Abstract:
The present disclosure relates to a drug delivery device, comprising a housing, a cartridge, the cartridge containing a drug in a quantity sufficient for a plurality of doses of the drug, a bung, the bung being movably retained within the cartridge to dispense a dose of the drug from the cartridge upon movement of the bung with respect to the cartridge, and a drive mechanism, the drive mechanism being operable to transfer a driving force to the bung to dispense the dose of the drug from the cartridge. The drug delivery device is configured such that the maximal driving force which is transferrable to the bung via the drive mechanism varies and is adjusted to the current position of the bung within the cartridge.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a U.S. national stage application under 35 USC §371 of International Application No. PCT/EP2015/077496, filed on Nov. 24, 2015, which claims priority to European Patent Application No. 14306862.5, filed on Nov. 24, 2014, the entire contents of which are incorporated herein by reference. 
     
    
     TECHNICAL FIELD 
       [0002]    The present disclosure is generally directed to a drug delivery device, particularly to a drug delivery device which is suitable for selecting and dispensing a number of, preferably user variable, doses of a drug or medicament. 
       BACKGROUND 
       [0003]    Drug delivery devices, such as 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 disclosure is, in general not limited to variable dose devices, but would also be applicable for so called fixed dose devices which only allow dispensing of a predefined dose without the possibility for the user to increase or decrease the set dose. 
         [0004]    There are basically two types of drug delivery devices: resettable devices (i.e., reusable) and non-resettable (i.e., disposable) devices. 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. The present disclosure is applicable for both types of devices, i.e. for disposable devices as well as for reusable devices. 
         [0005]    Drug delivery devices, particularly pen delivery devices (so named because they often resemble an enlarged fountain pen), generally comprise 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 or drug (e.g., insulin). A movable, e.g. rubber type, bung or stopper is typically located at one end of the cartridge reservoir, and a top having a pierceable, e.g. rubber, seal or septum is typically 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. 
         [0006]    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. 
         [0007]    The dosing section or dose setting mechanism is typically the portion of the pen device that is used to set (select) a dose. During an injection, a spindle or piston rod contained within the dose setting mechanism, often also called drive mechanism, presses against the bung or stopper of the cartridge. This force causes the drug 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. 
         [0008]    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. 
         [0009]    WO 2014/033197 A1 describes a manually driven drug delivery device with a housing, a dose setting button operable to set a dose by rotation relative to the housing, a number sleeve arranged within the housing such that at least a portion of the number sleeve is visible through a first aperture in the housing, a piston rod coupled to the housing and to a driver such that rotation of the driver relative to the housing causes the piston rod to translate relative to the housing, and a clutch mechanism releasably coupling the number sleeve and the driver. The piston rod is in threaded engagement with an inner housing and in threaded engagement with the driver such that the piston rod advances by a fixed displacement for each revolution of the drive sleeve. 
       SUMMARY 
       [0010]    One aspect of the present disclosure relates to a drug delivery device. In an embodiment, the drug delivery device comprises a housing. The housing, which is preferably an exterior housing of the device, may be provided to house interior parts of the drug delivery device, such as a cartridge and/or one or more parts of a drive mechanism of the device, like a piston rod, for example. The housing may have a proximal end and a distal end. The distal end of the housing or any other part of the drug delivery device may be that end which faces, or should be arranged to face, the dispensing end of the device. The dispensing end of the device is usually that end, where the needle or needle assembly is mounted. The proximal end of the housing or of a component of the device is preferably that end which faces away or shall be arranged to face away from the dispensing end of the device. The housing may be of unitary structure or may be a multipart housing. For example, the housing may comprise a cartridge holder and a body, the cartridge holder retaining a cartridge and the body retaining one or more parts of a drive mechanism of the device. Body and cartridge holder are preferably secured to one another. 
         [0011]    In an embodiment, the drug delivery device comprises a cartridge. The cartridge may contain the drug or medicament, preferably in a quantity sufficient for a plurality of doses of the drug or medicament, which should be delivered by the device. The drug may be a liquid drug. 
         [0012]    The term “drug” or “medicament”, as used herein, preferably means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
         [0013]    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, 
         [0014]    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, 
         [0015]    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, 
         [0016]    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. 
         [0017]    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. 
         [0018]    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-(w-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
         [0019]    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. 
         [0020]    Exendin-4 derivatives are for example selected from the following list of compounds: 
         [0021]    H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
         [0022]    H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
         [0023]    des Pro36 Exendin-4(1-39), 
         [0024]    des Pro36 [Asp28] Exendin-4(1-39), 
         [0025]    des Pro36 [IsoAsp28] Exendin-4(1-39), 
         [0026]    des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
         [0027]    des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
         [0028]    des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
         [0029]    des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
         [0030]    des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), 
         [0031]    des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or 
         [0032]    des Pro36 [Asp28] Exendin-4(1-39), 
         [0033]    des Pro36 [IsoAsp28] Exendin-4(1-39), 
         [0034]    des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
         [0035]    des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
         [0036]    des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
         [0037]    des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
         [0038]    des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), 
         [0039]    des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
         [0040]    wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; 
         [0041]    or an Exendin-4 derivative of the sequence 
         [0042]    des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010), 
         [0043]    H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0044]    des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2, 
         [0045]    H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
         [0046]    H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
         [0047]    des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0048]    H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0049]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0050]    H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0051]    H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2, 
         [0052]    H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
         [0053]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
         [0054]    des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0055]    H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0056]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0057]    H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0058]    des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2, 
         [0059]    H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
         [0060]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
         [0061]    des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0062]    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0063]    H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0064]    H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0065]    H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2) 25 ] Exendin-4(1-39)-NH2, 
         [0066]    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
         [0067]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
         [0068]    des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0069]    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, 
         [0070]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2; 
         [0071]    or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative. 
         [0072]    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. 
         [0073]    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. 
         [0074]    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. 
         [0075]    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. 
         [0076]    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. 
         [0077]    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 (C H ) and the variable region (V H ). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, 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. 
         [0078]    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. 
         [0079]    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. 
         [0080]    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&#39;) 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. 
         [0081]    Pharmaceutically acceptable solvates are for example hydrates. 
         [0082]    In an embodiment, the drug delivery device comprises a bung. The bung is preferably movably retained within the cartridge. Expediently, the bung is movable to dispense a dose of the drug from the cartridge upon movement of the bung with respect to the cartridge, particularly in the distal direction. The bung may sealingly contact one or more inner walls of the cartridge, preferably in order to seal the proximal end of the cartridge such that drug cannot leave the cartridge via its proximal end. For dispensing drug from the cartridge the bung may be moved towards an outlet of the cartridge, which is positioned at the distal end of the cartridge, and dispense drug from the cartridge. Expediently, for dispensing drug from the cartridge, fluid communication is established between the interior of the cartridge and the outside, for example by a needle piercing the seal or septum of the cartridge. The distance which the bung is displaced to dispense the dose of drug from the cartridge may correspond to the size of the dose which was, for example, previously set by the user of the device. 
         [0083]    In an embodiment, the drug delivery device comprises a drive mechanism. The drive mechanism is expediently operable or operated to transfer a driving or dispensing force to the bung, particularly in order to dispense a drug, such as the previously set dose of drug, from the cartridge. The drive mechanism may be designed to transfer a maximal driving force to the bung, e.g. the maximal force transferred to the bung during the dispensing action for dispensing a single dose of drug from the cartridge. The maximal driving force may be defined by the design of the drive mechanism. For example, if the drive mechanism operates using an energy storage means comprised by the device the maximal driving force may be the maximal force that can be generated by the energy stored in the energy storage means when the energy is released in a dispensing action. Additionally or alternatively, particularly if the drive mechanism requires a user exerted force for a dispensing action—either for providing the whole driving force which is necessary for the particular dispensing action or only a part of that force—the device may comprise a force limiting mechanism which limits the force transferrable to the bung to the maximal driving force which is still sufficient to move the bung relative to the cartridge and dispense drug from the cartridge. The maximal driving force may be the maximal force transferred to the bung during the dispensing of a single dose of the drug, for example in case the driving force varies over the duration of the dispensing action for dispensing the dose. 
         [0084]    In an embodiment, the drug delivery device, particularly the drive mechanism, is configured such that the maximal driving force which is transferred to or can be transferred to the bung via the drive mechanism varies, preferably between different doses of drug which are delivered from the device. 
         [0085]    In an embodiment, the maximal driving force which is transferred to or transferrable to the bung via the drive mechanism, depends on the filling level or filling status, particularly the current filling level or filling status of the cartridge. Consequently, the maximal driving force may vary dependent on the current filling level of the cartridge. 
         [0086]    In an embodiment, the maximal driving force which is transferred to or transferrable to the bung via the drive mechanism is adjusted to the current position of the bung within the cartridge. Consequently, the maximal driving force may vary dependent on the current position of the bung within the cartridge. Preferably, the maximal driving force is adjusted to a stiction force of the bung with respect to the cartridge in the current position of the bung. The stiction force may be that force which has to be overcome to move the bung relative to the cartridge. The stiction force may be that force which has to be overcome to get the bung to move with respect to the cartridge starting from a resting bung. The stiction force may act, at least partly, between the bung and the cartridge, particularly the inner wall thereof 
         [0087]    In the case of a new cartridge, e.g. a cartridge which has the same filling level or filling status as provided originally from the manufacturer, where no drug has yet been dispensed from the cartridge, the force required to move the bung relative to the cartridge in order to dispense the drug from the cartridge may be different from the force required to move the bung when the drug has already been dispensed from the cartridge. This may be due to an increase in stiction between bung and cartridge during storage of the cartridge, e.g. before the user is provided with the device or even before the cartridge is assembled with the remainder of the components of the device to form the device. Once the initial stiction force has been overcome, the subsequently acting stiction forces between cartridge and bung when the bung rests relative to the cartridge are usually less than the initial stiction force. Thus, a lower force is sufficient to get the bung to move relative to the cartridge. 
         [0088]    Preferably, the drug delivery device is operable in two modes of operation, an initial mode of operation and a subsequent mode of operation. If the maximal driving force is adjusted to the stiction force in the current bung position, in the initial mode of operation, the drive mechanism may be designed to transfer an initial maximal driving force to the bung, which is greater than the initial stiction force. In the subsequent mode of operation, when the initial stiction force has been overcome, the drive mechanism may be designed to transfer a subsequent maximal driving force to the bung which is less than the initial maximal driving force but greater than the stiction force in the current position of the bung within the cartridge. Once the device is no longer in the initial mode of operation, the maximal driving force transferred to or transferrable to the bung by the drive mechanism is expediently always less than the initial maximal driving force. Thus, the device may be configured to provide an increased maximal driving force only in the initial mode of operation. 
