Patent Publication Number: US-2018050160-A1

Title: Drug Delivery Device

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a U.S. national stage application under 35 USC §371 of International Application No. PCT/EP2015/073420, filed on Oct. 9, 2015, which claims priority to European Patent Application No. 14306586.0 filed on Oct. 9, 2014, the entire contents of which are incorporated herein by reference. 
    
    
     TECHNICAL FIELD 
     The present disclosure is generally directed to an injection device, i.e. a drug delivery device for automatic spring driven injection of a liquid drug, i.e. a medicament, by which doses of an individual size can be set by a user. 
     BACKGROUND 
     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. 
     There are basically two types of drug delivery devices: resettable devices (i.e., reusable) and non-resettable (i.e., disposable). For example, disposable drug 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. Some embodiments are applicable for both types of devices, i.e. for disposable devices as well as for reusable devices. 
     A further differentiation of drug delivery device types refers to the drive mechanism: There are devices which are manually driven, e.g. by a user applying a force to an injection button, devices which are driven by a spring or the like and devices which combine these two concepts, i.e. spring assisted devices which still require a user to exert an injection force. The spring-type devices involve springs which are preloaded and springs which are loaded by the user during dose selecting. Some stored-energy devices use a combination of spring preload and additional energy provided by the user, for example during dose setting. Further types of energy storage may comprise compressed fluids or electrically driven devices with a battery or the like. Although many aspects are applicable for all of these types of devices, i.e. for devices with or without a drive spring or the like energy storage, the preferred embodiments require some kind of energy storage. These types of delivery devices generally comprise three primary elements: a cartridge section that includes a cartridge often contained within a housing or body 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 device that is used to set (select) a dose. During an injection, a lead screw, a plunger or piston rod contained within the dose setting mechanism presses against the bung or stopper or piston 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. 
     The dosing section of drug delivery devices for selecting and dispensing a number of user variable doses of a medicament often comprises a display for indicating the selected dose to a user. This is especially important where a user may select a different dose each time depending on the state of health. There are mechanical displays, e.g. a drum with printed numbers on its outer surface, wherein the number corresponding to the actually selected dose is visible through a window or opening in the device. Although such mechanical displays are simple and reliable, they usually require a relatively large construction space which makes the devices bulky. 
     SUMMARY 
     Advantages of some embodiments may provide an injection device requiring low actuation forces and may additionally. reduce the number of components of the injection device needed to make the injection device economically efficient. 
     According to a first embodiment, the injection device comprises a housing defining an interior space and having a longitudinal window, a rotatable dose dial axially retained in relation to the housing, a rotatable scale drum carrying indicia for indicating the size of the set dose, wherein the scale drum is functionally coupled to the dose dial to rotate when the dose dial is rotated to set a dose, a sliding element provided with a sliding window, wherein the sliding element is adapted to slide axially in relation to the housing during dose setting, and through which sliding window the indicia carried by the scale drum is visible such that the longitudinal window and the sliding window in combination with the indicia form the dose size display, and wherein the rotatable scale drum rotates within the interior space defined by the housing during dose setting wherein the inner surface of sliding element is provided with an internal feature engaging an external thread provided on the outer surface of the scale drum and wherein the sliding element is axially guided in the housing such that the sliding element moves axially when the scale drum is rotated and wherein a drive spring is attached to the scale drum with one end and to the housing with another end such that relative rotation between the scale drum and the housing charges the drive spring. 
     In some aspects the injection device reduces the number of parts of the injection device and generates less friction. 
     The dose dial may be configured as a dial grip for setting user variable doses of a medicament. The drive spring is charged by rotation of the dose drum scale and the energy stored in the drive spring during said charging is sufficient to provide the energy necessary to move a lead screw or the like in distal direction so as to drive a bung in a cartridge in the distal direction such that medicament is dispensed from the cartridge. The dose scale drum may be configured as a sleeve-like component, e.g. a number sleeve. The sliding element may be configured as a gauge component with an aperture or window, wherein the position of the gauge component is used to identify the set and/or dispensed dose. The combination of scale drum, sliding window and longitudinal window constitutes the display to indicate the set dose. Preferably, the sliding element and the sliding window are respectively configured such that the sliding element covers all indicia on the scale drum visible through the longitudinal window but one indicia on the scale drum, which corresponds to the set dose. For that purpose, the sliding element and the longitudinal window may be adapted such that when the sliding element slides axially in relation to the housing, the sliding element extends from a proximal end of the longitudinal window to a distal end of the longitudinal window such that the view on the scale drum through the longitudinal window is blocked wherein only though the sliding window, the one indicia corresponding to the set dose is visible. The sliding element may be axially movable from a position corresponding to a set dose of 0 units to a position corresponding to a maximum settable dose, wherein the sliding element is configured such that in both positions, the sliding element extends over the entire length of the longitudinal window in axial direction leaving only the sliding window through which one indicia, namely the indicia on the scale drum that corresponds to the set dose, is visible. 
