Abstract:
The present invention relates to a reservoir unit ( 40, 140, 240 ) for a drug delivery arrangement ( 1, 100, 200 ), the reservoir unit ( 40, 140, 240 ) comprising: a housing ( 41, 141, 241 ) adapted to accommodate a fluid substance and comprising a displaceable wall ( 43, 143, 243 ), a fluid transport member ( 50, 150, 250 ) comprising a fluid outlet ( 52, 152, 252 ), first fluid communication means ( 53, 153, 253 ) for providing fluid communication with an interior of another reservoir, and second fluid communication means ( 54, 154, 254 ) for providing fluid communication with an interior ( 44, 144, 244 ) of the housing ( 41, 141, 241 ), and coupling means ( 45, 145, 245 ) adapted for connection with mating coupling means associated with the other reservoir. The invention further relates to a drug delivery arrangement ( 1, 100, 200 ) employing the reservoir unit ( 40, 140, 240 ). The fluid transport member being a needle ( 50 ) fixedly retained by the outlet portion ( 42 ) and having a side hole ( 54 ) in the needle body ( 51 ) just proximally of the outlet portion ( 42 ).

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to drug delivery devices capable of sequential administration of two or more substances, as well as to substance reservoirs for such devices. 
       BACKGROUND OF THE INVENTION 
       [0002]    Within some medical treatment areas a combination therapy involving co-administration of at least two active agents is advantageous because of synergistic or additive effects. For example, within diabetes care, in the management of type 2 diabetes mellitus, concomitant use of certain insulin and glp-1 products has been shown to reduce HbA 1c  levels in subjects, thereby improving glycaemic control. 
         [0003]    Many drugs must be administered parenterally to be effective in the body and some of these, e.g. insulin and glp-1, may require one or more doses to be delivered subcutaneously on a daily basis. Subcutaneous drug delivery is often associated with discomfort as many people dislike the thought of having an injection needle inserted through the skin. An undisclosed number of people even suffer from needle-phobia, and these people have a particular strong desire to escape multiple daily injection therapy. 
         [0004]    One attractive scenario, therefore, is to reduce the number of required skin penetrations by administering the injectable media at the same time, or substantially the same time. In that respect prefabricated mixtures of the involved media are not always an optimal solution. For one, some substances are only stable in mixed form short-term, and it may accordingly be necessary to keep those substances apart until just prior to administration. Adding to that, the individual subject users may have different needs in terms of dose ratios of the constituent active ingredients. Even a single subject user may sometimes require varying dose ratios of the active ingredients in a relatively short time span, e.g. during a titration period. It may thus not be feasible to cover all the individual needs by premixed pharmaceutical products. 
         [0005]    U.S. Pat. No. 3,911,916 (Stevens) discloses an injection syringe for sequential injection of two or more medicaments through a single cannula. The syringe comprises a barrel which is partitioned by a number of plugs defining a number of medicament receiving compartments. By this arrangement it is possible to inject two or more medicaments at substantially the same time, thereby avoiding multiple cannula insertions. However, the syringe offers no flexibility with respect to the specific medicaments to be delivered in the sense that it is not possible to sequentially deliver other drugs than the ones already contained in the compartments. Furthermore, it is not possible to vary the volumetric ratios of the contained medicaments, which means that the syringe is only able to cover the needs of a certain group of subjects requiring a particular volumetric combination of the medicaments. 
         [0006]    WO 2010/149736 (Sanofi-Aventis Deutschland GmbH) discloses a cannula arrangement for an injection device which cannula arrangement is adapted to contain a medication for co-delivery with a medication in the injection device. The cannula arrangement is adapted to be connected to the injection device and operated to expel the medicament contained therein just prior to a dose of medicament being expelled from the injection device. While this arrangement enables greater flexibility with respect to the specific medicaments to be delivered than the syringe disclosed in U.S. Pat. No. 3,911,916, the solution appears to have several drawbacks. The medicament in the cannula arrangement must be delivered by the application of a transversal force to a collapsible reservoir, whereafter an axial force must be applied to the injection device to deliver a dose of the medicament contained therein. This entails a rather complex delivery procedure which appears difficult to execute without the user having to change grip on the injection device along the way. Furthermore, it is virtually impossible to deliver the two medicaments in an exact volumetric ratio because even if the cannula arrangement could be emptied, which is difficult using a flexible reservoir, it is not possible to estimate, and account for, the degree of re-filling of the cannula reservoir during the subsequent flushing of the cannula arrangement with the medicament from the injection device. In other words, the dosing of at least one of the two medicaments will be subject to uncertainty. 
       SUMMARY OF THE INVENTION 
       [0007]    It is an object of the invention to overcome the above described shortcomings of the prior art. In particular, it is an object of the invention to provide an arrangement which is capable of precise dosing of liquid volumes from more than one reservoir through a single delivery member. 
         [0008]    It is a further object of the invention to provide an arrangement for sequential delivery of liquid volumes which offers high flexibility vis-à-vis specific substances to be delivered and/or specific volumetric ratios of the substances. 
         [0009]    It is an even further object of the invention to provide such an arrangement which is simple to handle and which is easy to carry about during the day. 
         [0010]    In the disclosure of the present invention, aspects and embodiments will be described which will address one or more of the above objects and/or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments. 
         [0011]    In a first aspect of the invention a drug delivery arrangement is provided comprising a first variable volume reservoir adapted to hold a first substance and having a first axis, a second variable volume reservoir adapted to hold a second substance and having a second axis, the first variable volume reservoir and the second variable volume reservoir being distinct units which are co-axially connectable, means for varying (e.g. reducing) the volume of the first variable volume reservoir, and a fluid transport member comprising a fluid outlet, first fluid communication means for providing fluid communication with the first variable volume reservoir, and second fluid communication means for providing fluid communication with the second variable volume reservoir. The first variable volume reservoir and a portion of the second variable volume reservoir are adapted to undergo relative axial motion from a first relative position to a second relative position, when the first variable volume reservoir and the second variable volume reservoir are connected, and the connection is configured such that the act of bringing the first variable volume reservoir and the portion of the second variable volume reservoir from the first relative position to the second relative position causes a volume reduction of the second variable volume reservoir, whereby a predetermined volume of the second substance is expelled through the fluid outlet. 
