Patent Publication Number: US-10307544-B2

Title: Differential gear mechanism for a drug delivery device and drug delivery device

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a National Stage application under 35 U.S.C. § 371 of International Application No. PCT/EP2015/061629, filed May 27, 2015, which claims the benefit of EP Application No. 14170328.0, filed on May 28, 2014. The disclosures of the prior applications are incorporated by reference in their entirety. 
     The present disclosure is directed to a differential gear mechanism for a drug delivery device with a primary drug delivery assembly and a secondary drug delivery assembly. The present disclosure is also directed to a drug delivery device comprising a respective differential gear mechanism. 
     Certain disease states require treatment using one or more different medicaments. Some drug compounds need to be delivered in a specific relationship with each other in order to deliver the optimum therapeutic dose. Here, combination therapy may be desirable, but not possible in a single formulation for reasons such as, but not limited to, stability, compromised therapeutic performance and toxicology. 
     For example, in some cases it might be beneficial to treat a diabetic with a long acting insulin and with a glucagon-like peptide-1 (GLP-1), which is derived from the transcription product of the proglucagon gene. GLP-1 is found in the body and is secreted by the intestinal L cell as a gut hormone. GLP-1 possesses several physiological properties that make it (and its analogs) a subject of intensive investigation as a potential treatment of diabetes mellitus. Another example of a medicament combination is the administration of a pain reliever in combination with a medicament for treating osteoarthritis. 
     Drug delivery devices of the aforementioned kind often have applications where regular injection by persons without formal medical training occurs. This is increasingly common among patients having diabetes or the like, e.g. osteoarthritis. Self-treatment enables such patients to conduct effective management of their disease. 
     In combination therapy, a primary medicament and a secondary medicament are delivered in a specific relationship to deliver the optimum therapeutic dose. The injection devices of the generic kind usually comprise a housing in which two or more drug delivery assemblies are retained. Such devices include a primary drug delivery assembly for dispensing the primary medicament such as the long-acting insulin and a secondary drug delivery assembly for dispensing the secondary medicament, such as GLP-1. Some kinds of drug delivery assemblies comprise a compartment such as a cartridge holder for accommodating a replaceable medicament container such as a cartridge which stores the medicament. 
     In some cases, depending on the patient or the stage of the therapy, an effective treatment requires variations in the quantities and/or proportions of the medicaments making up the combined therapy. For example, the patient may require a non-adjustable fixed dose of the secondary medicament in combination with an adjustable variable dose of the primary medicament. 
     The effectiveness of a combined delivery of medicaments may require one or more doses to be delivered sequentially with one of the two medicaments being injected into the human body prior to the delivery of the other medicament. Such treatment may be conducted with devices that include two separate dispensing mechanisms that are actuated independently from each other such that the dispensing mechanisms are activated successively. This, however, may be hazardous for patients that are physically or mentally impaired or otherwise disadvantaged. It is desirable to have a device that is provided with merely one dispense button respectively an actuator which the patient can trigger and which leads to a sequential delivery of the primary and the secondary medicament. 
     Some aspects of the disclosure can be implemented to improve the setting and dispense capabilities of a drug delivery device of the aforementioned kind. Further, it is desired to enable the user to choose either to dispense a dose of only one the medicaments or a combined dose of both medicaments. 
     The above problem is solved by a differential gear mechanism for a drug delivery device as defined in claim  1  and a drug delivery device as defined in claim  4 . 
     The drug delivery devices of the aforementioned kind comprise a primary drug delivery assembly with a primary dose dial sleeve and a secondary drug delivery assembly with a secondary drive sleeve. The differential gear mechanism comprises a first toothing, a transmission element movable relative to the first toothing in a first axial direction and comprising at least one first gear wheel and at least one second gear wheel concentrically arranged with respect to the first gear wheel. Further, a second toothing that is configured to be axially constrained to the primary dose dial sleeve and a third toothing that is configured to the axially constrained to the secondary drive sleeve and a fourth toothing are provided. The second toothing, the third toothing and the fourth toothing are movable relative to the first toothing in axial direction. The first gear wheel is in meshed engagement with the first toothing and the fourth toothing while the second gear wheel is in meshed engagement with the second toothing and the third toothing. The first toothing may be arranged stationary at least in axial direction with respect to the second, third and fourth toothing. 
     Preferably, the dose dial sleeve comprises a number of indices for visually indicating the set dose. Accordingly, in the following, the primary dose dial sleeve is referred to as the primary number sleeve. 
     The differential gear mechanism enables for a drug delivery device where a user can choose whether he only wishes to set and dispense a dose of a primary medicament contained in the primary drug delivery device or to set and dispense a dose of the primary medicament in combination with a set dose of a second medicament in the secondary drug delivery assembly. The implementation of this mechanism delivers a very precise setting and delivery of medicament doses. For example, the differential gear mechanism can be used in combination with a drug delivery device which is configured to dispense a variable dose of a primary medicament and a secondary drug delivery assembly which is configured for the delivery of a fixed dose of a secondary medicament. The user has optimal conditions for combined therapy treatment. Further, the disclosure provides for improved dispensing properties, e.g. by operating a common dose dispense button. 
     The term “fixed dose” as used herein can be characterized as a dose value that is defined by the construction of the drug delivery assembly, wherein the user is only able to inject a specific dose. The user is not in the position to set lower or higher doses of medicament and/or to inject lower or higher doses of the medicament. The dose the user may effectively set and inject is restricted to a certain value. 
     On the contrary, the term “variable dose” can be characterized as a dose where the user is substantially free to choose the amount of medicament he wants to inject. The dose is variably adjustable, normally between upper and lower limits. 
     The transmission element may comprise at least one or more first and second gear wheels respectively. 
     According to another embodiment, the fourth toothing is movable relative to the second toothing in axial direction. The fourth toothing may be movable relative to the second toothing between a first relative position and a second relative position in axial direction. This enables for the convenient individual setting of the secondary drug delivery assembly without affecting a dose setting in the primary drug delivery assembly. Further, it enables for the effective setting of a fixed dose in a secondary drug delivery assembly. 
     Preferably, each of the toothings is formed as a gear rack with a number of teeth arranged side by side, the arrangement preferably extending in axial direction. 
     A further embodiment concerns a differential gear mechanism for a drug delivery device with a primary drug delivery assembly comprising a primary dose dial sleeve configured to move proximally in a helical movement during setting of a dose of a primary medicament contained in a primary reservoir of the primary drug delivery assembly, and with a secondary drug delivery assembly comprising a secondary drive sleeve configured to move in a proximal direction in a helical movement during setting of a dose of a secondary medicament contained in a secondary reservoir of the secondary drug delivery assembly; the differential gear mechanism comprising a first toothing; a transmission element movable relative to the first toothing in a first axial direction and comprising at least one first gear wheel and at least one second gear wheel concentrically arranged with respect to the first gear wheel; a second toothing axially constrained to the primary dose dial sleeve; a third toothing axially constrained to the secondary drive sleeve; and a fourth toothing. The second toothing, the third toothing and the fourth toothing are moveable relative to the first toothing in the first axial direction and the fourth toothing is movable relative to the second toothing in the axial direction; and the first gear wheel is in meshed engagement with the first toothing and the fourth toothing; and the second gear wheel is in meshed engagement with the second toothing and third toothing such that when the secondary drive sleeve moves proximally, axial motion of the third toothing causes relative axial movement between the second toothing and the fourth toothing, and such that when the primary dose dial sleeve moves proximally motion of the second toothing in proximal direction causes the second toothing and the forth toothing to move together in proximal direction. 