     By providing the sliding window, a sleeve or other separate means to cover all indicia but the one that corresponds to the set dose is not necessary. In fact, through the longitudinal window, without the sliding element, the user would see a number of indicia, not knowing what the currently set dose is. The sliding element is configured to shield or cover all the indicia except the one that corresponds to the set dose. The indicia corresponding to the set dose is visible through the sliding window. The sliding element may be configured to have an extension that extends in the axial direction wherein the distal end and the proximal end of the sliding element is formed such that is does not collide with borders or edges of the window. For that purpose, the distal border of the longitudinal window may have a receiving section for receiving the extension such that the window of the sliding element can be placed over every single number on the scale drum. 
     The internal feature on the sliding element may be an internal thread feature such as a helical feature, preferably an internal male thread feature, such as a projection or the like engaging the external thread of the scale drum. 
     The sliding element may be provided with teeth or an axially extending splined portion configured to engage an axially extending groove on the inner surface of the housing. By such teeth/groove interface, the sliding element is rotationally constrained with respect to the housing but may move axially relative to the housing. 
     According to a further embodiment, the inner surface of the sliding element is in sliding contact with the outer surface of the scale drum between adjacent thread turns of the scale drum. Thereby, an improved support of the sliding element is provided. Blocking effects resulting from high friction are reduced. 
     According to a further embodiment, the drive spring is attached to a radially inner section of the scale drum. This effectively reduces the dimensions of the injection device, making it more compact. 
     A high degree of accuracy is achieved, when the drive spring is pre-wound or pre-charged upon assembly such that it applies a force or torque to the scale drum when the injection device is at zero units dialed. Thereby, when the user rotates the dial grip to set a dose, he rotates the number sleeve, and hence also the dose scale such that the drive spring is charged. This minimizes force or torque between components. By providing a minimum of force or torque, play between the components is effectively prevented. 
     The sliding element may be a shell-like component that at least partly extends circumferentially around the dose scale drum. The sliding element may have the form of a shield or strip extending in the longitudinal direction of the injection device. As an alternative, the sliding element may be at least partly formed as a sleeve. The sliding element may be used to shield or cover a portion of the indicia on the drum scale and to allow view only a limited portion of the drive scale. 
     In another embodiment, the sliding element extends about an angle of less than 360° in circumferential direction with respect to a longitudinal axis of the scale drum. The size of the device is further reduced. In other words, the sliding element does not surround the scale drum in a sleeve-like manner but only covers a section of the scale drum. 
     According to a further embodiment, the injection device comprises a trigger button or actuation button which the user may press to initiate dispense of a set dose of a liquid drug such as a medicament. The dial grip and the trigger button are rotationally fixed but axially movable relative to each other. Further, a clutch for releasably coupling the trigger button to the scale drum is provided by corresponding splined portions on the trigger button and the scale drum, wherein—preferably axial—movement of the trigger button from a first position into a second position causes the clutch to disengage. The trigger button and the dial grip may be rotationally fixed but axially movable relative to each other by means of a splined interface wherein the trigger button and the dial grip are provided with corresponding teeth and/or grooves that rotationally constrain the components to each other when engaged. By moving the trigger button from the first position into the second position, the splined interface is disconnected such that the scale drum may rotate relative to the trigger button. This mechanism provides for a convenient actuation of the device. The scale drum may be driven by the drive spring. Thus, when the user actuates the trigger button to dispense liquid medicament, the user disconnects the trigger button from the scale drum, and hence the actuation element is disconnected from the driving force. 
     According to a further embodiment, the trigger button is provided with splined features configured to engage corresponding splined features on the housing, wherein movement of the trigger button from the first position into the second position causes the splined features to engage such that the button is rotationally locked to the housing. 