         [0012]    Such an arrangement offers not only sequential delivery of substances from different reservoirs through a single, common outlet but also accurate dosing of the individual substances and, optionally, a user selectable volumetric dose ratio. In addition, since the two reservoirs are initially separated, the user may be able to select between various combinations of substances for administration in accordance with the principles of the invention. 
         [0013]    In specific embodiments the connection is configured such that the act of bringing the first variable volume reservoir and the portion of the second variable volume reservoir from the first relative position to the second relative position collapses the second variable volume reservoir completely. Thereby, the second variable volume reservoir can be provided as a fixed dose, single use disposable offering. 
         [0014]    The first variable volume reservoir may be a stand-alone reservoir, such as e.g. an ampoule or a bag. Alternatively, it may form part of a drug delivery device comprising an injection mechanism adapted to cause a reduction of the reservoir volume. Either way, the first variable volume reservoir may comprise a rigid, flexible, or partly flexible first reservoir body. Particularly, the first variable volume reservoir may be at least partially accommodated in a drug injection device, such as e.g. in an injection pen of the type well known in the art of medical devices. In some embodiments the first variable volume reservoir is closed by a penetrable seal, whereas in other embodiments the first variable volume reservoir is open. 
         [0015]    A drug injection device as mentioned above may be of the variable dose type which offers user selective dose setting and delivery of one or more doses of the first substance. Alternatively, or additionally, the drug injection device may be of the fixed dose type offering delivery of either a single fixed dose or a limited number of fixed doses. 
         [0016]    The injection mechanism may be activated to expel a dose of the first substance by operation of an injection activator, e.g. an injection button. In particular embodiments a first operation of the injection activator activates the injection mechanism to expel a dose of the first substance from the first variable volume reservoir, and a second operation of the injection activator brings the first variable volume reservoir and the portion of the second variable volume reservoir from the first relative position to the second relative position. 
         [0017]    In this context the terms “first operation” and “second operation” do not imply any particular sequence of the operations. The terms merely signify that the operations are different. In other words, the first variable volume reservoir and the portion of the second variable volume reservoir may be brought from the first relative position to the second relative position by a particular operation of the injection activator before or after the injection mechanism is activated to expel a dose of the first substance from the first reservoir. 
         [0018]    By incorporating a dual operability in the injection activator a sequential substance delivery in accordance with the principles of the present invention may be performed without the user having to change hand position at any time during the execution. A steady hand position is desirable regardless of whether the substances are delivered through a percutaneous injection needle or a jet nozzle. When using a percutaneous injection needle the risk of needle breakage in the skin is significantly reduced, whereas when injecting through a jet nozzle the risk of performing a wet shot is significantly reduced with a steady hand position. 
         [0019]    The second variable volume reservoir may be rigid, flexible or partly flexible. In particular embodiments the second variable volume reservoir comprises a piston arranged slidably in a predominantly rigid second reservoir body. The second reservoir body, or an element associated with the second reservoir body, may comprise coupling means for use in connecting the second variable volume reservoir with the first variable volume reservoir. Such coupling means may e.g. comprise a screw thread, a bayonet interface, a snap fit surface, a friction fit surface, or the like. 
         [0020]    The connection between the first variable volume reservoir and the second variable volume reservoir may be configured such that when the first variable volume reservoir and the portion of the second variable volume reservoir are brought from the first relative position to the second relative position the piston slides axially in the second reservoir body. In some embodiments the piston and the first variable volume reservoir may accordingly undergo joint motion, whereas in other embodiments the piston and the first variable volume reservoir may accordingly undergo relative motion. 
         [0021]    Axial displacement of a piston in a rigid reservoir body is widely used for precision dosing of medicaments. An arrangement based on two individual such solutions thus provides for accurate delivery of both the first and the second substance and thereby for a reliable volumetric dose ratio. 
         [0022]    One or both of the first variable volume reservoir and the second variable volume reservoir may be delivered prefilled by the manufacturer. Alternatively, one or both of the first variable volume reservoir and the second variable volume reservoir may be user fillable. 
         [0023]    The first variable volume reservoir and the second variable volume reservoir may be connectable via a coupling element, which coupling element may comprise a base member, first coupling means for coupling with the first variable volume reservoir and second coupling means for coupling with the second variable volume reservoir. At least one of the first coupling means and the second coupling means may be structured to provide multi-stable positioning of the first variable volume reservoir or the second variable volume reservoir relative to the base member. 
         [0024]    In the present context the term “stable”, as used in any form in connection with the position or positioning of a particular element, is interchangeable with the term “well-defined”. Accordingly, “to provide multi-stable positioning” of a first element relative to a second element means to provide for a plurality of well-defined positions of the first element relative to the second element. 
         [0025]    Depending on the number of stable positions of the first variable volume reservoir or the second variable volume reservoir relative to the base member offered by the coupling element the second variable volume reservoir may be usable for one or more administrations. In particular embodiments the at least one of the first coupling means and the second coupling means is structured to provide bi-stable positioning of the first variable volume reservoir or the second variable volume reservoir relative to the base member. Thereby, an arrangement may be provided in which a relative motion between the first variable volume reservoir or the second variable volume reservoir and the base member from the first stable position to the second stable position causes a collapse of the second variable volume reservoir, i.e. in which a fixed dose of the second substance is accurately expelled from a single use, disposable reservoir unit. 