     In this regard, it is preferred when the first toothing is arranged stationary with respect to the housing. 
     The above embodiment provides for a clear indication mechanism whether a dose of the secondary medicament in the secondary drug delivery assembly has been set or not. Setting the dose of the primary medicament, which is connected with proximal displacement of the primary dose dial sleeve, does not cause said relative displacement so that the user can get a clear indication that he is about to inject a dose of the primary medicament only. The relative displacement between the second toothing and the forth toothing, which takes place when the secondary drive sleeve is moved proximally when the dose of the secondary medicament is set, can be effectively used to implement a common actuation mechanism. In this regard, whether or not the primary dose dial sleeve or the secondary drive sleeve rotate during dose setting is not important as the differential gear mechanism merely depends on the axial displacement of the primary dose dial sleeve or the secondary drive sleeve during the setting of a dose of the primary or the secondary medicament. 
     Some aspects of the disclosure relate to a drug delivery device comprising a primary drug delivery assembly with a primary dose dial sleeve and a secondary drug delivery assembly with a secondary drive sleeve and a differential gear mechanism as described herein, wherein the first toothing is fixed stationary with respect to a drug delivery housing, wherein the second toothing axially constrained to the primary dose dial sleeve, and wherein the third toothing is axially constrained to the secondary drive sleeve. 
     The implementation of the differential gear mechanism enables for a precise coupling of the drug delivery assembly. In particular, the fourth toothing may be efficiently used for indication that a dose in the secondary drug delivery assembly is set. 
     Preferably, the secondary drive sleeve is configured to move proximally in a helical movement during dose setting and to move distally in a pure axial motion during dose dispense. A helical movement can be characterized as a movement of combination of a longitudinal motion in combination with a rotation about the axis of motion. 
     Preferably, the primary number sleeve is configured to move proximally a helical movement during dose setting and to move distally in the opposite direction in an opposite helical movement during dose dispense. 
     The drug delivery housing may extend from a proximal end to a distal end along a first longitudinal axis and accommodates the primary and the secondary drug delivery assembly. The distal end is usually referred to as the dispensing end, where the drug delivery device may be equipped with a single dispense interface, such as an injection needle. The proximal end is usually referred to as the actuation end, where a user presses a button or the like to start injection. 
     The drug delivery device may comprise a movable element movable with respect to the primary dose dial sleeve between a first e.g. distal position, and a second position, e.g. proximal position. The fourth toothing may engage the movable element when the secondary drive sleeve is moved in proximal direction, resp. when the dose of the secondary medicament is set, e.g. by rotating the secondary drive sleeve in a helical movement in proximal direction such that movement of third toothing is transferred though the differential gear mechanism to the fourth toothing in proximal direction and to the movable element. Herewith, the actuation mechanisms are efficiently coupled and a clear indication that a dose of medicament in the secondary drug delivery assembly has been set can be provided. 
     The primary drug delivery assembly may be retained in or attached to the drug delivery device housing and may be configured such as to deliver a variable dose of a first medicament and the secondary drug delivery assembly may be retained in or attached to the drug delivery device housing and may be configured to deliver only a fixed dose of a second medicament. The primary and secondary drug delivery assembly may each contain a medicament reservoir. A primary medicament, e.g. a long-acting insulin may be contained in the primary reservoir and a secondary medicament, e.g. GLP-1, may be contained in the secondary reservoir. 
     The primary drug delivery assembly may comprise a primary dose setting mechanism and a primary dose dispense mechanism. The secondary drug delivery assembly may comprise a secondary dose setting mechanism and a secondary dose dispense mechanism. The drug delivery device may include a variable dose setting mechanism which is associated with the primary drug delivery assembly to set a variable dose of the primary medicament and a fixed dose setting mechanism which is associated with the secondary drug delivery assembly to set a fixed dose of the secondary medicament. The primary drug delivery assembly and the secondary drug delivery assembly may each extend along a longitudinal axis, which runs preferably parallel to the longitudinal axis of the housing 
     The primary drug delivery assembly may include a primary drug delivery assembly housing. Alternatively, the housing of the drug delivery device may constitute the primary drug delivery assembly housing. The secondary drug delivery assembly may include a secondary drug delivery assembly housing. Alternatively, the housing of the drug delivery device may constitute the secondary drug delivery assembly housing. 
     The primary drug delivery assembly may further comprise an actuation element such as a dose setter or a dose dial grip configured to be rotationally fixed to the number sleeve during dose setting such that rotation of the actuation element causes the number sleeve to rotate and to wind out of the housing in a combination of translational and rotational movement. 
     The movable element may be a dispense button or the like with an abutment surface arranged proximally from an engagement section or abutment surface of the fourth toothing so that movement of the fourth toothing in proximal direction causes engagement with the button and axial movement of the fourth toothing is transferred to the movable element. For example, the fourth toothing may formed as a gear rack with a proximally oriented engagement section which abuts a distally oriented engagement section of the dispense button such that fourth toothing moves the dispense button proximally with respect to a dose dial grip and a proximal surface of the dispense button projects or protrudes from a proximal end of the dose dial grip. 
     The first toothing may be arranged stationary at least in axial direction with respect to the second, third and fourth toothing by being provided, e.g. formed, on the secondary drug delivery assembly housing or a housing element of the secondary drug delivery assembly. Alternatively, the first toothing may be fixed stationary within the drug delivery housing. Preferably, the first toothing is formed as a gear rack 
     The second toothing may be axially constrained to the primary number sleeve by being connected or coupled to the primary number sleeve such that movement of the primary number sleeve in axial direction is transferred to the second toothing. The second toothing may be formed as an elongated gear rack extending in axial direction and arranged parallel to the primary number sleeve. The second toothing may be coupled to the primary number sleeve such that relative rotation between the primary number sleeve and the second toothing is possible but relative axial movement is prevented. Alternatively, the second toothing may be connected or coupled to the primary number sleeve by engaging a dosing element such as an actuation element, which is rotationally coupled to the primary number sleeve during dose setting, such that relative rotation between the primary number sleeve or the actuation element and the second toothing is possible but relative axial movement is prevented. For example, the second toothing may comprise a collar or the like engaging a groove on the outer surface of the primary number sleeve or the actuation element. The second toothing may be axially guided by the housing, e.g. by means of axially extending guidance grooves in the housing engaged by a projection on the second toothing to form a splined connection or the like. 