     For safe and convenient dose setting, a further embodiment includes a drive sleeve and a clutch plate, wherein the clutch plate is rotationally constrained to the scale drum, e.g. by a splined interface preventing relative rotational movement between the clutch plate and the scale drum while allowing relative axial motion. The drive sleeve is movable from a first axial position to a second axial position relative to the housing and is configured to engage the housing in the first axial position such that the drive sleeve is rotationally constrained to the housing. For this purpose, the drive sleeve may be provided with a number of teeth on its outer surface that engage corresponding teeth and/or grooves on an inner surface of the housing when the drive sleeve is in the first axial position. The clutch plate is coupled to the drive sleeve via a ratchet interface such that the energy stored in the drive spring is prevented from being released when the drive sleeve is in the first position. The clutch plate may have a surface provided with angled teeth directly facing a surface of the drive sleeve that is provided with corresponding angled teeth. The injection device may further be provided with a clutch spring arranged such as to bias the clutch plate onto the drive sleeve. The angled teeth of the drive sleeve and the clutch plate may be arranged such that when the surfaces contact each other, relative rotation generates an audible click. In the direction of the spring torque, the torque can be transferred from the scale drum and the clutch plate to the drive sleeve. 
     According to a further embodiment, the drive sleeve is free to rotate relative to the housing in the second position. The drive sleeve and the housing may be provided with a splined interface configured such that when the drive sleeve is moved from the first into the second position, the splined interface disengages and the drive sleeve is free to rotate relative to the housing. 
     Preferably, the drive sleeve is rotationally constrained to a lead screw via a splined interface. When the drive sleeve is rotated, the lead screw is forced to move axially relative to the drive sleeve as the lead screw is threadedly engaged with the housing or a housing body. By rotation of the lead screw, the lead screw is displaced in the axial direction. The lead screw may be provided with a bearing at its distal end which bearing is in contact with a cartridge bung in a cartridge. By displacement of the lead screw in the distal direction, medicament in the cartridge is dispensed. 
     In order to initiate the dispense of the injection device, a further embodiment of the injection device is configured such that the trigger button displaces or moves the drive sleeve into the second axial position when the trigger button is moved from the first into the second position. The drive sleeve is further configured to engage the scale drum in the second position such that the drive sleeve is rotationally constrained to the scale drum. The drive sleeve and the scale drum may be provided with corresponding teeth and/or grooves to constitute a splined tooth interface. When the drive sleeve is moved into the second, preferably distal position, the drive sleeve disengages from its rotational lock with the housing and forms a rotational lock with the drum scale, so that the charged energy of the drive spring can be directly transferred from the drum scale to the drive sleeve. 
     In a further embodiment, the injection device comprises rotational stops defining a zero dose position and preferably also a maximum dose position. The rotational stops may be provided on the scale drum and a corresponding rotational stop may be provided on the sliding element. The rotational stops may be formed, e.g. as protrusions and/or abutments, preferably formed in the thread engagement between the scale drum and the sliding element. 
     In accordance with the further embodiment, the drive spring is a torsion spring. The torsion spring may be formed from a helical wire with at least two different pitches. In a central portion, the torsion spring may have open coils, meaning that the coils do not contact each other while adjacent coils at the ends of the torsion spring contact each other. The open coils allow the spring to compress to accommodate additional turns of wire without increasing the total length of the spring. Further, the open coils allow the spring to be compressed during assembly. 
     It has been proven effective, when the scale drum is provided with a receiving section configured to firmly receive an end of the spring configured as a hook, wherein the receiving section comprises a lead-in section and/or a groove section followed by an anchor point for the end of the drive spring. The incorporated lead-in is preferably large in diameter and the groove on the scale drum provides for automated assembly of the drive spring into the drum scale. As the drive spring is rotated during assembly, the hook-end form locates in the groove feature before engaging the anchor point in the drum scale. Further, a one-way clip feature may be provided that has to prevent the drive spring disengaging the anchor point during the assembly. 
     The housing may be a body like component that houses the scale drum. The body may also be a body element that is fixed to an outer housing or casing. 
     Preferably, the cartridge contains a liquid drug such as a medicament. 
     The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
     wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, 
     wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, 
     wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, 
     wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4. 
     Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
     Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-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 13 sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
     There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. 
     Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ, and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
     In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. 
     Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three on the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity. 
     An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv). 
     Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
     Pharmaceutically acceptable solvates are for example hydrates. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Non-limiting, exemplary embodiments will now be described with reference to the accompanying drawings, in which: 
         FIG. 1  shows an exploded view of an injection device in accordance with a first embodiment; 
         FIG. 2  shows an exploded view of an injection device in accordance with a second embodiment; 
         FIG. 3  a perspective view of the sliding element of the device in  FIG. 2 ; 
         FIG. 4  a perspective view of the number sleeve of the device in  FIG. 2 ; 
         FIG. 5  a perspective view of another section of the number sleeve in  FIG. 4 ; 
         FIG. 6  a perspective view of the drive spring of the device in  FIG. 2 ; 
         FIGS. 7 a,b    perspective views of the button and the number sleeve of the device in  FIG. 2 ; 
         FIG. 8  a perspective view of parts of the drive mechanism of the device in  FIG. 2 ; 
         FIGS. 9 a,b    perspective views of the drive sleeve and the clutch plate of the device in  FIG. 2 ; 
         FIGS. 10 a,b    a dose setting sequence of the device in  FIG. 2  in a side view; 
         FIG. 11  a perspective view of the button and the housing of the device in  FIG. 2 ; 
         FIG. 12  the device in  FIG. 2  in a cut view; and 
         FIGS. 13 a,b    interaction between the drive sleeve and the number sleeve of the device in  FIG. 2 . 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 1  shows an exploded view of a first embodiment of the injection device  1  with its components which are a dose dial  2  in the form of a dial button, a housing or body  3 , a dose scale drum or number sleeve  4  which has an outer thread  5  on its outer peripheral surface extending in a helical pattern from a distal end to a proximal end. The scale drum  4  carries indicia  6  which are printed on the scale drum. The indicia  6  are helically provided on the scale drum  4 . 