         [0026]    At least one of the first coupling means and the second coupling means may further be structured to automatically cause relative motion between the first variable volume reservoir or the second variable volume reservoir and the base member from a first stable relative position to a second stable relative position in response to a connection of the first variable volume reservoir with the second variable volume reservoir. For example, at least one of the first coupling means and the second coupling means may be structured to automatically move the first variable volume reservoir from a first stable position relative to the base member to a second stable position relative to the base member in response to the second variable volume reservoir being coupled to the second coupling means. This provides for an automatic loading or re-loading of the drug delivery arrangement during preparation of the arrangement for a first or a next administration. 
         [0027]    The respective first and second coupling means may e.g. a comprise a screw thread interface, a bayonet interface, a snap fit surface, a friction fit surface, or the like. 
         [0028]    In particular embodiments the coupling element comprises a tubular base member structured to receive an injection pen, e.g. of the type conventionally used within diabetes care. The base member may encase the body of the injection pen, e.g. leaving only a dose dial and injection button accessible for user manipulation. In that case, the base member may be provided with a window allowing the user to read a dose scale on the injection pen. Alternatively, the base member encases only a portion of the injection pen, e.g. only a distal portion of the injection pen. 
         [0029]    The fluid transport member may be arranged to traverse the second variable volume reservoir from a first end wall portion of the second reservoir body to and at least partly through the piston. Particularly, the fluid transport member may extend from an outlet opening in the second reservoir body to and at least partly through the piston. In some embodiments the fluid transport member comprises a hollow needle or cannula having a tubular body, a proximal needle end portion and a distal needle end portion. The distal needle end portion may be adapted for penetration of a skin surface and may be comprise the fluid outlet, e.g. in the form of an open, pointed distal needle end. The proximal needle end portion may be adapted for penetration of a seal member, such as e.g. a rubber septum, and may comprise the first fluid communication means for providing fluid communication with the first variable volume reservoir, e.g. in the form an open, pointed proximal needle end. The tubular body extends between the proximal needle end portion and the distal needle end portion and may comprise the second fluid communication means for providing fluid communication with the second variable volume reservoir, e.g. in the form of one or more holes in the tubular body wall. 
         [0030]    In particular embodiments the hollow needle projects both outwardly and inwardly from the outlet opening of the second reservoir body, the outward projection corresponding to the depth of deposition of the substances in the body of the subject user. The hollow needle may be arranged fixedly or slidably relative to the outlet opening of the second reservoir body. In case the hollow needle is arranged slidably relative to the outlet opening of the second reservoir body, the needle may be arranged fixedly relative to the piston, and the depth of insertion of the distal needle end portion in the skin may therefore be varied during the sequential administration, thereby allowing for dispersed deposition of the total delivered volume, e.g. going from a deposition of the first substance in the intradermal layer to a deposition of at least a portion of the second substance in subcutis, or simply a deposition of the two substances in different areas of subcutis. The one or more holes in the tubular body wall may accordingly be arranged on the inwardly projecting portion of the tubular body that is housed within the second reservoir body between the outlet opening and the piston. In particular embodiments at least one such hole is arranged just distally of the piston to thereby provide for easy emptying of the second variable volume reservoir. 
         [0031]    In case the hollow needle is arranged fixedly relative to the outlet opening of the second reservoir body the outward projection may be of a magnitude comparable to conventionally used needle lengths within diabetes care, i.e. of a magnitude which provides for placement of the fluid outlet in the subcutaneous tissue of the subject user. The one or more holes in the tubular body wall may accordingly be arranged on the inwardly projecting portion of the tubular body that is housed within the second reservoir body between the outlet opening and the piston. In particular embodiments at least one such hole is arranged just proximally of the outlet opening to thereby provide for easy emptying of the second variable volume reservoir. 
         [0032]    The piston may be provided with a through-going bore for fixed or slidable reception of a portion of the fluid transport member. In case the fluid transport member is arranged slidably relative to the piston the fluid transport member may in the initial state of the second variable volume reservoir extend partly or fully through the through-going bore. The initial position of the fluid transport member relative to the piston may decide the particular delivery sequence of the first substance and the second substance, as will be exemplified in the following. 
         [0033]    If the fluid transport member comprises a hollow needle as described in the above the proximal needle end portion may in the initial state of the second variable volume reservoir be positioned within the through-going bore or proximally of the piston. In case of the latter the proximal needle end portion may be arranged to penetrate a closure of the first variable volume reservoir during connection of the first variable volume reservoir and the second variable volume reservoir. If a pressure is subsequently applied to the first variable volume reservoir, e.g. as a consequence of an operation of the injection activator, the first substance will flow through the needle and out through the fluid outlet, as the pressure of the second substance in the second variable volume reservoir will prevent the first substance from entering the second variable volume reservoir through the hole(s) in the tubular body wall. A further operation of the injection activator may then cause the first variable volume reservoir and the portion of the second variable volume reservoir to undergo relative axial motion from the first relative position to the second relative position, thereby collapsing the second variable volume reservoir and expelling the second substance through the fluid outlet via the hole(s) in the tubular body wall. 
         [0034]    In case the needle is initially positioned within the through-going bore of the piston, a connection of the first variable volume reservoir and the second variable volume reservoir may not automatically cause a penetration of the closure of the first variable volume reservoir. An operation of the injection activator may therefore firstly bring the first variable volume reservoir and the portion of the second variable volume reservoir from the first relative position to the second relative position, expelling the second substance through the fluid outlet via the hole(s) in the tubular body wall. In the course of this relative motion between the first variable volume reservoir and the portion of the second variable volume reservoir the proximal needle end portion may penetrate the closure of the first variable volume reservoir to establish fluid communication with the first variable volume reservoir. A further operation of the injection activator may then cause a volume of the first substance to be expelled through the needle and the fluid outlet, the second variable volume reservoir now being collapsed. 
