Abstract:
The invention is related to an apparatus comprising: a valve body comprising two inlet openings, one outlet opening and a central space connecting the inlet openings and the outlet opening, and a spherical element movably contained inside the central space configured for translatory movement and configured to seal either the first inlet opening or the second inlet opening, wherein each of the inlet openings are configured for fluid communication with a first reservoir and with a second reservoir and wherein the outlet opening is configured for fluid connection with a septum. This apparatus solves the object to make the exchange of used parts including the valve construction less complex. A further object of the invention is to make the exchange easier to handle. The invention is also related to a medical device comprising a dispense interface and an apparatus of the afore-mentioned type.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    The present application is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/EP2012/058261 filed May 4, 2012, which claims priority to European Patent Application No. 11165122.0 filed May 6, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
     
    
     FIELD OF INVENTION 
       [0002]    The present patent application relates to medical devices of 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 automatically or manually by the user. Especially the present invention relates to a needle hub and a valve construction for such a needle hub. 
       BACKGROUND 
       [0003]    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. 
         [0004]    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. 
         [0005]    For example, in some cases it might 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). 
       SUMMARY 
       [0006]    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. 
         [0007]    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. 
         [0008]    The drug delivery device may have a single dispense interface. This interface may be configured for fluid communication with the 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. 
         [0009]    The combination of compounds as discrete units or as a mixed unit can be delivered to the body via a double-ended needle assembly. This would provide a combination drug injection system that, from a user&#39;s perspective, would be achieved 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: 
         [0010]    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. 
         [0011]    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. 
         [0012]    3. Dial up/set a desired dose of the primary compound from the injection device, for example, via a graphical user interface (GUI). 
         [0013]    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. 
         [0014]    5. Optionally, after the second dose has been computed, the device may be placed in an armed condition. In such an optional armed condition, this may be achieved by pressing and/or holding an “OK” button on a control panel. This condition may provide for greater than a predefined period of time before the device can be used to dispense the combined dose. 
         [0015]    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). 
         [0016]    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. 
         [0017]    During the use of the dispense interface with two different liquid drug components, wherein either the first or the second liquid drug component is applied to the user, it is necessary to minimize or even eliminate any mixing between both liquid drug components. Therefore the needle hub assembly of the dispense interface includes a valve construction, which is positioned between both fluid pathways built inside needle hub construction being positioned in the dispense interface. Since a multiple use of those parts, which are in contact with the liquid drug components, shall be restricted, those parts have be exchanged regularly. 
         [0018]    Thus it is an object of the invention to make the exchange of used parts including the valve construction less complex. A further object of the invention is to make the exchange easier to handle. 
         [0019]    These objects may be solved by an apparatus comprising: a valve body comprising two inlet openings, one outlet opening and a central space connecting the inlet openings and the outlet opening, and a spherical element movably contained inside the central space configured for translatory movement and configured to seal either the first inlet opening or the second inlet opening, wherein each of the inlet openings are configured for fluid communication with a first reservoir and with a second reservoir and wherein the outlet opening is configured for fluid connection with a septum. 
         [0020]    The valve construction as described before is simple and therefore cheap to produce. The only moving part of the valve construction is the spherical element, which can be inserted into the valve body easily. Thus the exchange of the valve body together with the spherical element is facilitated. At the same time, the pathway for the liquid can be made short, since the volume of the valve body can be restricted to size of minimum movement of the spherical element. Therefore the loss of liquid, especially of a liquid drug component can be reduced. 
         [0021]    The valve construction corresponds to a two-way valve. Further the valve construction is controlled by the pressure in the system itself. For example if the first liquid reservoir is set under pressure by activating an injection, the pressure in the liquid pathway into the direction of the first inlet opening of the valve body is raised. This pressure forces the spherical element inside the valve body into the direction of the second inlet opening, until the spherical element is pressed onto the second inlet opening from inside of the valve body. Since the pressure resulting from the first reservoir is strong enough, the second inlet opening is sealed off and hinders the entrance of the second liquid, especially the second liquid drug component into the valve body. 
         [0022]    In other words, the spherical element is configured to be pressed against the first inlet opening, while a pressure of a fluid in the other inlet opening is larger than the pressure of a fluid in the first inlet opening. It is further advantageous that the outer diameter of the spherical element is larger than the inner diameter of the inlet opening. Further it is necessary that the diameter of the spherical element and the distance between both inlet openings is adapted, so that, if the spherical element is pressed onto one of the inlet openings, the outlet opening is in fluidic contact with the other inlet opening. 
