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

Full Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/EP2013/067863 filed Aug. 29, 2013, which claims priority to European Patent Application No. 12182568.1 filed Aug. 31, 2012, and U.S. Provisional Patent Application No. 61/697,078, filed Sep. 5, 2012. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
    
    
     TECHNICAL FIELD 
     The present invention is generally directed to drug delivery devices. More particularly, the present invention is directed to disposable drug delivery devices. 
     BACKGROUND 
     Pen type drug delivery devices have application where regular injection by persons without formal medical training occurs. This may be increasingly common among patients having diabetes where self-treatment enables such patients to conduct effective management of their disease. In practice, such a drug delivery device allows a user to individually select and dispense a number of user variable doses of a medicament. The present invention is not directed to so called fixed dose devices which only allow dispensing of a predefined dose without the possibility to increase or decrease the set dose. 
     There are basically two types of drug delivery devices: resettable devices (i.e., reusable) and non-resettable (i.e., disposable). For example, disposable pen delivery devices are supplied as self-contained devices. Such self-contained devices do not have removable pre-filled cartridges. Rather, the pre-filled cartridges may not be removed and replaced from these devices without destroying the device itself. Consequently, such disposable devices need not have a resettable dose setting mechanism. 
     These types of pen delivery devices (so named because they often resemble an enlarged fountain pen) are generally comprised of three primary elements: a cartridge section that includes a cartridge often contained within a housing or holder; a needle assembly connected to one end of the cartridge section; and a dosing section connected to the other end of the cartridge section. A cartridge (often referred to as an ampoule) typically includes a reservoir that is filled with a medication (e.g., insulin), a movable rubber type bung or stopper located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often necked-down, end. A crimped annular metal band is typically used to hold the rubber seal in place. While the cartridge housing may be typically made of plastic, cartridge reservoirs have historically been made of glass. 
     The needle assembly is typically a replaceable double-ended needle assembly. Before an injection, a replaceable double-ended needle assembly is attached to one end of the cartridge assembly, a dose is set, and then the set dose is administered. Such removable needle assemblies may be threaded onto, or pushed (i.e., snapped) onto the pierceable seal end of the cartridge assembly. 
     The dosing section or dose setting mechanism is typically the portion of the pen device that is used to set a dose. During an injection, a spindle or piston rod contained within the dose setting mechanism presses against the bung or stopper of the cartridge. This force causes the medication contained within the cartridge to be injected through an attached needle assembly. After an injection, as generally recommended by most drug delivery device and/or needle assembly manufacturers and suppliers, the needle assembly is removed and discarded. 
     Disposable and reusable drug delivery devices have certain perceived disadvantages. One perceived disadvantage is that such devices have a high number of parts and therefore such devices are typically complicated from a manufacturing and from an assembly standpoint. In addition, because such devices use a large number of components parts, such devices tend to be large and bulky, and therefore not easy to carry around or easy to conceal. 
     SUMMARY 
     A disposable drug delivery device according to the present invention typically comprises a housing, a cartridge holder for retaining a cartridge containing a medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver. The device is delivered to the user in a fully assembled condition ready for use. Such a disposable drug delivery device is known e.g. from WO 2004/078241 A1. 
     It is an object of the present invention to provide an improved drug delivery device which has a reduced number of component parts and reduced manufacturing costs while also making the device less complex to assemble and manufacture. It is a further object to simplify the steps required for a user to set and dispense a dose while also making the device less complex and more compact in size. 
     According to a first embodiment of the present invention, this object is solved by a disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver, wherein the housing comprises an outer body and an inner body with the outer body being a one-piece component with the cartridge holder. Combining the cartridge holder and the outer body part of the housing into one single component reduces the number of component parts and thus assembling complexity. Further, the risk of a misuse, where a user attempts to exchange an empty cartridge in a disposable drug delivery device, is reduced. 
     According to a second embodiment of the present invention, this object is solved by a disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver, wherein the driver is in threaded engagement with the piston rod, permanently rotationally locked to the button and axially displaceable relative to the button in a proximal direction against the force of a resilient member which is a one piece component with either the driver or the button (or the button is displaceable relative to the driver in a distal direction). In other words, a spring or the like resilient member for biasing the button in a first direction which is usually provided as a separate component in known devices is integrated in the button or driver to thus reduce the number of component parts and assembling complexity. 
     Preferably, the driver comprises at least one elastically deformable finger having a free end engaging the button to bias the button in the proximal direction. 