     The housing or body  3  has an elongated window or aperture  7  of rectangular shape with two longitudinal borders  8  extending parallel to the longitudinal axis  9  of the injection device and two radial borders  10  perpendicular to the longitudinal axis  9 . Through the window  7 , the user can inspect the drum scale  4 . 
     The dose dial  2  is axially retained in the housing  3  and the scale drum  4  is directly coupled to the dial button  2  to follow the rotation of the dial button  2  such that when a user rotates the dial button  2  to select a dose, the scale drum  4  rotates together with the dial button  2 . The dial button  2  and the scale drum  4  are arranged such that they both rotate without any axial displacement. The dose dial  2  also has the function of a dose or trigger button. The dial button  2  and the scale drum  4  are releasably coupled such that when the set dose is injected, the dial button  2  does not necessarily rotate back with the scale drum  4 . 
     The external helical thread  5  of the scale drum  4  is engaged by a corresponding male thread of a sliding element  11 . The sliding element  11  has a tubular section and a window or sliding window  12 , wherein on two sides of the window  12  in axial direction, the male thread for engaging the helical thread  5  of the scale drum  4  is formed. In a further embodiment of the device shown, the inner surface of the sliding element  11  is in sliding contact with the outer surface of the scale drum between adjacent thread turns of the scale drum. 
     The inner surface of the housing  3  is provided with longitudinal bars that guide the sliding element  11  in axial direction but prevent relative rotation between the sliding element  11  and the housing  3 . The longitudinal bars engage longitudinal recesses  13  on the outer surface of the sliding element  11 . Due to this engagement in combination with the engagement between the threads of the housing  3  and the sliding element  11 , the sliding element  11  moves axially whenever the scale drum  4  is rotated. The axial movement of the sliding element  11  and thus of the sliding window  12  relative to the longitudinal window  7  in the housing  3  is coordinated with the helical pattern of the indicia  6  printed on the scale drum  4  such that only one indicia  6  is present in the longitudinal window  7  and the sliding window  12  at the same time. 
     A drive spring  14  is connected to the scale drum  4  with one end and to the housing  3  with another end such that relative rotation between the scale drum  4  and the housing charges  3  the drive spring. The axial length of the sliding element  11  is sufficient to cover the visible part of the helical track  5  of the drum scale  4  in order to fully prevent the user from viewing the indicia  6  not in sight through the sliding window  12 . For that purpose, the sliding element  11  has an extension  15  that extends in the axial direction wherein the distal end  16  and proximal end  17  of the sliding element  11  is formed such that is does not collide with the borders  10  of the window  7 . For that purpose, the distal border  10  may have a receiving section for receiving the extension such that the window  12  of the sliding element  11  can be placed over every single number on the scale drum  4 . 
       FIG. 2  shows an exploded view of the components of a further embodiment of the injection device. 
     The device  1  comprises a dose dial  2  in the form of a dial grip, a housing and/or housing body  3  with an elongated window  7 , a dose scale drum in the form of a number sleeve  4  which has an outer thread  5  on its outer peripheral surface extending in a helical pattern from a distal end to a proximal end. The number sleeve  4  carries indicia  6  which are printed on the scale drum. The indicia  6  are on the scale drum  4  in a helical pattern. The device further comprises a trigger button  18 , a sliding element  11  configured as a gauge component with a sliding window  12 , a clutch plate  19 , a last dose nut  20 , a drive sleeve  21 , a clutch spring  22 , a lead screw  23 , a bearing  24  provided at a distal end of the lead screw  23 , a drive spring  14  in the form of a torsion spring, a cartridge holder  25  that can be attached to the distal end of the housing  3  and that receives a cartridge  26  which is filled with a medicament and which has a bung (not shown) inside wherein when the bearing  24  is moved in distal direction, the bearing displaces the bung such that medicament is dispensed from the cartridge when a dispense interface such as a double ended needle cannula is attached to the distal end of the cartridge. The number sleeve  4  comprises an upper number sleeve part  27  referred to a number sleeve upper and a lower number sleeve part  28  referred to as number sleeve lower. In contrast to the embodiment in  FIG. 1 , the dose dial  2  and the button  18  are separate individual components. All components are located concentrically about a common principal longitudinal axis of the mechanism. The body  3  may also be a body element that it fixed to an outer housing or casing. 