         [0035]    The first variable volume reservoir and the second variable volume reservoir may be detachably connectable in which case the same first variable volume reservoir may over time be used with a plurality of second variable volume reservoirs. Furthermore, it allows for discarding of the second variable volume reservoir in a separate waste container. This may be particularly useful if the fluid transport member is carried by the second reservoir body and a pointed needle projects therefrom, because such a product is typically recommended for placement in a special sharps container after use to minimise the risk of needle stick injuries. 
         [0036]    In a second aspect of the invention a drug delivery arrangement for sequential delivery of substances is provided comprising a first variable volume reservoir adapted to hold a first substance, a second variable volume reservoir adapted to hold a second substance, the first variable volume reservoir and the second variable volume reservoir being distinct units, means for varying (e.g. reducing) the volume of the first variable volume reservoir in response to a first force acting along a general axis, and a fluid transport member comprising a fluid outlet, first fluid communication means for providing fluid communication with the first variable volume reservoir, and second fluid communication means for providing fluid communication with the second variable volume reservoir. The second variable volume reservoir is connectable (e.g. detachably connectable) with the first variable volume reservoir and collapsible responsive to a second force acting along an axis parallel to (e.g. coinciding with) the general axis. 
         [0037]    In a third aspect of the invention a drug delivery arrangement for sequential delivery of substances is provided comprising an injection device comprising a first reservoir, or means for receiving a first reservoir, the first reservoir being adapted to hold a first substance, and an injection mechanism adapted to cause a volume reduction of the first reservoir in response to a first mode of operation of an activation button, a second reservoir adapted to hold a second substance and comprising a displaceable wall, and a fluid transport member comprising a fluid outlet, first fluid communication means for providing fluid communication with the first reservoir, and second fluid communication means for providing fluid communication with the second reservoir. The injection device and the second reservoir are connectable (e.g. detachably connectable), and when the injection device and the second reservoir are connected the displaceable wall is movable in response to a second mode of operation of the activation button. 
         [0038]    By such an arrangement a sequential administration of two substances can be effected without the user having to change hand positions during the execution. 
         [0039]    The first mode of operation of the activation button may comprise applying a first depressive force of a first magnitude to the injection button, and the second mode of operation of the activation button may comprise applying a second depressive force of a second magnitude to the injection button. Thereby, once one of the first or second substances has been delivered the other substance may be delivered simply by the user changing the applied injection force. This provides a very intuitive and simple to handle delivery device. 
         [0040]    According to the third aspect of the invention the drug delivery arrangement may further comprise positioning means for holding the injection device and the second reservoir in a first relative position and for enabling relative motion between the injection device and a portion of the second reservoir from the first relative position to a second relative position. The relative motion between the injection device and the portion of the second reservoir from the first relative position to the second relative position may be executed in response to the second mode of operation of the activation button. 
         [0041]    The positioning means may be adapted to enable relative translational motion between the injection device and the second reservoir from a first relative axial position to a second relative axial position, and the displaceable wall may be a piston adapted to move axially in the second reservoir in response to the injection device and the second reservoir undergoing relative motion from the first relative axial position to the second relative axial position. 
         [0042]    In a fourth aspect of the invention a reservoir unit is provided comprising a housing adapted to accommodate a fluid substance and comprising a displaceable wall, a fluid transport member comprising a fluid outlet, first fluid communication means for providing fluid communication with an interior of another reservoir, and second fluid communication means for providing fluid communication with an interior of the housing. Further, the reservoir unit comprises coupling means adapted for connection with mating coupling means associated with the other reservoir. 
         [0043]    In the present context the term “associated with the other reservoir” should be understood as on the other reservoir or on an element related thereto, e.g. on an element coupled with the other reservoir. 
         [0044]    The reservoir may be of the type previously outlined, and it may be adapted for use in a drug delivery arrangement according to any of the above summarised other aspects of the invention. 
         [0045]    In a fifth aspect of the invention a coupling element is provided comprising a base member defining a cavity for reception of at least a portion of a first reservoir, coupling means for connection with a second reservoir, and positioning means structured to enable bi-stable positioning of the first reservoir or the second reservoir relative to the base member. 
         [0046]    The coupling element may specifically be designed as the coupling element previously outlined, and it may be adapted for connecting first and second reservoirs in an arrangement as described in connection with the first three aspects of the invention, or for connecting a reservoir unit as described in connection with the fourth aspect of the invention with another reservoir. 
         [0047]    Some embodiments of the invention are summarised in the following: 
         [0048]    Embodiment 1: A drug delivery arrangement for sequential delivery of substances, the drug delivery arrangement comprising: a) a first variable volume reservoir adapted to hold a first substance, b) a second variable volume reservoir adapted to hold a second substance, c) means for varying the volume of the first variable volume reservoir, and d) a fluid transport member comprising d1) a fluid outlet, d2) first fluid communication means for providing fluid communication with the first variable volume reservoir, and d3) second fluid communication means for providing fluid communication with the second variable volume reservoir, wherein the first variable volume reservoir and the second variable volume reservoir are co-axially connectable distinct units, wherein the first variable volume reservoir and a portion of the second variable volume reservoir are adapted to undergo relative axial motion from a first relative position to a second relative position, when the first variable volume reservoir and the second variable volume reservoir are connected, and wherein bringing the first variable volume reservoir and the portion of the second variable volume reservoir from the first relative position to the second relative position causes a volume reduction of the second variable volume reservoir. 
         [0049]    Embodiment 2: An arrangement according to embodiment 1, wherein bringing the first variable volume reservoir and the portion of the second variable volume reservoir from the first relative position to the second relative position collapses the second variable volume reservoir. 
         [0050]    Embodiment 3: An arrangement according to embodiment 1 or 2, wherein the first variable volume reservoir forms part of a drug injection device, and wherein the means for selectively varying the volume of the first variable volume reservoir comprises an injection mechanism adapted to cause displacement of a movable reservoir wall. 