         [0089]    Accordingly, the driving forces acting in the device can be adjusted to the specific needs without excessive force being generated in the device, which are not needed when the initial stiction force has been overcome and the first drug has already been dispensed from the device. 
         [0090]    The respective maximal driving force in the respective mode of operation is expediently greater but not to a too great extent than the stiction force in the current position of the bung. 
         [0091]    In other words, the drug delivery device may be configured such that the maximal driving force, which can be transferred to the bung by the drive mechanism, is greater for a new cartridge than for a cartridge from which drug has already been dispensed. The maximal driving force may have a first value for a new cartridge which is greater than a second value for a cartridge which is already in use, the second value preferably being smaller than the first value for every dose subsequent to that dose when the maximal driving force has been lowered from the first value to the second value, e.g. after the first, second or third dose has been dispensed. 
         [0092]    In an embodiment, the bung is displaceable from an initial position, preferably when all of the drug is still within the cartridge, e.g. when the cartridge is new, with respect to the cartridge via an intermediate position, preferably when the cartridge is partially emptied, to an end position, preferably when no more drug can be dispensed from the drug delivery device, e.g. when no or not enough drug is left in the cartridge or further operation of the drive mechanism is prevented after the last dose, for which the mechanism was designed, has been delivered, such as by a locking mechanism. Expediently, the maximal driving force is greater when the bung is in the initial position and/or between the initial position and the intermediate position, than when the bung is in the intermediate position and/or between the intermediate position and the end position. The intermediate position of the bung may have been reached, for example, after the first, the second or the third dose has been dispensed from the device. Before the intermediate position is reached, the maximal driving force may be greater than the maximal driving force which is transferred or transferable to the bung on the whole way from the intermediate position to the end position. The intermediate position may be that position of the bung, when the current stiction force is significantly less than the initial stiction force. In the intermediate position, the current stiction force may be 70% or less, 60% or less, or even 50% or less than the initial stiction force in the initial position of the bung. 
         [0093]    In an embodiment, when the bung is in its initial position, e.g. when all of the drug is still within the cartridge, the maximal driving force is greater than the stiction force which has to be overcome to move the bung with respect to the cartridge. Preferably, the maximal driving force is sufficient to move the bung with respect to the cartridge away from the initial position, particularly taking into account the higher initial stiction force. When the bung is in the intermediate position, the maximal driving force, which is preferably sufficient to displace the bung with respect to the cartridge to dispense drug from the cartridge, is expediently less than the force required to move the bung away from the initial position but greater than a stiction force of the bung in the intermediate position. In the intermediate position, the maximal driving force may be less than the stiction force in the initial position of the bung. 
         [0094]    In other words, the drug delivery device is configured such that when the bung is in its initial position, the maximal driving force is greater than the maximal driving force when the bung has already been displaced away from the initial position. 
         [0095]    In an embodiment, the maximal driving force varies between two subsequent doses. The maximal driving force may be greater for one of the doses, e.g. the first dose, which is dispensed from the cartridge than for a subsequent dose, preferably for any subsequent dose, which is dispensed from the cartridge. 
         [0096]    In an embodiment, the drug delivery device comprises an energy storage member, for example a spring. The energy storage member is expediently adapted to store energy which, when released, provides at least a fraction of the driving force, such as only a fraction of the driving force, or the whole driving force. Accordingly, the drug delivery device may be an automatic drug delivery device where the force required to dispense drug from the device is provided by the energy storage member, preferably only by the energy storage member, particularly when the bung travels from the intermediate position towards the end position. On its way from the initial position to the intermediate position the drive mechanism may be configured to assist the energy storage member in order to provide an initially increased driving force. This is disclosed in more detail below. The energy storage member may be a mechanical energy storage member. The energy storage member may be a torsion spring. Torsion springs are particularly suitable to reliably provide driving forces in drug delivery devices. The energy storage member is expediently part of the drive mechanism. 
         [0097]    In an embodiment, the drug delivery device comprises a dose setting member which is operable by the user to set the dose. For setting the dose, the user may for example rotate the dose setting member relative to the housing with or without concurrent axial movement with respect to the housing. The energy may be stored within the energy storage member by the user when operating the dose setting member to set the dose which is preferably subsequently dispensed from the device. In the case of a torsion spring, torque may be required by the user to store the energy within the energy storage member. During dose delivery, it is preferred that no user-exerted force is necessary to assist the dispensing action. This is particularly user-friendly. 
         [0098]    In an embodiment, the drug delivery device is an automatic dispensing device, preferably where no user-exerted force is transferred to the bung to dispense the drug from the cartridge during dispensing of the drug or during a dispensing action. Rather, the energy required for the force may be already stored in the device, such as in the energy storage member. The energy may have been stored in the energy storage member before or during assembling of the device or the user may have to exert a force during dose setting to store the energy necessary for the subsequent dispensing of the dose in the energy storage member. 
         [0099]    In an embodiment, the drug delivery device is configured such that the maximal force transferable to the bung and originating from the energy released from the energy storage member is only a fraction of the driving force required to move the bung from the initial position towards the intermediate position. In this case, it is preferred that supplemental energy—either by a member within the device or by the user—is provided, in addition to the energy stored in the energy storage member to enable provision of the driving force required to move the bung. 
         [0100]    In an embodiment, the drug delivery device comprises a supplemental storage member within which supplemental energy is stored. The supplemental energy is expediently provided to, when released, provide energy, preferably in addition to that provided by the energy storage member, for a supplemental force to move the bung from the initial position towards the intermediate position. The energy stored in the supplemental storage member may be less than the energy required to move the bung away from the initial position. Consequently, a fraction of the driving force required to move the bung away from the initial position may be provided by the supplemental storage member and another fraction, preferably the remaining fraction of this driving force, may be provided by the energy storage member. This is particularly suitable, if the energy stored in the energy storage member is not sufficient to move the bung away from the initial position. 
         [0101]    The supplemental storage member may be configured to assist, preferably to only temporarily assist, the energy storage member in providing the driving force. The supplemental storage member may be configured to assist the energy storage member in providing the driving force at the beginning, preferably only at the beginning, of the emptying of the cartridge, i.e. when the bung is moved from the initial position to the intermediate position. Once the intermediate position has been reached, the supplemental energy is expediently no longer provided as only a lower driving force is required to move the bung in the intermediate position. The supplemental energy may be stored in the supplemental storage member when the device is assembled. Preferably, the user has no influence on the energy stored in the storage member except that he may release the energy when operating the drug delivery device. The supplemental storage member can preferably not be reloaded once all of the energy has been released from the supplemental storage member. 
         [0102]    In an embodiment, the supplemental storage member is a mechanical storage member. The supplemental storage member may be or may comprise a spring. The spring may be pre-biased, such as during assembly of the device. Preferably, the spring may be not user-loadable or biasable during operation of the drug delivery device. The supplemental storage member may, for example, be a compression spring, a leaf spring, or a washer spring. Alternatively or additionally, the supplemental storage member may be or may comprise a cartridge or reservoir which is filled with gas, preferably pressurized gas. When the pressurized gas expands, e.g. once the interior of the cartridge or reservoir is in fluid communication, for example because an outer shell of the cartridge is destroyed during the initial operation of the drive mechanism, with the exterior, supplemental energy can be transferred to the bung in order to increase the driving force to displace the bung from its initial position towards the intermediate position. 
         [0103]    In an embodiment, the drive mechanism comprises a piston rod. The piston rod may be configured to transfer the driving force to the bung. The piston rod may be coupleable to a dose dispensing member of the device, for example to a button, immediately or via further components of the drive mechanism. Actuation of the dose dispensing member by the user may initiate the dispensing action for a previously set dose. By means of the piston rod, movement of the bung with respect to the cartridge may be driven during the dispensing action. For contacting the bung of the cartridge, a bearing may be attached to the piston rod, particularly to a distal end thereof. The piston rod may be rotatably connected to the bearing such that the piston rod may rotate relative to the bearing. Alternatively, a bearing surface may be provided by a, preferably unitary, piston rod. The piston rod may be configured to rotate relative to the housing. In this case, the piston rod is preferably coupled to the housing via a threaded interface. Consequently, rotation of the piston rod is converted into axial displacement of the piston rod with respect to the housing. Alternatively, the piston rod is threadedly engaged with a nut and is prevented from rotating with respect to the housing where the nut is allowed to rotate relative to the housing, thereby displacing the piston rod with respect to the housing. 
         [0104]    In an embodiment, the piston rod is displaceable away from an initial position, preferably towards an end position of the piston rod, as the bung is displaced relative to the cartridge. In the initial position of the piston rod, the bung is expediently also in its initial position. 
         [0105]    In an embodiment, in the initial position of the bung and/or of the piston rod, the piston rod is mechanically decoupled from the bung. That is to say, in the initial position, there may be a gap between piston rod and bung and/or between bung and bearing. Alternatively in the initial position of the bung and/or of the piston rod the piston rod is mechanically coupled to the bung. In this case, the piston rod, or the bearing attached to the piston rod, may be in mechanical contact with the bung in the initial position. Expediently, in this case the piston rod or the bearing and the bung abut. 
         [0106]    In an embodiment, the supplemental storage member mechanically cooperates with the piston rod and is arranged to assist movement of the piston rod to drive movement of the bung. 
         [0107]    In an embodiment, the supplemental storage member acts, e.g. directly or indirectly, on the piston rod. 
         [0108]    As the energy stored in the supplemental storage member is preferably less than the energy required to move the bung away from the initial position, i.e. the maximum force exertable by the energy stored in the supplemental storage member is preferably less than the initial stiction force, it can be avoided that medicament or a drug is dispensed from the cartridge due to a pre-bias of the bung when the needle is attached to the drug delivery device and provides fluid communication between the interior of the cartridge and the outside, even if the bung and the piston rod are mechanically coupled in the initial position. 
         [0109]    In an embodiment, the supplemental storage member is arranged to bias or biases the piston rod. The supplemental storage member may bias the piston rod in the distal direction and/or away from the initial position of the piston rod. The supplemental storage member may bias the piston rod in the direction towards the bung, expediently in an initial position of the piston rod. 
