Patent Publication Number: US-2013253441-A1

Title: Drug Delivery Device and Method for Sequentially Delivering at Least Two Medicaments

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/EP2011/071115 filed Nov. 28, 2011, which claims priority to European Patent Application No. 10192843.0 filed Nov. 29, 2010 and U.S. Provisional Patent Application No. 61/433,672 filed Jan. 18, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
    
    
     FIELD OF INVENTION 
     The present patent application relates to medical devices and methods of delivering at least two medicaments via a single dispense interface, where the medicaments are contained in two or more cartridges (also commonly referred to as “reservoirs”), containers or packages, each containing independent (single compound) or pre-mixed (co-formulated multiple compounds) drug agents. 
     BACKGROUND 
     Certain disease states are preferably treated using one or more different drug agents (i.e., combination therapy). 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. fjfjfididhf When combination therapy is used, certain drug agents may need to be delivered in a specific relationship to other drug agents in order to deliver the optimum therapeutic dose. 
     Although combination therapy may be preferred to treat certain disease states, there are a number of potential problems associated with the storage and delivery of two active drug agents. For instance, if two active drug agents are pre-mixed in a single medicament formulation they may interact with each other during long-term storage. Therefore, it is advantageous to store the active drug agents separately and only combine them at the point of delivery via injection, needle-less injection, pumps, or inhalation. However, the process for combining the two active drug agents needs to be simple and convenient for the user to perform reliably, repeatedly, and safely. 
     A further problem is that the quantities and/or proportions of each active drug agent making up the combination therapy may need to be varied for each user or at different stages of their therapy. For example, certain active drug agents may require a titration period to gradually introduce a patient to a “maintenance” dose. A further example is if one active drug agent requires a non-adjustable fixed dose while the other is varied in response to a patient&#39;s symptoms or physical condition. This problem means that pre-mixed medicament formulations of multiple active drug agents may not be suitable as these pre-mixed formulations would have a fixed ratio of the active drug agents, which could not be varied by the healthcare professional or user. 
     One known method for delivering a combination therapy is to use two separate devices each containing a cartridge with a different medicament. Accordingly, the user must take independent action with respect to the dose setters of the two devices in order to set doses of both medicaments. However, many users cannot cope with having to use more than one device and/or make the necessary accurate calculations to properly administer the required dose combination. This is especially true for users with dexterity or computational difficulties. Accordingly, there exists a strong need to provide devices and methods for the delivery of two or more drug agents that are simple for the user to perform (e.g., don&#39;t require user action with respect to multiple dose setters of multiple devices). 
     The disclosed device and corresponding method helps overcome the above-mentioned problems by providing separate cartridges for two or more active drug agents making up a desired combination therapy. The two or more active drug agents are only combined during delivery. Thus, the two or more active drug agents will not interact with each other during long-term storage. Additionally, the disclosed device and corresponding method is capable of achieving a wide variety of therapeutic dose profiles, therefore, making combination therapy that needs to be varied for each user or at different stages of their therapy possible. Further, the disclosed device and corresponding method allows for combination therapy without the need for users to independently set doses of multiple medicaments using different dose setters of different devices. 
     These and other advantages will become evident from the following more detailed description of the invention. 
     SUMMARY 
     Disclosed herein are various examples of a drug delivery device and corresponding method for sequentially delivering (herein, sometimes referred to as “dispensing”) at least two medicaments, where each medicament contains independent (single compound) or pre-mixed (co-formulated multiple compounds) drug agents. In particular, the disclosed device and corresponding method allows a user to set and sequentially deliver (via a single dispense interface) respective doses of at least two medicaments using a single dose setter that controls at least two dose setting mechanisms, where each dose setting mechanism is associated with a different medicament. 
     The disclosed device and corresponding method is of particular benefit where the therapeutic response can be optimized for a specific target patient group, through control and definition of the therapeutic dose profile (i.e., the quantitative relationship between two or more medicaments (and their respective drug agents) that can be delivered to a patient). Further, the disclosed device and corresponding method is also of particular benefit where combination therapy is desirable, but not possible in a single medicament formulation for reasons such as, but not limited to, stability, compromised therapeutic performance, and toxicology. 
     An example advantage of sequential medicament delivery is a reduction in user force required to deliver multiple medicaments. The reduction of force is a direct consequence of maintaining a lower volumetric flow rate (multiple volumes in sequence as opposed to multiple volumes in parallel over a given time period) of medicament through the single dispense interface coupled with the fact that sequential delivery requires that only one set of mechanical losses (friction of the cartridge bung, friction or inefficiency in the delivery mechanism) is present at any given time during delivery. 
     The dose setter (e.g., a dial) of the device is configured to control the dose setting mechanisms (each operably coupled to a respective cartridge containing a respective medicament) such that a predefined combination of drug agents can be set via the dose setter. After the predefined combination of drug agents is set, it can be dispensed through the single dispense interface (e.g., a needle cannula). Although principally described herein as a drug delivery device capable of injecting a patient, the basic principle could be applicable to other forms of drug delivery, such as, but not limited to, inhalation, nasal, ophthalmic, oral, topical, and like devices. 
