Abstract:
The present disclosure relates to a drive mechanism which is suitable for an injection device, especially a pen type drug delivery device and to such a drug delivery device. The mechanism comprises a spring driven rotatable drive member, a rotatable driven member, a clutch rotationally coupling the driven member and the drive member in a coupled state and allowing relative clockwise and anti-clockwise rotation between the driven member and the drive member in a decoupled state, and a spring biasing the clutch into its coupled state and allowing relative axial movement between the drive member and the driven member into the decoupled state of the clutch against the bias of the spring. The clutch comprises a first ring of crown teeth on the drive member and a second ring of corresponding crown teeth on the driven member with each crown tooth having in the clockwise and the anti-clockwise direction different ramped tooth angles such that the teeth are allowed to override each other in the de-coupled state of the clutch with a different resistance in the clockwise and the anti-clockwise direction.

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/EP2015/073429, filed on Oct. 9, 2015, which claims priority to European Patent Application No. 14306591.0, filed on Oct. 9, 2014, the entire contents of which are incorporated herein by reference. 
     
    
     TECHNICAL FIELD 
       [0002]    The present disclosure relates to a drive mechanism which is suitable for an injection device, especially a pen type drug delivery device for selecting and dispensing a number of user variable doses of a medicament. Further, the disclosure relates to such a drug delivery device. 
       BACKGROUND 
       [0003]    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. 
         [0004]    There are basically two types of drug delivery devices: resettable devices (i.e., reusable) and non-resettable (i.e., disposable). For example, disposable pen delivery devices are supplied as self-contained devices. Such self-contained devices do not have removable pre-filled cartridges. Rather, the pre-filled cartridges may not be removed and replaced from these devices without destroying the device itself. Consequently, such disposable devices need not have a resettable dose setting mechanism. Some embodiments are directed to reusable devices which allow resetting of the device and a replacement of a cartridge. Resetting of the device typically involves moving a piston rod or lead screw from an extended (distal) position, i.e. a position after dose dispensing, into a more retracted (proximal) position. 
         [0005]    These types of 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 (e.g., insulin), a movable rubber type bung or stopper located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often necked-down, end. A crimped annular metal band is typically used to hold the rubber seal in place. While the cartridge housing may be typically made of plastic, cartridge reservoirs have historically been made of glass. 
         [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 presses against the bung or stopper of the cartridge. This force causes the medication contained within the cartridge to be injected through an attached needle assembly. After an injection, as generally recommended by most drug delivery device and/or needle assembly manufacturers and suppliers, the needle assembly is removed and discarded. 
         [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. 
       SUMMARY 
       [0009]    In certain aspects, a drive mechanism comprises a spring driven rotatable drive member, a rotatable driven member, a clutch for rotationally coupling the driven member and the drive member in a coupled state and allowing relative clockwise and anti-clockwise rotation between the driven member and the drive member in a decoupled state, and a (clutch) spring biasing the clutch into its coupled state and allowing relative axial movement between the drive member and the driven member into the decoupled state of the clutch against the bias of the spring. 
         [0010]    Preferably, the clutch comprises a first ring of crown teeth on the drive member and a second ring of corresponding crown teeth on the driven member with each crown tooth having in the clockwise and the anti-clockwise direction different ramped tooth angles such that the teeth are allowed to override each other in the de-coupled state of the clutch with a different resistance in the clockwise and the anti-clockwise direction. 
         [0011]    Some embodiments may provide a drive mechanism and a drug delivery device with a reliable and repeatable clutch interface. 
         [0012]    Creating a reliable and repeatable clutch interface may be achieved by controlling the parameters influencing the torque necessary to overhaul the clutch. In some embodiements, the material of the drive member may be polybutylene terephthalate (PBT) or polyoxymethylene (POM) whereas the material of the rotatable driven member may be PBT, POM or polycarbonate (PC). Preferably, the material of the drive member is PBT and the material of the rotatable driven member is PBT, PC or, preferably, POM. As an alternative, if the material of the drive member is POM, the material of the rotatable driven member is POM or PC. In a further preferred alternative, the material of the drive member is PC and the material of the rotatable driven member is PBT or POM. These materials are suitable for injection molding and in combination, provide a reliable and robust interface for generating a torque necessary to overhaul the clutch in a repeatable manner. 
         [0013]    According to a further aspect, the coefficient of friction between the teeth is 0.05≦μ≦0.3, preferably 0.09≦μ≦0.11, for example μ=0.1. According to a further aspect, the teeth have a surface roughness of 0.2≦Ra≦10 micrometers, preferably 0.7≦Ra≦0.9, for example Ra=0.8. 
         [0014]    A clutch is a component or feature suitable for connecting two component parts either by form fit (positive fit), e.g. with teeth suitable for engaging and disengaging each other, or by a non-positive (frictional) connection or a combination thereof. Actuation of a clutch, i.e. the act of coupling or decoupling, may include a relative movement of clutch parts or clutch features, for example for disengaging clutch teeth, and/or may include a change in a force exerted on clutch parts or clutch features. 