     The third toothing is axially constrained to the secondary drive sleeve. For this purpose, the third toothing may comprise a pin, a projection or the like engaging a circumferential recess or the like on the secondary drive sleeve such the third toothing and the secondary drive sleeve are coupled for mutual movement in axial direction while relative rotational movement is allowed. The third toothing may be axially guided by the housing, e.g. by means of guidance grooves or the like. Preferably, the third toothing is formed as a gear rack 
     The fourth toothing may be constrained to slide axially relative to the second toothing. Preferably it is formed as a gear rack extending in axial direction. The fourth toothing may be formed as part of a sleeve arranged radially inwardly with respect to the second toothing which may also be formed as part of a sleeve. The fourth toothing may be axially guided by the second toothing such that relative rotation is prevented but relative axial movement is possible. For that purpose, guidance means such as guidance grooves or the like can be formed on the inner surface of the second toothing and engage an outer surface of the fourth toothing. The fourth toothing and the second toothing may be adapted to each other such that motion of fourth toothing in the distal direction relative to the second toothing is limited by an abutment against the second toothing, at which point the fourth toothing and the second toothing become fixed relative to each other in distal direction. Relative motion of the fourth toothing in proximal direction may generate an abutment with the movable element. Additional relative motion in proximal direction may cause the moveable element to move relative to the second toothing, the primary number sleeve, the drug delivery housing and a dose dial grip. 
     The transmission element may be formed as or comprise a gear shaft with the first gear wheel and the second gear wheel arranged on the shaft comparable to a gear shaft. The first gear wheel may be rotationally fixed to or formed on the shaft. The second gear wheel may be rotationally supported by the shaft such that relative rotation between the first gear wheel and the second gear wheel is possible. The transmission element is constrained to move axially relative to the housing of the drug delivery device, resp. the first toothing. This may be achieved by the meshed engagement of the gear wheels with the respective toothing. 
     According to a further embodiment, the primary number sleeve is configured to move proximally a helical movement during dose setting and to move distally in the opposite direction in an opposite helical movement during dose dispense. The actuation element may be axially constrained with respect to the second toothing at least during movement of the actuation element in distal direction but free to rotate relative to the second toothing such that during dose setting of the primary drug delivery assembly, the actuation element moves in proximal direction which efficiently indicates that a dose of the primary medicament is set. Accordingly, when the actuation element is moved in distal direction, this axial movement is transferred to the primary number sleeve. The actuation element may at least partly accommodate the movable element. The primary number sleeve may comprise a groove which is formed in a helical pattern on its outer surface in axial direction and the housing of the drug delivery device or of the primary drug delivery assembly may comprise a projection or the like engaging the groove such that rotation of the number sleeve forces the number sleeve to move axially as well. The second toothing may comprises a collar or the like engaging a recess on the actuation element such that axial motion in proximal direction is directly transferred to the second toothing. Alternatively, second toothing may comprises a collar or the like engaging a recess on the number sleeve such that axial motion of the number sleeve in proximal direction is directly transferred to the second toothing. 
     According to a further embodiment, the movable element is configured to move the fourth toothing in distal direction when moved from the second position into the first position. This enables for the direct dispense of a set dose of the secondary medicament in the secondary drug delivery assembly prior to the dispense of the primary medicament. The fourth toothing may engage the dispense button of the drug delivery device when moved in proximal direction such that the dispense button is moved from its first proximal position into its second distal position. By moving the dispense button back into the first proximal position, the movement is transferred to the fourth toothing and through the differential gear mechanism to the third toothing which is axially constrained to the secondary drive sleeve so that axial movement is transferred to secondary drive sleeve which is moved in distal direction such that the secondary medicament is dispensed. 
     According to a further embodiment, the movable element is moveable relative to the actuation element in axial direction, preferably between its first, e.g. distal, position and its second, e.g. proximal, position, wherein when the actuation element is moved from its second position to its first position, the movable element engages the actuation element such that further movement of the moveable element in distal direction is transferred to the actuation element. This enables for an effective sequential delivery of secondary and primary medicament. When the movable element is moved from its proximal position towards its distal position, the displacement is transferred to the fourth toothing and through the differential gear mechanism to the secondary drive sleeve. When the movable element reaches the second position further axial movement is transferred to the actuation element. 
     It is preferred, when at least one of the cartridges of the drug delivery device is filled with the medicament. Also, the drug delivery device can be a disposable injection device. Such devices can be thrown away or recycled after the content of the medicament has been exhausted. However, the present disclosure is also applicable with re-usable devices designed to replace an emptied cartridge with a filled one after the whole content of the former cartridge has been administered. 
     The term “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, 
     wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, 
     wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4. 
     Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
     Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-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-carboxyhepta-decanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
     Exendin-4 derivatives are for example selected from the following list of compounds: 
     H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
     H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
     des Pro36 Exendin-4(1-39), 
     des Pro36 [Asp28] Exendin-4(1-39), 
     des Pro36 [IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or 
     des Pro36 [Asp28] Exendin-4(1-39), 
     des Pro36 [IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
     wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; 
     or an Exendin-4 derivative of the sequence 
     des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010), 
     H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2, 
     des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2, 
     H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
     H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2, 
     des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2, 
     H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
     H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2; 
     or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative. 
     Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
     A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
     Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. 
     The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
     There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. 
     Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (C H ) and the variable region (V H ). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
     In mammals, there are two types of immunoglobulin light chain denoted by A and K. 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, K or A, 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. 
    
    
     
       Exemplary embodiments will now be described with reference to the accompanying drawings, in which: 
         FIG. 1 : shows in perspective sectional view, a drug delivery device in accordance with the present disclosure; 
         FIG. 2 : shows a perspective view of the components of the differential gear mechanism; 
         FIG. 3 : shows a sectional view of a part of the drug delivery device; 
         FIG. 4 : shows another sectional view of a part of the drug delivery device; 
         FIG. 5 : shows a perspective view of the number sleeve; 
         FIG. 6 : shows a perspective view of the third gear rack; 
         FIG. 7 : shows a perspective view the selection switch assembly 
         FIG. 8 : shows a perspective view part of the secondary drug delivery assembly; 
         FIG. 9 : shows a sectional view another part of the drug delivery device; 
         FIG. 10 : shows a sectional view a further part of the drug delivery device; 
         FIG. 11 a - c   : show the elements of  FIG. 10  in different conditions; 
         FIG. 12 : shows the element of  FIG. 10  in a further condition; 
         FIG. 13 : shows in a sectional view a further part of the drug delivery device in accordance with a further embodiment; 
         FIG. 14 : shows the elements of  FIG. 13  in a further condition; 
         FIG. 15 : shows a drug delivery device in accordance with a further embodiment; 
         FIG. 16 a, b   : show different housing parts of the drug delivery device of  FIG. 15 . 
     
    
    
     The drug delivery device  1  comprises a housing  2  in which a primary drug delivery assembly  3  and a secondary drug delivery assembly  4  are retained. The housing  2  extends along a longitudinal axis  5  from a proximal end  6  to a distal end  7  of the drug delivery device  1 . A primary reservoir  8  (medicament cartridge) is arranged in the primary drug delivery assembly  3  at its distal end. A secondary reservoir  9  (medicament cartridge) is arranged in the secondary drug delivery assembly  4  at its distal end. Each of the cartridges  8  and  9  is sealed at its distal end by a septum  10 . A single dispense interface (not shown) with a single injection needle can be attached to the distal end  7  of the drug delivery device housing  2 , the single dispense interface having two proximal needles, each of the needles piercing through one of the septa  10  so that a primary medicament  11  in the primary reservoir  8  and a secondary medicament  12  in the secondary reservoir  9  can be dispensed through the single dispense interface through the injection needle. 