         [0051]    Embodiment 4: An arrangement according to embodiment 3, wherein the injection mechanism is activated to expel a dose of the first substance by a first operation of an injection button, and wherein the first variable volume reservoir and the portion of the second variable volume reservoir are adapted to be brought from the first relative position to the second relative position by a second operation of the injection button. 
         [0052]    Embodiment 5: An arrangement according to embodiment 3 or 4, wherein the drug injection device further comprises a dose setting mechanism for user selective dose setting. 
         [0053]    Embodiment 6: An arrangement according to any of the preceding embodiments, wherein the first variable volume reservoir and the second variable volume reservoir are connectable via a coupling element comprising a base member, first coupling means for coupling with the first variable volume reservoir, and second coupling means for coupling with the second variable volume reservoir, at least one of the first coupling means and the second coupling means being structured for bi-stable positioning of the first variable volume reservoir or the second variable volume reservoir relative to the base member. 
         [0054]    Embodiment 7: An arrangement according to embodiment 6, wherein the at least one of the first coupling means and the second coupling means is further structured to move the first variable volume reservoir or the second variable volume reservoir from a first stable position relative to the base member to a second stable position relative to the base member in response to a connection of the first variable volume reservoir with the second variable volume reservoir. 
         [0055]    Embodiment 8: An arrangement according to any of the preceding embodiments, wherein the second variable volume reservoir comprises an axially slidable piston having a through-going bore, and wherein a portion of the fluid transport member extends from an outlet of the second variable volume reservoir at least partly through the through-going bore. 
         [0056]    Embodiment 9: An arrangement according to embodiment 8, wherein the fluid transport member further comprises a hollow needle having a tubular body and a proximal needle end portion adapted for penetration of a seal, wherein the first fluid communication means comprises a hole in the proximal needle end portion, and wherein the second fluid communication means comprises a side hole in the tubular body arranged between the outlet of the second variable volume reservoir and the piston. 
         [0057]    Embodiment 10: An arrangement according to embodiment 8 or 9, wherein bringing the first variable volume reservoir and the portion of the second variable volume reservoir from the first relative position to the second relative position causes an axial displacement of the piston in the second variable volume reservoir. 
         [0058]    Embodiment 11: An arrangement according to embodiment 9 or 10, wherein the needle is fixedly connected to the piston. 
         [0059]    Embodiment 12: An arrangement according to embodiment 9 or 10, wherein the needle is arranged slidably relative to the piston. 
         [0060]    Embodiment 13: A reservoir for use as the second reservoir in a drug delivery arrangement according to any of the preceding embodiments, the reservoir comprising: a) a housing adapted to accommodate a fluid substance and comprising a displaceable wall, b) a fluid transport member comprising b1) a fluid outlet, b2) first fluid communication means for providing fluid communication with an interior of the first reservoir, and b3) second fluid communication means for providing fluid communication with an interior of the housing, and c) coupling means adapted for connection with mating coupling means associated with the first reservoir. 
         [0061]    Embodiment 14: A coupling element for use in a drug delivery arrangement according to embodiment 6 or 7, the coupling element comprising: a) a base member defining a cavity for reception of at least a portion of the first reservoir, b) coupling means for connection with the second reservoir, and c) positioning means structured to enable bi-stable positioning of the first reservoir or the second reservoir relative to the base member. 
         [0062]    The drug delivery arrangement as described herein may be used for sequential delivery of substances in a number of different situations and for a number of different purposes. Particularly, the drug delivery arrangement is suitable for one or more of 1) delivering volumes of different substances to the body of a subject user through a single delivery member (e.g. a cannula), 2) offering variable volumetric ratios, e.g. as a titration device (i.e. at least one of the substances being deliverable in variable doses), 3) delivering volumes of different substances to a third reservoir, e.g. for mixing of the substances therein, and 4) delivering two volumes of the same substance to the body of a subject user through a single delivery member, e.g. for offering an additional dose to an almost empty injection device (which reduces or eliminates drug waste without adding to the number of required needle sticks). 
         [0063]    In the foregoing, insulin and glp- 1  have been specifically mentioned as candidates for coadministration. It is emphasized, however, that other agents, as well as insulin and glp-1 analogues, derivatives and mixtures thereof, are applicable for sequential delivery in accordance with the principles of the invention. Indeed, any combination of suitable substances may be envisioned for being delivered using an arrangement as herein described. 
         [0064]    In the present specification, reference to a certain aspect or a certain embodiment (e.g. “an aspect”, “a first aspect”, “one embodiment”, “an exemplary embodiment”, or the like) signifies that a particular feature, structure, or characteristic described in connection with the respective aspect or embodiment is included in, or inherent of, at least that one aspect or embodiment of the invention, but not necessarily in/of all aspects or embodiments of the invention. It is emphasized, however, that any combination of features, structures and/or characteristics described in relation to the invention is encompassed by the invention unless expressly stated herein or clearly contradicted by context. 