     By pre-defining the therapeutic relationship (i.e., the therapeutic dose profile) between various drug agents of various respective medicaments, by providing a dose setter that controls more than one dose setting mechanism, and by delivering the various medicaments via a single dispense interface, Applicants&#39; drug delivery device helps ensure that a patient receives the optimum therapeutic combination dose without the inherent risks associated with multiple inputs and/or user error in calculating and setting the correct combination dose using multiple devices and/or multiple dose setters. Accordingly, the disclosed device and corresponding method is of particular benefit to users with dexterity or computational difficulties in terms of both improved compliance with a prescribed therapy and patient safety. 
     One or more of the medicaments making up the combination dose may be a fluid, defined herein as a liquid, gas or powder that is capable of flowing and that changes shape at a steady rate when acted upon by a force tending to change its shape. One or more of the medicaments may be a solid, powder, suspension of slurry that may be carried, solubilized or otherwise dispensed with another fluid medicament. In one example, the therapeutic combination dose comprises a first and a second medicament contained in respective cartridges. Both medicaments may be fluids or one medicament may be a fluid and the other may be a powder that is either dissolved or entrained in the fluid medicament before it is delivered via the a single dispense interface. 
     Possible drug combinations may include insulin, insulin analogs or insulin derivatives, and GLP-1 or GLP-1 analogs, however, other drugs or drug combinations, such as an analgesics, hormones, beta agonists or corticosteroids, or a combination of any of the above-mentioned drugs could be used with Applicants&#39; proposed device and method. 
     As used herein, the term “insulin” shall mean insulin, insulin analogs, insulin derivatives or mixtures thereof, including human insulin or a human insulin analogs or derivatives. Examples of insulin analogs are, without limitation, 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 or Des(B30) human insulin. Examples of insulin derivatives are, without limitation, 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. 
     As used herein the term “GLP-1” shall mean GLP-1, GLP-1 analogs, or mixtures thereof, including without limitation, exenatide (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-NH 2 ), Exendin-3, Liraglutide, or AVE0010 (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-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH 2 ). 
     Examples of beta agonists are, without limitation, salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol. 
     Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
     In one example of the drug delivery device, the drug delivery device includes a dose setter for setting a user settable dose of a first medicament and a fixed dose (i.e., non-user settable dose) of a second medicament, a dose button, a single dispense interface, a first cartridge containing multiple doses of the first medicament, and a second cartridge containing multiple doses of the second medicament. The dose button can be any type of mechanism that triggers the delivery procedure, whether driven mechanically or through a combination of electronics and mechanics. The button can physically move or be a touch sensitive virtual button, for example, a touch sensitive screen. 
     As used herein, a “user settable dose” means a dose that the user (e.g., a patient or health care provider) can choose and physically manipulate the device to set. In other examples, a user settable dose can be set remotely through the use of wireless communication (Bluetooth, WiFi, satellite, etc.) or the dose could be set by another integrated device, such as a blood glucose monitor after performing a therapeutic treatment algorithm. By “fixed dose,” it is meant that a user (or any other input) cannot set a desired dose, rather, the user can only set a predetermined dose that is defined by the fixed dose setting mechanism. 
     The single dispense interface is configured for fluid communication with the first and second cartridges. The dispense interface can be any type of outlet that allows the two or more medicaments to exit the device and be delivered to the patient. Types of interfaces include needle cannulas, catheters, atomizers, pneumatic injectors, needle-less injectors, mouthpieces, nasal-applicators, and the like. The combination of medicaments may be delivered via the single dispense interface as discrete units or as a mixed unit, thus providing a combination therapy that, from a user&#39;s perspective, is achieved in a manner that very closely matches the currently available injection devices that use standard needles. 
     In another example, the drug delivery device includes a rotationally driven variable dose setting mechanism operably connected to a first cartridge containing a first medicament, a fixed dose setting mechanism operably connected to a second cartridge containing a second medicament, a dose setter for setting a user settable dose of the first medicament and a fixed dose of the second medicament, and a connecting feature for detachably connecting the rotationally driven variable dose setting mechanism to the fixed dose setting mechanism. During setting of the fixed dose of the second medicament, the rotationally driven variable dose setting mechanism and the fixed dose setting mechanism are connected via the connecting feature, however, during setting of the user settable dose of the first medicament, the rotationally driven variable dose setting mechanism and the fixed dose setting mechanism are not connected via the connecting feature. 
     The dose setter may include the connecting feature and may be axially slidably linked (via at least one splined (i.e., axial) groove in the dose setter) to the rotationally driven variable dose setting mechanism while being detachably linked (via the connecting feature) to the fixed dose setting mechanism. When the dose setter is linked to the fixed dose setting mechanism via the connecting feature, the dose setter may be axially displaced in a proximal direction to set the fixed dose of the second medicament, and when the dose setter is detached from the fixed dose setting mechanism, the dose setter can be rotated to set the user settable dose of the first medicament. Alternatively, the dose setter may be configured to set both the fixed dose of the second medicament and the user settable dose of the first medicament by merely rotating the dose setter. Such a dose setter may be part of the rotationally driven variable dose setting mechanism. 