     The button  18  is permanently splined to the dose dial  2 . It is also splined to the number sleeve upper  28  when the button  18  is not pressed, but this spline interface is disconnected when the button  18  is pressed. When the button  18  is pressed, splines on the button  18  engage with splines on the housing  3  preventing rotation of the button  18  (and hence the dose dial  2 ) during dispense. 
     These splines disengage when the button  18  is released, allowing a dose to be dialed. The dose dial  2  is axially constrained to the housing  3 . It is rotationally constrained, via the splined interface to the button  18 . The number sleeve lower  28  is rigidly fixed to the number sleeve upper  27  during assembly to form the number sleeve  4  and is a separate component to simplify number sleeve  4  mold tooling and assembly. This sub assembly is constrained to the housing  3  by holding elements (not shown) towards the distal end to allow rotation but not translation. The number sleeve lower  28  is marked with indices in the form of a sequence of numbers, which are visible through the window  12  of the sliding element  11  and the window  7  in the housing  3  to denote the dialed dose of medicament. 
     The clutch plate  19  is splined to the number sleeve  4 . It is also coupled to the drive sleeve  21  via a ratchet interface. The ratchet provides a detented position between the number sleeve  4  and the drive sleeve  21  corresponding to each dose unit and engages different ramped tooth angles during clockwise and anti-clockwise relative rotation. The sliding element  11  is constrained to prevent rotation but allow translation relative to the housing  3  via a splined interface. The sliding element  11  has a helical feature on its inner surface which engages with the helical thread  5  cut in the number sleeve  4  such that rotation of the number sleeve  4  causes axial translation of the sliding element  11 . This helical feature on the sliding element  11  also creates stop abutments against the end of the helical cut in the number sleeve  4  to limit the minimum and maximum dose that can be set. 
     The last dose nut  20  is located between the number sleeve  4  and the drive sleeve  21 . It is rotationally constrained to the number sleeve  4  via a splined interface. It moves along a helical path relative to the drive sleeve  21  via a threaded interface when relative rotation occurs between the number sleeve  4  and drive sleeve  21 . The drive sleeve  21  extends from the interface with the clutch plate  19  to the contact with the clutch spring  22 . A splined tooth interface with the number sleeve  4  is not engaged during dialing, but engages when the button  18  is pressed, preventing relative rotation between the drive sleeve  21  and number sleeve  4  during dispense. A further splined tooth interface with the housing  3  prevents rotation of the drive sleeve  21  during dose setting. When the button  18  is pressed, the drive sleeve  21  and the housing  3  disengage allowing the drive sleeve  21  to rotate. 
     The helical drive spring  14  is charged and stores energy during dose setting by the action of the user rotating the dose dial  2 . The spring energy is stored until the mechanism is triggered for dispense at which point the energy stored is used to deliver the medicament from the cartridge to the user. The drive spring  14  is attached at one end to the housing  3  and at the other end to the number sleeve  4 . The drive spring  14  is pre-wound upon assembly, such that it applies a torque to the number sleeve  4  when the mechanism is at zero units dialed. The action of rotating the dose dial  2  to set a dose, rotates the number sleeve  4  relative to the housing  3  and charges the drive spring  14  further. 
     The lead screw  23  is rotationally constrained to the drive sleeve  21  via a splined interface. When rotated, the lead screw  23  is forced to move axially relative to the drive sleeve  21 , through a threaded interface with the housing  3  (not shown). The bearing  24  is axially constrained to the lead screw  23  and acts on a bung within the liquid medicament cartridge  26 . 
     The axial position of the drive sleeve  21 , clutch plate  19  and button  18  is defined by the action of the clutch spring  22 , which applies a force on the drive sleeve  21  in the proximal direction. This spring force is reacted via the drive sleeve  21 , clutch plate  19  and button  18 , and when ‘at rest’ it is further reacted through the dose dial  2  to the housing  3 . The spring force ensures that the ratchet interface is always engaged. In the ‘at rest’ position, it also ensures that the button splines are engaged with the number sleeve  4  and that the drive sleeve teeth are engaged with the housing  3 . The housing  3  provides location for the liquid medication cartridge and cartridge holder  25 , windows for viewing the dose number and the sliding element, and a feature on its external surface to axially retain the dose dial  2  (not shown). A removable cap fits over the cartridge holder  25  and is retained via clip features on the housing  3 . 