     According to a third embodiment of the present invention, this object is solved by a disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver, wherein the housing comprises an inner surface with splines and the driver comprises at least one protrusion which in a first axial position of the button relative to the driver is allowed to elastically move in a radial direction and which in a second axial position of the button relative to the driver is forced by the button in a radially outer position thus rotationally locking the driver to the housing. In known devices a clutch member rotationally coupling the driver and the housing or a clicker member for producing a tactile and/or audible feedback during use of the device is usually provided with at least one separate component. In the present embodiment of the invention, these functions of the device are realized without adding component parts. 
     Preferably, the driver comprises at least one protrusion interacting with splines of the housing wherein the protrusion is elastically movable in a radial direction, and wherein the button comprises a recess or opening suitable for at least partly receiving the protrusion of the driver. If the button is moved relative to the driver, the protrusion cannot engage the recess or opening such that the radially inward movement of the protrusion is prevented, thus locking the protrusion in its radial position. 
     According to a fourth embodiment of the present invention, this object is solved by a disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver, wherein a first rotationally acting clutch is formed by the button and the display member which is in its coupled state during dose setting and in its decoupled state during dose dispensing, and a second rotationally acting clutch is formed by the driver and the housing which is in its decoupled state during dose setting and in its coupled state during dose dispensing. In known devices clutches usually require additional components either being interposed between the components to be coupled or decoupled or being used for actuation of the clutch. In contrast to that, with the present invention two clutches are provided without additional component parts. 
     Preferably, the button comprises a set of clutch teeth and the display member comprises a further set of corresponding clutch teeth, wherein axial movement of the button relative to the display member engages or disengages the sets of clutch teeth. The second clutch may be formed by the above mentioned at least one protrusion of the driver interacting with splines of the housing. 
     According to a fifth embodiment of the present invention, this object is solved by a disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver, wherein a first clicker, which is active during dose setting, is formed by the driver and the housing and a second clicker, which is active during dose dispensing, is formed by the button and the display member. In other words, a clicker for producing a tactile and/or audible feedback during use of the device is provided without adding separate components to the device. 
     According to a sixth embodiment of the present invention, this object is solved by a disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament, comprising a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver, wherein the number of components of the drug delivery device including the cartridge and a cap for shielding the cartridge holder is ten or less. In this respect, the cartridge including its movable rubber type bung, its pierceable rubber seal and e.g. its crimped annular metal band is considered as one component. Known disposable drug delivery devices usually comprise twelve or more parts, often nearly twenty separate component parts. Taking into account that disposable drug delivery devices are mass-produced, such a significant reduction of component parts results in reduced manufacturing costs. 
     The housing may comprise a transparent or translucent outer body, wherein at least a part of the outer body is coated by an opaque layer. This is especially preferred if the outer body is a one-piece component with usually the transparent or translucent cartridge holder. A further benefit of the outer body being transparent or translucent is that additional window inserts may be omitted. The opaque, i.e. not-transparent and not-translucent, layer may cover the part of the outer body containing the mechanical dosing components. Especially, the display member, which is typically provided with numbers or the like for displaying the set dose, may be at least partly shielded by the opaque layer such that only the number corresponding to the actually set dose is visible. The opaque layer may be an inner or outer coloured layer, a label or tag attached to the outer body, a lining attached or otherwise fixed to the outer body or a frosted or scarified surface. 
     Preferably, the piston rod is a double threaded piston rod having a first outer thread engaging an internal thread of the housing and a second outer thread engaging an internal thread of the driver, wherein the first and second outer threads may overlap each other at least partially. This allows to provide a mechanical advantage, i.e. a transmission (gear) ratio, in the device. Typically, the dial extension of the button, i.e. the distance the button winds out of the housing during dose setting, will be larger than the distance the piston rod is displaced relative to the cartridge holder and thus the cartridge. This allows dispensing even small amounts of a medicament with a maximum of dispensing control by the user. 
     A further reduction of the number of component parts may be achieved if the piston rod comprises a bearing attached to the piston rod by at least one predefined breakage point. The bearing is axially constrained but rotatable with respect to the piston rod after detachment of the bearing by destroying the at least one predefined breakage point during or after assembly. Thus, only one single component has to be handled during assembly which in use fulfils the function of two separate components. 
