Abstract:
The invention faces the technical problem of reducing the uncertainty over exact doses ejected from a medical device and at the same time providing a homogeneous, but controlled mixture of at least two fluids while a simple production should be maintained. A medical device comprising a first valve, a second valve, a first pre-valve ullage, a second pre-valve ullage, a post-valve ullage with a first end and a second end and a needle is presented. The first pre-valve ullage is connected to the post-valve ullage by the first valve and the second pre-valve ullage is connected to the post-valve ullage by the second valve. A first fluid is guidable from the first pre-valve ullage to the post-valve ullage and a second fluid is guidable from the second pre-valve ullage to the post-valve ullage.

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/EP2012/057682 filed Apr. 26, 2012, which claims priority to U.S. Provisional Patent Application No. 61/480,063 filed Apr. 28, 2011, and European Patent Application No. 11173269.9 filed Jul. 8, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
    
    
     FIELD OF DISCLOSURE 
     The present patent application relates to medical devices for delivering at least two drug agents from separate reservoirs. Such drug agents may comprise a first and a second medicament. The medical device includes a dose setting mechanism for delivering the drug agents automatically or manually by the user. 
     The medical device can be an injector, for example a hand-held injector, especially a pen-type injector, that is an injector of the kind that provides for administration by injection of medicinal products from one or more multidose cartridges. In particular, the present invention relates to such injectors where a user may set the dose. 
     The drug agents may be contained in two or more multiple dose reservoirs, containers or packages, each containing independent (single drug compound) or pre-mixed (co-formulated multiple drug compounds) drug agents. 
     BACKGROUND 
     Certain disease states require treatment using one or more different medicaments. Some drug compounds need to be delivered in a specific relationship with each other in order to deliver the optimum therapeutic dose. The present patent application is of particular benefit where combination therapy is desirable, but not possible in a single formulation for reasons such as, but not limited to, stability, compromised therapeutic performance and toxicology. 
     For example, in some cases it may be beneficial to treat a diabetic with a long acting insulin (also may be referred to as the first or primary medicament) along with a glucagon-like peptide-1 such as GLP-1 or GLP-1 analog (also may be referred to as the second drug or secondary medicament). 
     Accordingly, there exists a need to provide devices for the delivery of two or more medicaments in a single injection or delivery step that is simple for the user to perform without complicated physical manipulations of the drug delivery device. The proposed drug delivery device provides separate storage containers or cartridge retainers for two or more active drug agents. These active drug agents are then only combined and/or delivered to the patient during a single delivery procedure. These active agents may be administered together in a combined dose or alternatively, these active agents may be combined in a sequential manner, one after the other. 
     SUMMARY 
     The drug delivery device also allows for the opportunity of varying the quantity of the medicaments. For example, one fluid quantity can be varied by changing the properties of the injection device (e.g., setting a user variable dose or changing the device&#39;s “fixed” dose). The second medicament quantity can be changed by manufacturing a variety of secondary drug containing packages with each variant containing a different volume and/or concentration of the second active agent. 
     The drug delivery device may have a single dispense interface. This interface may be configured for fluid communication with a primary reservoir and with a secondary reservoir of medicament containing at least one drug agent. The drug dispense interface can be a type of outlet that allows the two or more medicaments to exit the system and be delivered to the patient. 
     The combination of compounds from separate reservoirs can be delivered to the body via a double-ended needle assembly. This provides a combination drug injection system that, from a user&#39;s perspective, achieves drug delivery in a manner that closely matches the currently available injection devices that use standard needle assemblies. One possible delivery procedure may involve the following steps: 
     1. Attach a dispense interface to a distal end of the electro-mechanical injection device. The dispense interface comprises a first and a second proximal needle. The first and second needles pierce a first reservoir containing a primary compound and a second reservoir containing a secondary compound, respectively. 
     2. Attach a dose dispenser, such as a double-ended needle assembly, to a distal end of the dispense interface. In this manner, a proximal end of the needle assembly is in fluidic communication with both the primary compound and secondary compound. 
     3. Dial up/set a desired dose of the primary compound from the injection device, for example, via a graphical user interface (GUI). 
     4. After the user sets the dose of the primary compound, the micro-processor controlled control unit may determine or compute a dose of the secondary compound and preferably may determine or compute this second dose based on a previously stored therapeutic dose profile. It is this computed combination of medicaments that will then be injected by the user. The therapeutic dose profile may be user selectable. Alternatively, the user can dial or set a desired dose of the secondary compound. 
     5. Optionally, after the second dose has been set, the device may be placed in an armed condition. The optional armed condition may be achieved by pressing and/or holding an “OK” or an “Arm” button on a control panel. The armed condition may be provided for a predefined period of time during which the device can be used to dispense the combined dose. 
     6. Then, the user will insert or apply the distal end of the dose dispenser (e.g., a double ended needle assembly) into the desired injection site. The dose of the combination of the primary compound and the secondary compound (and potentially a third medicament) is administered by activating an injection user interface (e.g., an injection button). 