       FIG. 3  shows the inside of the sliding element  11  with the window  12  and the male thread feature  29  on the inner surface of the sliding element  11  that engages the outer thread  5  on the number sleeve  4  (see  FIG. 4 ). The thread feature  29  has a zero dose abutment  30  and a maximum dose abutment  31 . As shown in  FIG. 4 , the outer thread  5  has a zero dose abutment  32  at one end of the thread  5  and a maximum dose abutment  33  at the other end of the thread  5  so that any dose size can be selected between zero and a pre-defined maximum, in increments to suit the medicament and user profile. The drive spring  14 , which has a number of pre-wound turns applied to it during assembly of the device, applies a torque to the number sleeve  4  and is prevented from rotating by the zero dose abutment. 
     As shown in  FIG. 5 , the inner surface of the number sleeve  4  has a lead-in  34  followed by a groove  35  and an anchor point  36 . Automated assembly of the drive spring  14  into the number sleeve is achieved by incorporating the large lead-in  34  and the groove feature  35 . As the drive spring  14  is rotated during assembly, a hook end form  37  at the one end of the drive spring  14  (see  FIG. 6 ) is located in the groove feature  35  before engaging the anchor point  36  in the number sleeve  4 . 
     As shown in  FIG. 6 , the drive spring  14  is formed from a helical wire with at least two different pitches. Both ends are formed from ‘closed’ coils  38 , i.e. the pitch equals the wire diameter and each coil contacts the adjacent coil. The central portion has ‘open’ coils  39 , i.e. the coils do not contact each other. This has the following advantages. When a dose is set, the drive spring  14  is charged. If all the coils were closed, winding up the spring would increase the length of the spring by one wire diameter for each turn, and so the hook ends would no longer be aligned with their anchor points on the housing and number sleeve. The open coils allow the spring to compress to accommodate the additional turns of wire, without increasing the total length of the spring. Further, the open coils  39  allow the spring to be compressed during assembly. The spring is manufactured longer than the space available in the device. It is then compressed during assembly, ensuring that the axial positions of the hook ends are better aligned with their anchor points on the housing and the number sleeve. Also, it is easier to manufacture the spring to a specified length if most of the coils are closed, as the length of these coils is only a function of the wire diameter. Moreover, following assembly, compression in the spring biases the number sleeve axially relative to the housing in a consistent direction, reducing the effects of geometric tolerances. Further, the addition of closed coils at each end makes the springs less prone to tangling with each other when they are stored together between manufacture and assembly and closed coils at the ends provide a flat surface for contact with the housing and the number sleeve. 
     For selecting a dose, the user rotates the dial grip  2  clockwise. As shown in  FIGS. 7 a  and 7 b   , the button has inner splines  40  for engaging corresponding splines  41  on the upper part of number sleeve  4  to create a splined interface  40 / 41 . The dial grip is splined to the button  18 , wherein the button  18  has a further set of splines  42  for engagement with corresponding splines of the housing  3 . During dose selection, rotation of the dial grip is transferred to the button  18 . The button  18  is in turn splined to the upper number sleeve (during dose selection only) via the splines  40 . The upper number sleeve is permanently fixed to the lower number sleeve to form the number sleeve  4 . Therefore, rotation of the dial grip  2  generates an identical rotation in the number sleeve  4 . Rotation of the number sleeve  4  causes charging of the drive spring, increasing the energy stored within it. As the number sleeve  4  rotates, the sliding element  11  translates axially due to its threaded engagement with the number sleeve  4  thereby showing the value of the dialed dose. 
     As shown in  FIG. 8 , the drive sleeve  21  has splines  43  for engaging corresponding splines  44  formed on the inside of the housing  3  to create a splined interface  43 / 44 . The drive sleeve  21  is prevented from rotating as the dose is set and the number sleeve is rotated, due to the engagement of its splined teeth  43  with the teeth  44  of the housing  3 . Relative rotation therefore occurs between the clutch plate that is driven by the number sleeve and the drive sleeve via the ratchet interface. 