         [0023]    In this way, any mixing of the different liquid components within the valve chamber is prevented and both components can be applied to the user separately with only minimal interference with the other component. 
         [0024]    A preferred embodiment is characterized in that the spherical element consists of a core material and a shell like outer material, wherein the core material is harder than the outer material. This shell-like construction of the spherical element is advantageous in that the core material is hard enough to prevent, that the spherical element is drawn into the inlet opening onto which it is pressed. On the other hand the softer outer layer or shell of the spherical element enables that the inlet opening is correctly sealed off, and that any unevenness of the rim of the inlet opening can be compensated. 
         [0025]    The above described object can also be solved by a dispense interface configured for fluid communication with a first reservoir and a second reservoir of liquids, especially liquid drug components, comprising a needle hub, wherein the needle hub comprises a valve body comprising two inlet openings, one outlet opening and a central space connecting the inlet openings and the outlet opening, and a spherical element movably contained inside the central space configured for translatory movement and configured to seal either the first inlet opening or the second inlet opening, wherein each of the inlet openings are configured for fluid communication with a first reservoir and with a second reservoir respectively and wherein the outlet opening is configured for fluid connection with a septum. 
         [0026]    In a further preferred embodiment the inlet openings are connected via inlet pathways with needles which are configured for fluid communication with the corresponding reservoir. The inlet pathways may be built inside the body of the needle hub, wherein the needle hub may be comprised of at least two parts being detachably connected to each other. 
         [0027]    Further the outlet opening can be connected via a holding chamber with a septum, wherein the septum is used to apply a dispense needle for applying the drug component into the skin of a user. 
         [0028]    It is thus preferred that the needle hub includes the structure of the valve body and the fluid pathways from the liquid reservoirs to the valve body and from the valve body to the outlet septum. On one hand the valve body, the inlet pathways and the holding chamber are built inside a needle hub of a dispense interface, wherein different parts of the needle hub are matching to each other thereby leaving the spaces building the valve chamber and the fluid pathways. Thus the fluid pathway structure and the valve body may be constructed by two halves of the needle hub to build the structure when fit together. 
         [0029]    In another embodiment of the dispense interface the valve body, the inlet pathways and the holding chamber are built as separate elements which are configured to be positioned in a needle hub of a dispense interface. Preferably the separate elements of the fluid pathways are built from thin tubes and needles, wherein the valve chamber is also built by a separate element, to which the fluid pathway elements can be connected by sticking, screwing and/or welding. 
         [0030]    Thus the valve and fluid pathway construction described above can be used within a dispense interface of a medical device for applying liquid drug components to a user. It is advantageous that the parts to be changed after the use of the dispense interface during an injection procedure are reduced to a smaller number of parts. Thus waste and costs can be saved. 
         [0031]    Further to the embodiments discussed before, the above objects can be solved by a medical device of delivering at least two drug agents from separate reservoirs comprising: 
         [0032]    a dispense interface configured for fluid communication with a first reservoir and a second reservoir of liquids, especially liquid drug components, and a needle hub being a part of the dispense interface, wherein the needle hub comprises a valve body comprising two inlet openings, one outlet opening and a central space connecting the inlet openings and the outlet opening, and a spherical element movably contained inside the central space configured for translatory movement and configured to seal either the first inlet opening or the second inlet opening, wherein each of the inlet openings are configured for fluid communication with a first reservoir and with a second reservoir respectively and wherein the outlet opening is configured for fluid connection with a septum. 