     At the proximal end of the primary cartridge  8 , a bung  13  is provided and at the proximal end of the secondary cartridge  9 , a bung  14  is provided. When the single dispense interface is properly attached to the drug delivery device  1  and the bungs  13  and  14  are moved in distal direction, the medicaments  11  and  12  are forced out of the respective reservoir  8 ,  9  through the single dispense interface. 
     The primary drug delivery assembly  3  comprises a variable dose setting and dose dispensing mechanism  15  and the secondary drug delivery assembly  4  comprises a fixed dose setting and dispense mechanism  16 . 
     The variable dose setting and dispense mechanism  15  includes a number sleeve (dosing sleeve)  17 , a primary drive sleeve  18 , a lead screw  19 , an inner body  20 , a last dose nut  21  and a dial grip  22  (actuation element). The inner body  20  is fixed relative to the housing  2 . 
     The fixed dose mechanism  16  includes a secondary lead screw  23 , a secondary drive sleeve  24  and a fixed dose mechanism housing  25 . A differential gear mechanism  26  connects the variable dose setting and dispense mechanism  15  and the fixed dose setting and dispense mechanism  16 . 
     When the dose dial grip  22  is rotated about an axis extending from the proximal end to the distal end of the primary drug delivery assembly  3  to set or dial a dose, the dose dial grip  22  is rotationally fixed to the primary number sleeve  17  by means of a clutch (not shown). The number sleeve  17  is in threaded engagement with the inner body  20  via a helical thread such that upon rotation of the dose dial grip  22 , the number sleeve  17  is constrained to move relative to the inner body  20  along a helical path. During dose setting, resp. dose dialing, the number sleeve  17  winds out of the inner body  20  in proximal direction. 
     The primary drive sleeve  18  is a tubular element having different diameter regions and is rotationally locked to the dial grip  22 . The primary lead screw  19  is an elongated element with an outer surface  27  having two external threads  28 ,  29  with opposite hands which overlap each other. The distal region of the primary drive sleeve  18  has an inner thread or projection  32  that engages one of the external threads  28 ,  29  of the lead screw  19 . One of the threads  28 ,  29  engages an inner thread resp. projection  30  of the inner body  20 . A disc-like bearing  31  is provided at the distal end of the lead screw  19 . A moveable button  33  is provided at the proximal end of the housing  2 . 
     During dose setting, the dial grip  22 , the number sleeve  17  and the primary drive sleeve  18  are rotationally and axially locked by a clutch mechanism (not shown). Clockwise rotation of the dial grip  22  causes the primary drive sleeve  18  to rotate and in doing so, it advances along the lead screw  19  which remains fixed throughout dialing. 
     When the desired dose is dialed, the dial grip  22  can be depressed in distal direction. Dial grip  22 , primary drive sleeve  18  and inner body  20  are rotationally locked, while dial grip  22 , primary drive sleeve  18  and number sleeve  17  are axially coupled. The rotational constraint between the dial grip  22  and number sleeve  17  is removed as a result of a small relative axial displacement between them. The dial grip  22 , the inner body  20  and primary drive sleeve  18  are rotationally locked. As the dial grip  22  is depressed via the button  33 , the primary number sleeve  17  moves along its helical path relative to the inner body  20  in distal direction and the dial grip  22  moves axially with the number sleeve  17  but does not rotate due to its rotational constrain to the inner body  20 . Axial movement of the drive sleeve  18  results in the primary lead screw  19  to be driven forward to the dispense drug from the cartridge  8 . 
     In the fixed dose mechanism  16 , the secondary drive sleeve  24  is constrained to move relative to the housing  25  along a pre-defined path. The secondary drive sleeve  24  consists of helical segments, alternating with pure axial segments to return the secondary drive sleeve  24  and the fixed dose mechanism housing  25  to the same relative axial position. 
     During setting of the fixed dose, the secondary drive sleeve  24  moves relative to the housing  25  along a helical path in proximal direction. Once the secondary drive sleeve  24  has reached the end of the helical segment, a fixed dose is set. For dispense, the drive sleeve  24  is moved forward in a pure axial motion in distal direction to deliver the fixed dose. Inner helical segments on the secondary drive sleeve  24  are matched to an outer helical track  34  on the secondary lead screw  23 . The secondary lead screw  23  remains stationary during helical motion of the drive sleeve  24  in proximal direction. Axial motion of the secondary drive sleeve  24  causes the secondary lead screw  23  to advance towards the distal end. The bung  14  in the secondary cartridge is moved in distal direction so that the secondary medicament is dispensed. 
     The dose setting and dose dispense elements of the primary drug delivery assembly  3  and the secondary drug delivery assembly  4  are linked by the differential gear mechanism  26 , its components being displayed in  FIG. 2  in an explosive view. The differential gear mechanism comprises a first toothing (first gear rack)  35  provided on the fixed dose mechanism housing  25 , a second toothing (second gear rack)  36 , a third toothing (third gear rack)  37  and a firth toothing (fourth gear rack)  38 . Further, a transmission element  39  comprising a first gear wheel  40  and two second gear wheels  41  that are concentrically arranged such that a first gear wheel  40  and the second gear wheels  41  rotate along a common axis of rotation. 
     The first gear rack  35  is formed on the outside of the fixed dose mechanism housing  25  and also has a gear rack extending in axial direction of the drug delivery device. 
     The second gear rack  36  is an elongated element having a gear rack at its distal (here left side) end, the gear rack consisting of two sets of toothings respectively arranged side by side in a direction from the distal end of the housing towards the proximal end of the housing. The proximal end of the second gear rack  36  is configured to be axially constrained with respect to the primary number sleeve and has a sleeve-like proximal end section  42 . The housing  2  is formed such that the second gear  36  rack is axially guided and is prevented from rotating. The second gear rack may be referred to as the “variable dose rack”. 
     The third gear rack  37  is axially constrained to the secondary drive sleeve  24 . It is further accommodated in the housing  2  such that relative rotation with respect to the housing  2  is prevented. The third gear rack  37  may only slide in axial direction of the housing  2 . The housing  2  is formed such that the third gear rack  37  is axially guided and is prevented from rotating. 
     The fourth gear rack  38  is constrained to slide axially relative to the second gear rack  36 . The fourth gear rack  38  is formed as part of a sleeve arranged radially inwardly with respect to the second gear rack  36 , which is also formed as part of a sleeve. The fourth gear rack  38  is axially guided by the second gear rack  36  such that relative rotation is prevented but relative axial movement is possible. Motion of the fourth gear rack  38  relative to the second gear rack  36  in distal direction is limited by an abutment on the inner surface of the sleeve section of the second gear rack  36 . 