     The dose setter may be configured to set the fixed dose of the second medicament before the user settable dose of the first medicament and to deliver the user settable dose of the first medicament before the fixed dose of the second medicament. After the fixed dose of the second medicament is set, the dose setter may detach from the fixed dose setting mechanism. After (i) the user settable dose of the first medicament and the fixed dose of the second medicament are set and (ii) the user settable dose of the first medicament is delivered, the dose setter may re-attach to the fixed dose setting mechanism via the connecting feature such that axial displacement of the dose setter (whether caused by rotation of the dose setter along a helical path or axial translation) in the distal direction causes the fixed dose of the second medicament to be delivered. 
     The drug delivery device disclosed herein may be designed in such a way as to limit its use to exclusive first and second cartridges through employment of dedicated or coded features. 
     Applicants&#39; present disclosure also covers a method of setting and delivering a variable dose of a first medicament and a fixed dose of a second medicament from separate cartridges of a drug delivery device. In one example, the method uses a device as described above and involves the steps of first setting a dose of the second medicament followed by a dose of the first medicament using a dose setter. Next, the device is activated and the user settable dose of the first medicament is delivered followed by the fixed dose of the second medicament. Both doses are delivered via a single dispense interface. To set the fixed dose of the second medicament, the dose setter may be pulled in the proximal direction. After the fixed dose of the second medicament is set, the user settable dose of the first medicament may be set by merely rotating the dose setter. Alternatively, the doses of the first and second medicaments may both be set by rotating the dose setter. 
     In another example, the method involves (i) attaching a single dispense interface to the distal end of a drug delivery device such that the proximal end of the single dispense interface is in fluidic communication with both a first medicament and a second medicament, (ii) using a dose setter to set both a user settable dose of the first medicament and a fixed dose of the second medicament, (iii) inserting the distal end of the single dispense interface into the patient at the desired administration site, and (iv) dispensing the fixed dose of the second medicament followed by the user settable dose of the first medicament. 
     These as well as other advantages of various aspects of the present invention will become apparent to those of ordinary skill in the art by reading the following detailed description, with appropriate reference to the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Various examples of Applicants&#39; drug delivery device and corresponding method are described herein with reference to the following drawings, wherein like numerals denote like entities: 
         FIG. 1  illustrates an example therapeutic dose profile that can be achieved with the drug delivery device of Applicants&#39; disclosure; 
         FIG. 2  illustrates an example of the drug delivery device; 
         FIG. 3  illustrates another example of the drug delivery device; 
         FIG. 4  illustrates some of the internal structure of the variable dose setting mechanism of the drug delivery device shown in  FIG. 3 ; 
         FIG. 5  illustrates the internal structure of the variable dose setting mechanism shown in  FIG. 3 ; 
         FIG. 6   a  illustrates the drug delivery device shown in  FIG. 3  at the beginning of dose setting of a fixed dose of the second medicament; 
         FIG. 6   b  illustrates the drug delivery device shown in  FIG. 3  during dose setting of a fixed dose of the second medicament; 
         FIG. 6   c  illustrates the drug delivery device shown in  FIG. 3  during dose setting of a user settable dose of the first medicament; 
         FIG. 6   d  illustrates the drug delivery device shown in  FIG. 3  during dose delivery of the user settable dose of the first medicament; and 
         FIG. 6   e  illustrates the drug delivery device shown in  FIG. 3  during dose delivery of the fixed dose of the second medicament. 
     
    
    
     DETAILED DESCRIPTION 
     The drug delivery device disclosed herein is capable of sequentially delivering at least two medicaments through a single dispense interface. 
     In one example, the drug delivery device includes a dose setter for setting both a user settable (i.e., variable) dose of a first medicament and a fixed dose of a second medicament. After both doses have been set, the user activates the drug delivery device and the user settable dose of the first medicament is delivered followed by the fixed dose of the second medicament. Herein, “activating” the drug delivery device may comprise a single action or multiple actions. The therapeutic dose profile  100  representing the relationship between the user settable dose of the first medicament and the fixed dose of the second medicament is illustrated in  FIG. 1 , where Compound A represents the first medicament and Compound B represents the second medicament. As shown, the user settable dose of the first medicament may vary while the dose of the second medicament remains fixed, which may be beneficial for certain therapies. Profiles of this type are not achievable with a device having a single cartridge that contains a co-formulated combination dose where the concentration of the various constituent parts is constant (x mg/ml). 
       FIG. 2  illustrates an example of the drug delivery device  102 . As shown, the drug delivery device  102  includes a rotationally driven variable dose setting mechanism  104  (a “variable dose setting mechanism”) operably connected to a first cartridge  106  containing a first medicament  108 , a fixed dose setting mechanism  110  operably connected to a second cartridge  112  containing a second medicament  114 , a splined dose setter  116 , and a needle assembly  118  having a single dispense interface  119 . 