         [0015]    The crown teeth of the clutch are preferably provided as axially extending teeth located at the distal end face of one component part, e.g. the drive member, and the proximal end face of the other component part, e.g. the driven member. However, it is also possible to provide crown teeth in a recess or on a flange. 
         [0016]    In a preferred embodiment, the drive mechanism further comprises a torsion spring which is directly or indirectly coupled to the drive member such that rotation of the drive member in a first rotational direction charges (strains) the spring and that rotation of the drive member in a second, opposite rotational direction discharges (releases) the spring. To reduce the torque necessary to overhaul the clutch during dose setting, while preventing unintended discharging of the torsion spring, the teeth may have a steeper ramped tooth angle in the second rotational direction and have a shallower ramped tooth angle in the first rotational direction. In addition, or as an alternative, the teeth may have a higher friction coefficient in the second rotational direction and have a lower friction coefficient in the first rotational direction. 
         [0017]    The drive member may be a separate component part which is rotationally constrained to a dose setting member, e.g. a number sleeve or a dose selector. The drive member may be rotatable and axially constrained, e.g. to a housing, or may be rotatable along a helical path. The driven member may be a tubular element located e.g. inside the number sleeve. On the other hand, the driven member may drive a further component part, for example a piston rod. 
         [0018]    A drug delivery device for selecting and dispensing a number of user variable doses of a medicament preferably comprises a drive mechanism as defined above and further a housing, a dose setting member located within the housing, and a piston rod engaging the driven member, wherein the drive member is operatively interposed between the driven member and the dose setting member. In this embodiment the drive member may act as a clutch element for coupling and decoupling the driven member and the dose setting member, e.g. to allow relative rotation during dose setting (or dose correcting) and to prevent relative rotation during dose dispensing. 
         [0019]    The drug delivery device may further comprise a second clutch for rotationally coupling and decoupling the driven member and the housing. Preferably, the driven member is axially displaceable relative to the housing between a first position in which the second clutch rotationally couples the driven member and the housing and a second position in which the second clutch rotationally decouples the driven member from the housing. In other words, the drug delivery device may be switched between a dose setting (or correcting) state in which rotation of the driven member is prevented and a dose dispensing state in which rotation of the driven member is allowed by axial movement of the driven member. In this respect, a button may be provided acting directly or indirectly on the driven member for axial displacement, e.g. against the bias of the clutch spring. 
         [0020]    When switching between the dose setting (or correcting) state and the dose dispensing state it is desirable to avoid uncontrolled movement of the driven member, especially in embodiments where the driven member is coupled to a piston rod or the like effecting dose dispensing. Such uncontrolled movement of the driven member could result in amending the set dose prior to dispensing, i.e. underdosage or overdosage. To avoid uncontrolled movement of the driven member the teeth of the clutch are preferably in a coupled state when the driven member and the housing are decoupled by the second clutch. Further, the driven member and the housing are preferably coupled by the second clutch when the teeth of the clutch are in a decoupled state. In other words, the driven member is permanently coupled to at least one of the drive member and the housing. 
         [0021]    Further, the drug delivery device may comprise a cartridge containing a medicament. The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
         [0022]    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, 
         [0023]    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, 
         [0024]    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, 
         [0025]    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. 
         [0026]    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. 
         [0027]    Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
         [0028]    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. 
         [0029]    Exendin-4 derivatives are for example selected from the following list of compounds:
   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   des Pro36 Exendin-4(1-39),   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),   
 
         [0049]    wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; 
         [0050]    or an Exendin-4 derivative of the sequence
   des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;   
 
         [0080]    or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative. 
         [0081]    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. 
         [0082]    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. 
         [0083]    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. 
         [0084]    The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
         [0085]    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. 
         [0086]    Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
         [0087]    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. 
         [0088]    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. 
         [0089]    An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv). 
         [0090]    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. 
         [0091]    Pharmaceutically acceptable solvates are for example hydrates. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0092]    Non-limiting, exemplary embodiments will now be described with reference to the accompanying drawings, in which: 
           [0093]      FIG. 1  shows a top view of a drug delivery device; 
           [0094]      FIG. 2  shows an exploded view of the components of the device of  FIG. 1 ; 
           [0095]      FIG. 3  shows a sectional view of the proximal end of the device of  FIG. 1 ; and 
           [0096]      FIG. 4  shows a detail of the driven member and the drive member of the device of  FIG. 1 . 
       