     The transmission element  39  comprises a shaft on which the first gear wheel  40  is formed. The second gear wheels  41  are rotationally supported by the shaft and concentrically arranged with respect to the first gear wheel  40  such that the first gear wheel  40  and the second gear wheels  41  share a common rotational axis. The first gear wheel  40  meshes with both the fourth gear rack  38  and the first gear rack  35 . The second gear wheels  41  mesh with both the second gear rack  36  and the third gear rack  37 . 
     The first gear rack  35  may be referred to as the “housing gear rack”. 
     The second gear rack  36  may be referred to as the “variable dose rack”. 
     The third gear rack  37  may be referred to as the “fixed dose rack” 
     The fourth gear rack  38  may be referred to as the “dosing rack”. 
     The first wheel  40  may be referred to as the “dosing gear”. 
     The second wheels  41  may be referred to as the “variable dose/fixed dose gear”. 
     The interaction of the linear differential gear mechanism components are now described with respect to  FIG. 3 . The secondary drive sleeve  24  is connected to the third gear rack  37  via an engagement section  43  where a projection of the third gear rack  37  engages a recess in the secondary drive sleeve  24  such that the third gear rack  37  and the secondary drive sleeve  24  are axially constrained. The primary number sleeve  17  has a proximal flange-like engagement section  44 , which urges the sleeve section  42  of the second gear rack  36  in proximal direction during dose setting. 
     When a fixed dose is not set be the delivered, the secondary drive sleeve  24  is not actuated and does not displace in proximal direction. The third gear rack  37  remains stationary. Setting a dose of the primary medicament by operating the dose dial grip  22  results in displacement of the number sleeve  17  and in displacement of the second gear rack  36  in proximal direction. As the second gear rack  36  moves in proximal direction  6 , the first gear wheel  40  and the second gear wheel  41  mesh with the associated gear rack. The axial motion of the fourth gear rack  38  is the same axial displacement of the second gear rack  36  so that the fourth gear rack  38  and the second gear rack  36  move together in proximal direction. When a set dose of the primary medicament is injected, the primary number sleeve  17  moves back in distal direction  7  thereby moving the fourth gear rack  38  and the second gear rack  36  back to their initial, so called “at rest” position. 
     If a fixed dose is set to be delivered, the secondary drive sleeve  24  and the third gear rack  37  are moved in proximal direction relative to the first gear rack  35  and the primary number sleeve  17 . Axial motion of the third gear rack  37  causes rotation of the gear wheel  41  and axial movement of the transmission element  39 . As a result there is relative axial motion between the second gear rack  36  and the fourth gear rack  38 , which is equal to the axial motion of the secondary sleeve  24 . 
       FIG. 4  shows a detailed view of the proximal end of the drug delivery device after a dose in the secondary drug delivery assembly has been set. The button  33  is arranged movable with respect to the dial grip  22  and can move relative to the dial grip  22  between the proximal position as shown in  FIG. 4  and a distal position, in which a distal surface of the button  33  engages a proximal surface of the dial element  22 . During the setting of a fixed dose, the relative axial motion between the fourth gear rack  38  and the second gear  36  rack results in the fourth gear rack  38  abutting the button  33  and displacing the button  33  relative to the dial grip  22  in proximal direction such that the button  33  protrudes proximally from the dial grip  22  as displayed in  FIG. 4 . 
     When the button  33  extends above the dial grip  22 , it is indicated that a dose in the secondary drug delivery assembly has been set. Setting of a variable dose can continue through rotation of the dial grip  22  along its helical path which causes the dial grip  22  to move in proximal direction. As the primary number sleeve  17  is displaced helically, the second gear rack  36  is moved in proximal direction. The differential gear mechanism transfers the same axial motion to the fourth gear rack  38  such that the second gear rack  36  and the fourth gear rack  38  move axially together. The relative position between the second gear rack  36  and the fourth gear rack  38  remains constant during the setting of the primary dose of medicament. Due to the abutment between the fourth gear rack  36  and the button  33  and the contact between the first gear wheel  40  and the first gear rack  35 , the extension of the button  33  relative to the dial grip  22  is maintained as both components move away from the housing. 
     When the doses of the primary medicament and the secondary medicament are to be dispensed, the user presses against the proximal face of the button  33 . As the button  33  is in an engagement with the fourth gear rack  38 , this displacement of the button  33  in distal direction forces the fourth gear rack  38  in the same. The axial motion is transferred via the differential gear mechanism to the third gear rack  37 . The force applied to the second gear rack  36  is reacted by the number sleeve  17 , which resists axial motion due to an interlock clutch (not shown) between the number sleeve  17  and the dial grip  22 . The force applied to the third gear rack  37  is transferred to the secondary drive sleeve  24  such that a fixed dose is dispensed. During dispense of the fixed dose, the button  33  enters back into the dial grip  22 . When the button  33  is back in its proximal position, the user force is transferred directly to the dial grip  22  so that dispense of the variable dose of the second medicament begins. Thereby, it is ensured that the set fixed dose of medicament is dispensed prior to the dispense of the variable dose. 
     During dispensing of the fixed dose, the secondary drive sleeve  24  and the third gear rack  37  displace axially to their initial position. As the third gear rack  37  moves axially and the second gear rack  38  remains stationary, the fourth gear rack  38  and the button  33  move relative to the second gear rack  36  and the dial grip  22  until abutment occurs between the button  33  and the dial grip  22 . At this point, the fixed dose is fully dispensed and dispensing of the variable dose can continue with the user force being transferred from the button directly to the dial grip  22 . During dispense of the variable dose, the number sleeve  17  winds back into the housing  2  in distal direction along its helical path. 
     When the button  33  is not extended, the user force is transferred directly to the dial grip  22  and the primary drive sleeve  18  so that the primary medicament is dispensed as described above. The dial grip  22  and the button  33  move axially in distal direction and the second gear rack  36  and the fourth gear rack  38  move axially until the dispensing has been completed. The third gear rack  37  remains stationary. 
       FIG. 5  shows the dose scale on the number sleeve  17  of the primary drug delivery assembly, which is viewable by the user through a window in the housing. When a variable dose of the primary medicament is dialed, the number sleeve  17  moves along a helical path relative to the housing and the dialed dose is displayed through the window. Two separate dose scales  46 ,  47  are marked helically on the surface of number sleeve  17  in a parallel relationship. The first dose scale  45  represents the set dose if no fixed dose in the secondary drug delivery assembly is set. The second dose scale  46  represents the set dose as a combination of a dialed variable dose and a fixed dose, resp. a combination of a set dose in the primary drug delivery assembly and a set dose in the secondary drug delivery assembly. In this embodiment, the second dose scale  46  represents an additional 5 units of the parallel first dose scale  45 , such that for a given number sleeve position the dose marked onto the second dose scale  46  is 5 units greater than that marked onto the first dose scale  45 . 
     An elongated window (not shown) is provided in the drug delivery device housing through which both dose scales  45 ,  46  are visible. A masking window  47  ( FIG. 6 ) is incorporated into the third gear rack  37 , such that one of the dose scales  45 ,  46  is obscured from view depending on the axial position of the third gear rack  37 . During setting of a fixed dose, the third gear rack  37  is moved in proximal direction relative to the number sleeve  17  as explained above. The masking window  47  displaces in proximal direction, thereby hiding the respective dose unit on first dose scale  45  (e.g. 2 units) and giving view to respective combined dose on the second dose scale  46  (e.g. 7 units). In the meantime, the button  33  projects from the dial grip  22  as explained above. 