         [0110]    In an embodiment, the energy stored in the supplemental storage member is less than the energy required to move the piston rod away from the initial position of the piston rod. The piston rod may remain in the initial position, even though the piston rod is mechanically decoupled from the bung and even though the supplemental storage member exerts a force on the piston rod in the distal direction. The biasing force exerted by the supplemental storage member may, in this case, be lower than the internal static friction forces in the drive mechanism in the initial position of the piston rod. 
         [0111]    In an embodiment, the supplemental storage member acts on the piston rod or biases the piston rod only temporarily. Accordingly, there is a certain point in time during the travel of the piston rod towards its end position from which point onwards the supplemental storage member no longer acts on the piston rod. When the supplemental storage member no longer exerts a force on the piston rod, the bung may be in the intermediate position. 
         [0112]    In an embodiment, the supplemental storage member acts on the piston rod via the bearing. Particularly, the supplemental storage member may be retained between an element fixed, preferably axially and rotationally, to the housing and the bearing or between the housing and the bearing. Consequently, in the initial position of the piston rod there may be a state of tension between piston rod and bearing. Particularly, a distal surface of the bearing and a proximal surface of the piston rod may be in contact with each other in the initial position of the piston rod. When the piston rod is displaced from the initial position and moves the bung away from its initial position, it is preferred that a proximal surface of the bearing and a distal surface of the piston rod abut before the bung moves. Thereby, a state of compression may be established between piston rod and bearing before the first dose is delivered. The state of compression may be established continuously after the bung has been displaced away from its initial position. Thus, the piston rod and bearing may be in the state of compression all the time when drug has already been dispensed form the device, preferably also when there is no movement of the piston rod. A constant compression state is more reliable when dispensing doses than varying between a tension state and a compression state. A switch from the state of tension to the state of compression before the first amount of drug is dispensed from the cartridge may be achieved by choosing the supplemental storage member to have an energy stored therein which is less than the one required to move the bung away from the initial position. 
         [0113]    In an embodiment, the supplemental storage member, e.g. the cartridge with the pressurized gas, is arranged between the piston rod or bearing and the bung. 
         [0114]    In an embodiment, the piston rod comprises a thread, e.g. a helical thread. The piston rod may be coupled to the housing via the thread. The thread may have a variable pitch and/or a variable lead. The thread is expediently configured such that the maximal dispensing force which is transferrable to the bung varies, e.g. even if the same torque is exerted by the energy storage member. Particularly, the energy storage member may, in this case, be configured to supply the whole energy required to move the bung with respect to the cartridge. The supplemental storage member may be, but does not need to be, dispensed with in this case. For example, if the thread has a section with a finer pitch or lower lead, a given torque acting on the piston rod results in less axial displacement and a correspondingly increased force acting on the bung than in a section with coarser pitch or higher lead. 
         [0115]    In an embodiment, the thread has a distal section, particularly a distal end section, facing a distal end of the piston rod and a proximal section, the proximal section being arranged further away from the distal end of the piston rod than the distal section. In the distal section the pitch of the thread and/or the lead of the thread is preferably less than the pitch of the thread and/or the lead of the thread in the proximal section. Accordingly, in the distal section the pitch/lead may be less than the pitch/lead in the proximal section. Particularly, in the distal section the thread may be more finely pitched than in the proximal section. Preferably, the pitch/lead in the respective section is constant and changes only in an intermediate section arranged between the distal section and the proximal section. There may be only one intermediate section. Consequently, as the distal section is the one which governs displacement of the piston rod away from the initial position and also the initial movement of the bung, the distal section is designed to increase the driving force in the initial bung position. 
         [0116]    By means of the according thread design, it can be achieved that, provided a given torque provided by the energy storage member is used to drive the piston rod distally, there is less axial displacement when the distal section is used to drive movement of the piston rod on account of its finer pitch or lower lead which results in a higher force being transferred to the bung, this force being expediently greater than the stiction force in the initial position of the bung. 
         [0117]    In an embodiment, the piston rod is coupled to the housing via a threaded interface with constant pitch. In this case, the thread of the piston rod may have a constant pitch. 
         [0118]    In an embodiment, the piston rod is coupled to the housing via a first threaded interface. The first threaded interface may have a constant pitch and/or lead. The first threaded interface may be formed by means of the thread of the piston rod described above, for example in cooperation with an engagement member which is axially fixed relative to the housing. The pitch of the thread of the piston rod which threadedly couples the piston rod to the housing may be constant. The piston rod may be coupled to a further component of the drug delivery device via a second threaded interface. The first and second threaded interfaces may have different pitches and/or leads. The second threaded interface and the first threaded interface may be adjusted with respect to each other, in particular with respect to the pitches and/or leads, such that, when the second threaded interface is active, for example if the further component threadedly interacts with the piston rod via the second threaded interface, the force acting on the bung is increased when the first threaded interface is also active. The pitch and/or lead of the second threaded interface may be smaller than the pitch and/or lead of the first threaded interface. The second threaded interface may be active only temporarily, for example in order to provide only an increased initial driving force in order to displace the bung away from its initial position. The first threaded interface may be active continuously. The second threaded interface may be formed by a further thread of the piston rod, e.g. a helical thread. The further thread may have a smaller pitch and/or a smaller lead than the thread which couples the piston rod to the housing. The further component which is coupled to the piston rod via the second threaded interface may be the bearing described above. 
         [0119]    In a particularly advantageous embodiment, a drug delivery device is provided, comprising a housing, a cartridge, the cartridge containing a drug in a quantity sufficient for a plurality of doses of the drug, a bung, the bung being movably retained within the cartridge to dispense a dose of the drug from the cartridge upon movement of the bung with respect to the cartridge, a drive mechanism, the drive mechanism being operable to transfer a driving force to the bung to dispense the dose of the drug from the cartridge, wherein the drug delivery device is configured such that the maximal driving force which is transferrable to the bung via the drive mechanism varies and is adjusted to the current position of the bung within the cartridge. 
         [0120]    This embodiment has a number of advantages which will be readily apparent from the description above and below. 
         [0121]    Of course, features described in conjunction with different embodiments, aspects, etc. herein above and below can be combined with one another. 
         [0122]    Further features, advantages and advantageous refinements of the present disclosure become apparent from the following description of the exemplary embodiments in conjunction with the drawings. The description of the exemplary embodiments does not limit the scope of the present disclosure. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0123]      FIG. 1  shows a top view of an exemplary embodiment of a drug delivery device of the present disclosure in a minimum dose position; 
           [0124]      FIG. 2  shows an exploded view of the components of the device of  FIG. 1 ; 
           [0125]      FIG. 3  shows a sectional view of the device of  FIG. 1 ; 
           [0126]      FIG. 4 a    shows an enlarged sectional view of a detail of the device of  FIG. 1  in a dose setting mode; 
           [0127]      FIG. 4 b    shows an enlarged sectional view of a detail of the device of  FIG. 1  in a dose dispensing mode; 
           [0128]      FIG. 5  shows an interface between the number sleeve and the button of the device of  FIG. 1 ; 
           [0129]      FIG. 6  shows an interface between the housing and the button of the device of  FIG. 1 ; 
           [0130]      FIGS. 7 a, b    show an interface between the number sleeve and the drive sleeve of the device of  FIG. 1  in the dose setting mode and in the dose dispensing mode; 
           [0131]      FIG. 8  shows an interface between a piston rod and a bearing of the device of  FIG. 1 ; 
           [0132]      FIG. 9  shows an interface between the clutch plate and the button of the device of  FIG. 1 ; 
           [0133]      FIG. 10  shows in a sectional view the components of an end of dose clicker of the device of  FIG. 1 ; 
           [0134]      FIGS. 11 a - c    show in enlarged views the sequence of generating a click at the end of dose dispensing of the device of  FIG. 1 ; 
           [0135]      FIGS. 12 a - c    show in enlarged sectional views the sequence of generating a click at the end of dose dispensing of the device of  FIG. 1 ; 
           [0136]      FIG. 13  shows the gauge element of the device of  FIG. 1 ; 
           [0137]      FIG. 14  shows a portion of the number sleeve of the device of  FIG. 1 ; 
           [0138]      FIG. 15  shows a further portion of the number sleeve of the device of  FIG. 1 ; 
           [0139]      FIG. 16  shows a portion of the drive spring of the device of  FIG. 1 ; 
           [0140]      FIGS. 17 a, b    show top views of the device of  FIG. 1  with 0 units dialed and with 96 units dialed; 
           [0141]      FIG. 18  shows an interface between the housing and the drive sleeve of the device of  FIG. 1 ; 
           [0142]      FIG. 19  shows an interface between the clutch plate and the drive sleeve of the device of  FIG. 1 ; 
           [0143]      FIG. 20  shows a last dose mechanism of the device of  FIG. 1 ; 
           [0144]      FIG. 21  shows the torsion spring of the device of  FIG. 1 ; 
           [0145]      FIGS. 22 a - c    show different embodiments of the threads between the piston rod and the housing of the device of  FIG. 1 ; 
           [0146]      FIG. 23 a, b    show again different embodiments of the threads between the piston rod and the housing of the device of  FIG. 1 , where the embodiment in  FIG. 23 b    provides for an initially increased driving force; and 
           [0147]      FIG. 24  shows an embodiment of the device of  FIG. 1 , which uses a supplemental storage member to provide an initially increased driving force. 
       
    
    
       [0148]    Identical features, features of the same kind and/or identically acting features may be provided with the same reference numerals throughout the figures. 
       DETAILED DESCRIPTION 
       [0149]      FIG. 1  shows a drug delivery device in the form of an injection pen. The device has a distal end (left end in  FIG. 1 ) and a proximal end (right end in  FIG. 1 ). The component parts of the drug delivery device are shown in  FIG. 2 . The drug delivery device comprises a body or housing  10 , a cartridge holder  20 , a lead screw or piston rod  30 , a drive sleeve  40 , a nut  50 , a dose indicator or number sleeve  60 , a button  70 , a dial grip or dose selector  80 , a torsion spring  90 , a cartridge  100 , a gauge element  110 , a clutch plate  120 , a clutch spring  130  and a bearing  140 . A needle arrangement (not explicitly shown) with a needle hub and a needle cover may be provided as additional components, which can be exchanged as explained above. The device comprises a principal axis  1  (see  FIG. 3 ). All components are preferably located concentrically about the common principal axis I of the mechanism. 