     According to a preferred embodiment, the driver is a tubular element having a distal portion engaging a nut interposed between the housing and the driver, and a proximal portion which at least partly surrounds a tubular portion of the button. Preferably, one of the housing and the driver comprises at least one spline and the other of the housing and the driver comprises a threaded portion with the nut interposed between the housing and the driver, wherein the nut comprises at least one protrusion engaging the at least one spline and a thread engaging the threaded portion, and wherein the threaded portion of the housing or the driver comprises a rotational end stop. If the nut abuts the rotational end stop, further movement of the nut in the thread is prevented which thus prevents further rotation of the driver relative to the housing which is required during dose setting. Thus, the nut may be used to limit the settable dose. This is e.g. required to prevent setting a dose exceeding the amount of medicament in the cartridge. 
     Preferably, one of the driver and the display member comprises a circular groove or a circular track defined by two walls and the other of the driver and the display member comprises a circular bulge engaging the groove or track. This allows to constrain the driver and the display member in the axial direction but to allow relative rotation. 
     If the housing comprises an outer body and an inner body, the inner body may be rotationally and axially constrained within the outer body such that a cylindrical gap exists between the inner body and the outer body. Preferably, the inner body comprises an outer thread engaging an inner thread of the display member and comprises at least one inner spline engaging a protrusion of the driver. 
     In a standard embodiment, the splines of the inner body are axially aligned with the pen device. In an alternative embodiment, it is possible to reduce dispense force, increase the velocity ratio and to increase the thread pitch of the display member (i.e. increase of friction coefficient asymptote), by providing the inner body with at least one inner spline which is helically twisted. In other words, the splines are not axially aligned, which results in the driver and the button traveling helically during dose dispensing. This may require adding an over-cap for the button as an additional component preventing relative rotation with respect to a user&#39;s hand, typically the thumb, during dose dispensing. 
     The basic function of the drug delivery device according to the present invention may include that a dose is selected by rotating a button component, which travels helically during dose setting. A dose may be delivered by pressing on the same button component, which now moves axially during dispensing. Preferably, any dose size can be selected, in predefined increments, between zero and a predefined maximum dose, e.g. 80 units. It is a further advantage if the mechanism permits cancelling of a dose without medicament being dispensed, e.g. by rotation of the button component in the opposite direction to when selecting a dose. 
     It is preferred if during dose setting the button is rotated which entrains the driver and the display member such that the button, the driver and the display member are moved on a helical path with respect to the housing and the piston rod. Further, during dose dispensing the button is axially displaced which entrains the driver and the display member such that the button, the driver and the display member are axially moved with respect to the housing and the piston rod, with the display member and the piston rod rotating with respect to the housing, the button and the driver. 
     To prevent malfunction or misuse of the device, the dose setting mechanism may be provided with stops preventing dialling of a dose below zero units or dialling of a dose above a maximum dose. Preferably, rotational hard stops are provided, e.g. between the display member and the inner body as a zero unit stop and/or as a maximum units stop. 
     The drug delivery device may comprise a cartridge containing a medicament. The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
     wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, 
     wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, 
     wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, 
     wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4. 
     Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
     Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
     Exendin-4 derivatives are for example selected from the following list of compounds:
     H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   des Pro36 Exendin-4(1-39),   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
 
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
 
or an Exendin-4 derivative of the sequence
   des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
 
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
   

     Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
     A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
     Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. 
     The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
     There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. 
     Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
     In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. 
     Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity. 
     An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv). 
     Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17 . . . ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
     Pharmaceutically acceptable solvates are for example hydrates. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       Exemplary embodiments of the invention will now be described with reference to the accompanying drawings, in which: 
         FIG. 1  shows a perspective view of a drug delivery device in accordance with the present invention; 
         FIG. 2  shows in an exploded view the components of the drug delivery device of  FIG. 1 ; 
         FIG. 3 a    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a zero unit position; 
         FIG. 3 b    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a 47 units position; 
         FIG. 3 c    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a maximum units position; 
         FIGS. 4 a, b    show sectional views of a detail of the drug delivery device of  FIG. 1 ; 
         FIGS. 5 a, b    show sectional views of a further detail of the drug delivery device of  FIG. 1 ; 
         FIG. 6 a    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a zero unit position; 
         FIG. 6 b    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a maximum units position; 
         FIG. 7  shows a cut-away view of a detail of the drug delivery device of  FIG. 1 ; 
         FIG. 8  shows a sectional view of a further detail of the drug delivery device of  FIG. 1 ; 
         FIGS. 9 a - d    show cut-away views of further details of the drug delivery device of  FIG. 1 ; 
         FIG. 10  shows a perspective view of a nut of the drug delivery device of  FIG. 1 ; 
         FIG. 11  shows a sectional view of the nut of  FIG. 10 ; 
         FIGS. 12 a, b    show cut-away views of further details of the drug delivery device of  FIG. 1 ; 
         FIGS. 13 a - c    show cut-away views of further details of the drug delivery device of  FIG. 1 ; 
         FIG. 14  shows a perspective view of a nut of the drug delivery device of  FIG. 1 ; 
         FIGS. 15 a, b    show cut-away views of further details of the drug delivery device of  FIG. 1 ; 
         FIG. 16 a    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a maximum units position; 
         FIG. 16 b    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a maximum units position with the button pressed; 
         FIG. 16 c    shows a cut-away view of the proximal part of the drug delivery device of  FIG. 1  in a zero unit position; and 
         FIGS. 17 a - c    show cut-away and sectional views of further details of the drug delivery device of  FIG. 1 . 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 1  shows a drug delivery device  1  in the form of an injection pen. The device has a distal end (upper end in  FIG. 1 ) and a proximal end (lower end in  FIG. 1 ). The component parts of the drug delivery device  1  are shown in  FIG. 2  in more detail. The drug delivery device  1  comprises an outer housing part  10 , an inner body  20 , a piston rod  30 , a driver  40 , a nut  50 , a display member  60 , a button  70 , a cartridge  80  and a cap  90 , i.e. in total nine separate component parts. As shown in  FIG. 2 , a needle arrangement comprising a needle hub  2  and a needle cover  3  may be provided as additional components, which can be exchanged as explained above. 
     The outer housing part  10  is a generally tubular element having a distal part, which forms a cartridge holder  11  for receiving cartridge  80 , and a proximal part, which forms an outer body  12 . In a preferred embodiment, the outer housing part  10  is transparent, with the outer body  12  being provided with an opaque layer  13 . In  FIG. 2 , the opaque layer  13  covers most of the outer body  12  with the exception of a transparent window  14 . Apertures  15  may be provided in the cartridge holder  11 . Further, at its distal end the cartridge holder  11  has a thread  16  or the like for attaching the needle hub  2 . 
     The inner body  20  is a generally tubular element having different diameter regions. As can be seen in  FIGS. 16 a  to 16 c   , the inner body  20  is received in the outer body  12  and permanently fixed therein to prevent any relative movement of the inner body  20  with respect to the outer body  12 . An external thread  21  is provided on the outer surface of the inner body  20 . Further, splines  22  are provided on the inner surface of the inner body  20  which are shown in  FIGS. 8 and 11 . As can be taken from  FIG. 7 , the inner body  20  has near its distal end an inner thread  23 . 
     The piston rod  30  is an elongate element having two external threads  31 ,  32  with opposite hand which overlap each other. One of these threads  31  engages the inner thread  23  of the inner body  20 . A disk-like bearing  33  is provided at the distal end of the piston rod  30 . As shown in  FIG. 2 , the bearing  33  may be attached to the piston rod  30  as a one-piece component via a predetermined breaking point. This allows that the bearing  33  is separated from the piston rod  30  such that the bearing  33  remains seated on the distal end of the piston rod  30  to allow relative rotation between the bearing  33  and the piston rod  30 . 
     The driver  40  is a generally tubular element having different diameter regions. A distal region of the driver  40  has an external thread  41 . An inner surface of the driver  40  has an inner thread  42  ( FIGS. 12 a  and 12 b   ) engaging one of the external threads  32  of the piston rod  30 . The driver  40  surrounds the piston rod  30  and is at least partly located within inner body  20 . The driver has at least one proximal opening  43  which will be explained in more detail below. Further, a resilient finger  44  ( FIGS. 6 a  and 6 b   ) is provided on the driver  40  by a U-shaped cut in the skirt of the driver  40 . The finger  44  is allowed to flex in the axial direction and engages button  70 . In addition, a flexibly hinged protrusion  45  ( FIGS. 8 and 9   a ) is provided on the driver  40  by a similar cut out in the skirt of the driver  40 . The protrusion  45  is allowed to flex radially inwardly and is provided with lateral flaps  46 . Protrusion  45  engages splines  22  of the inner body  20 . 