     Both medicaments may be delivered via one injection needle or dose dispenser and in one injection step. This offers a convenient benefit to the user in terms of reduced user steps compared to administering two separate injections. 
     Using a single device and especially using a single injection needle to reduce the normally two injection steps to a single step generates the problem of an uncontrolled mixture of the two drug agents used. 
     It is always necessary for a successful therapy to deliver the two different drug agents to the patient in a very particular dose. Since the two drug agents share a common injection needle the two different drug agents need to mix at some point in the medical device, in case the two drug agents are administered in a combined dose. Due to the comparable big volumes and long paths the drug agents need to pass between the reservoirs and the injection site an uncontrollable mixture of the medicaments can often not be avoided, producing an uncertainty on the exact dose administered. 
     In case the two drug agents are administered in a sequential manner one after another, there is also an uncertainty over the exact dose administered, especially the exact dose of the second drug agent, since the fluidic channels in the drug delivery device are of course at least partially filled with remainders of the first drug agents, leading again to an uncontrolled mixing of the two medicaments. 
     The invention faces the technical problem of reducing the uncertainty over exact doses ejected from a medical device and reducing the risk of cross-contamination of the two or more medicaments. 
     The technical problem is solved by a medical device comprising a first valve, a second valve, a first pre-valve ullage, a second pre-valve ullage, a post-valve ullage with a first end and a second end and a needle. The first pre-valve ullage is connected to the post-valve ullage by the first valve and the second pre-valve ullage is connected to the post-valve ullage by the second valve. A first fluid is guidable from the first pre-valve ullage to the post-valve ullage and a second fluid is guidable from the second pre-valve ullage to the post-valve ullage. A first end of the needle is inserted into the post-valve ullage and the post-valve ullage is designed such that there is a flow inversion between the post-valve ullage and the needle. 
     By providing two separate valves for each of the at least two fluids, the fluids are kept separate in their own pre-valve ullages. This limits the region, where the different fluids can mix, to the post-valve ullage. It has been found that this way a much more precise, controlled and predictable mixture of the different fluid, in particular drug agents, can be ejected from the medical device. Of course, the pre-valve ullages do not have a direct connection to each other apart from their connection to the common post-valve ullage over the respective valves. 
     The two separate valves for each fluid also prevent the first fluid to be pushed into the second pre-valve ullage or even further back, for example into a reservoir for the second fluid and vice versa. 
     In case the fluids are ejected from the medical device one after another, the inventive medical device improves the uncertainty over exact doses, since the common fluidic passage is reduced to the post-valve ullage. That means that the amount of the first fluid remaining in the common fluidic passage is effectively reduced, thus providing a better control of the second dose. 
     The volume of the post-valve ullage though is still sufficient to provide a region, in which both medicaments can mix sufficiently, so that a homogeneous mixture of the fluids is provided in case the fluids are ejected together. 
     According to another embodiment the medical device further comprises a first reservoir and a second reservoir, wherein the first reservoir is connected to the first pre-valve ullage and the second reservoir is connected to the second pre-valve ullage. These reservoirs provide separate storage vessels for the first and second fluid. This is particularly useful for drug agents, which must not be stored together or in a ready-made mixture. This way, the fluids, in particular drug agents, mix in the post-valve ullage for the first time, right before the mixture is ejected from the medical device and/or injected at the injection site, for example. 
     The reservoirs are preferably detachably attached to the respective pre-valve ullages. This connection can in particular be provided by needles or cannulas, which are preferably made from metal, for example steel. This accounts for the fact, that the reservoirs might be exchanged with different frequencies than the part of the medical device containing said ullages and valves. 
     The first and second pre-valve ullages can be in constant fluid communication with the respective reservoir. The valves prevent the fluids to enter the post-valve ullage while the medical device is not used. 
     According to another embodiment of the medical device, a first end of the needle is inserted into the post-valve ullage at the second end of the post-valve ullage. This provides a simple possibility to guide either fluid or a mixture of both fluids to an injection site. No further guiding by complicated fluidic systems is needed and the overall fluidic system from the reservoir to the injection site, in particular from the post-valve ullage to the injection site is minimized. This further reduces unnecessary volume for the fluids to pass and improves the accuracy of the doses. The needle is preferably made of metal, in particular steel, to provide a biocompatible material and to be able to directly inject the fluids into the skin of a user, for example. 
     Such a needle can in particular be a double ended needle, which can be attached to the medical device, providing an exchangeable injection needle. 
     It is further preferred when the first end of the needle is substantially in the center of the post-valve ullage. On the one hand, this reduces the danger of damaging the post valve ullage with the first end of the needle. 