     The splined dose setter  116  is operably connected to both dose setting mechanisms  104 ,  110  such that a user can set both a user settable dose of the first medicament  108  and a fixed dose of the second medicament  114  via the splined dose setter  116 . The splined dose setter  116  is operably connected to the variable dose setting mechanism  104  via engagement of the four radial protrusions  120  of the variable dose setting mechanism and the four splined (i.e., axial) grooves  122  located on an inner surface of the dose setter  116 . As shown, the four radial protrusions  120  are connected to the dose setter  124  of the variable dose setting mechanism  104 . Accordingly, rotating the splined dose setter  116  of the device  102  causes corresponding rotation of the dose setter  124  of the variable dose setting mechanism  104 , which sets a dose of the first medicament  108 . Other examples of the device  102  may include any number of radial protrusions  120  and corresponding axial grooves  122 . The radial protrusions  120  may be separate parts that are connected to the dose setter  124  of the variable dose setting mechanism  104 , perhaps by pins or screws, or they may be part of the dose setter  124  itself. 
     The splined dose setter  116  is operably detachably connected to the fixed dose setting mechanism  110  via the splined dose setter&#39;s connecting feature  126 . The connecting feature  126  engages the proximal end  128  of the fixed dose setting mechanism  110  (i.e., the dose setter of the fixed dose setting mechanism) via a 2-way clip, bump or snap connection mechanism (not shown). When the splined dose setter  116  is connected to the dose setter  128  of the fixed dose setting mechanism  110  (via the connecting feature  126 ), proximal axial movement  130  of the splined dose setter  116  causes corresponding axial movement of the dose setter  128  of the fixed dose setting mechanism  110 , which sets a dose of the second medicament  114 . 
     Once the fixed dose of the second medicament has been set, stop features in the fixed dose setting mechanism (not shown, but such as those known in the art) prevent further proximal axial movement of dose setter  128 . At this point the detachability of the connecting feature  126  allows the variable dose setting mechanism  104  to transition from being connected to the fixed dose setting mechanism  110  (via the connecting feature  126  of the splined dose setter  116 ) during dose setting of the second medicament  114  to being disconnected from the fixed dose setting mechanism  110  during dose setting of the first medicament  108 . During medicament delivery, the detachability of the connecting feature  126  allows the variable dose setting mechanism  104  to transition from being disconnected from the fixed dose setting mechanism  110  during delivery of the user settable dose of the first medicament  108  to being connected to the fixed dose setting mechanism  110  (via the connecting feature  126  of the splined dose setter  116 ) upon full delivery of the fixed dose of the second medicament  114 . 
     To further illustrate the various features of the above-described example of the drug delivery device  102 , an example method using the device  102  will now be described. First, a user sets a fixed dose of the second medicament  114 . To set the fixed dose, the user pulls the splined dose setter  116  of the device  102  upwards (i.e., in the proximal direction  130 ). Because the connecting feature  126  is engaged with the dose setter  128  of the fixed dose setting mechanism  110 , as the splined dose setter  116  is pulled upwards, the dose setter  128  of the fixed dose setting mechanism  110  is forced in the proximal direction  130  as well, thereby setting a fixed dose of the second medicament  114 . In order to accomplish this result, the force required to disengage the connecting feature  126  from the fixed dose setting mechanism  110  would preferably be a safe margin greater than the force required to set the fixed dose of the second medicament  114 . 
     While the connecting feature  126  is engaged with the fixed dose setting mechanism  110  it is not possible for the user to rotate the splined dose setter  116  and therefore not possible to set a dose of the first medicament  108 . Rather, the dose setter  116  can only slide in the axial direction. Engagement of the radial protrusions  120  with the splined grooves  122  in the splined dose setter  116  help guide the axial movement of the splined dose setter  116  during dose setting of the second medicament  114 . The axial distance traveled by the splined dose setter  116  during dose setting of the second medicament  114  has no effect on the variable dose setting mechanism  104 . 
     After the fixed dose of the second medicament  114  is set, the user sets a user settable dose of the first medicament  108 . When the fixed dose of the second medicament  114  is fully set, the dose setter  128  of the fixed dose setting mechanism  110  cannot be further displaced in the proximal direction  130  (i.e., the dose setter  128  of the fixed dose setting mechanism  110  is fully extended). Consequently, as the user continues to pull the splined dose setter  116  of the device  102  in the proximal direction  130  (to a predefined axial position) the connecting feature  126  disengages from the dose setter  128  of the fixed dose setting mechanism  110 . As noted above, the connecting feature  126  is designed such that its disengagement force is a safe margin greater than that required to set a dose of the second medicament  114 , but not so high that it is outside user capabilities. This ensures that the user can disengage the connecting feature  126  from the fixed dose setting mechanism  110  and also that disengagement does not occur until after the fixed dose of the second medicament  114  is fully set. 