     The nut  50  is provided between the inner body  20  and the driver  40 . External ribs  51  of the nut  50  engage splines  22  of the nut  50 . An internal thread  52  of the nut engages the external thread  41  of the driver  40 . As an alternative, splines and ribs could be provided on the interface between the nut  50  and the driver  40  and threads could be provided on the interface between the nut  50  and the inner body  20 . As a further alternative, the nut  50  may be designed as e.g. a half nut. Further, in the embodiment of  FIG. 10 , four rotational hard stops  53  are provided on nut  50  for interaction with corresponding stops  47  on the driver  40  at the proximal end of thread  41 . 
     The display member  60  is a generally tubular element with an internal thread  61  engaging the external thread  21  of the inner body  20 . Thus, the display member  60  is interposed between the inner body  20  and the outer body  12 . A series of numbers is provided, e.g. printed, on the outer surface of the display member  60 . The numbers are arranged on a helical line such that only one number or only a few numbers are visible in through window  14  of the outer body  12 . As will be explained in more detail below, the display member  60  is attached to the driver  40  preventing relative axial movement but allowing relative rotation. 
       FIGS. 4 a  and 4 b    show in more detail a zero unit rotational hard stop formed by a stop wall  62  in thread  61  of the display member  60  and a corresponding stop face  24  on the inner body  20 .  FIGS. 5 a  and 5 b    show in more detail a maximum dose (e.g. a 80 units) rotational hard stop formed by a finger  63  at the distal end of the display member  60  and a protrusion  25  in thread  21  of the inner body  20 . Thus, a user is prevented from dialing below zero units and above e.g. 80 units. 
     The button  70  has a proximal end with an, e.g. serrated, flange or outer skirt  71  allowing a user to easily grip and dial button  70 . A sleeve-like part  72  of the button  70  with a reduced diameter extends in the distal direction and is inserted into the driver  40  such that a limited relative axial movement is allowed but relative rotation is prevented. This is achieved by a rib  73  on the sleeve-like part  72  which is guided in a proximal opening  43  of the driver  40 . A recess  73  which generally has the outline of the protrusion  45  and its lateral flaps  46  is provided in the sleeve-like part  72  of button  70 . 
     A clutch is provided between the display member  60  and the button  70  by corresponding teeth  64  and  74  ( FIGS. 13 a  and 13 b   ). If teeth  74  of the button  70  engage teeth  64  of the display member  60 , these components are rotationally locked. The resilient finger  44  of the driver  40  biases the button  70  in the proximal direction of the device  1 , i.e. in a direction engaging the clutch teeth. The clutch can be released allowing relative rotation by shifting the button  70  axially with respect to the display member  60  against the bias of finger  44 . 
     Further, a dispense clicker is provided by flexible arms  65  on the display member  60  and a toothed profile  75  on the inner side of flange  71  of button  70 . This clicker is shown in  FIGS. 17 a    to  17   c.    
     The cartridge  80  includes a pre-filled, necked-down cartridge reservoir  81 , which may be typically made of glass. A rubber type bung  82  or stopper is located at the proximal end of the cartridge reservoir  81 , and a pierceable rubber seal (not shown) is located at the other, distal, end. A crimped annular metal band  83  is used to hold the rubber seal in place. The cartridge  80  is provided within the cartridge holder  11  with bearing  33  of piston rod  30  abutting bund  82 . 
       FIG. 1  shows the cap  90  attached to the distal end of the device  1 , thus covering the cartridge holder  11 . The cap  90  may be releasable snapped onto the outer housing  10  and can be taken off for use of the device  1 . 
     In the following, the function of the disposable drug delivery device  1  and its components will be explained in more detail. 
     To use the device, a user has to select a dose. In the start (at rest) condition as shown in  FIGS. 3 a  and 6 a    the display member  60  indicates the number of doses dialed to the user. The number of dialed units can be viewed through the dose window  14  in the outer body  12 . Due to the threaded engagement between the display member  60  and the inner body  20  rotation of the button  70  in a clockwise fashion causes the display member  60  to wind out of the device and incrementally count the number of units to be delivered.  FIG. 3 b    shows an intermediate stage of dialing (47 of 80 units). 
     During dose setting button  70 , driver  40  and display member  60  are rotationally locked together via clutch teeth  64 ,  74 . Further, button  70 , driver  40  and display member  60  are axially coupled. Thus, these three components wind out of the outer housing  10  during dose setting. 
     Clockwise rotation of the button  70  causes the driver  40  to rotate and in doing so it advances along the piston rod  30  which remains fixed throughout dialing. 