     On the other hand, this provides a flow inversion and thus further improves the flow efficiency. The fluids enter the post-valve ullage, for example at its first end or at its second end, and the fluids exit the post-valve ullage through the needle in or near the center or at or near an opposite end of the post-valve ullage. This configuration makes the fluid change directions and thus provides an excellent mixing of the fluids and an improved flow-out. This effect is especially distinct, when the fluids enter the post-valve ullage at its second end, since the flow directions of the fluids during entering and exiting the post-valve ullage are anti-parallel. 
     According to another embodiment of the medical device, the first fluid and/or the second fluid enter the post-valve ullage substantially tangentially. That means, if the post valve ullage has a substantially cylindrical shape for example, the first fluid and/or the second fluid enter the post-valve ullage tangentially to its curved surface area. In this way, a particularly effective mixing of the fluids can be achieved. 
     According to the invention the post-valve ullage is designed such that there is a flow inversion between the post valve ullage and the needle. This effect can in particular be achieved by providing a post-valve ullage, into which the fluids enter at the second end of the post-valve ullage, while the first end of the needle is located in or near the center or at or near the first end of the post-valve ullage. This results in the effect that the fluids flow into the post-valve ullage substantially from the second end towards the first end of the post-valve ullage and exit the post-valve ullage through the first end of the needle flowing substantially from the first end of the post valve ullage in the direction of the second end of the post valve ullage. Thus, an antiparallel upward and downward movement of the fluids provides in this case the flow inversion and therefore an effective mixing of the fluids. 
     The same effect is achieved in case the fluids enter the post valve ullage at the first end of the post-valve ullage for example, since at least a part of the fluids will reach the second end of the post-valve ullage and the fluids will have to flow towards the first end of the post-valve ullage to reach the center of the post-valve ullage and to exit through the first end of the needle. Thus, a flow inversion is achieved in the post-valve ullage and a particularly effective mixing of the fluids can be achieved. 
     According to another embodiment of the medical device, it is advantageous, when the first pre-valve ullage and the second pre-valve ullage are provided by an inner body and the first valve and the second valve are provided by a first and a second elastic part respectively adjacent to an outer body of the medical device. 
     This facilitates the production of the medical device. The valve is provided between outer and inner body, such that no stand-alone parts are necessary in this arrangement as for example for diaphragm valves. The first and second elastic parts seal the fluidic connection between the respective pre-valve ullages and the post-valve ullage. 
     Preferably, the elastic parts have flexible portions such that the flexible portions can move freely and the valves are opened and closed depending on the pressure of the respective fluids in the pre-valve ullages. If the pressure is high enough in the first pre-valve ullage, the flexible portion is preferably pushed out of the way opening the first valve and establishing a fluid connection between the first pre-valve ullage and the post valve ullage. The second valve can work in the same way. Though, it is also possible that the valves are activated automatically by a mechanical mechanism, for example. 
     Preferably the valves are of such design, that the valve is a one way valve and a backpressure from the post-valve ullage cannot open the valves. 
     Such a so called “sleeve valve” can be easily implemented by a circular diaphragm valve, for example. 
     The elastic part might also be designed integrally with the outer body of the medical device. 
     It is preferred, when the post-valve ullage is configured such that the fluid enters the post-valve ullage at the second end of the post valve ullage. The fluid can be guided to the second end of the post-valve ullage by fluidic channels connecting the respective valve with the second end of the post-valve ullage. This way a more homogenous mixing of the fluids can be achieved and an efficient guiding of the fluids with a minimal length of the fluidic system, since the fluids do not need to be guided to the first end of the post-valve ullage again. This further promotes the reduction of the uncertainty over exact doses ejected, while at the same time a homogeneous, but controlled mixture is provided. 
     According to another embodiment of the Medical device, the first valve and the second valve are provided by valves located at the first end of the post-valve ullage. This arrangement provides a minimal channel length from the pre-valve ullages or the reservoirs to the post-valve ullage or the injection site. This further reduces the uncertainty over exact doses ejected from the medical device and at the same time provides a homogeneous, but controlled mixture of two fluids. 
     The valves can be designed as standard umbrella or diaphragm valves, but may preferably be designed as so called “beak valves”. Such beak valves are substantially funnel shaped with a point-shaped opening or an opening in form of a slit. In the closed state the elastic material adjacent to the opening is pre-stressed such that the opening is closed. The pressure of the fluid can open force the elastic material aside, so that the beak valve opens. 
     It is especially preferred, when the first valve is configured to be controlled by the pressure of the fluid in the first pre-valve ullage and/or the second valve is configured to be controlled by the pressure of the fluid in the second pre-valve ullage. This provides a very simple and cost-sensitive implementation of the valves into the medical device, because no external control of the valves is necessary, for example by mechanical actuators or the like. 
     It is especially preferred when the first valve and/or the second valve is at least in part made from one or more materials selected from the group of TPE, PTFE, silicone and EPDM. These materials are especially suitable since they show a high biocompatibility, for example requirements for sterilization, and at the same time provide a sufficient sealing function between the pre-valve ullage and the post-valve ullage. 