     If a fixed dose has been set, the fixed dose will be dispensed prior to the variable when the button  33  is pressed. The third gear rack  37  moves relative to the housing in distal direction, while the number sleeve  17  remains stationary. The marking window  47  moves from the second dose scale  46  to the first dose scale  45  during delivery of the fixed dose. After the fixed dose has been delivered, the first dose scale  45  is visible to the user and as the variable dose is delivered, the displayed dose will reduce due to rotation of the number sleeve  17  along its helical path. 
       FIG. 7  displays a fixed dose selection mechanism to enable the user to select whether or not the fixed dose medicament (the secondary medicament) will be dispensed along with the variable dose. 
     The mechanism is configured such that if a user selects to dispense a dose of the secondary medicament, resp. the fixed dose liquid medicament, the secondary dose setting and dose dispensing mechanism is automatically set to deliver the fixed dose medicament and a predetermined number of units of variable dose liquid medicament. In the embodiment explained below, the predetermined number of units is 5 units. The fixed dose selection mechanism includes a selection switch  48 , a clutch  49 , a latch lever  50 , a spring  51 , a first advance lever  52  and a second advance lever  53 . These elements interact with the primary number sleeve  17 , the secondary drive sleeve  24  and the housing  2  as explained in the following. 
     As shown in  FIG. 8 , the clutch  49  comprises a sleeve-like main section  54 . Reference numerals  6  and  7  are included to indicate proximal and distal direction when the components are assembled in the drug delivery device. The proximal end  6  of the clutch  49  has a smaller outer diameter than the main section  54  and is provided with a splined outer surface  55  with splines extending in axial direction. The distal end  7  of the clutch  49  has engagement arms  56  in a circular formation around a longitudinal axis  57  of the clutch  49  and extending in axial direction towards the secondary drive sleeve  24 . The main section  54  is hollow such that the proximal end of the drive sleeve  24  is insertable into the main section  54 . 
     The proximal end section of the secondary drive sleeve  24  is provided with a number of axially extending grooves  58  that are open at the proximal end such that the radially inner surface of the engagement arms  56  may enter the groove. The radially inner surface of the engagement arms  56  and the grooves  58  form a groove/nut or splined connection by which rotational movement may be transferred between the clutch  49  and the secondary drive sleeve  24 , while allowing relative axial movement. 
     On the outer surface of the main section  54 , a pin  59  is formed. The pin  59  forms an interface with a groove  60  on the inside of the fixed dose mechanism housing  25  as shown in  FIG. 9 . The groove  60  has two sections extending in circumferential direction of the fixed dose mechanism housing  25 , wherein the first section  61  is separated from a second section  62  by a sloped or inclined transition  63 . Towards the proximal end  6 , the first section  61  is set back with respect to the second section  62 . The pin  59  can run or slide in the groove  60  from the first section  61  into the second section  62  via the transition  63  and back. Travel of the pin  59  between the sections  61  and  62  causes the clutch  49  to move in axial direction. This interface between the clutch  49  and the fixed dose mechanism housing  25  controls the axial position of the clutch  49  when the clutch  49  is rotated about the longitudinal axis  57 . As also obvious from  FIG. 9 , the fixed dose mechanism housing  25  has projections  64  that engage a recess  65  in the housing  2  of the drug delivery device to ensure the fixated position of fixed dose mechanism housing  25 . 
     The sleeve-like selection switch  48  is supported rotatable in the drug delivery housing  2  and may rotate around the longitudinal axis  57 . The clutch  49  is rotationally constrained to the rotation of the selection switch  48  via the splined surface  55 , which engages a correspondingly formed inner surface of the selection switch  48  in a splined hole to form a splined interface that allows relative axial movement but prevents relative rotational movement between the clutch  49  and the selection switch  48 . The selection switch  48  has a lever surface (not shown) that extends in radial direction through an opening (not shown) in the drug delivery housing  2 . The opening is formed such that a user can actuate the lever and rotate the selection switch around the longitudinal axis  57 . 
     The selection switch  48  is rotatable between three positions. The first position is an intermediate “at rest” or central position. In this position, the clutch  49  is in a rotational position relative to the pin  59  as shown in  FIG. 9 . From the “at rest” position, the user rotates the selection switch to set the device to deliver a fixed dose of the secondary medicament in combination with a variable dose of the primary medicament or a variable dose of the primary medicament only. 
     When the selection switch  48  is rotated from the intermediate “at rest” position in clockwise direction when viewed from the proximal end  6 , the rotation is transferred to the clutch  49  and the pin  59  moves towards the right end in the first section  61  into a second position. The clutch  49  maintains its axial position. This actuation corresponds to the situation in which the user selects to set and inject a dose of the secondary medicament. This position of the selection switch  48  may be referred to a “fixed dose on” position. Rotation of the clutch  49  is transferred to the secondary drive sleeve  24  which rises towards the clutch  49  in a helical movement. If the selection switch  48  is rotated back to the central position, the clutch  49  and secondary drive sleeve rotate in the same direction and the secondary drive sleeve  24  returns along its helical path to unset the set dose. The groove  60  also defines a range, in which the selection switch can be rotated. The maximum value of rotational movement of the selection switch  48 , the clutch  49  and the drive sleeve is limited. 
     When the selection switch  48  is rotated from the intermediate “at rest” position in counterclockwise direction when viewed from the proximal end  6 , the pin  59  engages the intermediate section  63  and enters the second section  62  and moves toward the left end of the second section  62  into a third position. This actuation corresponds to the situation in which the user selects not to set and inject a dose of the secondary medicament. This position of the selection switch  48  may be referred to a “fixed dose off” position. The clutch  49  moves axially towards the selection switch  48  due to the inclined intermediate surface and away from the drive sleeve  24  such that the arms disengage from the grooves  58  ( FIG. 8 ) and rotation of the clutch  49  is not transferred to the drive sleeve  24 . 
     During dispense of the fixed dose after setting the selection switch  48  in the “fixed dose on” position, axial movement of the third gear rack is transferred to the secondary drive sleeve  24 , which moves in distal direction. Due to the splined engagement between the engagement arms  56  of the clutch  49  and the grooves  60  of the secondary drive sleeve  24 , the selection switch  48  and the clutch  49  remain stationary in axial direction during dispense of a dose of the secondary medicament. 
     As shown in  FIG. 8 , at the proximal end of the grooves  58 , a ratchet element  66  is provided, which engages the engagement arms  56  of the clutch and allows relative rotation between the clutch  49  and the secondary drive sleeve  24  in a first direction and prevents relative rotation in the opposite direction. This ratchet interface enables the clutch  49  to rotate back to its central “at rest” position without causing a rotation of the secondary drive sleeve  24 . Further, when the selection switch  48  is moved from its “at rest position” into the “fixed dose off” position, rotation of the clutch  49  is not transferred to the secondary drive sleeve, as the engagement arms  56  merely engage the ratchet element  66  and rotation of the clutch  49  cannot be transferred though the ratchet interface. 
