dose number scale. The threaded distal end  84  is used to attach disposable pen needles. 
     A tubular clutch  90  is provided between the display member  60  and the button  70 . The clutch is fixed relative to and retains the button  70  and together they travel axially relative to the proximal drive sleeve  42  when the button  70  is depressed during dispense, disengaging the clutch teeth from the dial sleeve  62 . It also transfers torque from the button to the proximal drive sleeve  42 , and the dialing and 0 U /80 U stop loads from the button via the clutch teeth to the dial sleeve and number sleeve. 
     Drive sleeve splines  91  provided on an inner surface of the clutch engage with the proximal drive sleeve  42 . At the distal end face, clutch biasing teeth  92  are provided which mate with similar teeth  109  on the proximal clicker part  102  to ensure that in the button out position (dialed dose) the clutch is locked in rotation to the proximal clicker part  102  under the biasing action of the clutch spring  103 . The teeth  92  are shallow in height to prevent the proximal clicker part  102  from engaging with splines on the proximal drive sleeve  42  during dialing. Four snap apertures  93  serve to retain the snap features  74  of button  70 . Near its proximal end, the clutch has splines  94  which at the end of dispense with the button  70  depressed lock to the inner body  20  to prevent the user from rotating the button  70  below the 0 U position. 
     Clutch teeth  95  engage with clutch teeth  65  of the dial sleeve to rotationally couple the button  70  via the clutch to the number sleeve  61 . During dispense the clutch is moved axially so as to disengage these clutch teeth  95  releasing the dial sleeve  62  to rotate back into the device whilst the clutch  90  and hence driver  40  move axially to dispense the dose. 
     The clicker  100  comprises a distal clicker part  101 , a proximal clicker part  102  and a spring  103 . The clutch spring  103  serves to bias the button  70  out so that at the end of a dose the button  70  pops out, re-engaging the clutch  90  with the dial sleeve  62  ready for dialing. Further, it provides the spring force for the clicker components to act as clickers and also as detent positions for the number sleeve  61 . In addition, it holds the two halves of the drive sleeves  41 ,  42  in rotational engagement during dialing and dispense, whilst allowing them to disengage during device reset. 
     The distal clicker part  101  is permanently splined to the proximal drive sleeve  42  and engages with the proximal clicker part  102  which in turn is splined to the inner body  20 . During dialing when the drive sleeve is rotated relative to the inner body, the two clickers  101 ,  102 , rotate relative to each other under the compression force of the clutch spring  103 . This force combined with the clicker teeth formed on the end face of each clicker provides the clicks and also the detent dialing positions. 
     During dispense the two clickers  101 ,  102  are pressed together under the dispense load and therefore prevent relative rotation between the proximal drive sleeve  42  and inner body  20 , driving the piston rod forwards to deliver the dose. The splines  104  on the inner bore rotationally couple the distal clicker part  101  to the proximal drive sleeve  42  at all times, but allow free axial movement when the button  70  is depressed during dispense and when the two clickers ride over each other during dialing. The profile of the clicker teeth  105 ,  106  on both distal clicker part  101  and proximal clicker part  102  are identical and ride over each other under the compressive load from the spring  103  during dialing. 
     The proximal clicker part  102  is permanently splined to the inner body  20  by external splines  107  which prevent relative rotation with the inner body during both dialing and dispense, providing clicks during dialing and locking the proximal drive sleeve  42  in rotation during dispense. Additional cylindrically shaped splines  108  also couple the proximal clicker part  102  rotationally to the proximal drive sleeve  42  when the button  70  is depressed, this preventing the user from dialing past 80 units with the button depressed. Proximal clicker part  102 , in addition to the primary clicker teeth  106 , has clutch biasing teeth  109  on the opposite end face. These teeth mate with similar teeth  92  on the clutch to ensure that in the button out position (dialed dose) the clutch is locked in rotation to the proximal clicker part  102  under the biasing action of clutch spring  103 . 
     The cartridge bias spring  110  is assembled as two components one after the other, the lower first and the upper second. The spring combination serves to apply an end load to the cartridge  81  at extremes of tolerance so as to bias it forwards onto the end face of the ferrule in the cartridge holder  80 . This ensures that when the user removes and attaches a needle, the friction between the needle cannula and septum of the cartridge does not move the cartridge  81  axially relative to the cartridge holder  80 . The bias spring  110  also acts to provide a force against which the user has to connect the cartridge holder  80  and this may add to the tactile feedback of this bayonet joint. The spring  100  also serves to eject the cartridge holder  80  if the cartridge holder is not rotated into a secure position, highlighting this error to the user. 
     The cap  120  serves to protect the cartridge holder  80  from damage and the cartridge  81  itself from dust dirt ingress on to the area around the septum. The cap is designed to accommodate a standard pen injector needle. 
     The window insert  130  may include a lens to magnify the dose numbers e.g. by approximately 25% from their printed size. The window insert  130  may be back printed to protect the printed surface from abrasion and also to maximize the light entering through the window aperture, giving uniform illumination of the dose numbers and white area around these numbers. Arrows may be printed adjacent to the window aperture that indicate the dose dialed. 