     Valves from thermoplastic elastomers (TPE) are especially easy to produce since they can be molded and only little or no compounding is necessary to achieve the desired material properties. 
     Polytetrafluoroethylene (PTFE) shows a very low coefficient of friction optimizing the fluidic properties of the medical device. Moreover PTFE is subjected to material creep, which can be advantageous when used in valves and seals, since the valve or seal creeps a certain amount and can thus match the corresponding counter-surface to establish a tight seal. 
     Silicone is readily tested in medical appliances and provides good sealing properties combined with good biocompatibility. 
     Valves made from ethylene propylene diene monomer rubber (EPDM) provide a high resistivity against humidity and ozone. Furthermore EPDM has a high chemical stability and a high elasticity, providing excellent properties for sealing applications. 
     In particular the medical device is a drug delivery system. Especially for drug delivery systems it is of utmost importance to reduce the uncertainty over exact doses ejected and at the same time providing a homogeneous, but controlled mixture of the ejected fluids. 
     It is especially advantageous if the medical device further comprises a dispense interface comprising the first valve, the second valve, the first pre-valve ullage, the second pre-valve ullage and the post-valve ullage with the first end and said second end. The dispense interface can hence be exchanged or replaced independently from the rest of the medical device, especially a cartridge holder, containing the first and second reservoir. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       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, in which: 
         FIG. 1  illustrates a perspective view of a delivery device with an end cap of the device removed; 
         FIG. 2  illustrates a perspective view of the delivery device distal end showing the cartridge; 
         FIG. 3  illustrates a perspective view of the delivery device illustrated in  FIG. 1 or 2  with one cartridge retainer in an open position; 
         FIG. 4  illustrates a dispense interface and a dose dispenser that may be removably mounted on a distal end of the delivery device illustrated in  FIG. 1 ; 
         FIG. 5  illustrates the dispense interface and the dose dispenser illustrated in  FIG. 4  mounted on a distal end of the delivery device illustrated in  FIG. 1 ; 
         FIG. 6  illustrates a needle assembly that may be mounted on a distal end of the delivery device; 
         FIG. 7  illustrates a perspective view of the dispense interface illustrated in  FIG. 4 ; 
         FIG. 8  illustrates another perspective view of the dispense interface illustrated in  FIG. 4 ; 
         FIG. 9  illustrates an exemplary embodiment of the invention in a cross-sectional view of the dispense interface illustrated in  FIG. 4 ; 
         FIG. 10  illustrates an exploded view of the dispense interface illustrated in  FIG. 4 ; 
         FIG. 11  illustrates a cross-sectional view of the dispense interface and needle assembly mounted onto a drug delivery device, such as the device illustrated in  FIG. 1 ; 
         FIG. 12  illustrates another exemplary embodiment according to the invention in a cross sectional view; 
         FIG. 13  illustrates another exemplary embodiment according to the invention in a cross sectional view. 
     
    
    
     DETAILED DESCRIPTION 
     The drug delivery device illustrated in  FIG. 1  comprises a main body  14  that extends from a proximal end  16  to a distal end  15 . At the distal end  15 , a removable end cap or cover  18  is provided. This end cap  18  and the distal end  15  of the main body  14  work together to provide a snap fit or form fit connection so that once the cover  18  is slid onto the distal end  15  of the main body  14 , this frictional fit between the cap and the main body outer surface  20  prevents the cover from inadvertently falling off the main body. 
     The main body  14  contains a micro-processor control unit, an electro-mechanical drive train, and at least two medicament reservoirs. When the end cap or cover  18  is removed from the device  10  (as illustrated in  FIG. 1 ), a dispense interface  200  is mounted to the distal end  15  of the main body  14 , and a dose dispenser (e.g., a needle assembly) is attached to the interface. The drug delivery device  10  can be used to administer a computed dose of a second medicament (secondary drug compound) and a variable dose of a first medicament (primary drug compound) through a single needle assembly, such as a double ended needle assembly. 
     The drive train may exert a pressure on the bung of each cartridge, respectively, in order to expel the doses of the first and second medicaments. For example, a piston rod may push the bung of a cartridge forward a pre-determined amount for a single dose of medicament. When the cartridge is empty, the piston rod is retracted completely inside the main body  14 , so that the empty cartridge can be removed and a new cartridge can be inserted. 
     A control panel region  60  is provided near the proximal end of the main body  14 . Preferably, this control panel region  60  comprises a digital display  80  along with a plurality of human interface elements that can be manipulated by a user to set and inject a combined dose. In this arrangement, the control panel region comprises a first dose setting button  62 , a second dose setting button  64  and a third button  66  designated with the symbol “OK.” In addition, along the most proximal end of the main body, an injection button  74  is also provided (not visible in the perspective view of  FIG. 1 ). 
     The cartridge holder  40  can be removably attached to the main body  14  and may contain at least two cartridge retainers  50  and  52 . Each retainer is configured so as to contain one medicament reservoir, such as a glass cartridge. Preferably, each cartridge contains a different medicament. 