     In  FIG. 10 , a sectional view of the drug delivery device from the proximal side end in longitudinal direction is presented. The first advance lever  52  is support by a pin  67  formed on the housing  2  so that the first advance lever  52  can pivot or swivel about an axis running though the pin  67  in viewing direction. The second advance lever  53  is support by a pin  68  formed on the housing  2  so that the second advance lever  53  can pivot or swivel about an axis running though the pin  68  in viewing direction. 
     The first advance lever  52  is a basically u-shaped element with legs connected by an intermediate section. A first leg has is provided with a first engagement section  69  formed as a projection for engagement with a counter projection resp. a first abutment surface  70  formed on the outer surface of the number sleeve  17 . The first leg further ends in a second engagement section  71  formed as a projection for engagement with a counter engagement section  72  formed on the inside of the housing  2 . The second leg is provided with an opening to receive the pin  67  and ends in third engagement section  73  for engagement with a second abutment surface  74  formed as a raised boss on the outer surface of the number sleeve  17 . 
     The second advance lever  53  is a t-shaped element with a first section that has at its end an opening to receive the pin  68 . The first section ends in a second section that runs substantially perpendicular to the first section. A first projection  75  engages the first advance lever  52  such that the first advance lever  52  swivels or articulates around the pin  67  in clockwise direction when the second advance lever  53  rotates or swivels around the pin  68  in clockwise direction. 
     Opposite the first projection  75  lies a second projection  76  for engagement with a first abutment surface  77  formed on the selection switch  48 , which is shown in  FIG. 10  in its “at rest” or central rotational position. Rotation of the selection switch  48  in clockwise direction causes the first abutment surface  77  to engage the second projection  76 . As a result, the second advance lever  53  articulates about the pin  68  and the first projection  75  on the second advance lever  53  moves the first advance lever  52  around the pin  67  in clockwise direction. A second abutment surface  78  is provided on the selection switch  48  for engagement with a fourth engagement section  79  on the first advance lever  52 . Rotation of the selection switch  48  in counter-clockwise direction causes the second abutment surface  77  to engage the fourth engagement section  79 . As a result, the first advance lever  52  articulates about the pin  67  in clockwise direction. Irrespective of whether the selection switch  48  is rotated clockwise or counter-clockwise, the first advance lever  52  swings in the clockwise direction. The spring  51  is located on a pivot within the housing, and provides a restoring force to return the selection switch  48  to its centralized ‘at rest’ position. 
     As shown in  FIG. 10 , the selection switch  48  is in its “at rest position”. The distance in rotational direction between the raised boss  74  and the third engagement section  73  is such that the number sleeve  17  can be rotated about a predetermined angular range in clockwise direction. In the described embodiment this angular range corresponds to 2 set units of the primary medicament. When the selection switch is at its “at rest” position, the settable dose in the primary drug delivery assembly is limited to 2 units. The dial grip  22  may only be rotated up to 2 units in clockwise direction. When the dial grip is rotated to 2 units, the boss  74  abuts the third engagement section  73  and prevents further rotation of the number sleeve  17  until the first advance lever  52  is displaced through activation of the selection switch  48  such that the third engagement section  73  is moved away from the boss  74 . This mechanism limits a settable dose of the primary medicament to 2 units, which then can be dispensed by depressing the button  33 . If the user wishes to dispense a larger variable dose they must activate the selection switch  48 . 
     Rotation of the selection switch  48  (“fixed dose on”) in clockwise direction causes the levers  52 ,  53  to articulate. Simultaneously, the clutch  49  and the secondary drive sleeve  24  are operated and a dose of the secondary medicament is set. The second lever  53  causes the first lever  52  to rotate about the pin  67  so that the third engagement section  73  swings away from the number sleeve  17  and the boss  74  so that the lock between the housing and the number sleeve  17  is removed, allowing the user to continue to dial a variable dose beyond the 2 units limit. 
     The user may choose to activate the selection switch  48  prior to dialing the dose in the primary drug delivery assembly. With regard to  FIGS. 11 a  to 11 c   , when the selection switch  48  is rotated into its “fixed dose on” state prior to rotation of the dial grip, the first engagement section  69  engages the first abutment surface  70  on number sleeve  17  causing the number sleeve  17  to rotate in correspondence to 2 units ( FIGS. 11 a  and 11 b   ). The first advance lever  52  articulates in clockwise direction until the second engagement section  71  engages the abutment surface  72  on the housing  2  which causes the first engagement section  69  to move away from the number sleeve  17  at the end of the articulation. The dose of primary medicament that is dialed with the number sleeve  17  corresponds to 2 units. This situation is shown in  FIG. 11 c   . Articulation of the first advance lever also moves the third engagement section  73  away from the number sleeve  17  so that the user is free to dial beyond the 2 units limit of the primary medicament by rotating the dose dial grip. Rotation of selection switch  48  into the “fixed dose on” position is transferred to the clutch  49  as described above and is transferred to the secondary drive sleeve  24  to set a dose of the secondary medicament. 
       FIG. 12  shows the situation, in which the user chooses not to set and inject a dose of the secondary medicament. The selection switch  48  is rotated from its central “at rest position” in counterclockwise direction to its “fixed dose off” state. Rotation of the selection switch in counterclockwise direction causes the clutch  49  to rotate in counter-clockwise direction and to move in proximal direction (see  FIG. 8 ). The secondary drive sleeve  24  remains stationary due the ratchet  66  on the drive sleeve  24  and the axial displacement of the clutch  49 . A dose of the secondary medicament is not set. During rotation of the selection switch  48  to the left, the first advance lever  52  is pivoted about the pin  67  by engagement of the second abutment surface  78  on selection switch  48  with the fourth engagement section  79  on the first advance lever  52 . 2 units of the primary medicament are set and further dialing of the number sleeve  17  is allowed. 
     The advance levers  52 ,  53  are held in their articulated position by their abutments with the selection switch  48 . In this embodiment the levers  52 ,  53  act against sprung pivots, such that they return to their ‘at rest’ position as shown in  FIG. 10  when the selection switch  48  returns to its central position. The levers  52 ,  53  may be accommodated in the housing in a prestressed condition such that the levers  52 ,  53  tend to return back to their “at rest” state. Alternatively, the levers  52 ,  53  may be formed elastically and mounted in the drug delivery device in prestressed condition wherein the prestress forces tend to urge the levers  52 ,  53  into their “at rest” position. 
     As shown in  FIG. 13 , the selection switch  48  is held in the “fixed dose on” or fixed dose off” position by the latch lever  50 . The latch lever  50  is provided to restrain the selection switch  48  in its set position, until the latch lever  50  is articulated by the number sleeve  17 . The number sleeve  17  is provided with a ramp feature  80  on its outer surface, whose outer surface moves away from the axis of rotation of the number sleeve  17  in circumferential direction. The latch lever  50  is pivotably support in the housing  2  and can pivot around a pivot point  81  around an axis running parallel to the rotational axis of the number sleeve  17 . The latch lever  50  comprises two legs extending from the pivot point in different directions. A first engagement section  82  is provided for engagement with the ramp  80  and a projection  83  formed as a latch is provided on the other leg for engagement with either a first slot  84  or a second slot  85  each provided on the selection switch  48 , depending on the direction the selection switch  48  is rotated from the “at rest” position. When the selection switch  48  is rotated in clockwise direction, the projection  83  engages the first slot  84 . When the selection switch  48  is rotated in counterclockwise direction, the projection  83  engages the second slot  85 . 