     Disengagement of the connecting feature  126  from the fixed dose setting mechanism  110  allows the user to rotate the splined dose setter  116  and thus to rotate the dose setter  124  of the variable dose setting mechanism  104  in order to set a desired dose of the first medicament  108 . Rotating the splined dose setter  116  causes corresponding rotation of the dose setter  124  of the variable dose setting mechanism  104 . Thus, the user can rotate the splined dose setter  116  until the desired user settable dose of the first medicament  108  is set. To eliminate axial movement of the splined dose setter  116  during dose setting of the first medicament, the distal ends of the splined grooves  122  may include cutouts  132  in which the radial protrusions  120  preferably enter upon initial rotation of the splined dose setter  116 . In order to facilitate this, the axial length of the splined grooves  122  and the relative axial position of the cutouts  132  with respect to the connecting feature  126  are such that after the fixed dose of the second medicament  114  is set and the connecting feature  126  disengages from the fixed dose setting mechanism  110 , the radial protrusions  120  enter the cutouts  132  upon counter-clockwise rotation  134  of the splined dose setter  116 . 
     Once the first medicament  108  is set to the desired user settable dose, the splined dose setter  116  of the device  102  can be pushed downwards (in the distal direction  136 ) to deliver the set dose of the first medicament  108 . When the user pushes down on the splined dose setter  116 , the protrusions  120  are forced down by the proximal surfaces  138  of the cutouts  132 , which activates the variable dose setting mechanism  104  by actuating the dose setter  124  of the variable dose setting mechanism  104 . 
     After the user settable dose of the first medicament  108  has been delivered and the dose setters  124 ,  116  of the variable dose setting mechanism  104  and the device  102  have retuned to their pre-first-medicament-setting position, the connecting feature  126  is realigned with the fixed dose setting mechanism  110 . Thus, by pushing the splined dose setter  116  in the distal direction  136  (i.e., further activating the device  102 ), the connecting feature  126  re-attaches to the dose setter  128  of the fixed dose setting mechanism  110  and continued pushing in the distal direction  136  causes delivery of the fixed dose of the second medicament  114 . After the fixed dose of the second medicament  114  is delivered, the device  102  is ready for setting of the next doses. 
     In another example (not shown) of the drug delivery device  102 , the dose setter  116  of the device  102  has a helical groove (e.g., threads) instead of splined (i.e., axial) grooves  122  and the dose setter  124  of the variable dose setting mechanism  104  has a compatible helical protrusion (e.g., threads) instead of radial protrusions  120 . The helical groove and corresponding protrusion are configured such that after a fixed dose of the second medicament  114  is set and the connecting feature  126  has disengaged from the fixed dose setting mechanism  110 , the dose setter  116  cannot move further in the proximal direction  130  without rotating the dose setter  124  of the variable dose setting mechanism  104  (i.e., the distal end of the helical groove of the dose setter has been reached and further rotation causes the dose setter  124  of the variable dose setting mechanism  104  to rotate). 
     In this example, to set a fixed dose of the second medicament  114 , the user rotates the dose setter  116  of the device  102  instead of pulling it upwards  130 . Thus, the connecting feature  126  in this example is preferably a separate part that interfaces with the dose setter  116  of the device  102  in such a way that it remains rotationally fixed as the user rotates the dose setter  116 . This may be accomplished if the portion of the connecting feature  126  that interfaces with the dose setter  116  is not fixed to the dose setter  116 , thus allowing the dose setter  116  to rotate relative to the connecting feature  126 . However, axial movement of the dose setter  116  should cause corresponding axial movement of the connecting feature  126  in order to set the fixed dose of the second medicament  114 . This example only requires the user to perform one action (i.e., rotation) to set respective doses of both the first and second medicaments  108 ,  114 . The user simply rotates the dose setter  116  until a fixed dose of the second medicament  114  is set and then continues to rotate the dose setter  116  until a user settable dose of the first medicament  108  is set. 
       FIG. 3  shows another example of the drug delivery device  202 . As shown, like the examples described above, the drug delivery device  202  includes a rotationally driven variable dose setting mechanism  204  operably connected to a first cartridge  206  containing a first medicament  208 , a fixed dose setting mechanism  210  operably connected to a second cartridge  212  containing a second medicament  214 , a connecting feature  226 , and a needle assembly  218  having a single dispense interface  219 . However, unlike the examples described above, the device  202  utilizes the dose setter  224  (i.e., dial) of the variable dose setting mechanism  204  to set the user-settable dose of the first medicament  208  and the non user-settable dose of the second medicament  214 . This eliminates the need for a splined dose setter  216  and only requires the user to perform one action (i.e., rotation) to set respective doses of both medicaments  208 ,  214 . 