     In addition, at the distal end of the cartridge holder  40 , the drug delivery device illustrated in  FIG. 1  includes a dispense interface  200 . As will be described in relation to  FIG. 4 , in one arrangement, this dispense interface  200  includes a main outer body  212  that is removably attached to a distal end  42  of the cartridge housing  40 . As can be seen in  FIG. 1 , a distal end  214  of the dispense interface  200  preferably comprises a needle hub  216 . This needle hub  216  may be configured so as to allow a dose dispenser, such as a conventional pen type injection needle assembly, to be removably mounted to the drug delivery device  10 . 
     Once the device is turned on, the digital display  80  shown in  FIG. 1  illuminates and provides the user certain device information, preferably information relating to the medicaments contained within the cartridge holder  40 . For example, the user is provided with certain information relating to both the primary medicament (Drug A) and the secondary medicament (Drug B). 
     As shown in  FIG. 3 , the first and second cartridge retainers  50 ,  52  may be hinged cartridge retainers. These hinged retainers allow user access to the cartridges.  FIG. 3  illustrates a perspective view of the cartridge holder  40  illustrated in  FIG. 1  with the first hinged cartridge retainer  50  in an open position.  FIG. 3  illustrates how a user might access the first cartridge  90  by opening up the first retainer  50  and thereby having access to the first cartridge  90 . 
     As mentioned above when discussing  FIG. 1 , a dispense interface  200  is coupled to the distal end of the cartridge holder  40 .  FIG. 4  illustrates a flat view of the dispense interface  200  unconnected to the distal end of the cartridge holder  40 . A dose dispenser or needle assembly  400  that may be used with the interface  200  is also illustrated and is provided in a protective outer cap  420 . 
     In  FIG. 5 , the dispense interface  200  illustrated in  FIG. 4  is shown coupled to the cartridge holder  40 . The axial attachment means between the dispense interface  200  and the cartridge holder  40  can be any known axial attachment means to those skilled in the art, including snap locks, snap fits, snap rings, keyed slots, and combinations of such connections. The connection or attachment between the dispense interface and the cartridge holder may also contain additional features (not shown), such as connectors, stops, splines, ribs, grooves, pips, clips and the like design features, that ensure that specific hubs are attachable only to matching drug delivery devices. Such additional features would prevent the insertion of a non-appropriate secondary cartridge to a non-matching injection device. 
       FIG. 5  also illustrates the needle assembly  400  and protective cover  420  coupled to the distal end of the dispense interface  200  that may be screwed onto the needle hub of the interface  200 .  FIG. 6  illustrates a cross sectional view of the double ended needle assembly  402  mounted on the dispense interface  200  in  FIG. 5 . 
     The needle assembly  400  illustrated in  FIG. 6  comprises a double ended needle  406  and a hub  401 . The double ended needle or cannula  406  is fixedly mounted in a needle hub  401 . This needle hub  401  comprises a circular disk shaped element which has along its periphery a circumferential depending sleeve  403 . Along an inner wall of this hub member  401 , a thread  404  is provided. This thread  404  allows the needle hub  401  to be screwed onto the dispense interface  200  which, in one preferred arrangement, is provided with a corresponding outer thread along a distal hub. At a center portion of the hub element  401  there is provided a protrusion  402 . This protrusion  402  projects from the hub in an opposite direction of the sleeve member. A double ended needle  406  is mounted centrally through the protrusion  402  and the needle hub  401 . This double ended needle  406  is mounted such that a first or distal piercing end  405  of the double ended needle forms an injecting part for piercing an injection site (e.g., the skin of a user). 
     Similarly, a second or proximal piercing end  406  of the needle assembly  400  protrudes from an opposite side of the circular disc so that it is concentrically surrounded by the sleeve  403 . In one needle assembly arrangement, the second or proximal piercing end  406  may be shorter than the sleeve  403  so that this sleeve to some extent protects the pointed end of the back sleeve. The needle cover cap  420  illustrated in  FIGS. 4 and 5  provides a form fit around the outer surface  403  of the hub  401 . 
     Referring now to  FIGS. 4 to 11 , one preferred arrangement of this interface  200  will now be discussed. In this one preferred arrangement, this interface  200  comprises: 
     a. a main outer body  210 , 
     b. an first inner body  220 , 
     c. a second inner body  230 , 
     d. a first piercing needle  240 , 
     e. a second piercing needle  250 , 
     f. a valve seal  260 , and 
     g. a septum  270 . 
     The main outer body  210  comprises a main body proximal end  212  and a main body distal end  214 . At the proximal end  212  of the outer body  210 , a connecting member is configured so as to allow the dispense interface  200  to be attached to the distal end of the cartridge holder  40 . Preferably, the connecting member is configured so as to allow the dispense interface  200  to be removably connected the cartridge holder  40 . In one preferred interface arrangement, the proximal end of the interface  200  is configured with an upwardly extending wall  218  having at least one recess. For example, as may be seen from  FIG. 8 , the upwardly extending wall  218  comprises at least a first recess  217  and a second recess  219 . 