         [0033]    Thus the advantages of the afore described dispense interface can be achieved with a medical device of delivering at least two drug agents from separate reservoirs. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0034]    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: 
           [0035]      FIG. 1  illustrates a perspective view of the delivery device illustrated in  FIGS. 1   a  and  1   b  with an end cap of the device removed; 
           [0036]      FIG. 2  illustrates a perspective view of the delivery device distal end showing the cartridge; 
           [0037]      FIG. 3  illustrates a perspective view of the cartridge holder illustrated in  FIG. 1  with one cartridge retainer in an open position; 
           [0038]      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 ; 
           [0039]      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 ; 
           [0040]      FIG. 6  illustrates one arrangement of the dose dispenser that may be mounted on a distal end of the delivery device; 
           [0041]      FIG. 7  illustrates a perspective view of the dispense interface illustrated in  FIG. 4 ; 
           [0042]      FIG. 8  illustrates another perspective view of the dispense interface illustrated in  FIG. 4 ; 
           [0043]      FIG. 9  illustrates a cross-sectional view of the dispense interface illustrated in  FIG. 4 ; 
           [0044]      FIG. 10  illustrates an exploded view of the dispense interface illustrated in  FIG. 4 ; 
           [0045]      FIG. 11  illustrates a cross-sectional view of the dispense interface and dose dispenser mounted onto a drug delivery device, such as the device illustrated in  FIG. 1 ; 
           [0046]      FIG. 12  illustrates a cross-sectional view of an embodiment of the valve body as part of a needle hub including a spherical element in a first position; 
           [0047]      FIG. 13  illustrates a cross-sectional view of the embodiment of the valve body shown in  FIG. 12  with a spherical element in a second position; 
           [0048]      FIG. 14  illustrates a cross-sectional view of the embodiment of the spherical element showing two different materials; 
           [0049]      FIG. 15  illustrates a cross-sectional view of an embodiment of the needle hub including the valve body and the spherical element in a first position as shown in  FIG. 12 , mounted in a dispense interface; 
           [0050]      FIG. 16  illustrates a perspective view of an embodiment of the valve body, including a spherical element, and of fluid pathways and the holding chamber built as separate elements; 
           [0051]      FIG. 17  illustrates a cross-sectional view of the embodiment shown in  FIG. 16 ; 
           [0052]      FIG. 18  illustrates a cross-sectional view of an embodiment of the needle hub, wherein the valve construction of  FIGS. 16 and 17  is mounted onto the needle hub; 
           [0053]      FIG. 19  illustrates a perspective view of a half of the needle hub assembly of  FIG. 18  and 
           [0054]      FIG. 20  illustrates a cross-sectional view of the needle hub assembly shown in  FIG. 18  mounted in a dispense interface. 
       
    
    
     DETAILED DESCRIPTION 
       [0055]    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. 
         [0056]    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. 
         [0057]    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 ). 
         [0058]    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. 
         [0059]    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 . 
         [0060]    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). 
         [0061]    As shown in  FIG. 3 , the first and a second cartridge retainers  50 ,  52  comprise 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 . 
         [0062]    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 that may be used with the interface  200  is also illustrated and is provided in a protective outer cap  420 . 
         [0063]    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. 
         [0064]      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 . 
         [0065]    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). 
         [0066]    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 . 
         [0067]    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: 
         [0068]    a. a main outer body  210 , 
         [0069]    b. an first inner body  220 , 
         [0070]    c. a second inner body  230 , 
         [0071]    d. a first piercing needle  240 , 
         [0072]    e. a second piercing needle  250 , 
         [0073]    f. a valve seal  260 , and 
         [0074]    g. a septum  270 . 
         [0075]    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 . 
         [0076]    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. 
         [0077]    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. 
         [0078]    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. 
         [0079]    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 . 
         [0080]    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 . 
         [0081]    Preferably, this dispense interface  200  further comprises a valve arrangement. Such a valve arrangement could be constructed so as to prevent cross contamination of the first and second medicaments contained in the first and second reservoirs, respectively. A preferred valve arrangement may also be configured so as to prevent back flow and cross contamination of the first and second medicaments. 
         [0082]    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  264  and second fluid groove  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. Preferably, 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  264 , for example a groove in the seal valve  260 , from returning back into this pathway  264 . Similarly, the second non-return valve  268  prevents fluid transferring along the second fluid pathway  266  from returning back into this pathway  266 . 
         [0083]    Together, the first and second grooves  264 ,  266  converge towards the non-return valves  262  and  268  respectively, to then provide for an output fluid path or a holding chamber  280 . This holding chamber  280  is defined by an inner chamber defined by a distal end of the second inner body both the first and the second non return valves  262 ,  268  along 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 . 
         [0084]    The holding chamber  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. 
         [0085]    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  264  and the second groove  266  of the valve seal. 
         [0086]    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. 
         [0087]      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. 
         [0088]    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 . 
         [0089]    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 . 
         [0090]      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 . 
         [0091]    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  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 chamber  280 . 
         [0092]    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 . 