         [0065]    The use of any and all examples, or exemplary language (e.g., such as, etc.), in the text is intended to merely illuminate the invention and does not pose a limitation on the scope of the same, unless otherwise claimed. Further, no language or wording in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0066]    In the following the invention will be further described with references to the drawings, wherein 
           [0067]      FIG. 1  shows a first reservoir according to an embodiment of the invention, 
           [0068]      FIGS. 2   a - 2   c  show different second reservoirs according to different embodiments of the invention, 
           [0069]      FIG. 3  shows a drug delivery arrangement according to an embodiment of the invention, in a pre-use, connected state, 
           [0070]      FIG. 4  shows the drug delivery arrangement of  FIG. 3  in a state where a dose has been set, 
           [0071]      FIG. 5  shows the drug delivery arrangement of  FIG. 3  in a state where a dose has been delivered from the first reservoir, 
           [0072]      FIG. 6  shows the drug delivery arrangement of  FIG. 3  in a state where a dose has further been delivered from the second reservoir, 
           [0073]      FIG. 7  shows a drug delivery arrangement according to another embodiment of the invention, in a pre-use, connected state, 
           [0074]      FIG. 8  shows the drug delivery arrangement of  FIG. 7  in a state where a dose has been set, 
           [0075]      FIG. 9  shows the drug delivery arrangement of  FIG. 7  in a state where a dose has been delivered from the second reservoir, 
           [0076]      FIG. 10  shows the drug delivery arrangement of  FIG. 7  in a state where a dose has further been delivered from the first reservoir, 
           [0077]      FIG. 11  shows a drug delivery arrangement according to yet another embodiment of the invention, in a pre-use, connected state, 
           [0078]      FIG. 12  shows the drug delivery arrangement of  FIG. 11  in a state where a dose has been set, 
           [0079]      FIG. 13  shows the drug delivery arrangement of  FIG. 11  in a state where a dose has been delivered from the first reservoir, and 
           [0080]      FIG. 14  shows the drug delivery arrangement of  FIG. 11  in a state where a dose has further been delivered from the second reservoir. 
       
    
    
       [0081]    In the figures like structures are mainly identified by like reference numerals. 
       DESCRIPTION OF EXEMPLARY EMBODIMENTS 
       [0082]    When in the following relative expressions, such as “backwards” and “forwards”, are used, these refer to the appended figures and not necessarily to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only. 
         [0083]      FIG. 1  is a cross-sectional view of an exemplary first part of a drug delivery arrangement according to an embodiment of the invention. The figure shows an injection device  20  housed within a tubular shell structure  10 . The injection device  20  comprises a housing  21  which holds a cartridge  22  having a cartridge interior  23  accommodating a volume of a liquid drug. The cartridge  22  is at its distal end closed by a penetrable rubber septum  24  and at its proximal end sealed by a slidable piston  25 . The piston  25  is adapted to be advanced distally in the cartridge  22  by a piston rod  26  whose movements are guided inter alia by a threaded nut  31 . The piston rod  26  and the nut  31  form parts of a dose setting and injection system which further comprises a dose setting button  27 , a scale drum  29  provided with a number of dose indicia for indicating a currently set dose, and an injection button  28 . The dose setting and injection system as well as the detailed functionality of the injection device  20  will not be discussed further in this text, as these may in principle resemble the particular system in, and functionality of, an injection device chosen among a variety of well-known injection pens. 
         [0084]    Different non-exhaustive examples of a drug injection device suitable for use, potentially in a slightly modified version, in the present type of arrangement are given in WO 99/38554, this reference being incorporated herein in its entirety. Specifically, the embodiment disclosed in relation to  FIGS. 15-17  of WO 99/38554 may be used in the present drug delivery arrangement in a version incorporating an extended proximal portion of the dose setting button. 
         [0085]    The tubular shell structure  10  comprises a shell body  11  which at its open distal end portion is provided with an exterior screw thread  12 , and at its open proximal end portion is provided with an interior circumferential proximal indentation  15  and an interior circumferential distal indentation  16 . The respective proximal and distal indentations  15 ,  16  are adapted for reception of protrusions  14  on resilient arms of a clip  13  arranged just proximally of the housing  21  in the assembled state of the injection device  20  and the shell structure  10 , and are shaped to allow the protrusions  14  to move back and forth between them in response to alternating forward and backward directed forces of appropriate magnitudes, as will be described in more detail below. In the shown state of the first part of the drug delivery arrangement the protrusions  14  rest in the distal indentation  16 , corresponding either to an activated device or to a device as supplied by the manufacturer, i.e. before a first use thereof. A window (not visible) is provided in the shell body  11  to allow a user to see the currently set dose. 
         [0086]      FIG. 2   a  is a cross-sectional view of an exemplary second part of a drug delivery arrangement according to an embodiment of the invention, which second part is adapted to be connected to the first part described above.  FIG. 2   a  shows a reservoir adaptor  40  in a pre-use state comprising a reservoir body  41  in which a piston  43  is slidably arranged. The reservoir body  41  has an outlet portion  42  defining a hub for a hollow needle  50 . Opposite the outlet portion  42  the reservoir body  41  is provided with a collar portion defining a space  46  for reception of the respective distal end portions of the shell body  11  and the cartridge  22 . The collar portion comprises an interior screw thread  45  which mates the exterior screw thread  12 , thereby allowing a mounting of the reservoir adaptor  40  on the shell structure  10 . The needle  50  comprises a needle body  51 , a portion of which projects outwardly from the outlet portion  42 . The outwardly projecting portion of the needle body  51  comprises a sharpened outlet end  52  adapted for penetration of a skin surface (not shown). The needle body  51  further projects inwardly from the outlet portion  42 , through a reservoir interior  44 , holding a volume of another liquid drug, and a bore  48  in the piston  43  to terminate at a sharpened inlet end  53  adapted for penetration of the rubber septum  24 . The needle  50  is fixedly retained by the outlet portion  42  and has a side hole  54  in the needle body  51  just proximally of the outlet portion  42 . 