     In this example, the connecting feature  226  is part of, or operably connected to, the fixed dose setting mechanism  210  and is detachably connected (shown detached in  FIG. 3 ) to the dial sleeve  240  of the variable dose setting mechanism  204  via the lifting collar  242 . The connecting feature  226  and lifting collar  242  are configured such that the variable dose setting mechanism  204  can transition from being connected to the fixed dose setting mechanism  210  (via engagement of the connecting feature  226  and collar  242 ) during dose setting of the second medicament  214  to being disconnected from the fixed dose setting mechanism  210  during dose setting of the first medicament  208 . When the variable dose setting mechanism  204  is connected to the fixed dose setting mechanism  210 , proximal axial movement  230  of the dial sleeve  240  of the variable dose setting mechanism  204  causes corresponding axial movement of the dose setter  228  of the fixed dose setting mechanism  210 , thus setting a fixed dose of the second medicament  214 . During medicament delivery, the connecting feature  226  and lifting collar  242  allow the variable dose setting mechanism  204  to transition from being disconnected from the fixed dose setting mechanism  210  during delivery of the first medicament  208  to being connected to the fixed dose setting mechanism  210  (via engagement of the connecting feature  226  and collar  242 ) during delivery of the second medicament  214 . 
       FIGS. 4 and 5  illustrate example features of the internal structure of the variable dose setting mechanism  204  that enable sequential delivery of the first and second medicaments  208 ,  214 . As shown in  FIG. 4 , the body/housing  244  includes one or more continuous grooves  246  that are helical near the distal end and transitions to being generally vertical/axial. During operation (i.e., during rotation of the dose setter  224  of the variable dose setting mechanism  204  to set doses of both the first and second medicaments  208 ,  214 ), the clicker  248  and the 300 unit counter  250  (the “counter”) are initially located in the helical portions  251  of the body/housing grooves  246 . As the dose setter  224  is rotated, the clicker  248  and the counter  250  follow the helical path of the body/housing grooves  246  at which time a fixed dose of the second medicament  214  is being set. Then, at a first predetermined axial position that corresponds to the fixed dose of the second medicament  214  being fully set, the clicker  248  enters the vertical portion  253  of the body/housing grooves  246 , however, the counter  250  is still located in the helical portion  251  of the grooves  246 . At a second axial position, the counter  250  enters the vertical portion  253  of the body/housing grooves  246 . When the clicker  248  is in the vertical portion  253  of the grooves  246 , the user settable dose of the first medicament  208  is being set. 
     The counter  250  is configured to count the cumulative number of variable doses set over the life of the variable dose setting mechanism  204  and limits the cumulative total to a maximum dose limit (for example the available volume in the cartridge), whereas the clicker  248  counts the amount of the variable dose set during a single setting action of the device  204 . Variable dose counting (using the clicker  248 ) for a single setting action occurs when the clicker  248  is engaged with the vertical portion  253  of the body/housing grooves  246 . The cumulative number of variable doses counted (using the counter  250 ) starts when both the counter  250  and clicker  248  are engaged with the vertical portion  253  of the body/housing grooves  246  during dose setting but also when the clicker  248  is in the vertical portion  253  of the grooves  246  and the counter  250  is in the helical portion  251  of the grooves  246  during delivery. The body/housing grooves  246  are configured so that when the 300 unit stop (not shown) is reached, the variable dose setting mechanism  204  has dialed a total of 300 units. At this point, during delivery, the counter  250  enters the helical portion  251  at the same time as the clicker  248 , so that no further counting occurs during delivery and the variable dose setting mechanism  204  remains locked after delivery so that further dose setting is not possible. 
     In functional terms, initial rotation of the dose setter  224  of the variable dose setting mechanism  204  causes rotation of the dial sleeve  240  and drive sleeve  252  (including the clicker  248  and the counter  250 ) around a prescribed helical path defined by a groove  254  in the dial sleeve  240 . The helical path of the dial sleeve groove  254  matches that of the internal helical groove  246  in the body/housing  244  of the variable dose setting mechanism  204  into which the clicker  248  and the counter  250  engage. As these helical paths are identical, the clicker  248  does not incur any relative movement with respect to the drive sleeve  252  and therefore does not begin counting. In addition, while the counter  250  rotates in the helical portion  251  of the body/housing groove  246 , it does not incur any relative movement with respect to the drive sleeve  252  and thus does not count any doses towards the cumulative total. 
     The axial component of this helical (and un-counted) motion is used to lift the dose setter  228  of the fixed dose setting mechanism  210  to its fully set point. After the fixed dose of the second medicament  214  is set, the lifting collar  242  disconnects from the connecting feature  226  and the clicker  248  enters the vertical portion  253  of the body/housing grooves  246 . Further rotation of the dose setter  224  of the variable dose setting mechanism  204  sets a variable dose of the first medicament  208 . This rotation causes the dial and drive sleeves  240 ,  252  to rotate relative to the clicker  248 , thus resulting in the clicker  248  counting the variable dose. During dose setting of the first medicament  208 , the clicker  248  is constrained by the vertical portion  253  of the body/housing grooves  246  such that it only moves axially. At some point the counter  250  enters the vertical portion  253  of the body/housing groove  246  and begins counting doses towards the cumulative total (as it is constrained to move axially, whereas the drive sleeve  252  continues to follow the helical path defined by the groove  254  in the dial sleeve  240 ). 