     The protrusion  45  and splines  22  form a clicker arrangement that provides tactile and audible feedback to the user when dialing doses. This clicker arrangement has the further functions of defining discrete positions for the display member  60  when dialing and of providing a method of locking the rotation of the driver  40  and hence button  70  when dosing. During dialing (dose setting) the button  70  is in an axial position relative to the driver  40  such that the pocket or recess  73  is located radially inwards of the protrusion. Thus, the protrusion  45  is allowed to flex radially inwards to overcome splines  22  thereby providing a tactile and audible feedback to the user.  FIG. 8  shows the flexible protrusion arm  45  located between splines  22  which are e.g. 15° apart. 
     At the maximum settable dose of 80 units, the stop features  63 ,  25  shown in  FIGS. 5 a  and 5 b    engage to prevent further dialing. This position of the device is shown in  FIGS. 3 c    and  6   b.    
     The last dose nut  50  provides the function of counting the number of dispensed units. The nut  50  locks the device  1  at the end of life and as such no more drug can be dialed or dispensed by the user. The last dose nut  50  and the driver  40  are connected via a threaded interface  41 ,  52  as explained above. Further, the last dose nut  50  is assembled into splines  22  as shown in  FIG. 11  such that the nut  50  and the inner body  20  are rotationally locked together (at all times). Rotation of the driver  40  during dialing causes the nut  50  to advance along the driver  40  thread  41 . The nut  50  is free to slide axially within the inner body  20  at all times which allows advancement of the nut. The change in pitch shown in  FIGS. 12 a  and 12 b    towards the final doses axially accelerates the advancement of the nut  50  towards the end of life lockout condition. At the end of life condition, the stop features  53  of the last dose nut  50  contact the corresponding features  47  on the driver  40 . The splined contact with inner body  20  reacts any torque transmitted by these stop features  47 . 
     With the desired dose dialed, the device  1  is ready for dose dispensing. This basically requires pushing button  70  which will result in a disengagement of the clutch teeth  64 ,  74 . As mentioned above, when dialing a dose the button  70  is ‘biased out’ and the clutch features  64 ,  74  which rotationally lock the driver  40 , button  70  and display member  60  together are engaged as shown in  FIG. 15 a   . Upon pressing the button  70  the clutch features  64 ,  74  disengage as shown in  FIG. 15 b    and relative rotation between the display member  60  and the button  70  is possible. In all conditions the driver  40  and the button  70  are rotationally locked together by engagement rib  73  and opening  43 . Thus, with the clutch  64 ,  74  disengaged (button  70  pushed in) button  70  and driver  40  are rotationally locked together with the button  70 , the driver  40  and the display member  60  still being axially coupled. 
     At the same time the relative axial movement of the button  70  with respect to the driver  40  results in the pocket or recess  73  being shifted relative to the protrusion  45 . Thus, the protrusion  45  is prevented from flexing inwards because flaps  46  rest on a non-recessed area of button  70 . A comparison of  FIGS. 9 c  and 9 d    shows this activation of the lockout feature preventing the flexible protrusion arm  45  from overcoming splines  22  if the button  70  is pressed. In this condition, the driver  40  and the button  70  are rotationally constrained to the inner body  20  thus preventing any rotation relative to the outer housing  10  if the splines  22  are axially aligned with the device as shown in  FIG. 13 c   . The above mentioned alternative embodiment with twisted splines  22  is shown in  FIG. 14 . 
     With the desired dose dialed the button  70  can be depressed and the piston rod  30  driven forward to dispense drug from the cartridge. The interaction of mating threads between the piston rod  30 , driver  40  and inner body  20  delivers a mechanical advantage of 2:1. The sequence of dispensing is depicted in  FIGS. 16 a  to 16 c    with  FIG. 16 a    showing the device  1  with 80 units dialed prior to pushing button  70 ,  FIG. 16 b    shows the device  1  with 80 units dialed and button  70  pushed and  FIG. 16 c    shows the device  1  with 80 units dispensed. 
     During dose dispensing a dispense clicker is active which involves button  70  and display member  60 . The dispense clicker provides primarily audible feedback to the user that drug is being dispensed. The interaction between the flexible arms  65  on the display member  60  and the toothed profile  75  on the button flange  71  provide this dispense click. Relative rotation is only allowed in one direction. This occurs when the components are decoupled during dispense and a click is produced for every unit.

Technology Classification (CPC): 0