         [0087]      FIG. 2   b  is a cross-sectional view of an exemplary second part of a drug delivery arrangement according to another embodiment of the invention, which second part is adapted to be connected to the first part described above.  FIG. 2   b  shows a reservoir adaptor  140  in a pre-use state comprising a reservoir body  141  in which a piston  143  is slidably arranged. The reservoir body  141  has an outlet portion  142  defining a hub for a hollow needle  150 . Opposite the outlet portion  142  the reservoir body  141  is provided with a collar portion defining a space  146  for reception of the respective distal end portions of the shell body  11  and the cartridge  22 . The collar portion comprises an interior screw thread  145  which mates the exterior screw thread  12 , thereby allowing a mounting of the reservoir adaptor  140  on the shell structure  10 . The needle  150  comprises a needle body  151 , a portion of which projects outwardly from the outlet portion  142 . The outwardly projecting portion of the needle body  151  comprises a sharpened outlet end  152  adapted for penetration of a skin surface (not shown). The needle body  151  further projects inwardly from the outlet portion  142 , through a reservoir interior  144 , holding a volume of another liquid drug, and partly through a bore  148  in the piston  143  to terminate at a sharpened inlet end  153  adapted for penetration of the rubber septum  24 . The needle  150  is fixedly retained by the outlet portion  142  and has a side hole  154  in the needle body  151  just proximally of the outlet portion  142 . In the shown pre-use state of the reservoir adaptor  140  the inlet end  153  is positioned within the bore  148 . The needle body  151  is adapted to slide in the bore  148  during distal advancement of the piston  143  in the reservoir body  141  and to eventually project proximally from the piston  143  as the reservoir interior  144  is emptied, thereby exposing the inlet end  153  for penetration of the rubber septum  24 . 
         [0088]      FIG. 2   c  is a cross-sectional view of an exemplary second part of a drug delivery arrangement according to yet another embodiment of the invention, which second part is adapted to be connected to the first part described above.  FIG. 2   c  shows a reservoir adaptor  240  in a preuse state comprising a reservoir body  241  in which a piston  243  is slidably arranged. The reservoir body  241  has an outlet portion  242  defining a hub for a hollow needle  250 . Opposite the outlet portion  242  the reservoir body  241  is provided with a collar portion defining a space  246  for reception of the respective distal end portions of the shell body  11  and the cartridge  22 . The collar portion comprises an interior screw thread  245  which mates the exterior screw thread  12 , thereby allowing a mounting of the reservoir adaptor  240  on the shell structure  10 . The needle  250  comprises a needle body  251 , a portion of which projects outwardly from the outlet portion  242 . The outwardly projecting portion of the needle body  251  comprises a sharpened outlet end  252  adapted for penetration of a skin surface (not shown). The needle body  251  further projects inwardly from the outlet portion  242 , through a reservoir interior  244 , holding a volume of another liquid drug, and a bore  248  in the piston  243  to terminate at a sharpened inlet end  253  adapted for penetration of the rubber septum  24 . The needle  250  is fixedly retained by the piston  243  and has a side hole  254  in the needle body  251  just distally of the piston  243 . 
         [0089]    Each of the above described pistons  25 ,  43 ,  143 ,  243  may comprise entirely of elastomeric material (e.g. rubber) or may comprise a rigid (e.g. plastic, ceramic or metal) core with an elastomeric coating. 
         [0090]      FIGS. 3-6  show cross-sectional views of a drug delivery arrangement  1  according to an embodiment of the invention, in different states during use. This particular embodiment employs the first part depicted in  FIG. 1  in combination with the second part depicted in  FIG. 2   a . In  FIG. 3  the reservoir adaptor  40  has been mounted on the shell structure  10  via the mating screw threads  12 ,  45 , whereby the inlet end  53  has penetrated the rubber septum  24  and established fluid connection to the cartridge interior  23 . During screwing of the collar portion of the reservoir body  41  onto the distal end portion of the shell body  11  the injection device  20  is moved backwards in the shell structure  10 , following the axial movement of the protrusions  14  as they are forced from a resting position in the distal indentation  16  to a resting position in the proximal indentation  15 . The axial movement of the clip  13  is accomplished because of a particular curved configuration of the protrusions  14  and a corresponding curved configuration of the distal indentation  16 , allowing the protrusions  14  to slide along the surface of the distal indentation  16  when subjected to a longitudinal force, whereby the resilient arms of the clip  13  are deflected elastically inwards. When the protrusions  14  have moved a certain distance backwards they will be pressed into the proximal indentation  15  by the elastic recovery of the arms of the clip  13 . A particular curved configuration of the proximal indentation  15  ensures a stable positioning of the protrusions  14  therein. By the backward movement of the injection device  20  in the shell structure  10 , a small clearance of magnitude d is established between a stop surface  17  in the shell body  11  and a distal end surface  39  of the housing  21 . This distance d corresponds both to the axial distance between the vertex of the proximal indentation  15  and the vertex of the distal indentation  16  and to the axial distance which the piston  43  needs to travel in the reservoir body  41  to empty the reservoir interior  44  (to the degree practically possible). 
         [0091]    Operation of the dose setting button  27  now leads to the setting of a dose to be delivered from the cartridge  22 . This is shown in  FIG. 4 . Revolving the dose setting button  27  about the longitudinal axis of the drug delivery arrangement  1  causes a helical track  34  on the surface of the scale drum  29  to travel a distance along a helical rib  35  on the interior surface of the housing  21 , thereby forcing the dose setting button  27  axially away from the shell body  11 . In the present embodiment the dose setting button  27  and the scale drum  29  are shown as rotationally coupled separate elements, but it is understood that they could just as well be formed as a single element, e.g. as disclosed in relation to  FIGS. 15-17  of WO 99/38554. 
         [0092]      FIG. 5  shows a situation where the injection button  28  has been depressed towards the shell body  11  to activate the injection mechanism in the injection device  20  to cause the piston rod  26  to force the piston  25  forwards in the cartridge  22 . This results in an ejection of the set dose through the needle body  51  and the outlet end  52 , as the incompressibility of the liquid drug in the reservoir interior  44  prevents the liquid drug from the cartridge  22  from entering through the side hole  54 . 