     When the number sleeve  17  is at a “at rest” position as shown in  FIG. 13  and the number sleeve  17  has not been rotated to set a dose, the ramp feature  80  acts on the engagement section  82  and urges the projection  83  away from the selection switch  48 . When the number sleeve  17  is rotated in clockwise direction, the abutment between the ramp  80  and the engagement section  82  is removed as shown in  FIG. 14 . The latch lever  50  rotates about its sprung pivot point  81  in counterclockwise direction. If the selection switch  48  has not been activated by the user, the latch  83  abuts the outer cylindrical surface of the selection switch  48 . 
     When the selection switch  48  is operated, e.g. by moving the selection switch into the “fixed dose on” state as shown in  FIG. 14 , the latch  83  engages with the first slot  84 , which enables the latch lever  50  to fully rotate about its sprung pivot point  81 . The engagement between the latch lever  50  and the selection switch  48  restrains the selection switch  48  in its set position. If the selection switch  48  is moved into the “fixed dose off” state, the latch  83  engages with the second slot  85  and the engagement between the latch lever  50  and the selection switch  48  restrains the selection switch  48  in its “fixed dose off” position. 
     The selection switch  48  remains in its set position until the latch lever  50  is articulated by the abutment with the ramp  80  of the number sleeve  17 . During dispense, the number sleeve  17  rotates backward in distal direction and rotates in counterclockwise direction. At the end of the return movement of the number sleeve  17 , the ramp  80  engages the engagement section  82  and the removes the engagement between the latch  83  and he selection switch  48 . The selection switch  48  returns to its ‘at rest’ position under the action of the spring  51  ( FIG. 12 ). 
     The latch lever  50  is preferably accommodated in the housing in a prestressed condition such that the latch lever  50  tends to pivot against the selection switch  48 . Alternatively, the latch lever  50  may be formed elastically and mounted in the housing of the drug delivery device in a prestressed condition wherein the prestress force tends to urge the latch lever  50  against the selection switch about the pivot point  81 . 
     The embodiment in  FIG. 14  also shows possible constructive measures which enable to define the value of the fixed dose that can be set with the secondary drug delivery assembly. On the outer surface of the selection switch  48 , a selection bar  86  is provided. The selection bar  86  is aligned such that it extends in axial direction  57  as also shown in  FIG. 9 . The maximum value of rotational movement of the selection switch  48  from the “at rest” position in clockwise direction as well as in counterclockwise direction is limited by the selection bar  86  engaging abutment surfaces  87  and  88  on the housing  2 . 
     In  FIG. 15 , the housing  2  of the drug delivery device  1  is split into two separable components, a main housing  89  and a second housing, which in this case is the fixed dose mechanism housing  25 . The main housing  89  contains the variable dose setting and dose dispense mechanism, the selection switch assembly and the differential gear mechanism, except for the first gear rack  35 , which is provided on the fixed dose mechanism housing  25 . The fixed dose mechanism housing  25  contains the fixed dose setting and dispense mechanism and the clutch only. 
     As shown in  FIGS. 16 a  and 16 b   , a separable interface is provided between the third gear rack and the secondary drive sleeve in the fixed dose mechanism housing  25  for axial fixation. Arms  90  ( FIG. 16 b   ) extend from the third gear rack. When the fixed dose mechanism housing  25  is attached to the main housing  89 , the arms  90  engage through an aperture  91  ( FIG. 16 a   ) into a circumferential recess  92  or collar on the outer surface of the drive sleeve  24  such that that the secondary drive sleeve  24  is axially constrained to the third gear rack  37 . A separable interface is provided between the selection switch  48  and the clutch  49 . The splined outer surface  55  of the clutch  49  is insertable into a splined hole  93  of the selection switch  48 . This interface provides a rotational constraint between these components, but allows for relative axial movement. 
     The fixed dose mechanism housing  25  can be attached to the main housing  89  by latching clips or the like. Releasable connections enable the a sub-assembly relating to a single cartridge, to be discarded and replaced when that cartridge is expended. 
     REFERENCE NUMERALS 
     
         
         
           
               1  drug delivery device 
               2  housing 
               3  primary drug delivery assembly 
               4  secondary drug delivery assembly 
               5  longitudinal axis of housing 
               6  proximal end 
               7  distal end 
               8  primary reservoir (medicament cartridge) 
               9  secondary reservoir (medicament cartridge) 
               10  septum 
               11  primary medicament 
               12  secondary medicament 
               13  bung 
               14  bung 
               15  variable dose setting and dispense mechanism 
               16  fixed dose setting and dispense mechanism 
               17  number sleeve 
               18  primary drive sleeve 
               19  primary lead screw 
               20  inner body 
               21  primary last dose nut 
               22  dial grips (actuation element) 
               23  secondary lead screw 
               24  secondary drive sleeve 
               25  fixed dose mechanism housing 
               26  differential gear mechanism 
               27  outer surface 
               28  thread 
               29  thread 
               30  inner thread 
               31  bearing 
               32  thread 
               33  button (movable element) 
               34  thread 
               35  first toothing (fixed dose mechanism housing rack) 
               36  second toothing (second gear rack/variable dose rack) 
               37  third toothing (third gear rack/fixed dose rack) 
               38  fourth toothing (fourth gear rack/dosing rack) 
               39  transmission element 
               40  first gear wheel (“dose gear”) 
               41  second gear wheel (“variable dose/fixed dose gear”) 
               42  sleeve element 
               43  engagement section 
               44  flange-like section 
               45  first dose scale 
               46  second dose scale 
               47  masking window 
               48  selection switch 
               49  clutch 
               50  latch lever 
               51  spring 
               52  first advance lever 
               53  second advance lever 
               54  main section 
               55  splined surface 
               56  engagement arms 
               57  longitudinal axis 
               58  grooves 
               59  pin 
               60  groove 
               61  first section 
               62  second section 
               63  transition 
               64  projection 
               65  recess 
               66  ratchet 
               67  pin 
               68  pin 
               69  first engagement section 
               70  first abutment surface on number sleeve 
               71  second engagement section 
               72  abutment surface of housing 
               73  third engagement section 
               74  second abutment surface on number sleeve (raised boss) 
               75  first projection 
               76  second projection 
               77  first abutment surface on selection switch 
               78  second abutment surface on selection switch 
               79  fourth engagement section 
               80  ramp feature on number sleeve 
               81  pivot point 
               82  engagement section on latch lever 
               83  projection on latch lever (latch) 
               84  first slot 
               85  second slot 
               86  selection bar 
               87  abutment surface 
               88  abutment surface 
               89  main housing 
               90  arms 
               91  aperture 
               92  circumferential recess (collar) 
               93  splined hole