         [0150]    The housing  10  or body is a generally tubular element having a proximal end with an enlarged diameter. The housing  10  provides location for the liquid medication cartridge  100  and cartridge holder  20 , windows  11   a,    11   b  for viewing the dose number on the number sleeve  60  and the gauge element  110 , and a feature on its external surface, e.g. a circumferential groove, to axially retain the dose selector  80 . A flange-like or cylindrical inner wall  12  comprises an inner thread engaging the piston rod  30 . The housing  10  further has at least one internal, axially orientated slot or the like for axially guiding the gauge element  110 . In the embodiment shown in the Figures, the distal end is provided with an axially extending strip  13  partly overlapping cartridge holder  20 . The Figures depict the housing  10  as a single housing component. However, the housing  10  could comprise two or more housing components which may be permanently attached to each other during assembly of the device. 
         [0151]    The cartridge holder  20  is located at the distal side of housing  10  and permanently attached thereto. The cartridge holder may be a transparent or translucent component which is tubular to receive cartridge  100 . The distal end of cartridge holder  20  may be provided with means for attaching a needle arrangement. A removable cap (not shown) may be provided to fit over the cartridge holder  20  and may be retained via clip features on the housing  10 . 
         [0152]    The piston rod  30  is rotationally constrained to the drive sleeve  40  via a splined interface. When rotated, the piston rod  30  is forced to move axially relative to the drive sleeve  40 , through its threaded interface with the inner wall  12  of housing  10 . The lead screw  30  is an elongate member with an outer thread  31  ( FIG. 3 ) engaging the corresponding thread of the inner wall  12  of housing  10 . The thread  31  may have a large lead-in, for example a wedge shape form, at its distal end to engage a corresponding housing thread form on the first rotation. The interface comprises at least one longitudinal groove or track and a corresponding protrusion or spline  45  of the driver or drive sleeve  40 . At its distal end, the lead screw  30  is provided with an interface for clip attachment of the bearing  140 . In the present embodiment, this interface comprises two clip arms  32  extending in the distal direction defining an insertion space between them for insertion of a bearing  140  interface. As an alternative, the interface may comprise only one single clip arm extending more than 180° about the longitudinal axis, or may comprise one or several clip arms  32 . The clip arm(s)  32  may have a bent form with a recessed clip portion as shown in  FIG. 8 . Preferably, the clip arm(s) form a cylindrical outer face having a diameter equal to or smaller than the outer diameter of the lead screw  30  at the base of the groove (flute base) of the outer thread  31 . A concave contact surface  33  is provided between the clip arms  32  for abutment of a corresponding portion of bearing  140 . 
         [0153]    The drive sleeve  40  is a hollow member surrounding the lead screw  30  and arranged within number sleeve  60 . It extends from an interface with the clutch plate  120  to the contact with the clutch spring  130 . The drive sleeve  40  is axially movable relative to the housing  10 , the piston rod  30  and the number sleeve  60  in the distal direction against the bias of clutch spring  130  and in the opposite proximal direction under the bias of clutch spring  130 . 
         [0154]    A splined tooth interface with the housing  10  prevents rotation of the drive sleeve  40  during dose setting. This interface which is shown in  FIG. 18  in detail comprises a ring of radially extending outer teeth  41  at the distal end of drive sleeve  40  and corresponding radially extending inner teeth  14  of the housing component  10 . When the button  70  is pressed, the drive sleeve  40  and housing  10  spline teeth  14 ,  41  are disengaged allowing the drive sleeve  40  to rotate relative to housing  10 . 
         [0155]    A further splined tooth interface with the number sleeve  60  is not engaged during dialing, but engages when the button  70  is pressed, preventing relative rotation between the drive sleeve  40  and number sleeve  60  during dispense. In the preferred embodiment shown in  FIGS. 7 a  and 7 b    this interface comprises inwardly directed splines  61  on a flange  62  on the inner surface of the number sleeve  60  and a ring of radially extending outer splines  42  of drive sleeve  40 . The corresponding splines  61 ,  42  are located on the number sleeve  60  and the drive sleeve  40 , respectively, such that axial movement of the drive sleeve  40  relative to the (axially fixed) number sleeve  60  engages or disengages the splines to rotationally couple or decouple the drive sleeve  40  and the number sleeve  60 . 
         [0156]    Preferably, the splines  61 ,  42  are arranged such that they are decoupled when teeth  41  of drive sleeve  40  and inner teeth  14  of housing component  10  mesh and engage when teeth  41  and inner teeth  14  disengage. In a preferred embodiment the splines  61 ,  42  are longer in the axial direction compared with teeth  41 ,  14 . This allows engagement of the splines  61 ,  42  shortly before disengagement of teeth  41 ,  14 . In other words, the splines  61 ,  42  and the teeth  41 ,  14  are designed and arranged such that actuation of the button  70  rotationally constrains the drive sleeve  40  to the number sleeve  60  before the drive sleeve  40  is allowed to rotate relative to housing  10 . Similarly, as the button  70  is released after dose dispensing axial movement of the drive sleeve  40  first rotationally constrains the drive sleeve  40  to the housing and thereafter decouples splines  61 ,  42 . As an alternative to the corresponding splines  61 ,  42  teeth may be provided. As a further alternative or in addition to splines  61 ,  42 , drive sleeve  40  and number sleeve  60  may be rotationally coupled to each other during dose dispensing via clutch plate  120 . 
         [0157]    An interface of the drive sleeve  40  which is shown in  FIG. 19  comprises a ring of ratchet teeth  43  located at the proximal end face of drive sleeve  40  and a ring of corresponding ratchet teeth  121  of clutch plate  120 . 
         [0158]    The driver or drive sleeve  40  has a threaded section  44  providing a helical track for the nut  50  ( FIG. 20 ). In addition, a last dose abutment or stop  46  is provided which may be the end of the thread  44  track or preferably a rotational hard stop for interaction with a corresponding last dose stop  51  of nut  50 , thus limiting movement of the nut  50  on the thread  44 . At least one longitudinal spline  45  engages a corresponding track of the lead screw  30 . Further, the drive sleeve is provided with a ramp  47  interacting with a clicker arm  67  when the drive sleeve  40  is in its distal position during dose dispensing, i.e. when button  70  is depressed. 
         [0159]    The last dose nut  50  is located between the number sleeve  60  and the drive sleeve  40 . It is rotationally constrained to the number sleeve  60 , via a splined interface (splines  52  on nut  50 ). It moves along a helical path relative to the drive sleeve  40 , via a threaded interface (thread  44 ), when relative rotation occurs between the number sleeve  60  and drive sleeve  40  which is during dialing only. This is shown in  FIG. 20 . As an alternative, the nut  50  may be splined to the driver  40  and threaded to the number sleeve  60 . In the embodiment shown in the Figures, the nut  50  is a full nut, but in alternative embodiments it may be a half nut, i.e. a component extending approximately 180° around the center axis of the device. A last dose stop  51  is provided engaging stop  46  of drive sleeve  40  when a dose is set corresponding to the remaining dispensable amount of medicament in the cartridge  100 . 
         [0160]    The dose indicator or number sleeve  60  is a tubular element as shown in  FIGS. 2 and 3 . The number sleeve  60  is rotated during dose setting (via dose selector  80 ) and dose correction and during dose dispensing by torsion spring  90 . Together with gauge element  110  the number sleeve  60  defines a zero position (‘at rest’) and a maximum dose position. Thus, the number sleeve  60  may be seen as a dose setting member as may the dose selector. 
         [0161]    For manufacturing reasons the number sleeve  60  of the embodiment shown in the Figures comprises a number sleeve lower  60   a  which is rigidly fixed to a number sleeve upper  60   b  during assembly to form the number sleeve  60 . Number sleeve lower  60   a  and number sleeve upper  60   b  are separate components only to simplify number sleeve  60  mold tooling and assembly. As an alternative, the number sleeve  60  may be a unitary component. The number sleeve  60  is constrained to the housing  10  by features towards the distal end to allow rotation but not translation. The number sleeve lower  60   a  is marked with a sequence of numbers, which are visible through the gauge element  110  and the openings  11 a,  11 b in the housing  10 , to denote the dialed dose of medicament. 
         [0162]    Further, the number sleeve lower  60   a  has a portion with an outer thread  63  engaging the gauge element  110 . End stops  64 ,  65  are provided at the opposite ends of thread  63  to limit relative movement with respect to the gauge element  110 . 
         [0163]    Clutch features which have the form of a ring of splines  66  in the embodiment of  FIG. 5  are provided inwardly directed on number sleeve upper  60   b  for engagement with splines  73  of the button  70  during dose setting and dose correction. A clicker arm  67  is provided on the outer surface of number sleeve  60  which interacts with the drive sleeve  40  and the gauge member  110  for generating a feedback signal. In addition, the number sleeve lower  60   a  is rotationally constrained to the nut  50  and to the clutch plate  120  via a splined interface comprising at least one longitudinal spline. 
         [0164]    An interface for attachment of the torsion spring  90  to the number sleeve lower  60   a  comprises large lead-ins and a groove feature  68  with a pocket  69  or anchor point for receiving a first coil or hook portion of the spring. The groove  68  has an end feature in the form of a ramp that is in interference with the hook portion  91  of the spring. The design of the groove  68  is such that the spring  90  may be received within the pocket  69  without interfering with the gauge element  110 . 
         [0165]    The button  70  which forms the proximal end of the device is permanently splined to the dose selector  80 . A central stem  71  extends distally from the proximal actuation face of the button  70 . The stem  71  is provided with a flange  72  carrying the splines  73  for engagement with splines  66  of the number sleeve upper  60   b  ( FIG. 5 ). Thus, it is also splined via splines  66 ,  73  ( FIG. 5 ) to the number sleeve upper  60   b  when the button  70  is not pressed, but this spline interface is disconnected when the button  70  is pressed. The button  70  has a discontinuous annular skirt with splines  74 . When the button  70  is pressed, splines  74  on the button  70  engage with splines on the housing  10  ( FIG. 6 ), preventing rotation of the button  70  (and hence the dose selector  80 ) during dispense. These splines  74 ,  15  disengage when the button  70  is released, allowing a dose to be dialed. Further, a ring of ratchet teeth  75  is provided on the inner side of flange  72  ( FIG. 9 ) for interaction with clutch plate  120 . 
         [0166]    The dose selector  80  is axially constrained to the housing  10 . It is rotationally constrained, via the splined interface, to the button  70 . This splined interface, which includes grooves interacting with spline features formed by the annular skirt of button  70 , remains engaged irrespective of the dose button  70  axial positions. The dose selector  80  or dose dial grip is a sleeve-like component with a serrated outer skirt. 