     Preferably, the first and the second recesses  217 ,  219  are positioned within this main outer body wall so as to cooperate with an outwardly protruding member located near the distal end of the cartridge housing  40  of the drug delivery device  10 . For example, this outwardly protruding member  48  of the cartridge housing may be seen in  FIGS. 4 and 5 . A second similar protruding member is provided on the opposite side of the cartridge housing. As such, when the interface  200  is axially slid over the distal end of the cartridge housing  40 , the outwardly protruding members will cooperate with the first and second recess  217 ,  219  to form an interference fit, form fit, or snap lock. Alternatively, and as those of skill in the art will recognize, any other similar connection mechanism that allows for the dispense interface and the cartridge housing  40  to be axially coupled could be used as well. 
     The main outer body  210  and the distal end of the cartridge holder  40  act to form an axially engaging snap lock or snap fit arrangement that could be axially slid onto the distal end of the cartridge housing. In one alternative arrangement, the dispense interface  200  may be provided with a coding feature so as to prevent inadvertent dispense interface cross use. That is, the inner body of the hub could be geometrically configured so as to prevent an inadvertent cross use of one or more dispense interfaces. 
     A mounting hub is provided at a distal end of the main outer body  210  of the dispense interface  200 . Such a mounting hub can be configured to be releasably connected to a needle assembly. As just one example, this connecting means  216  may comprise an outer thread that engages an inner thread provided along an inner wall surface of a needle hub of a needle assembly, such as the needle assembly  400  illustrated in  FIG. 6 . Alternative releasable connectors may also be provided such as a snap lock, a snap lock released through threads, a bayonet lock, a form fit, or other similar connection arrangements. 
     The dispense interface  200  further comprises a first inner body  220 . Certain details of this inner body are illustrated in  FIG. 8-11 . Preferably, this first inner body  220  is coupled to an inner surface  215  of the extending wall  218  of the main outer body  210 . More preferably, this first inner body  220  is coupled by way of a rib and groove form fit arrangement to an inner surface of the outer body  210 . For example, as can be seen from  FIG. 9 , the extending wall  218  of the main outer body  210  is provided with a first rib  213   a  and a second rib  213   b . This first rib  213   a  is also illustrated in  FIG. 10 . These ribs  213   a  and  213   b  are positioned along the inner surface  215  of the wall  218  of the outer body  210  and create a form fit or snap lock engagement with cooperating grooves  224   a  and  224   b  of the first inner body  220 . In a preferred arrangement, these cooperating grooves  224   a  and  224   b  are provided along an outer surface  222  of the first inner body  220 . 
     In addition, as can be seen in  FIG. 8-10 , a proximal surface  226  near the proximal end of the first inner body  220  may be configured with at least a first proximally positioned piercing needle  240  comprising a proximal piercing end portion  244 . Similarly, the first inner body  220  is configured with a second proximally positioned piercing needle  250  comprising a proximally piercing end portion  254 . Both the first and second needles  240 ,  250  are rigidly mounted on the proximal surface  226  of the first inner body  220 . 
     Preferably, this dispense interface  200  further comprises a valve arrangement. The valve arrangement is constructed so as to prevent cross contamination of the first and second medicaments contained in the first and second reservoirs, respectively. Additionally, the valve arrangement is also configured so as to prevent back flow and cross contamination of the first and second medicaments. 
     In one preferred system, dispense interface  200  includes a valve arrangement in the form of a valve seal  260 . Such a valve seal  260  may be provided within a cavity  231  defined by the second inner body  230 , so as to form a holding chamber  280 . Preferably, cavity  231  resides along an upper surface of the second inner body  230 . This valve seal comprises an upper surface that defines both a first fluid groove or a first pre-valve ullage  264  and second fluid groove or a second pre-valve ullage  266 . For example,  FIG. 9  illustrates the position of the valve seal  260 , seated between the first inner body  220  and the second inner body  230 . During an injection step, this seal valve  260  helps to prevent the primary medicament in the first pathway from migrating to the secondary medicament in the second pathway, while also preventing the secondary medicament in the second pathway from migrating to the primary medicament in the first pathway. This seal valve  260  comprises a first non-return valve  262  and a second non-return valve  268 . As such, the first non-return valve  262  prevents fluid transferring along the first fluid pathway or first pre-valve ullage  264 , for example a groove in the seal valve  260 , from returning back into this pathway or pre-valve ullage  264 . Similarly, the second non-return valve or second pre-valve ullage  268  prevents fluid transferring along the second fluid pathway or second pre-valve ullage  266  from returning back into this pathway or pre-valve ullage  266 . 