    
    
     DETAILED DESCRIPTION 
       [0097]      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 (piston rod)  30 , a drive sleeve  40 , a nut  50 , a dose indicator (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 shown) with a needle hub and a needle cover may be provided as additional components, which can be exchanged as explained above. All components are located concentrically about a common principal axis of the mechanism. 
         [0098]    As will be explained in more detail below, the clutch plate  120  is a spring driven rotatable drive member driving the drive sleeve  40  during dose dispensing to rotate relative to the housing  10  to thereby advance piston rod  30 . The clutch plate  120  is in turn driven by the number sleeve  60  to which it is rotationally constrained which is attached to one end of the torsion spring  90 . Although driving the piston rod  30  during dose dispensing, the drive sleeve is considered a driven member because it is driven by the clutch plate  120  (and the number sleeve  60  and the torsion spring  90 ) during dose dispensing. 
         [0099]    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 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 . An insert 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 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. The drive spring  90  is attached with one end to the housing  10 . 
         [0100]    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 . 
         [0101]    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 insert of housing  10 . The lead screw  30  is an elongate member with an outer thread engaging the corresponding thread of the insert of housing  10 . The interface comprises at least one longitudinal groove or track and a corresponding protrusion or spline of the driver  40 . At its distal end, the lead screw  30  is provided with an interface for clip attachment of the bearing  140 . 
         [0102]    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 . At least one longitudinal spline of the driver  40  engages a corresponding track of the lead screw  30 . 
         [0103]    The clutch interface between the drive sleeve  40  and the clutch plate  120  comprises a ring of crown teeth  41  located on the proximal end face of the drive sleeve  40  and a ring of corresponding crown teeth  121  located on the distal end face of the clutch plate  120 . 
         [0104]    It may be beneficial to increase the slipping torque (the torque at which the clutch  41 ,  121  slips) in one direction relative to the other. For example, this allows the clutch  41 ,  121  to resist the torque applied by the torsion spring  90 . The slipping torque can be increased by increasing the ramp angle, so the teeth  41 ,  121  contacting in one direction are steeper than in the other and/or increasing the surface roughness of the teeth  41 ,  121 , so the teeth contacting in one direction are rougher than in the other. Alternatively, it may be beneficial to retain the same geometry for a range of devices but to change the slipping torque for each device. This might be achieved by changing the materials for different devices and/or changing the surface roughness for different devices and/or adding lubricant. Typical materials for the clutch interface  41 ,  121  are summarized in the table below. The first part may be the drive sleeve  40  and the second part may be the clutch plate  120 , or vice versa: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 First part 
                 Second part 
               
               
                   
                   
               
             
             
               
                   
                 PBT 
                 POM 
               
               
                   
                 PBT 
                 PC 
               
               
                   
                 PBT 
                 PBT 
               
               
                   
                 POM 
                 POM (with additives to change slip properties) 
               
               
                   
                 POM 
                 PC 
               
               
                   
                   
               
             
          
         
       