     In the following, the function of the drug delivery device and its components will be explained in more detail with reference to  FIGS. 17 to 19 . 
     To use the device, a user has to select a dose. In the start (at rest) condition as shown in  FIG. 17  the display member  60  indicates the number of doses dialed to the user. The number of dialed units can be viewed through the dose window  130  in the outer body  10 . Due to the threaded engagement between the display member  60  and the inner body  20  rotation of the button  70  in a clockwise fashion causes the display member  60  to wind out of the device and incrementally count the number of units to be delivered.  FIG. 18  shows an intermediate stage of dialing (e.g. 7 of 80 units). 
     During dose setting button  70 , driver  40  and display member  60  are rotationally locked together via clutch  90 . Further, button  70 , driver  40  and display member  60  are axially coupled. Thus, these three components wind out of the outer housing  10  during dose setting. Clockwise rotation of the button  70  causes the driver  40  to rotate and in doing so it advances along the piston rod  30  which remains fixed throughout dialing. The clicker arrangement  100  provides tactile and audible feedback to the user when dialing doses. At the maximum settable dose of 80 units, the stop features 12 and 67 engage to prevent further dialing. 
     The last dose nut  50  provides the function of counting the number of dispensed units. The nut  50  locks the device at the end of cartridge life and as such no more drug can be dialed by the user. The last dose nut  50  and the driver  40  are connected via a threaded interface as explained above. Further, the last dose nut  50  is assembled into splines  22  such that the nut  50  and the inner body  20  are rotationally locked together (at all times). Rotation of the driver  40  during dialing causes the nut  50  to advance along the thread  44 . The nut  50  is free to slide axially within the inner body  20  at all times which allows advancement of the nut. The change in pitch of thread  44  shown in  FIG. 9  towards the final doses axially accelerates the advancement of the nut  50  towards the end of cartridge life lockout condition. At the end of life condition, the stop features  51  of the last dose nut  50  contact the corresponding features  45  on the driver  40 . The splined contact with inner body  20  reacts any torque transmitted by these stop features  45 . 
     With the desired dose dialed, the device  1  is ready for dose dispensing. This basically requires pushing button  70  which will result in a disengagement of the clutch  90  from dial sleeve  62  thus allowing relative rotation between the display member  60  and the button  70 . In all conditions the driver  40  and the button  70  are rotationally locked together by engagement of arms  73  and fingers  48  and by splines  91  engaging corresponding splines on proximal drive sleeve  42 . Thus, with the clutch  90  disengaged (button  70  pushed in) button  70  and driver  40  are rotationally locked together with the button  70 , the driver  40  and the display member  60  still being axially coupled. 
     When dispensing a dose, the dose button  70  and clutch  90  are moved axially relative to the mechanism compressing the clutch spring  103 . Because the proximal clicker part  102  is splined to the inner body  20  and the axial load passing through the clicker teeth  105 ,  106  locks the distal clicker part  101  in rotation to the proximal clicker part  102 , the mechanism is forced to move axially whilst the dial sleeve  62  and number sleeve  61  are free to spin back into the outer housing  10 . The interaction of mating threads between the piston rod  30 , driver  40  and inner body  20  delivers a mechanical advantage of 2:1. In other words, axially advancing driver  40  causes the piston rod  30  to rotate which due to the threaded engagement of piston rod  30  with the inner body  20  advances the piston rod. During dose dispensing dispense clicker  68 ,  71  is active which involves button  70  and display member  60 . The dispense clicker provides primarily audible feedback to the user that drug is being dispensed. 
     The end of this step is shown in  FIG. 19 . At this point the dose is complete and when the user removes the force from the end of the dose button  70 , the clutch spring  103  pushes this dose button  70  rearwards, re-engaging the teeth  65  and  95  between the clutch and the dial sleeve. 
     Resetting the device starts with removal of the cartridge holder  80  and replacing an empty cartridge with a full cartridge  81 . As the cartridge holder is re-attached, the bung of the new cartridge contacts bearing  31 , thus pushing piston rod  30  back into the housing. Initially, the piston rod  30  screws into the inner body  20 , thereby axially disengaging the coupler  43  from the proximal drive sleeve  42  against the biasing force of spring  103 . Once disengaged the coupler  43  is free to start rotating together with distal drive sleeve  41  and continues to do so as the cartridge holder  80  is moved axially into engagement with the inner body  20 .Thus, the distal drive sleeve  41  rotates with respect to the proximal drive sleeve  42  which is still rotationally constrained in inner body  20  as clicker parts  101  and  102  are pressed together by compressed spring  103 . As the distal drive sleeve  41  rotates, last dose nut  50  is reset to its (distal) start position. Coupling the cartridge holder  80  to inner body  20  backs off the mechanism due to the bayonet structure  23  allowing re-engagement of the proximal drive sleeve  42  with coupler  43  and thus the distal drive sleeve  41 .