     Together, the first and second grooves or pre-valve ullages  264 ,  266  converge towards the non-return valves  262  and  268  respectively, to then provide for an output fluid path or a post-valve ullage in form of a holding chamber  280 . This holding chamber  280  is defined by an inner chamber defined by a distal end of the second inner body, a first end  281  with both the first and the second non return valves  262 ,  268  and a second end  282  with a pierceable septum  270 . As illustrated, this pierceable septum  270  is positioned between a distal end portion of the second inner body  230  and an inner surface defined by the needle hub of the main outer body  210 . 
     The holding chamber or post-valve ullage  280  terminates at an outlet port of the interface  200 . This outlet port  290  is preferably centrally located in the needle hub of the interface  200  and assists in maintaining the pierceable seal  270  in a stationary position. As such, when a double ended needle assembly is attached to the needle hub of the interface (such as the double ended needle illustrated in  FIG. 6 ), the output fluid path allows both medicaments to be in fluid communication with the attached needle assembly. 
     The hub interface  200  further comprises a second inner body  230 . As can be seen from  FIG. 9 , this second inner body  230  has an upper surface that defines a recess, and the valve seal  260  is positioned within this recess. Therefore, when the interface  200  is assembled as shown in  FIG. 9 , the second inner body  230  will be positioned between a distal end of the outer body  210  and the first inner body  220 . Together, second inner body  230  and the main outer body hold the septum  270  in place. The distal end of the inner body  230  may also form a cavity or holding chamber that can be configured to be fluid communication with both the first groove or first pre-valve ullage  264  and the second groove or second pre-valve ullage  266  of the valve seal. 
     Axially sliding the main outer body  210  over the distal end of the drug delivery device attaches the dispense interface  200  to the multi-use device. In this manner, a fluid communication may be created between the first needle  240  and the second needle  250  with the primary medicament of the first cartridge and the secondary medicament of the second cartridge, respectively. 
       FIG. 11  illustrates the dispense interface  200  after it has been mounted onto the distal end  42  of the cartridge holder  40  of the drug delivery device  10  illustrated in  FIG. 1 . A double ended needle  400  is also mounted to the distal end of this interface. The cartridge holder  40  is illustrated as having a first cartridge containing a first medicament and a second cartridge containing a second medicament. 
     When the interface  200  is first mounted over the distal end of the cartridge holder  40 , the proximal piercing end  244  of the first piercing needle  240  pierces the septum of the first cartridge  90  and thereby resides in fluid communication with the primary medicament  92  of the first cartridge  90 . A distal end of the first piercing needle  240  will also be in fluid communication with a first fluid path groove  264  defined by the valve seal  260 . 
     Similarly, the proximal piercing end  254  of the second piercing needle  250  pierces the septum of the second cartridge  100  and thereby resides in fluid communication with the secondary medicament  102  of the second cartridge  100 . A distal end of this second piercing needle  250  will also be in fluid communication with a second fluid path groove  266  defined by the valve seal  260 . 
       FIG. 11  illustrates a preferred arrangement of such a dispense interface  200  that is coupled to a distal end  15  of the main body  14  of drug delivery device  10 . Preferably, such a dispense interface  200  is removably coupled to the cartridge holder  40  of the drug delivery device  10 . 
     As illustrated in  FIG. 11 , the dispense interface  200  is coupled to the distal end of a cartridge housing  40 . This cartridge holder  40  is illustrated as containing the first cartridge  90  containing the primary medicament  92  and the second cartridge  100  containing the secondary medicament  102 . Once coupled to the cartridge housing  40 , the dispense interface  200  essentially provides a mechanism for providing a fluid communication path from the first and second cartridges  90 ,  100  to the common holding chamber  280 . This holding chamber or post-valve ullage  280  is illustrated as being in fluid communication with a dose dispenser. Here, as illustrated, this dose dispenser comprises the double ended needle assembly  400 . As illustrated, the proximal end of the double ended needle assembly is in fluid communication with the ullage  280 . 
     In one preferred arrangement, the dispense interface is configured so that it attaches to the main body in only one orientation, that is it is fitted only one way round. As such as illustrated in  FIG. 11 , once the dispense interface  200  is attached to the cartridge holder  40 , the primary needle  240  can only be used for fluid communication with the primary medicament  92  of the first cartridge  90  and the interface  200  would be prevented from being reattached to the holder  40  so that the primary needle  240  could now be used for fluid communication with the secondary medicament  102  of the second cartridge  100 . Such a one way around connecting mechanism may help to reduce potential cross contamination between the two medicaments  92  and  102 . 
     In an alternative valve arrangement, the dispense interface may comprise a valve arrangement comprising a sleeve valve arrangement. For example,  FIG. 12  illustrates a cross sectional view of an alternative valve arrangement for use in a dispense interface  200 . In this arrangement, the dispense interface  300  comprises a sleeve valve arrangement  302 . 