         [0093]    In the following, embodiments of the present invention will be described in detail with reference to  FIGS. 12 to 20 . 
         [0094]    In  FIGS. 12 and 13  cross-sectional views of an embodiment of the valve body  300  are shown, comprising two inlet openings  302  and  304 , one outlet opening  306  and a central space  308  connecting the inlet openings  304 ,  306  and the outlet opening  306 . A spherical element or ball  310  is movably contained inside the central space  308  and configured to seal either the first inlet opening  302  or the second inlet opening  304 . In this regard  FIG. 12  shows the ball  310  in the left position in front of the first inlet opening  302 , wherein  FIG. 13  shows the ball  310  in the right position in front of the second inlet opening  304 . 
         [0095]    The inlet openings  302  and  304  are in fluid communication with a first reservoir and with a second reservoir (generally shown for example in  FIG. 11  as reservoirs  90  and  100 ). Further the outlet opening  306  is configured for fluid connection with a septum  270 , which has been also discussed with reference to  FIG. 11 . 
         [0096]    The connection between outlet opening  306  and the central space  308  may be configured in such a way that the ball  310  cannot block it. For example, the connection may have a non-circular dimension, for example a rectangle or an oval form, and/or it may be covered by a sieve. 
         [0097]    The functionality of the valve is as follows. The spherical element or ball  310  is pressed against the first inlet opening  302  so as to provide a seal which does not allow liquid to pass through, while the fluid in the other inlet opening  304  is under a certain pressure, as is shown in  FIG. 12 . This pressure is applied, when the liquid drug component in the second reservoir  100  shall be applied and the corresponding drive mechanism is activated. When a pressure is induced in the first reservoir, the situation is as shown in  FIG. 13 , the ball  310  is pressed against the second inlet opening  304  and gives way for the first liquid drug component to flow from inlet opening  302  through the chamber  308  to the outlet opening  306 . As can be seen from  FIGS. 12 and 13 , the outer diameter of the spherical element  310  is larger than the inner diameter of the inlet openings  302  and  304 . 
         [0098]      FIG. 14  illustrates that the spherical element may consist of a core material  312  and an outer material  314 , wherein the core material  312  is harder than the outer material  314 . The different hardnesses of both materials  312  and  314  is advantageous, since the harder inner core of the ball  310  prohibits that the ball is pressed inside the inlet opening  302  or  304 , and the softer out material ensures that any unevenness of the rim of the inlet openings  302  and  304  is well sealed even if the pressure in the chamber  308  is low. 
         [0099]    As shown in  FIG. 15 , a dispense interface  320  is configured for fluid communication with a first reservoir and a second reservoir of liquids, especially liquid drug components. The dispense interface includes a needle hub  322  which is integrated into the dispense interface  320 . The needle hub  322  includes the valve construction as described with reference to  FIGS. 12 and 13  and is therefore suitable to be applied to a delivery device  100  with cartridge holder  40  as shown for example in  FIGS. 1 to 5 . 
         [0100]    The inlet openings  302  and  304  are connected via inlet pathways  330  and  332  with needles  340  and  342  which are configured for fluid communication with the corresponding reservoir. Further the outlet opening  306  is connected via a holding chamber  350  with a septum  352 . 
         [0101]    As can be seen from  FIG. 15  the valve body  300 , the inlet pathways  330  and  332  and the holding chamber  350  are built inside a needle hub  322  of a dispense interface  320 . Thus there are provided grooves and indentations, so that when all parts of the needle hub  322  are assembled, the corresponding hollow structure is built. 
         [0102]      FIG. 16  illustrates a perspective view of a further embodiment of the valve body  400 , including a spherical element  410 , and of fluid pathways  430  and  432  and the holding chamber  450  built as separate elements. 
         [0103]    As also can be seen from the cross-sectional view of  FIG. 17 , the valve body  400  includes inlet openings  402  and  404  as well as an outlet opening  406  limiting a central space  408 . The inlet pathways  430  and  432  and the holding chamber  450  are built as separate tubes, which can be connected to the valve chamber  400  simply by a frictional fit, by screwing, by gluing or by welding. The tubes  430  and  432  are further integrally connected with needles  440  and  442 . Before attaching all tubes  430 ,  432  and  450  to the valve chamber  400 , the ball  410  is introduced into the valve chamber  400 . 