     As shown in  FIGS. 9 a  and 9 b   , an end surface of the drive sleeve  21  is provided with angled teeth  45  to form a ratchet interface  45 / 46  with angled teeth  46  on the clutch plate  19 . On the outer circumference of the clutch plate  19 , splined teeth  47  for engaging a corresponding groove on the number sleeve are formed. The user torque required to rotate the dial grip is a sum of the torque required to wind up the drive spring, and the torque required to overhaul the ratchet feature  45 / 46 . The clutch spring is designed to provide an axial force to the ratchet feature  45 / 46  and to bias the clutch plate  19  onto the drive sleeve  21 . This axial load acts to maintain the ratchet teeth engagement of the clutch plate  19  and the drive sleeve  21 . The torque required to overhaul the ratchet in the dose set direction is a function of the axial load applied by the clutch spring, the clockwise ramp angle of the ratchet, the friction coefficient between the mating surfaces and the mean radius of the ratchet features. As the user rotates the dial grip sufficiently to increment the mechanism by 1 increment, the number sleeve  14  rotates relative to the drive sleeve  21  by 1 ratchet tooth. At this point the ratchet teeth re-engage into the next detented position. An audible click is generated by the ratchet re-engagement, and tactile feedback is given by the change in torque input required. 
     With no user torque applied to the dial grip  21 , the number sleeve  4  is prevented from rotating back under the torque applied by the drive spring  14 , due solely to the ratchet engagement  45 / 46  between the clutch plate  19  and the drive sleeve  21 . The torque necessary to overhaul the ratchet in the anti-clockwise direction is a function of the axial load applied by the clutch spring  22 , the anti-clockwise ramp angle of the ratchet  45 / 46 , the friction coefficient between the mating surfaces and the mean radius of the ratchet features. The torque necessary to overhaul the ratchet must be greater than the torque applied to the number sleeve  4  (and hence clutch plate  19 ) by the drive spring  14 . The ratchet ramp angle is therefore increased in the anti-clockwise direction to ensure this is the case whilst ensuring the dial-up torque is as low as possible. 
     The user may choose to increase the selected dose by continuing to rotate the dial grip in the clockwise direction. The process of overhauling the ratchet interfaces between the number sleeve  4  and drive sleeve  21  is repeated for each dose increment. Additional energy is stored within the drive spring  14  for each dose increment and audible and tactile feedback is provided for each increment dialled by the re-engagement of the ratchet teeth. The torque required to rotate the dial grip  2  increases as the torque required to wind up the drive spring  14  increases. The torque required to overhaul the ratchet in the anti-clockwise direction must therefore be greater than the torque applied to the number sleeve  4  by the drive spring  14  when the maximum dose has been reached. 
     If the user continues to increase the selected dose until the maximum dose limit is reached, the number sleeve  4  engages with its maximum dose abutment on the sliding element (see  FIGS. 3 and 4 ). This prevents further rotation of the number sleeve  4 , clutch plate  19  and dial grip  2 . 
     The last dose nut is splined to the number sleeve while the last dose nut is threaded to the drive sleeve such that relative rotation of the number sleeve and the drive sleeve during dose setting also causes the last dose nut to travel along its threaded path towards a last dose abutment on the drive sleeve. Depending on how many increments have already been delivered by the mechanism, during selection of a dose, the last dose nut may contact its last dose abutment with the drive sleeve. The abutment prevents further relative rotation between the number sleeve  4  and the drive sleeve  21  and therefore limits the dose that can be selected. The position of the last dose nut is determined by the total number of relative rotations between the number sleeve  4  and the drive sleeve  21 , which have occurred each time the user sets a dose. 
     When a dose has been set, the user is able to deselect any number of increments from this dose. Deselecting a dose is achieved by the user rotating the dial grip  2  anti-clockwise. The torque applied to the dial grip  2  by the user is sufficient, when combined with the torque applied by the drive spring  14 , to overhaul the ratchet between the clutch plate  19  and the drive sleeve  21  in the anti-clockwise direction. When the ratchet  45 / 46  is overhauled, anti-clockwise rotation occurs in the number sleeve  4  (via the clutch plate  19 ), which returns the number sleeve  4  towards the zero dose position, and unwinds the drive spring  14 . The relative rotation between the number sleeve  4  and drive sleeve  21  causes the last dose nut to return along its helical path, away from the last dose abutment. 
     As shown in  FIGS. 10 a  and 10 b   , the sliding element  11  has flanges or extensions on either side of the window area which cover the numbers printed on the number sleeve adjacent to the dialed dose to ensure only the set dose number is made visible to the user. The device includes a visual feedback feature in addition to the discrete dose number display typical on devices of this type. The distal end of the sliding element  11  has the extension  15  (see  FIG. 2 ) that creates a sliding scale through a small window  48  in the housing  3 . As a dose is set by the user, the sliding element  11  translates axially, the distance moved proportional to the magnitude of the dose set. This feature gives clear feedback to the user regarding the approximate size of the dose set. The dispense speed of an auto-injector mechanism may be higher than for a manual injector device, so it may not be possible to read the numerical dose display during dispense. The sliding element  11  provides feedback to the user during dispense regarding dispense progress without the need to read the dose number itself. 