     As illustrated, the dispense interface  300  comprises a first medicament pre-valve ullage  304  and a second medicament pre-valve ullage  306 . The first medicament pre-valve ullage  304  would contain ullage of the first medicament residing between the cartridge containing the first medicament and the first medicament valve  308 . Similarly, the second medicament pre-valve ullage  306  would contain ullage of the second medicament residing between the cartridge containing the second medicament and the second medicament valve  310 . 
     As in the valves of  308  and  310 , the flexible portion  311  of the elastic part is not jacked up by the outer housing of the dispense interface  300 . As such, these flexible portions  311  are free to flexibly move and are driven by pressure/backpressure, similar to the valve arrangement illustrated in  FIG. 9 . The flexible portions  311  are connected to the rest of the elastic component and, in this arrangement, do not comprise stand-alone components other solutions in the state of the art.  FIG. 12  shows a blow-up view of the valve  310  where flow direction arrows  311   a  indicate the flow of fluid through valve  310  due to movement of the flexible portion  311  of the valve  310 . 
     The post valve ullage  312  is provided as a holding chamber  314  of the dispense interface  300 . In this arrangement, both the first and the second cartridges contained within the drug delivery device comprise their own one-way valve that connect to a shared post valve ullage. Once a dispenser, such as a double ended needle assembly, is mounted to the distal end of the dispense interface, the shared post valve ullage would be in fluid communication with this dispenser acting as an outlet needle. 
     The post-valve ullage  312  has a first end  316  and a second end  318 . In this embodiment the medicaments enter the post-valve ullage  312  through the second end  318 . The end of a double ended needle  406  can be inserted through the same end  318 . 
     As can be further seen from  FIG. 12 , the ullages are provided by the inner body  320 , while the valves are positioned between the inner body  320  and the outer body  322 . Here, the drug agents  92 ,  102  are guided past the post-valve ullage  312  to be inserted into the post-valve ullage  312  at the second end  318  of the post-valve ullage  312 . A needle  406  as illustrated in  FIG. 13  is usually already inserted in to the post valve ullage  312 . This results in the effect that the drug agents  92 ,  102  flow into the post-valve ullage  312  substantially from the second end  318  towards the first end  316  of the post valve ullage  312  and exit the post-valve ullage  312  through the first end  405  of the needle  406  substantially from the first end  316  of the post valve ullage  312  in the direction of the second end  318  of the post valve ullage  312 . Thus, a flow inversion is achieved in the post-valve ullage  312  and a particularly effective mixing of the drug agents  92 ,  102  can be achieved. 
     Alternatively, the dispense interface may comprise a valve arrangement comprising a beak valve arrangement. For example,  FIG. 13  illustrates a cross sectional view of a beak valve arrangement  502  for use in a dispense interface  500 . As illustrated, the dispense interface  500  comprises a first medicament pre-valve ullage  504  and a second medicament pre-valve ullage  506 . In this arrangement, both the first and the second cartridges contained within the drug delivery device comprise a separate own one-way valve. For example, the first cartridge containing the primary medicament would comprise the first one-way valve  508  and the second cartridge containing the secondary medicament would contain the second one-way valve  510 . In this arrangement, both the first and the second cartridges contained within the drug delivery device comprise their own one-way valve that connect to a shared post valve ullage  512  in form of a holding chamber  514 . Once a doser, such as a double ended needle assembly, is mounted to the distal end of the dispense interface, the shared post valve ullage would be in fluid communication with this dispenser acting as an outlet needle. 
     In this case the drug agents enter the post-valve ullage  512  through the first end  516 . As can be further seen from  FIG. 13 , the first end  407  of the needle  406  is positioned substantially in the middle of the post-valve ullage  512 . Thus, while the drug agents  92 ,  102  enter the post valve ullage  512  at the first end  516  of the post-valve ullage  512  and at least a part of the drug agents  92 ,  102  will reach the second end  518  of the post-valve ullage  512 , the drug agents  92 ,  102  have to exit through the first end  405  of the needle  406  and therefore will have to flow again towards the first end  516  of the post-valve ullage  512  to reach the center of the post-valve ullage  512 . Thus, a flow inversion is achieved in the post-valve ullage  512  and a particularly effective mixing of the drug agents  92 ,  102  can be achieved. 
     In particular the valves  308 ,  310 ,  508 ,  510  illustrated in  FIGS. 12 and 13 , can be made of a material such as TPE, PTFE, silicone or EPDM. 
     The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
     wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, 
     wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, 
     wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, 
     wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exedin-3 or exedin-4 or an analogue or derivative of exedin-3 or exedin-4. 
     Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
     Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyhepta-decanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
     Exendin-4 derivatives are for example selected from the following list of compounds:
     H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or   des Pro36 [Asp28] Exendin-4(1-39),   des Pro36 [IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
 
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
 
or an Exendin-4 derivative of the sequence
   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
 
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exedin-4 derivative.
   

     Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
     A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
     Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. 
     The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
     There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. 
     Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
     In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. 
     Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity. 
     An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystallizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv). 
     Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
     Pharmaceutically acceptable solvates are for example hydrates.