         [0093]    To deliver the set dose from the cartridge  22  requires the user to apply a depressive force of a certain magnitude to the injection button  28 . Following this delivery the application of a slightly larger depressive force to the injection button  28  will force the protrusions  14  out of engagement with the proximal indentation  15 , whereby the clip  13  will move axially within the shell body  11  to take up a more distal position where the protrusions  14  are occupied in the distal indentation  16 . This is shown in  FIG. 6 . The movement of the clip  13 , which is accomplished in a manner similar to what is described in the above, causes the injection device  20  to move axially with respect to the shell structure  10  a distance, d, until the stop surface  17  and the distal end surface  39  abut one another. During this movement the cartridge  22  forces the piston  43  forward in the reservoir body  41 . Since the needle  50  is fixedly attached to the outlet portion  42  the forward movement of the piston  43  causes the needle body  51  to slide in the bore  48 , leading to a further penetration of the inlet end  53  into the cartridge  22 . The forward movement of the piston  43  reduces the volume of the reservoir interior  44 , forcing the liquid drug contained therein through the side hole  54  and further out through the outlet end  52 , the incompressibility of the liquid in the cartridge  22  preventing backflow through the needle body  51 . 
         [0094]    Hence, by this embodiment a variable dose of drug contained in the cartridge  22  and a fixed dose of drug from the reservoir body  41  are sequentially administrable, in the order indicated, through the needle  50  by simple operations that are well-known to users of conventional injection pens. 
         [0095]      FIGS. 7-10  show cross-sectional views of a drug delivery arrangement  100  according to another embodiment of the invention, in different states during use. This particular embodiment employs the first part depicted in  FIG. 1  in combination with the second part depicted in  FIG. 2   b . In  FIG. 7 , the reservoir adaptor  140  has been mounted on the shell structure  10  via the mating screw threads  12 ,  145 . However, contrary to the embodiment described above, this physical connection of the reservoir adaptor  140  and the injection device  20  has not lead to a penetration of the rubber septum  24  because of the initial arrangement of the inlet end  153  within the bore  148 . Otherwise, in this pre-activated state the assembled drug delivery arrangement  100  resembles the drug delivery arrangement  1 . 
         [0096]    A dose may now be set by operating the dose setting button  27 . This is done in a manner similar to what has previously been described in connection with  FIG. 4  and leads to a state as shown in  FIG. 8 . Following the dose setting a depression of the injection button  28  will firstly cause the injection device  20  to move axially forwards with respect to the shell structure  10  as the protrusions are forced to move from the proximal indentation  15  to the distal indentation  16 , this movement of the protrusions  14  being similar to what has been described above. The forward movement of the injection device  20  causes the cartridge  22  to force the piston  143  forward in the reservoir body  141  to collapse the reservoir interior  144  and expel the liquid drug contained therein through the side hole  154  and further out through the outlet end  152 . This is shown in  FIG. 9 . During the forward movement of the piston  143  the needle body  151  slides in the bore  148 , and at some point, just before collapse of the reservoir interior  144 , the sharpened inlet end  153  penetrates the rubber septum  24  and establishes fluid connection to the cartridge interior  23 . A further depression of the injection button  28 , as shown in  FIG. 10 , now activates the injection mechanism in the injection device  20  to cause the piston rod  26  to force the piston  25  forwards in the cartridge  22 , resulting in an ejection of the set dose through the needle body  151  and the outlet end  152 . 
         [0097]    Hence, by this embodiment a variable dose of drug contained in the cartridge  22  and a fixed dose of drug from the reservoir body  141  are sequentially administrable, in the reverse order, through the needle  150  by simple operations that are well-known to users of conventional injection pens. 
         [0098]      FIGS. 11-14  show cross-sectional views of a drug delivery arrangement  200  according to yet another embodiment of the invention, in different states during use. This particular embodiment employs the first part depicted in  FIG. 1  in combination with the second part depicted in  FIG. 2   c . In  FIG. 11 , the reservoir adaptor  240  has been mounted on the shell structure  10  via the mating screw threads  12 ,  245  and in this pre-activated state the drug delivery arrangement  200  resembles the drug delivery arrangement  1 , except from the configuration of the hollow needle  250 . Thus, the operation of the drug delivery arrangement  200  from the mounting of the reservoir adaptor  240  on the shell structure  10 , through the dose setting, as illustrated in  FIG. 11 , to the delivery of the dose of liquid drug from the cartridge  22 , as shown in  FIG. 12 , is similar to the one described above in connection with  FIGS. 3-5 . 
         [0099]    After having completed the delivery of the dose of drug from the cartridge  22 , a further depression of the injection button  28  will now lead to an axial forward movement of the clip  13  and the injection device  20  in the shell body  11 , similarly to what has been described in connection with  FIG. 6 . During this movement the cartridge  22  forces the piston  243  forward in the reservoir body  241 . Since the needle  250  is fixedly attached to the piston  243  the piston  243  brings along the needle body  251 , whereby the length of the portion of the needle  250  that protrudes outwardly from the outlet portion  242  gradually increases. The forward movement of the piston  243  reduces the volume of the reservoir interior  244 , forcing the liquid drug contained therein through the side hole  254  and further out through the outlet end  252 , the incompressibility of the liquid in the cartridge  22  preventing backflow through the needle body  251 . 
         [0100]    Hence, by this embodiment a variable dose of drug contained in the cartridge  22  and a fixed dose of drug from the reservoir body  241  are sequentially administrable, in the order indicated, through the needle  250  by simple operations that are well-known to users of conventional injection pens. In case the needle  250  has resided percutaneously in a subject during the sequential administration the dose of drug delivered from the cartridge  22  has been administered to one layer of the skin, whereas the dose of drug delivered from the reservoir adaptor  40  has been administered to gradually deeper layers of the skin. 
         [0101]    It is noted that the distal end portion of the cartridge  22 , or of a cartridge holder accommodating the cartridge  22 , may be configured to receive a conventional needle hub carrying a double pointed injection needle. In that case it is further possible to use the injection device  20  in the shell structure  10  as a stand-alone device without the reservoir adaptor  40 , thereby offering increased product flexibility as both conventional delivery and sequential delivery is at the user&#39;s disposal.