     After the fixed dose of the second medicament  214  and the user settable dose of the first medicament  208  are set, activation of the device  102  by actuating the dose button  256  disengages the dial sleeve  240  from the drive sleeve  252  rotationally, and causes delivery of the first medicament dose followed by the second medicament dose. During delivery, the dial sleeve  240  follows its helical path back in the distal direction  236 , however, the drive sleeve  252 , now de-coupled from the dial sleeve  240  through actuation of the clutch (not shown), but fixed in rotation by engagement of the clicker  248  in the vertical portion  253  of the body/housing grooves  246 , moves axially without rotation, thus causing the first medicament dose to be delivered as the lead screw  260  forces the bung (not shown) of the first cartridge  206  in the distal direction  236 . After the user settable dose of the first medicament  208  is delivered, the lifting collar  242  re-engages with the connecting feature  226  and as the dial sleeve  240  continues to move in the distal direction  236  along its helical path it causes the fixed dose setting mechanism  210  to deliver the fixed dose of the second medicament  214 . The dial sleeve follows an accurately defined path relative to the housing and will therefore reengage the connecting feature  226  as it rotates back distally. 
     When the lifting collar  242  re-engages with the connecting feature  226 , the clicker  248  enters the helical portion of the body/housing groove  246 , thus allowing the variable dose setting mechanism  204  to rotate back down the helical portion  251  of the body/housing grooves  246 . The first medicament  208  is not delivered as the variable dose setting mechanism  204  rotates back down the helical portion  251  of the body/housing grooves  246  since the pitch of the helical portion  251  of the body/housing groove  246  is designed to match the pitch of the helical thread  258  between drive sleeve  252  and lead screw  260 . During delivery, the counter  250  initially moves axially along the vertical portion  253  of the body/housing grooves  246 , after which it enters the helical portion  251  of the body/housing grooves  246 . When the counter  250  is located in the helical portion  251  of the body/housing grooves  246  but he clicker  248  is still located in the vertical portion  253  of the grooves  246 , the counter  250  counts doses towards the cumulative total as it rotates and the drive sleeve  240  travels axially. 
     To further illustrate the various features of the above-described example of the drug delivery device  202 , an example method using the device  202  will now be described with reference to  FIGS. 6   a - 6   e . In these figures, the arrows indicate the direction of motion and the circles indicate components that are fixed. First, the user sets a fixed dose of the second medicament  214 . As shown in  FIGS. 6   a  and  6   b , initial rotation of the dose setter  224  of the variable dose setting mechanism  204  causes the dial and drive sleeves  240 ,  252  (which are in clutched engagement) to rotate together up the helical path defined by the groove  254  in the dial sleeve  240 , thereby lifting the dose setter  228  of the fixed dose mechanism  210  to its set point via engagement of the lifting collar  242  and the connecting feature  226 . The counter  250  and the clicker  248  follow the helical path defined by the grooves  246  in the body/housing  244 , which is identical to the helical path defined by the groove  254  in the dial sleeve  240 , and thus do not count the dialed dose. Upon reaching its set point, the fixed dose setting mechanism  210  disengages from the variable dose setting mechanism  204 . The fixed dose piston rod  262  remains fixed during this phase through the operation of a one way ratchet (not shown). 
     Upon reaching the fixed dose set point, the clicker  248  engages the vertical portion  253  of the body/housing grooves  246 , throughout which the variable dose is counted. Continued rotation of the dose setter  224  and corresponding rotation of the dial sleeve  240  forces the drive sleeve  252  to rotate relatively to the lead screw  260  (see  FIG. 6   c ), which is held in place by a nut (not shown). During this phase, the counter  250  initially rotates relative to the body/housing and then, at some point, enters the vertical portion  253  of the body/housing grooves  246  and begins counting cumulative variable doses. 
     Turning to  FIG. 6   d , next, the user delivers the user settable dose of the first medicament  208  by activating the device  102  via actuation of the dose button  256 . During delivery of the user settable dose of the first medicament  208 , the dial sleeve  240  is rotationally de-coupled from the drive sleeve  252 . This action allows the dial sleeve  240  to rotate helically back into the body  244  of the device  204 , and the drive sleeve  252  to move axially thus causing the lead screw  260  to move in the distal direction  236  thereby delivering the first medicament dose by forcing the bung (not shown) of the first cartridge  206  in the distal direction  236 . Both the clicker  248  and the drive sleeve  240  move axially during this phase. The counter  250  initially moves axially along the vertical portion  253  of the body/housing grooves  246  after which it enters the helical portion  251  of the body/housing grooves  246  during which it counts doses as it rotates relative to the axially moving drive sleeve  252 . Eventually, the clicker  248  enters the helical portion  251  at which point the clicker  248  and counter  250  rotate together with the drive sleeve and the counter  250  stops counting doses. Note that when the 300 unit or other suitable unit stop (not shown) has been reached (a total of 300 units have been dialed) the counter  250  prevents further dialing. When this last dose is delivered, both the clicker  248  and counter  250  are designed to enter their respective helical grooves together so that in this final dose no counting occurs during delivery and at the end of the dose the device  204  is locked out against further dialing. 