         [0167]    The torsion spring  90  is attached at its distal end to the housing  10  and at the other end to the number sleeve  60 . The torsion spring  90  is located inside the number sleeve  60  and surrounds a distal portion of the drive sleeve  40 . As shown in  FIG. 16 , the spring has a hook  91  at one end for attachment on the number sleeve  60 . A similar hook end  92  is provided at the opposite end for attachment on the housing  10 . The torsion spring  90  is pre-wound upon assembly, such that it applies a torque to the number sleeve  60  when the mechanism is at zero units dialed. The action of rotating the dose selector  80 , to set a dose, rotates the number sleeve  60  relative to the housing  10 , and charges the torsion spring  90  further. 
         [0168]    The torsion spring  90  is formed from a helical wire with at least two different pitches. In  FIG. 21 , both ends are formed from ‘closed’ coils  93 , i.e. the pitch equals the wire diameter and each coil contacts the adjacent coil. The central portion has ‘open’ coils  94 , i.e. the coils do not contact each other. 
         [0169]    The cartridge  100  is received in cartridge holder  20  ( FIG. 3 ). The cartridge  100  may be a glass ampoule. A moveable rubber bung  101  may be received in the proximal end of the cartridge. The distal end of cartridge  100  is provided with a pierceable rubber seal which is held in place by a crimped annular metal band. The seal covers an outlet of the cartridge and prevents that fluid drug leaves the cartridge unless fluid communication is provided between the interior of the cartridge  100  and the outside. The drug is retained within the interior of the cartridge and can be dispensed from the cartridge by moving the bung  101  towards the outlet, provided fluid communication to the outside is established, e.g. by a needle assembly. In the embodiment depicted in the Figures, the cartridge  100  is a standard 1.5 ml cartridge. The device is designed to be disposable in that the cartridge  100  cannot be replaced by the user or health care professional. However, a reusable variant of the device could be provided by making the cartridge holder  20  removable and allowing backwinding of the lead screw  30  and the resetting of nut  50 . 
         [0170]    The gauge element  110  is constrained to prevent rotation but allow translation relative to the housing  10  via a splined interface. The gauge element  110  has a helical feature  111  on its inner surface which engages with the helical thread, which is preferably cut, in the number sleeve  60  such that rotation of the number sleeve  60  causes axial translation of the gauge element  110 . This helical feature on the gauge element  110  also creates stop abutments  112 ,  113  against the end of the helical cut in the number sleeve  60  to limit the minimum and maximum dose that can be set. 
         [0171]    The gauge element  110  has a generally plate or band like component having a central aperture  114  or window and two flanges  115 ,  116  extending on either side of the aperture. The flanges  115 ,  116  are preferably not transparent and thus shield or cover the number sleeve  60 , whereas the aperture  114  or window allows viewing a portion of the number sleeve lower  60   a.  Further, gauge element  110  has a cam  117  and a recess  118  ( FIGS. 11 a -12 c   ) interacting with the clicker arm  67  of the number sleeve  60  at the end of dose dispensing. 
         [0172]    As can be seen in  FIGS. 9 and 19 , the clutch plate  120  is a ring-like component. The clutch plate  120  is splined to the number sleeve  60  via splines  122 . It is also coupled to the drive sleeve  40  via a ratchet interface (ratchet teeth  43 ,  121 ). The ratchet provides a detented position between the number sleeve  60  and drive sleeve  40  corresponding to each dose unit, and engages different ramped tooth angles during clockwise and anti-clockwise relative rotation. A clicker arm  123  is provided on the clutch plate  120  for interaction with ratchet features  75  of the button. 
         [0173]    The clutch spring  130  is a compression spring. The axial position of the drive sleeve  40 , clutch plate  120  and button  70  is defined by the action of the clutch spring  130 , which applies a force on the drive sleeve  40  in the proximal direction. This spring force is reacted via the drive sleeve  40 , clutch plate  120 , and button  70 , and when ‘at rest’ it is further reacted through the dose selector  80  to the housing  10 . The spring force ensures that the ratchet interface (ratchet teeth  43 ,  121 ) is always engaged. In the ‘at rest’ position, it also ensures that the button splines  73  are engaged with the number sleeve splines  66 , and the drive sleeve teeth  41  are engaged with teeth  14  of the housing  10 . 
         [0174]    The bearing  140  is axially constrained to the piston rod  30  and acts on the bung  101  within the liquid medicament cartridge. It is axially clipped to the lead screw  30 , but free to rotate. The bearing  140  comprises a disc  141  having a stem  142  extending in the proximal direction. The stem  142  has at its proximal end a convex contact surface  143 . In addition, a recessed portion  144  is provided on the stem  142 . The curvature of the convex contact surface  143  and the concave contact surface  33  is chosen such that the contact diameter between the bearing  140  and lead screw  30  is small to minimize the frictional losses at this interface. The design of the clip interface between bearing  140  and lead screw  30  permits the lead screw  30  to be assembled axially, from the proximal end and through the thread engagement to the housing  10 , which simplifies assembly. In addition, this design allows a simple “open and shut” mold tooling for both components. 
         [0175]    With the device in the ‘at rest’ condition as shown in  FIGS. 4 a  and 17 a   , the number sleeve  60  is positioned against its zero dose abutment  64 ,  113  with the gauge element  110  and the button  70  is not depressed. Dose marking ‘0’ on the number sleeve  60  is visible through the windows  11   b  and  114  of the housing  10  and gauge element  110 , respectively. 
         [0176]    The torsion spring  90 , which has a number of pre-wound turns applied to it during assembly of the device, applies a torque to the number sleeve  60  and is prevented from rotating by the zero dose abutment  64 ,  113 . It is also possible to ‘back-wind’ the mechanism slightly due to an offset between the zero dose stop  64 ,  113  and the angular offset of the drive sleeve  40  spline teeth. This has the effect of preventing possible weepage when a dose is dialed and the zero dose abutment is disengaged. 
         [0177]    The automated assembly of the torsion spring  90  into the number sleeve  60  can be achieved by incorporating large lead-ins and a groove feature to the number sleeve  60 . As the torsion spring  90  is rotated during assembly, the hook end form  91  locates in the groove feature before engaging the anchor point in the number sleeve  60 . To help to prevent the torsion spring  90  disengaging the anchor point  69  during subsequent assembly steps it is possible to create an interference between the torsion spring  90  and the number sleeve  60 , or a one-way clip feature. 
         [0178]    The user selects a variable dose of liquid medicament by rotating the dose selector  80  clockwise, which generates an identical rotation in the number sleeve  60 . Rotation of the number sleeve  60  causes charging of the torsion spring  90 , increasing the energy stored within it. As the number sleeve  60  rotates, the gauge element  110  translates axially due to its threaded engagement thereby showing the value of the dialed dose. The gauge element  110  has flanges  115 ,  116  either side of the window area  114  which cover the numbers printed on the number sleeve  60  adjacent to the dialed dose to ensure only the set dose number is made visible to the user. 
         [0179]    A specific feature of this device is the inclusion of a visual feedback feature in addition to the discrete dose number display typical on devices of this type. The distal end (flange  115 ) of the gauge element  110  creates a sliding scale through a small window  11   a  in the housing  10 . As an alternative, the sliding scale could be formed using a separate component engaged with the number sleeve  60  on a different helical track. 
         [0180]    As a dose is set by the user, the gauge element  110  translates axially, the distance moved being 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 gauge feature provides feedback to the user during dispense regarding dispense progress without the need to read the dose number itself. For example, the gauge display may be formed by an opaque element on the gauge element  110  revealing a contrasting colored component underneath. Alternatively, the revealable element may be printed with coarse dose numbers or other indices to provide more precise resolution. In addition, the gauge display simulates a syringe action during dose set and dispense. 
         [0181]    The openings  11   a,    11   b  in the housing  10  allow the user to view the gauge feature and number display as shown in  FIGS. 17 a  and 17 b   . To reduce dust ingress and prevent the user from touching moving parts, these openings  11   a,    11   b  are covered by translucent windows. These windows may be separate components, but in this embodiment they are incorporated into the housing  10  using ‘twin-shot’ molding technology. A first shot of translucent material forms the internal features and the windows  11 a,  11 b, and then a ‘second shot’ of opaque material forms the outer cover of the housing  10 . 
         [0182]    The mechanism utilizes a dose selector  80  with an increased diameter relative to the housing  10  which aids dialing although this is not a requirement of the mechanism. This feature is particularly useful (but not essential) for an auto-injector mechanism where a power supply is charged during dose setting and the torque required to turn the dose selector  80  may be higher than for a non-auto injector device. 
         [0183]    The drive sleeve  40  is prevented from rotating as the dose is set and the number sleeve  60  rotates due to the engagement of its splined teeth  41  with teeth  14  of the housing  10 . Relative rotation must therefore occur between the clutch plate  120  and drive sleeve  40  via the ratchet interface  43 ,  121 . 
         [0184]    The user torque required to rotate the dose selector  80  is a sum of the torque required to wind up the torsion spring  90 , and the torque required to overhaul the ratchet interface  43 ,  121 . The clutch spring  130  is designed to provide an axial force to the ratchet interface  43 ,  121  and to bias the clutch plate  120  onto the drive sleeve  40 . This axial load acts to maintain the ratchet teeth engagement of the clutch plate  120  and drive sleeve  40 . The torque required to overhaul the ratchet  43 ,  121  in the dose set direction is a function of the axial load applied by the clutch spring  130 , the clockwise ramp angle of the ratchet teeth  43 ,  121 , the friction coefficient between the mating surfaces and the mean radius of the ratchet interface  43 ,  121 . 
         [0185]    As the user rotates the dose selector  80  sufficiently to increment the mechanism by one increment, the number sleeve  60  rotates relative to the drive sleeve  40  by one ratchet tooth. At this point the ratchet teeth  43 ,  121  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. 
         [0186]    Relative rotation of the number sleeve  60  and the drive sleeve  40  is allowed as splines  42 ,  61  are disengaged during dose setting. This relative rotation also causes the last dose nut  50  to travel along its threaded path, towards its last dose abutment on the drive sleeve  40 . 
         [0187]    With no user torque applied to the dose selector  80 , the number sleeve  60  is now prevented from rotating back under the torque applied by the torsion spring  90 , solely by the ratchet interface  43 ,  121  between the clutch plate  120  and the drive sleeve  40 . The torque necessary to overhaul the ratchet in the anti-clockwise direction is a function of the axial load applied by the clutch spring  130 , the anti-clockwise ramp angle of the ratchet, 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  60  (and hence clutch plate  120 ) by the torsion spring  90 . 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. 