     
         [0105]    The preferred combination is PBT for the drive sleeve  40  and POM for the clutch plate  120 . A preferred coefficient of friction is μ=0.1 and a preferred surface roughness is Ra=0.8. 
         [0106]    A splined tooth interface  11 ,  42  with the housing  10  prevents rotation of the drive sleeve  40  during dose setting. This interface comprises a ring of radially extending outer teeth  42  at the distal end of drive sleeve  40  and corresponding radially extending inner teeth  11  of the housing component  10 . When the button  70  is pressed, the drive sleeve teeth  40  and the housing teeth  11  are disengaged from each other allowing the drive sleeve  40  to rotate relative to housing  10 . 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 dose dispensing. In a preferred embodiment this interface comprises inwardly directed splines on a flange on the inner surface of the number sleeve  60  and a ring of radially extending outer splines of drive sleeve  40 . These corresponding splines 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 . 
         [0107]    The driver  40  has a threaded section providing a helical track for the nut  50 , i.e. a thread. In addition, a last dose abutment or stop is provided which may be the end of the thread track or preferably a rotational hard stop for interaction with a corresponding last dose stop of nut  50 , thus limiting movement of the nut  50  on the driver thread. 
         [0108]    A further interface of the drive sleeve  40  comprises a ring of ratchet teeth  42  located at the proximal end face of drive sleeve  40  and a ring of corresponding ratchet teeth on the clutch plate  120 . 
         [0109]    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. It moves along a helical path relative to the drive sleeve  40 , via a threaded interface, when relative rotation occurs between the number sleeve  60  and drive sleeve  40  which is during dialing only. As an alternative, the nut  50  may be splined to the driver  40  and threaded to the number sleeve  60 . When a dose is set corresponding to the remaining dispensable amount of medicament in the cartridge  100 , a last dose stop is provided on the nut  50  and on the drive sleeve  40 , which is engaged with the nut  50 . 
         [0110]    The dose indicator or number sleeve  60  is a tubular element. The number sleeve  60  is rotated by a torsion spring  90  during dose setting (via dose selector  80 ) and dose correction and during dose dispensing. The number sleeve  60  is axially constrained to the housing  10 , e.g. by snap engagement of a bead on an inner housing surface with a groove on an outer number sleeve surface, while being free to rotate relative to the housing  10 . The drive spring  90  is attached with one end to the number sleeve  60 . Further, the number sleeve  60  is in threaded engagement with the gauge element  110  such that rotation of the number sleeve causes axial displacement of the gauge element  110 . 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. The number sleeve  60  comprises a number sleeve lower  60   a  which is rigidly fixed to a number sleeve upper  60   b  during assembly, e.g. by snap engagement, to form the number sleeve  60 . 
         [0111]    Clutch features which have the form of a ring of splines are provided inwardly, directed on number sleeve upper  60   b  for engagement with splines of the button  70  during dose setting and dose correction. A clicker arm 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. Further, number sleeve lower  60   a  comprises an interface for attachment of the torsion spring  90 . 
         [0112]    The button  70  which forms the proximal end of the device is permanently splined to the dose selector  80 . A central stem extends distally from the proximal actuation face of the button  70 . The stem is provided with a flange carrying the splines for engagement with splines of the number sleeve upper  60   b . Thus, it is also splined via splines 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. When the button  70  is pressed, splines on the button  70  engage with splines on the housing  10 , preventing rotation of the button  70  (and hence the dose selector  80 ) during dispense. These splines disengage when the button  70  is released, allowing a dose to be dialed. Further, a ring of ratchet teeth is provided on the inner side of button flange for interaction with clutch plate  120 . 
         [0113]    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. 
         [0114]    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 . 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. 
         [0115]    The cartridge  100  is received in cartridge holder  20 . The cartridge  100  may be a glass ampoule having a moveable rubber bung at its proximal end. The distal end of cartridge  100  is provided with a pierceable rubber seal which is held in place by a crimped annular metal band. 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 . 
         [0116]    The gauge element  110  of  FIGS. 1 and 2  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 on its inner surface which engages with the helical thread 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 against the end of the helical cut in the number sleeve  60  to limit the minimum and maximum dose that can be set. 
         [0117]    The gauge element  110  has a generally plate or band like component having a central aperture or window and two flanges extending on either side of the aperture. The flanges are preferably not transparent and thus shield or cover the number sleeve  60 , whereas the aperture or window allows viewing a portion of the number sleeve lower  60   a . Further, gauge element  110  has a cam and a recess interacting with the clicker arm of the number sleeve  60  at the end of dose dispensing. 
         [0118]    The clutch plate  120  is a ring-like component. The clutch plate  120  is splined to the number sleeve  60  via splines. It is also coupled to the drive sleeve  40  via the ratchet clutch interface  41 ,  121 . The ratchet clutch  41 ,  121  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 is provided on the clutch plate  120  for interaction with ratchet features of the button  70 . 
         [0119]    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 between drive sleeve  40  and clutch plate  120  is always engaged. In the ‘at rest’ position, it also ensures that the button splines are engaged with the number sleeve splines, and the drive sleeve teeth are engaged with teeth of the housing  10 . 
         [0120]    The bearing  140  is axially constrained to the piston rod  30  and acts on the bung within the liquid medicament cartridge. It is axially clipped to the lead screw  30 , but free to rotate. 
         [0121]    With the device in the ‘at rest’ condition as shown in  FIG. 1 , the number sleeve  60  is positioned against its zero dose abutment with the gauge element  110  and the button  70  is not depressed. Dose marking ‘0’ on the number sleeve  60  is visible through the window of the housing  10  and gauge element  110 , respectively. 
         [0122]    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. 
         [0123]    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 either side of the window area 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. 