         [0104]    The functionality of this valve and pathway assembly is the same as described above with reference to  FIGS. 12 and 13 . The spherical element or ball  410  is able to seal both inlet openings  402  and  404  respectively, if the liquid in the corresponding other inlet opening  404  and  402  respectively is set under pressure. 
         [0105]      FIG. 18  illustrates a cross-sectional view of the needle hub  422 . The needle hub  422  is constructed on one hand to fit into the interior of a dispense interface  420 , shown in  FIG. 20 , and on the other hand to carry the valve and fluid pathway construction as shown in  FIGS. 16 and 17 . The needle hub  422  is therefore constructed of two halves  422   a  and  422   b,  which can be detachably connected to each other. 
         [0106]      FIG. 19  illustrates a perspective view of one half  422   a  of the needle hub assembly  422  of  FIG. 18 . Since all parts of the valve and pathway assembly are made as separate parts, they can be easily exchanged. That means, that if the valve and fluid pathway assembly has been used and has to be exchanged, the needle hub  422  is taken apart and the used valve and fluid pathway construction can be exchanged to a new one. Thus the amount of waste for every change of used materials is reduced to a minimum. 
         [0107]      FIG. 20  finally shows a cross-sectional view of the needle hub  422  assembly shown in  FIG. 18  mounted in a dispense interface  420 . The reference numbers used are taken from  FIGS. 16 to 19  as well as from  FIG. 11 , so that the description of these Figures apply here, too. Especially it can be seen from  FIG. 20 , that the valve and fluid pathway construction including the needles  440  and  442  is connected to reservoirs  90  and  100 , which are filled with two different liquid drug components. 
         [0108]    Thus a medical device of delivering at least two drug agents from separate reservoirs comprising dispense interface  420 , needle hub  422 , and the valve and fluid pathway construction according to  FIGS. 16 to 19  is described. 
         [0109]    Finally and as is shown in  FIG. 12 , the angle a between the needle  342  and inlet pathway  332  is larger than 100°, especially about 120°. This angle a deviating from a rectangular angle reduces the friction of the flow of liquid through the needle-pathway assembly and results in a better pressure transportation from the cartridge to the central space  308 . This again improves the functionality of the valve assembly. 
         [0110]    The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
         [0111]    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, 
         [0112]    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, 
         [0113]    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, 
         [0114]    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. 
         [0115]    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. 
         [0116]    Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
         [0117]    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. 
         [0118]    Exendin-4 derivatives are for example selected from the following list of compounds: 
         [0119]    H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
         [0120]    H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
         [0121]    des Pro36 [Asp28] Exendin-4(1-39), 
         [0122]    des Pro36 [IsoAsp28] Exendin-4(1-39), 
         [0123]    des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
         [0124]    des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
         [0125]    des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
         [0126]    des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
         [0127]    des Pro36 [Met(O)14 Trp(02)25, Asp28] Exendin-4(1-39), 
         [0128]    des Pro36 [Met(O)14 Trp(02)25, IsoAsp28] Exendin-4(1-39); or 
         [0129]    des Pro36 [Asp28] Exendin-4(1-39), 
         [0130]    des Pro36 [IsoAsp28] Exendin-4(1-39), 
         [0131]    des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
         [0132]    des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
         [0133]    des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
         [0134]    des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
         [0135]    des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), 
         [0136]    des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
         [0137]    wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; 
         [0138]    or an Exendin-4 derivative of the sequence 
         [0139]    H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0140]    des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2, 
         [0141]    H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
         [0142]    H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
         [0143]    des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0144]    H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0145]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0146]    H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0147]    H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2, 
         [0148]    H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
         [0149]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
         [0150]    des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0151]    H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0152]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0153]    H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0154]    des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2, 
         [0155]    H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
         [0156]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
         [0157]    des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0158]    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0159]    H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0160]    H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
         [0161]    H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2, 
         [0162]    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
         [0163]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
         [0164]    des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
         [0165]    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, 
         [0166]    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2; 
         [0167]    or a pharmaceutically acceptable salt or solvate of any one of the aforementioned Exedin-4 derivative. 
         [0168]    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. 
         [0169]    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. 
         [0170]    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. 
         [0171]    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. 
         [0172]    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. 
         [0173]    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. 
         [0174]    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. 
         [0175]    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. 
         [0176]    An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv). 
         [0177]    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. 
         [0178]    Pharmaceutically acceptable solvates are for example hydrates.