         [0188]    The user may now choose to increase the selected dose by continuing to rotate the dose selector  80  in the clockwise direction. The process of overhauling the ratchet interface  43 ,  121  between the number sleeve  60  and drive sleeve  40  is repeated for each dose increment. Additional energy is stored within the torsion spring  90  for each dose increment and audible and tactile feedback is provided for each increment dialed by the re-engagement of the ratchet teeth. The torque required to rotate the dose selector  80  increases as the torque required to wind up the torsion spring  90  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  60  by the torsion spring  90  when the maximum dose has been reached. 
         [0189]    If the user continues to increase the selected dose until the maximum dose limit is reached, the number sleeve  60  engages with its maximum dose abutment  65  on the maximum dose abutment  112  of gauge element  110 . This prevents further rotation of the number sleeve  60 , clutch plate  120  and dose selector  80 . 
         [0190]    Depending on how many increments have already been delivered by the mechanism, during selection of a dose, the last dose nut  50  may contact its last dose abutment  51  with stop face  46  of the drive sleeve  40 . The abutment prevents further relative rotation between the number sleeve  60  and the drive sleeve  40 , and therefore limits the dose that can be selected. The position of the last dose nut  50  is determined by the total number of relative rotations between the number sleeve  60  and drive sleeve  40 , which have occurred each time the user sets a dose. 
         [0191]    With the mechanism in a state in which a dose has been selected, the user is able to deselect any number of increments from this dose. Deselecting a dose is achieved by the user rotating the dose selector  80  anti-clockwise. The torque applied to the dose selector  80  by the user is sufficient, when combined with the torque applied by the torsion spring  90 , to overhaul the ratchet interface  43 ,  121  between the clutch plate  120  and drive sleeve  40  in the anti-clockwise direction. When the ratchet is overhauled, anti-clockwise rotation occurs in the number sleeve  60  (via the clutch plate  120 ), which returns the number sleeve  60  towards the zero dose position, and unwinds the torsion spring  90 . The relative rotation between the number sleeve  60  and drive sleeve  40  causes the last dose nut  50  to return along its helical path, away from the last dose abutment. 
         [0192]    With the mechanism in a state in which a dose has been selected, the user is able to activate the mechanism to commence delivery of a dose. Delivery of a dose is initiated by the user depressing the button  70  axially in the distal direction. 
         [0193]    When the button  70  is depressed, splines between the button  70  and number sleeve  60  are disengaged, rotationally disconnecting the button  70  and dose selector  80  from the delivery mechanism, i.e. from number sleeve  60 , gauge element  110  and torsion spring  90 . Splines  74  on the button  70  engage with splines  15  on the housing  10 , preventing rotation of the button  70  (and hence the dose selector  80 ) during dispense. As the button  70  is stationary during dispense, it can be used in the dispense clicker mechanism as shown in  FIG. 9 . A stop feature in the housing  10  limits axial travel of the button  70  and reacts any axial abuse loads applied by the user, reducing the risk of damaging internal components. 
         [0194]    The clutch plate  120  and drive sleeve  40  travel axially with the button  70 . This engages the splined tooth interface  42 ,  61  between the drive sleeve  40  and number sleeve  60  as shown in  FIGS. 7 a    (splines  42 ,  61  disengaged) and  7   b  (splines  42 ,  61  engaged), preventing relative rotation between the drive sleeve  40  and number sleeve  60  during dispense. The splined tooth interface  41 ,  14  between the drive sleeve  40  and the housing  10  disengages, so the drive sleeve  40  can now rotate and is driven by the torsion spring  90  via the number sleeve  60 , and clutch plate  120 . 
         [0195]    Rotation of the drive sleeve  40  causes the piston rod  30  to rotate due to their splined engagement, and the piston rod  30  then advances due to its threaded engagement to the housing  10 . The number sleeve  60  rotation also causes the gauge element  110  to traverse axially back to its zero position whereby the zero dose abutment  64 ,  113  stops the mechanism. 
         [0196]    The bearing  140  is axially clipped to the piston rod  30 , but free to rotate. Since the bearing  140  is in direct contact with the bung  101 , it does not rotate as the piston rod  30  rotates and advances during dose dispense. As described above, the contact diameter between the bearing  140  and piston rod  30  is small to minimize the frictional losses at this interface. The design of the piston rod  30  and bearing  140  eliminates delicate clip features or large contact diameters present on previous concepts. This embodiment also allows the piston rod  30  to be assembled axially, from the proximal end and through the thread engagement to the housing  10 , which simplifies assembly. 
         [0197]    Tactile feedback during dose dispense is provided via the compliant cantilever clicker arm  123  integrated into the clutch plate  120 . This arm  123  interfaces radially with ratchet features  75  on the inner surface of the button  70 , whereby the ratchet tooth spacing corresponds to the number sleeve  60  rotation required for a single increment dispense. During dispense, as the number sleeve  60  rotates and the button  70  is rotationally coupled to the housing  10 , the ratchet features  75  engage with the clicker arm  123  to produce an audible click with each dose increment delivered. 
         [0198]    Delivery of a dose continues via the mechanical interactions described above while the user continues to depress the button  70 . If the user releases the button  70 , the clutch spring  130  returns the drive sleeve  40  to its ‘at rest’ position (together with the clutch plate  120  and button  70 ), engaging the splines  14 ,  41  between the drive sleeve  40  and housing  10 , preventing further rotation and stopping dose delivery. 
         [0199]    During delivery of a dose, the drive sleeve  40  and number sleeve  60  rotate together, so that no relative motion in the last dose nut  50  occurs. The last dose nut  50  therefore travels axially relative to the drive sleeve  40  during dialing only. 
         [0200]    Once the delivery of a dose is stopped, by the number sleeve  60  returning to the zero dose abutment, the user may release the button  70 , which will re-engage the spline teeth  14 ,  41  between the drive sleeve  40  and housing  10 . The mechanism is now returned to the ‘at rest’ condition. 
         [0201]    It is possible to angle the spline teeth  14 ,  41  on either the drive sleeve  40  or housing  10  so that when the button  70  is released the re-engagement of the spline teeth  14 ,  41  fractionally ‘backwinds’ the drive sleeve  40  thereby removing the engagement of the number sleeve  60  to the zero dose stop abutment on the gauge element  110 . This compensates for the effect of clearances in the mechanism (for example due to tolerances) which could otherwise lead to slight advancement of the piston rod  30  and medicament dispense when the device is dialed for the subsequent dose due to the number sleeve  60  zero dose stop not restraining the mechanism and instead the restraint returning to the splines between the drive sleeve  40  and housing  10 . 
         [0202]    At the end of dose dispensing, additional audible feedback is provided in the form of a ‘click’, distinct from the ‘clicks’ provided during dispense, to inform the user that the device has returned to its zero position via the interaction of the clicker arm  67  on the number sleeve  60  with the ramp  47  on the drive sleeve  40  and the cam  117  and the recess  118  on the gauge element  110 . This embodiment allows feedback to only be created at the end of dose delivery and not created if the device is dialed back to, or away from, the zero position. 
         [0203]      FIG. 11 a    shows the position of the click features when the device is in the ‘at rest’ condition, with zero units dialed and the button  70  not depressed. It can be seen that the cam feature  117  on the gauge element  110  does not contact the clicker arm  67  on the number sleeve  60  when the button  70  is in the ‘at rest’ condition, so during storage or dialing the clicker arm  67  is not deflected. 
         [0204]    During dialing, the gauge element  110  translates in the proximal direction, so the cam  117  is no longer aligned axially with the clicker arm  67 . At the start of dose delivery when the drive sleeve  40  translates in the distal direction, the ramp  47  on the drive sleeve  40  pushes the clicker arm  67  radially outwards. During dose delivery, the gauge element  110  translates back in the distal direction, and towards the end of dose delivery, the clicker arm  67  contacts the cam  117  on the gauge element  110 . For small doses, the cam  117  and clicker arm  67  will be in contact at the start of the dose.  FIGS. 11 b  to 12 c    show the component interactions. After dose delivery, the button  70  is released and the end of dose mechanism returns to its ‘at rest’ position. 
         [0205]    In  FIG. 11 b    a dose is dialed and approximately one full dial turn is applied to number sleeve  60 . Gauge element  110  is axially translated away from zero-unit position, so that cam  117  is no longer aligned axially with clicker arm  67 .  FIG. 11 c    shows the start of dispensing, when button  70  is depressed to initiate dose dispense and which causes the drive sleeve  70  to translate axially. The ramp  47  on the drive sleeve  40  pushes the clicker arm  67  radially out and into radial alignment with the cam  117  on the gauge element  110 . 
         [0206]      FIG. 12 a    shows the mechanism at the end of dose dispensing with approximately 4 units remaining. The gauge element  110  returns axially towards its zero-unit position, so that cam  117  aligns axially with clicker arm  67 . Rotation of number sleeve  60  causes clicker arm  67  to contact cam  117  such that clicker arm  67  is pushed radially inwards. With approximately 2 units remaining the number sleeve  60  rotates further and clicker arm  67  follows the profile of cam  117  ( FIG. 12 b   ). This radial deflection ‘charges’ clicker arm  67  storing elastic energy. In  FIG. 12 c    dispensing is completed as the number sleeve  60  reaches its zero-unit rotational position. The clicker arm  67  drops off the sharp edge of cam  117  into recess  118 . Elastic energy is released causing clicker arm  67  to spring radially outwards to contact cam  117  and create a distinct ‘click’. 
         [0207]    In an embodiment, the lead screw  30  advances by a fixed displacement for each revolution of the drive sleeve  40 . In other embodiments, the rate of displacement may vary. For example, the lead screw  30  may advance a large displacement per revolution to dispense a first amount of medicament from the cartridge  100  and then a smaller displacement per revolution to dispense the rest of the cartridge  100 . This is advantageous, as it can compensate for the fact that the first dose dispensed from the cartridge  100  often has a lower volume than other doses, for a given displacement of the mechanism. 
         [0208]      FIG. 22  shows three embodiments with the threads  16  of the housing  10  and the threads  31  of the lead screw  30  projected around the circumference. Arrow R indicates the direction of revolution of the lead screw  30  with respect to housing  10  for all three views. 