         [0124]    A specific feature of some embodiments 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 of the gauge element  110  creates a sliding scale through the window 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. 
         [0125]    As a dose is set by the user, the gauge element  110  translates axially, the distance moved proportional to the magnitude of the dose. This feature gives clear feedback to the user regarding the approximate size of the dose. 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 setting and dispensing. 
         [0126]    The drive sleeve  40  is prevented from rotating as the dose is set and the number sleeve  60  rotated, due to the engagement of its splined teeth  42  with teeth  11  of the housing  10 . Relative rotation must therefore occur between the clutch plate  120  and drive sleeve  40  via the ratchet clutch interface  41 ,  121 . 
         [0127]    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 clutch interface  41 ,  121 . The clutch spring  130  is designed to provide an axial force to the ratchet clutch interface  41 ,  121  and to bias the clutch plate  120  onto the drive sleeve  40 . This axial load acts to maintain the teeth engagement of the clutch plate  120  and drive sleeve  40 . The torque required to overhaul the ratchet clutch  41 ,  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  41 ,  121 , the friction coefficient between the mating surfaces and the mean radius of the ratchet clutch interface  41 ,  121 . 
         [0128]    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 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. 
         [0129]    Relative rotation of the number sleeve  60  and the drive sleeve  40  is allowed. 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 . 
         [0130]    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 clutch interface  41 ,  121  between the clutch plate  120  and the drive sleeve  40 . The torque necessary to overhaul the ratchet clutch  41 ,  121  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  41 ,  121 , the friction coefficient between the mating surfaces and the mean radius of the ratchet clutch features  41 ,  121 . The torque necessary to overhaul the ratchet clutch  41 ,  121  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. 
         [0131]    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 clutch interface  41 ,  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 clutch  41 ,  121  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. 
         [0132]    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 on the maximum dose abutment of gauge element  110 . This prevents further rotation of the number sleeve  60 , clutch plate  120  and dose selector  80 . 
         [0133]    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 with stop face 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. 
         [0134]    With the mechanism in a state in which a dose has been selected, the user is able to deselect (correct) 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  41 ,  121  between the clutch plate  120  and drive sleeve  40  in the anti-clockwise direction. When the ratchet clutch  41 ,  121  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. 
         [0135]    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. 
         [0136]    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 on the button  70  engage with splines 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. A stop feature in the housing  10  limits axial travel of the button  70  and reacts to any axial abuse loads applied by the user, reducing the risk of damaging internal components. 
         [0137]    The clutch plate  120  and drive sleeve  40  travel axially with the button  70 . This engages the splined tooth interface  41 ,  121  between the drive sleeve  40  and number sleeve  60 , preventing relative rotation between the drive sleeve  40  and number sleeve  60  during dispense. The splined tooth interface  11 ,  42  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 . 
         [0138]    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 stops the mechanism. 
         [0139]    Tactile feedback during dose dispense is provided via the compliant cantilever clicker arm integrated into the clutch plate  120 . This arm interfaces radially with ratchet features 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 engage with the clicker arm to produce an audible click with each dose increment delivered. 
         [0140]    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 between the drive sleeve  40  and housing  10 , preventing further rotation and stopping dose delivery. 
         [0141]    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. 
         [0142]    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  11 ,  42  between the drive sleeve  40  and housing  10 . The mechanism is now returned to the ‘at rest’ condition. 
         [0143]    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 on the number sleeve  60  with the ramp on the drive sleeve  40  and the cam and the recess 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. 
         [0144]    The clutch interface  41 ,  121  may be included in any pen injector that requires a rotational clutch. It creates a reliable and repeatable clutch interface, allowing a defined slipping torque in both directions. 
         [0000]    
       
         
               
             
               
               
             
           
               
                   
               
               
                 Reference Numerals: 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 10 
                 housing (casing) 
               
               
                 11 
                 spline tooth 
               
               
                 20 
                 cartridge holder 
               
               
                 30 
                 piston rod (lead screw) 
               
               
                 40 
                 drive sleeve 
               
               
                 41 
                 crown tooth 
               
               
                 42 
                 spline tooth 
               
               
                 50 
                 nut 
               
               
                 60 
                 dose setting element 
               
               
                  60a 
                 number sleeve lower 
               
               
                  60b 
                 number sleeve upper 
               
               
                 70 
                 button 
               
               
                 80 
                 dose selector 
               
               
                 90 
                 torsion spring 
               
               
                 100  
                 cartridge 
               
               
                 110  
                 gauge element 
               
               
                 120  
                 clutch plate 
               
               
                 121  
                 crown tooth 
               
               
                 130  
                 clutch spring 
               
               
                 140  
                 bearing