     The window  48  may be formed by an opaque element on the sliding element  11  revealing a contrasting colored component  49  underneath. Alternatively, the revealable element  49  may be printed with coarse dose numbers or other indices to provide more precise resolution. In addition, this display simulates a syringe action during dose set and dispense. 
     To reduce dust ingress and prevent the user from touching moving parts, the viewing openings  7  and  48  in the housing  3  are covered by translucent windows. These windows may be separate components, but in this embodiment they are incorporated into the housing  3  using ‘twin-shot’ molding technology. A first shot of translucent material forms the internal features and the windows, and then a ‘second shot’ of opaque material forms the outer cover of the housing  3 . 
     Delivery of a dose is initiated by the user depressing the button axially. When the button  18  (see  FIGS. 7 a  and 7 b   ) is depressed, the splines  40  and  41  between the button  18  and the number sleeve  4  disengage, rotationally disconnecting the button  18  and dial grip  21  from the delivery mechanism. 
     As shown in  FIG. 11 , the splines  42  on the button  18  engage with splines  50  on the housing  3  preventing rotation of the button  18  (and hence the dial grip  21 ) during dispense. As the button  18  is stationary during dispense, it can be used in a dispense clicker mechanism. A stop feature in the housing  3  limits axial travel of the button  18  and reacts any axial abuse loads applied by the user, reducing the risk of damaging internal components. 
     As shown in  FIG. 12 , the clutch plate  19  arranged between the drive sleeve  21  and the button  18  is moved axially by the button and the drive sleeve  21  is moved axially by the clutch plate  19 . 
     As shown in  FIGS. 13 a  and 13 b   , the axial displacement of the drive sleeve  21  engages splines  51  on the drive sleeve  21  with splines  52  on the number sleeve  4  so that a splined tooth interface  51 / 52  is formed preventing relative rotation between the drive sleeve  21  and number sleeve  4  during dispense. The splined tooth interface  43 / 44  ( FIG. 8 ) between the drive sleeve  21  and the housing  3  disengages, so that the drive sleeve  21  can now rotate relative to the housing  3  and is driven by the drive spring via the number sleeve  4 , and clutch plate  19 . Rotation of the drive sleeve  21  causes the lead screw  23  to rotate due to their splined engagement, and the lead screw  23  then advances due to its threaded engagement to the housing  3 . The number sleeve  4  rotation also causes the sliding element to traverse axially back to its zero position whereby the zero dose abutment ( FIG. 3  and  FIG. 4 ) stops the mechanism. 
     It is possible to angle the spline teeth on either the drive sleeve  21  or the housing  3 , so that when the zero dose abutment  30  stops rotation of the number sleeve  4  and hence the drive sleeve  21  at the end of the dose and the button  18  is released the spline teeth between the drive sleeve  21  and the housing  3  rotate the drive sleeve  21  backwards by a small amount and hence move the lead screw  23  axially back away from the bung and rotates the number sleeve lower  28  from the zero dose stop position. This helps to prevent possible weepage. 
     REFERENCE NUMERALS 
     
         
           1  injection device (drug delivery device) 
           2  dose dial/dial grip 
           3  housing/body 
           4  dose scale drum/number sleeve 
           5  outer thread 
           6  indicia 
           7  window 
           8  longitudinal border 
           9  longitudinal axis 
           10  radial border 
           11  sliding element 
           12  sliding window 
           13  recess 
           14  drive spring 
           15  extension 
           16  distal end of sliding element 
           17  proximal end of sliding element 
           18  trigger button 
           19  clutch plate 
           20  last dose nut 
           21  drive sleeve 
           22  clutch spring 
           23  lead screw 
           24  bearing 
           25  cartridge holder 
           26  cartridge 
           27  upper number sleeve part 
           28  lower number sleeve part 
           29  male thread feature 
           30  zero dose abutment of sliding element 
           31  maximum dose abutment of sliding element 
           32  zero dose abutment of number sleeve 
           33  maximum dose abutment of number sleeve 
           34  lead-in 
           35  groove 
           36  anchor 
           37  hook 
           38  closed coils 
           39  open coils 
           40  splines of button 
           41  splines of number sleeve 
           42  splines of button 
           43  splines of drive sleeve 
           44  splines of body 
           45  angled teeth 
           46  angled teeth 
           47  splines of clutch plate 
           48  window 
           49  revealable element 
           50  splines on body 
           51  splines on drive sleeve 
           52  splines on number sleeve