     Turning to  FIG. 6   e , towards the end of the variable delivery phase, the lifting collar  242  re-engages with the connecting feature  226 . After re-engagement, delivery of the fixed dose of the second medicament  214  begins. As the dial sleeve  240  continues to move in the distal direction  236 , the lifting collar  242 , which is engaged with the dose setter/dispenser  228  (via the connecting feature  226 ) of the fixed dose setting mechanism  210 , forces the dose setter/dispenser  228  in the distal direction  236  thus forcing the piston  262  in the distal direction  236  through the operation of the ratchet. This distal movement  236  of the piston  262  causes the fixed dose of the second medicament  214  to be delivered as it forces the bung (not shown) of the second cartridge  212  in the distal direction  236 . The variable dose setting mechanism  204  does not dispense during this phase as the drive sleeve  252  and clicker  248  rotate around a helical path that matches that of the lead screw  260 . 
     In any of the above-described examples of the device  102 ,  202  the connecting feature  126 ,  226  may be configured to give an audible and/or tactile feedback to the user when the end of dose delivery has been reached. Similarly, disengagement of the connecting feature  126 ,  226  after setting a fixed dose of the second medicament  114 ,  214  may provide an audible and/or tactile feedback to the user, thus apprising the user that the fixed dose of the second medicament  114 ,  214  is set and that the user may now set the desired user settable dose of the first medicament  108 ,  208 . 
     The drug delivery device disclosed herein is most suitable to be a modular disposable or re-usable device in terms of managing medicament wastage because there is a reasonable probability that one of the medicaments will be exhausted before the other unless there is a strict 1:1 ratio between the delivered doses of the two medicaments. Where each drive mechanism is resettable, new cartridges can be inserted and the device can continue to be used. Likely embodiments for a modular disposable device could be, but are not limited to, replacement of the entire device fitted with new cartridges and replacement of the drive mechanisms fitted with new cartridges. Regardless of whether the device is modular disposable or re-usable, suitable re-engagement features may be integrated into the device to facilitate the alignment and fastening of the individual device components together in a robust, intuitive and user-friendly fashion. Such modular disposable arrangements may preferably be configured to render the individual elements inoperable until they are correctly connected together. 
     A re-usable device may feature spindles, lead screws and/or pistons that can be back wound into their respective drive mechanisms once they reach their respective limits of travel. This may be achieved by placing the device into a reset state, for example by removing one or both of the cartridges, after which the respective body nut(s) holding the spindles or pistons becomes free to rotate relative to the device body. Manual rotation of a body nut would then cause the respective spindle or piston to be rotated and this in turn will cause the spindle or piston to wind its way back up into the device body and return to its initial position. In addition to this functionality, the re-usable device may have a mechanism for easy replacement of the cartridges after resetting their respective spindles or pistons. 
     In all of the examples described above, the first and second medicaments are capable of being delivered via a single dispense interface  119 ,  219 . To attach a single dispense interface to the first and second cartridges, the first and second cartridges may have respective attachment means at their distal end. Alternatively, the cartridges may be housed in respective cartridge holders and the cartridge holders may have respective attachment means. 
     The attachment means may be compatible with a needle assembly  118 ,  218  that includes a hub  164 ,  264  and a single dispense interface  119 ,  219 . The needle assembly  118 ,  218  may be removable and may be either disposable or reusable. Such a needle assembly is shown in  FIGS. 2 and 3 . The needle assembly  118 ,  218  can take any form, provided that it allows for fluid communication between the first and second medicaments and the single dispense interface  119 ,  219 . An exemplary needle assembly  118 ,  218  may include what is referred to in the art as a “2-to-1 needle” configuration. 
     Although not shown, the needle assembly may be supplied by a manufacturer in a protective and sterile capsule or container that completely or partially contains the needle assembly. A user may peel and/or rip open a seal or the container itself to gain access to the sterile single dispense interface. In some instances it might be desirable to provide two or more seals for each end of the needle assembly. The seal may allow for the display of information required by regulatory labeling requirements. 
     Attachment of the needle assembly to the drug delivery device via the hub creates a fluid connection between dispense interface and the first and second medicaments. 
     Although the various examples of the drug delivery device described herein comprise a single dispense interface, other examples may comprise multiple dispense interfaces, for example, a different dispense interface for each respective cartridge/medicament. Multiple dispense interfaces may be advantageous when simultaneous injection of 2 or more medicaments is desirable, but where co-injection of a particular combination of these medicaments into the same injection site may adversely effect the Pharmaco-kinetic (PK) profile of one or more or the medicaments. By way of an example, it is understood that dilution of certain long-acting basal insulins may alter their PK profile in-vivo. 
     Examples of the drug delivery device and corresponding method have been described. Those skilled in the art will understand, however, that changes and modifications may be made to these examples without departing from the true scope and spirit of the present invention, which is defined by the claims.