         [0209]    View (a) shows the principal embodiment, where the pitch is equal on the housing  10  and lead screw  30 , so the lead screw  30  advances a fixed amount for every revolution of the drive sleeve  40 . In view (b), the first turn of thread  31  on the lead screw  30  has a large pitch, and the other turns have a small pitch. During the first revolution, the lead screw  30  displacement depends on the large pitch of the first turn of thread  31  on the lead screw  30 , so it displaces a large amount per revolution. For subsequent revolutions the lead screw  30  displacement depends on the smaller pitch of the lead screw thread  31 , so it displaces a smaller amount. In view (c), the housing  10  thread  16  has a larger pitch than the lead screw  30 . During the first revolution, the lead screw  30  displacement depends on the pitch of the housing thread  16 , so it displaces a large amount per revolution. For subsequent revolutions the lead screw  30  displacement depends on the pitch of the lead screw thread  31 , so it displaces a smaller amount. 
         [0210]    It has been found that, when dispensing the first liquid drug or medicament from the cartridge of a drug delivery device, the required force can be substantially higher than the one for subsequent dispenses. This is probably due to bung stiction/adhesion effects of the bung within the cartridge. The stiction/adhesive effects are particularly pronounced when the cartridge has been stored for a while. Consequently, the force which is required to move the bung in the cartridge for the first time when the cartridge is higher in an as-assembled condition, e.g. as provided by the manufacturer and all of the drug or medicament which was once filled into the cartridge is still present in the cartridge, than when drug has already dispensed from the device. 
         [0211]    In the following, different solutions are described which provide a higher dispensing force, particularly a higher maximal dispensing force, when the bung is in the initial position as provided by the manufacturer than during subsequent dispensing operations, for example during the dispensing of the second or third dose. The dispensing force, after the high initial dispensing force, may be constantly lower for any subsequent dose after the dispensing force, particularly the maximal dispensing force, has been lowered once from the initial high value to the subsequent or regular value. 
         [0212]    Solutions of this kind are particularly advantageous if a mechanical energy storage member such as spring  90  is used in the device to provide the driving force which is required to move the bung to dispense the drug from the cartridge. If the drive mechanism can be designed such that the initial driving or dispensing force is higher than during subsequent dispensing actions without changing the spring design and spring assembly, the requirements which the energy storage member has to meet may not be as stringent. For example, a spring of lesser spring strength may be used. This has a couple of advantages as, for example, the energy which has to be applied by the user to load the energy storage member during a dose setting operation is less as the regular driving force required to get the bung to move subsequent to the initial driving of the bung away from its initial position is lower and, thus, operation of the device is more effortless for the user as compared to a higher strength spring. Additionally, weaker springs may be more cost effective and also smaller. In the case of a torsion spring  90 , as is used in the device as described above, the dialing torque which has to be applied by the user to set up a dose, can be reduced if the initial driving force can be increased by means of design of the drive mechanism over the regular driving force which is required subsequent to dispensing of the first liquid. Reduction in size of the spring and a lower spring strength of the spring which is used as energy storage member may also result in an increased device robustness as forces and torques exerted in the drug delivery device are generally reduced subsequent to the initial dispensing. 
         [0213]    The proposed solutions may be applied in any drug delivery device, such as a pen injector, particularly a drug delivery device for delivery of a variable, user-selectable dose of medicament or drug into the body, such as by means of a needle. One exemplary embodiment to which the solutions described herein may be applied is the drug delivery device described in conjunction with  FIGS. 1 to 22   c . Consequently, some of the concepts disclosed herein are described in relation to the drug delivery device mentioned above, but it should be kept in mind that the solutions are not only applicable to these drug delivery devices but also to other drug delivery devices which employ a drive mechanism which transfers a force within a drug delivery device to a bung to move the bung with respect to the cartridge, and, particularly, to automatic dispensing devices where no user exerted force contributes to the dispensing force during the dispensing of the dose. 
         [0214]      FIGS. 23 a  and 23 b    disclose one embodiment which is suitable to provide a higher initial driving force for dispensing the first amount of drug from the cartridge than for dispensing the subsequent drug, i.e. when the initial bung stiction/adhesion of the bung  101  at the inner wall of the cartridge  100  has been overcome. 
         [0215]      FIGS. 23 a  and 23 b    show schematic views of the piston rod or lead screw  30  with its thread  31  and the inner thread  16  of the housing  10  similar to  FIGS. 22 a   - c.    FIG. 23 a   , which essentially corresponds to  FIG. 22 a   , shows a design where a driving force, provided a given torque is transferred from the torsion spring  90  to the piston rod  30 , is constant throughout the travel from the piston rod from its initial position in the distal direction to deliver drug from the cartridge to its end position, when the piston rod can no longer be moved into the distal direction, e.g. due to the last dose stop mechanism as described above. Thread  31  has a constant pitch and/or lead in  FIG. 23 a   . When the piston rod is rotated to the left—as indicated by arrow R—it translates in the distal direction on account of the cooperation of thread  31  with thread  16  in the housing  10 . The distal direction is the upper direction in  FIG. 23   a.    
         [0216]    In  FIG. 23 b    the piston rod  30  is also advanced in the distal direction, i.e. upwards, when rotating to the left with respect to the inner thread  16 . In order to advance the piston rod  30  in the distal direction, a proximal surface of the thread  31  may contact a distal surface of the thread  16 . However, in contrast to  FIG. 23 a   , the thread  31  on the piston rod  30  has a variable pitch and/or lead. Therefore, the distance by which the piston rod is displaced distally with respect to the housing in one revolution varies, depending on the particular pitch or lead of that section of the thread  31  which currently interacts with thread. Particularly, the distance between two consecutive windings of the thread may vary in the axial direction. The thread  31  is designed such that the pitch and/or lead of the thread is smaller in a distal (end) section  311  of the thread  31  than in a proximal section  312  of the thread  31  which may follow after the distal section  311 . The distal section  311  and the proximal section  312  are connected via an intermediate section where the lead and/or pitch changes from a first value in the distal section to a second value in the proximal section  312 . The first value is expediently smaller than the second value. In the proximal section  312  and/or in the distal section  311  the pitch and/or lead are preferably constant. 
         [0217]    The finer pitch and/or lower lead of the thread  31  in the distal end section  311  result in a first portion of rotation of the piston rod  30  with respect to the inner thread  16  having a lower rate of piston rod advancement than the following rotations. The finer pitch and/or lower lead results in a lower rate of advancement and means that for a given torque applied by the spring  90 , which causes the piston rod to rotate, the resulting axial force generated by the piston rod will be greater than for a thread with coarser pitch or greater lead. 
         [0218]    Preferably, there is only one change in pitch and/or lead of the thread  31 , thus ensuring a conform or constant axial advancement of the piston rod  30  when the thread  16  cooperates with the proximal section  312 . The driving force is increased only initially to overcome initial bung stiction. 
         [0219]    The inner thread  16  which, in cooperation with the thread  31 , establishes the threaded interface of the piston rod  31  and the housing  10 , is adjusted to the varying pitch and/or lead in the thread  31  of the piston rod in the  FIG. 23 b    embodiment. 
         [0220]    The thread  16  of the housing is adapted to cooperate with a thread having a varying pitch and/or lead. For this purpose, an angle of inclination of a surface of the thread  16  which is adapted to cooperate with the piston rod  30 , preferably a distal facing surface of the thread  16 , i.e. the upper surface in  FIG. 23 b   , with respect to the longitudinal axis  1  of the piston rod  30  changes. Particularly, the smaller angle of the two angles which the thread  16 , particularly the distal facing surface thereof, defines with the longitudinal axis  1  when seen in projection onto the longitudinal axis may increase in the direction of rotation of the piston rod relative to the inner thread  16  as indicated by the arrow R in  FIG. 23 b   . Furthermore, the clearance between two consecutive windings of the thread  31  is greater, on account of the specific angled design of the surface of the thread in  FIG. 23 b    than in  FIG. 23 a   , as, in  FIG. 23 b   , the modified design of the thread  16  has to be taken into account. In  FIG. 23 a   , both threads, i.e. thread  16  and thread  31 , have equal pitches and/or leads. In  FIG. 23 b   , the inner thread  16  may have one section  161 , which is adapted to cooperate with the distal section  311  of the thread  31 , and another section  162  which is adapted to cooperate with the proximal section  312  of the thread  31 . The section  162  may precede the section  161  as seen along the rotation direction. Sections  161  and  162 , particularly the distal surfaces of the respective sections, may be arranged angled—defining an angle different from 180°—with respect to each other. The distal surface of the respective section  161  or  162  may be smooth. Preferably, the angle with respect to the axis  1  which is defined by the section  161 , preferably the distal surface thereof, corresponds to the angle defined by the distal section  311  of the thread  31  and the axis  1  when seen in projection on the axis  1 . Section  162 , preferably the distal surface thereof, forms an angle with the axis  1  which corresponds to the angle which the proximal section  312  forms with the axis  1  as seen in projection on the axis  1 . 
         [0221]    Another solution to the problem of providing an initial high driving force to overcome the initial bung stiction is described in conjunction with  FIG. 24 . This solution can be applied instead of or together with the solution described in conjunction with  FIG. 23 b   . In  FIG. 24 , a supplemental storage member or auxiliary storage member  150  is used. The supplemental storage member  150  may be a spring, such as a compression spring, as depicted in  FIG. 24 , a leaf spring or a washer spring. 
         [0222]    The supplemental storage member  150  has energy stored therein in the initial position of the piston rod  30  where the device has not yet been operated, i.e. the piston rod  30  has not been moved yet. This situation is depicted in  FIG. 24 . The stored energy may be used, in addition to the energy provided by the spring  90 , to move the bung  101  away from the initial position depicted in  FIG. 24  and, consequently, may assist the force exerted by the spring  90  to overcome the initial bung stiction. 
         [0223]    The energy stored in supplemental storage member  150  is preferably less than the one required to move the bung  101  away from its initial position. In its initial position, the bearing may abut the bung. Consequently, excessive pressurization of the drug within the cartridge can be avoided, if the piston rod  30  contacts the bung  101  in the initial position of piston rod and bung and the energy stored in the member is not sufficient to provide a force to move the bung. Thus, in this case, when a needle is attached to the device, no fluid may drip unintentionally out of the device as the supplemental storage member does not have enough energy within it. 
         [0224]    Alternatively, in the initial position of the piston rod  30 , there may be a clearance between the distal surface of the piston rod  30  or bearing  140  and the proximal face of the bung  101 . In other words, instead of being mechanically coupled to the bung in the initial position, the piston rod may be mechanically decoupled from the bung in the initial position. Thus, before the bung  101  can be driven by the piston rod  30 , mechanical coupling has to be established, e.g. by moving the piston rod towards the bung to close the clearance. 
         [0225]    The supplemental storage member  150  biases the piston rod  30  into the distal direction. For this purpose, the supplemental storage member  150  may be arranged in a biased state between a surface of the housing  10 , particular a distal surface, and a surface of the bearing  140 , particular a proximal surface. As the bearing  140  is connected to the piston rod  30  as is depicted in  FIG. 8 , the supplemental storage member biases the piston rod  31  in the distal direction such that the force exerted by the supplemental storage member  150  onto the bearing  140  also acts on the piston rod. The force exerted by the supplemental storage member  150  may contribute to the initial driving force together with the energy storage member, i.e. spring  90 . However, the supplemental storage member preferably has less energy stored in it than which would be required to move the piston rod to close the clearance between bearing  140  and bung  101 . Thus, a reliable clearance may be established between piston rod and bung in the initial position. Also, it can be avoided that the drug in the cartridge is significantly pressurized. The maximal driving force providable by the spring  90  is preferably less than the one which is required to move the bung away from the initial position. Thus, the energy stored in the supplemental storage member is required to move the bung away from its initial position in order to dispense drug from the cartridge. Consequently the spring  90  can be chosen to be appropriately weak with the associated advantages and assisted by a second spring  150  which is also not too strong, big or expensive as supplemental storage member  150  to overcome the initial bung stiction. 
         [0226]    As the supplemental storage member acts on the bearing  140 , it biases the bearing away from the piston rod  31  such that a distal surface  145 , e.g. a surface of a radial protrusion of the bearing which is received between the clip arms  32  of the piston rod  30 , contacts a proximal surface  34  of the piston rod  30 , such as the proximal surface of a radially inwardly protruding portion of the clip arms  32 . As compared to the situation depicted in  FIG. 8 , the bearing is moved to the left until surfaces  145  and  34  abut in the situation depicted in  FIG. 24 . Consequently, in the situation depicted in  FIG. 24 , the piston rod  30  and the bearing  140  are under tension with respect to each other. The state of tension is in contrast to the situation when the bung  101  has been contacted by the bearing  140  and drug is being dispensed. During this state, the bearing and the piston rod are in a state of compression, i.e. the surfaces  33  and  143  abut as depicted in  FIG. 8 . It is advantageous that, in order to guarantee a constant dispensing state of the device from the first dose onwards, that drug is only dispensed from the device when the bearing and the piston rod are in the state of compression where a proximally facing surface of the bearing  140  abuts a distally facing surface of the piston rod  30 . This can be achieved by choosing the supplemental energy member such that the force, expediently the maximal force, transferrable by the supplemental energy member to the bung is less than the one required to move the bung away from the initial position such that bearing and piston rod are moved into the compressed state first and, afterwards, the bung is moved on account of the additional force provided by the spring  90 . This can increase the dose accuracy, as otherwise the transition from the tension state to the compression state of bearing and piston rod would not occur until the bearing separates from the compression spring, which could reduce the accuracy of the dose which is dispensed. Consequently, it is beneficial that the piston rod  30  and the bearing  140  are in the compression state as the first drug is dispensed from the cartridge even with the supplemental storage member  150  acting on the bearing  140 . This, as noted above, can be achieved by choosing a spring for the storage member  150  which is weaker than the bung stiction. Consequently, the supplemental storage member is chosen to only supplement the axial force transferred by means of the piston rod to the bung without being strong enough on its own to overcome the bung stiction and dispense the drug independently. The conversion from the state of tension to the state of compression should occur before the end of the first dispense movement of the bung and, ideally, before the start of the first dispense movement. 
         [0227]    The axial thrust achievable by the supplemental storage member, e.g. the length of the relaxed compression spring, is chosen to be sufficient to allow the supplemental storage member to act upon the bearing over the distance, preferably only over the distance, during which initial bung stiction effects are present which increase the force required to move the bung substantially. Beyond this point, the bearing and the supplemental storage member separate and the supplemental storage member plays no further role in the operation of the device. 
         [0228]    Alternatively to a spring as the supplemental storage member or as an additional supplemental storage member, a cartridge filled with pressurized gas could be positioned between the piston rod  30  or the bearing  140  and the bung  101  in order to provide the supplemental force to assist the energy storage member  90 , for example when the pressurized gas expands once an outer shell of the cartridge has been destroyed or punctuated to provide fluid communication between the interior of the cartridge and the outside, which may be effected by the force the piston rod transfers to the outer shell of the cartridge. This is not explicitly shown in figures. 
         [0229]    A further approach which can be used to provide an initially increased dispensing force is the provision of a second thread on the piston rod  30  in addition to the thread  31  which couples the piston rod to the housing  10 . This is not explicitly shown in the figures. Via the second thread, the piston rod in its initial position may be coupled to the bearing  140 , for example. The second thread has a smaller pitch and/or lead than the thread  31 . The second thread may be provided in a distal section of the piston rod and may, in the initial position of the piston rod, be threadedly coupled to the bearing. The second thread may be, in the proximal direction, followed by a section of the piston rod which cannot threadedly interact with the bearing, e.g. an unthreaded section. Proximally with respect to this section, the section of the piston rod with the thread  31  may be provided. The bearing may comprise a proximal threaded section designed to threadedly interact with the second thread and a distal unthreaded section which is arranged subsequent to the threaded section in the distal direction. 
         [0230]    In the initial position of the piston rod  30  the bearing  140  may be in contact with the bung or arranged at a distance therefrom. Consequently, during the first part of the movement of the piston rod the clearance between bearing and bung may be closed, depending on whether there is a clearance. Once the bearing is in contact with the bung and the piston rod rotates relative to the housing, the piston rod also rotates relative to the bearing and is in threaded interaction with the bearing. Due to the two threaded interfaces between the housing and the piston rod and between the bearing and the piston with different pitches and/or leads, the force acting on the bung is increased as long as both threaded interfaces are active. Once the section of the piston rod with the second thread has moved past the threaded section in the bearing in the distal direction, there is no longer a threaded interaction of bearing and piston rod, for example because the distal threaded section of the piston rod with the second thread is arranged within the unthreaded section of the bearing and the unthreaded section of the piston rod is arranged within the threaded section of the bearing. Consequently, the second threaded interface is inactivated and the dispensing force is no longer increased over the force transferred by the piston rod via the first threaded interface. It is advantageous to design the second thread with respect to pitch, lead and/or length such that an increased dispensing force is only provided when the increased initial bung stiction has to be overcome as outlined above for the other disclosed approaches in order to provide an increased initial dispensing force. 
         [0231]    All of the approaches described above permit the use of a weaker spring  90  in the device of  FIG. 1  while still delivering sufficient force at the start of a cartridge to overcome bung stiction. A weak spring is feasible as beyond the start of the cartridge, once initial stiction has been overcome, the dispense force requirement are less. The ability to choose a weaker torsion spring has many potential benefits including: lower dialing torque for the user, smaller, cheaper torsion spring and, consequently, a smaller and cheaper device and increased device robustness as forces and torques exerted within the device are generally reduced. 
         [0232]    It should be noted that the approaches described above are not only suitable for a rotating piston rod or lead screw which rotates relative to the body, but could also be applied to a piston rod or lead screw which is axially advanced by means of a rotating nut, where the piston rod or lead screw is secured against rotation with respect to the housing. Consequently, the approaches above may also be suitable for non-rotating piston rods. It may not even be necessarily a threaded piston rod or lead screw which is used. Especially the approach described in conjunction with  FIG. 24  with the supplemental storage member could also be used for a non-rotating non-threaded piston rod, which is embodied as a toothed rod, for example. 
       REFERENCE NUMERALS 
       [0233]      10  housing 
         [0234]      11   a, b  opening 
         [0235]      12  flange-like inner wall 
         [0236]      13  strip 
         [0237]      14  teeth 
         [0238]      15  spline 
         [0239]      16  inner thread 
         [0240]      161  section of the inner thread 
         [0241]      162  another section of the inner thread 
         [0242]      20  cartridge holder 
         [0243]      30  lead screw (piston rod) 
         [0244]      31  outer thread 
         [0245]      311  distal section 
         [0246]      312  proximal section 
         [0247]      32  clip arm 
         [0248]      33  concave contact surface 
         [0249]      34  surface 
         [0250]      40  driver (axially movable drive sleeve) 
         [0251]      41  teeth 
         [0252]      42  spline 
         [0253]      43  ratchet teeth 
         [0254]      44  threaded section 
         [0255]      45  spline 
         [0256]      46  last dose stop 
         [0257]      47  ramp 
         [0258]      50  nut 
         [0259]      51  last dose stop 
         [0260]      52  spline 
         [0261]      60  dose indicator (number sleeve) 
         [0262]      60   a  number sleeve lower 
         [0263]    
       60 
       b  
     
         [0264]    number sleeve upper 
         [0265]      61  spline 
         [0266]      62  flange 
         [0267]      63  outer thread 
         [0268]      64 ,  65  end stop 
         [0269]      66  spline 
         [0270]      67  clicker arm 
         [0271]      68  groove 
         [0272]      69  anchor point 
         [0273]      70  button 
         [0274]      71  stem 
         [0275]      72  flange 
         [0276]      73 ,  74  spline 
         [0277]      75  ratchet teeth 
         [0278]      80  dose selector 
         [0279]      90  torsion spring 
         [0280]      91 ,  92  hook 
         [0281]      93 ,  94  coil 
         [0282]      100  cartridge 
         [0283]      101  bung 
         [0284]      110  gauge element 
         [0285]      111  helical feature 
         [0286]      112 ,  113  stop 
         [0287]      114  aperture 
         [0288]      115 ,  116  flange 
         [0289]      117  cam 
         [0290]      118  recess 
         [0291]      120  clutch plate 
         [0292]      121  ratchet teeth 
         [0293]      122  protrusion 
         [0294]      123  clicker arm 
         [0295]      130  clutch spring 
         [0296]      140  bearing 
         [0297]      141  disc 
         [0298]      142  stem 
         [0299]      143  convex contact surface 
         [0300]      144  recessed portion 
         [0301]      145  surface 
         [0302]      150  supplemental storage member 
         [0303]    I longitudinal axis 
         [0304]    R direction of revolution