Abstract:
The invention provides a medical device having a valve mechanism which has an effective sealing, is simple and cost-saving to produce and at the same time provides an improved pressure control. Additionally, an improved biocompatibility can be provided. The medical device comprises a channel and at least one valve element. The channel comprises at least two openings, and the valve element comprises at least one sealing area. The valve element can be brought in a closed state, such that the sealing area of the valve element seals one of the openings of the channel and the valve element is at least in part flexible, such that the valve element can be brought into an open state by the pressure of a medium inside the channel and the medium can exit the channel between the valve element and the channel.

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/EP2012/061915 filed Jun. 21, 2012, which claims priority to European Patent Application No. 11170898.8 filed Jun. 22, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
     
    
     TECHNICAL FIELD 
       [0002]    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. 
         [0003]    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. 
         [0004]    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 
       [0005]    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. 
         [0006]    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). 
         [0007]    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 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 
       [0008]    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. 
         [0009]    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. 
         [0010]    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: 
         [0011]    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. 
         [0012]    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. 
         [0013]    3. Dial up/set a desired dose of the primary compound from the injection device, for example, via a graphical user interface (GUI). 
         [0014]    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. 
         [0015]    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. 
         [0016]    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). 
         [0017]    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. 
         [0018]    The medicaments in above mentioned devices are generally guided by fluidic channels with diameters similar to or slightly bigger than common injection needles. It is especially challenging to provide an effective seal with such small dimensions, which can be provided at a low cost. 
         [0019]    In the state of the art, valves, such as umbrella valves, are often used. They usually consist of elastic materials like TPE (thermoplastic elastomeres). It is disadvantageous though to use such materials, since they normally contain plasticisers or softening agents, in order to provide an effective seal, which can be opened and closed multiple times with a reasonable force. These chemicals are often not biocompatible and can cause various side effects for the user, because the chemicals can diffuse into the guided fluids. 
         [0020]    Moreover, in case at least two medicaments are delivered by the medical device, these medicaments often need to be delivered successively. This can be necessary to avoid contaminations of one medicament with the other medicament or to reduce or better control the pressure, with which the medicaments are ejected from the medical device into the skin of the user. 
         [0021]    Thus the invention faces the technical problem of providing a valve mechanism for a medical device which valve provides an effective sealing, is simple and cost-saving to produce and at the same time provides an improved pressure control. Additionally an improved biocompatibility should be provided. 
         [0022]    The technical problem is solved by a medical device comprising a channel comprising at least two openings, a valve element comprising at least one sealing area. The valve element is at least in part flexible and is configured to have a closed state, in which the sealing area of the valve element seals one of the openings of the channel, wherein the valve element is further configured to have an open state such that said valve element can be brought into the open state by the pressure of a medium inside the channel, and the medium can exit the channel between the valve element and the channel and wherein said valve element ( 300 ,  300 ′) is at least partially made of metal. 
         [0023]    By providing a valve element, which is at least in part flexible the medium inside the channel can bring the valve element into an open state. For this to happen the force originating from pressure inside the medium needs to be sufficiently high, so that it is higher than the force by the valve element acting against the pressure of the medium inside the channel. With an at least in parts flexible valve element, complicated mechanisms can be avoided and a simple and cost-saving production can be achieved. Moreover such a simple mechanism is less prone to errors. Since the force, with which the sealing area of the valve element seals the opening, can be adjusted by choosing the material or designing the flexibility of the valve element, for example by varying the thickness or varying the shape of the valve element, not only an effective sealing can be provided but also the pressure of the medium exiting the valve element can be controlled. 
         [0024]    The term “open state” is understood to mean that there must not necessarily be a single open state. Since the pressure and thus the force on the valve element can grow continuously there might be multiple open states for the valve element with possibly different cross sections between valve element and channel for the medium to go through. It might as well be possible that an open state or any open state can only be achieved if a certain threshold in the pressure is exceeded. 
         [0025]    The medium exits the channel in between the valve element and the channel. In this way, it is possible to dispense with chemicals like softening agents and make use of different materials. Umbrella valves, for example, need to be very flexible so that the medium can exit through the middle of the umbrella valve, which had to be realized with unwanted chemicals. The use of materials like metal would not be possible in such a case. Additionally a valve element like an umbrella valve needs to be tightly attached to the channel, which again necessitates the use of chemicals like adhesives. Now that the medium exits between the valve element and the channel, other materials, like metal, can be utilized and a higher degree of biocompatibility of the valve element can be achieved. Moreover the valve element does not need to be fixed to the channel with adhesives or the like, since the medium is supposed to exit the channel between channel and valve element and not through the valve element. 
         [0026]    In particular, the channel can be a needle or a cannula. Such a needle can be connected to a drug reservoir on the one side, while the other opening can be sealed by the valve element. 
         [0027]    Multiple of such valve elements can be provided in a medical device. For example, there can be provided a y-channel, which first guides two medicaments separately by the first and second arm of the y-channel and which then guides them through the common third arm of the y-channel to an injection site. A valve element according to the invention can be implemented before or in the two first arms of the y-channel, making it possible to guide the two medicaments through the common third arm successively by increasing the pressure in each channel successively. That means that first the pressure in the first medicament is increased, such that the first valve element is brought into an open state and after the pressure in the first medicament is decreased again and the first valve element is in a closed state, the pressure in the second medicament can be increased, such that the second valve element is brought into an open state. Finally the pressure in the second medicament is decreased again, and the second valve element is brought in a closed state again. As a result, the first medicament is flowing when the second medicament is not and vice versa. Of course, this also works with other mediums and an arbitrary number of channels or valve elements. 
         [0028]    As can be seen, the use of a medical device according to the invention is especially useful, since an effective sealing, a cost-saving production, an improved pressure control and an improved biocompatibility are desirable features for medical devices. 
         [0029]    According to a second embodiment of the invention, the sealing area of the valve element, when in the closed state, seals the opening of the channel by direct contact with the channel. In this way, no further elements like membranes need to be used. This further facilitates the production process and nevertheless provides an effective sealing. Moreover the risk of introducing non-biocompatible substances is reduced by using fewer elements made of different materials. 
         [0030]    In a further embodiment of the invention, the sealing area of the valve element can be bent by the pressure of the medium inside the channel in the axial direction of the channel and away from the channel. In this way, the force acting against the valve element can be efficiently used by pressing or bending away the sealing area of the valve element in the axial direction of the channel. In this way, the opening between the channel and the valve element is maximized with a low force, providing in particular an improved pressure control. 
         [0031]    The valve element is at least partially made of metal, in particular titanium or steel. Moreover, the whole valve element can be made of metal, in particular inert metals like titanium or steel. Especially steels like V2A or V4A are applicable. Since these metals are substantially inert with respect to chemical reactions with mediums used in the medical area, the biocompatibility is significantly improved, especially in comparison with valves made of TPE. Additionally the production can be facilitated by using above mentioned materials. 
         [0032]    It is likewise preferred that the channel is at least in part made of metal, in particular titanium or steel. Moreover the whole channel can be made of metal, in particular inert metals like titanium or steel, for example V2A or V4A steels. Again, the production can be facilitated by using these materials. 
         [0033]    In an example embodiment, the valve element is substantially flat. Substantially flat means that its width and length are significantly larger than its height. In this way, a space saving implementation of a valve can be achieved. Moreover a practicable way of controlling the ejection force or pressure after the valve element is attained by adjusting the height of the valve element and thus controlling its flexibility or deformability. 
         [0034]    According to another embodiment of the invention the valve element, in its closed state, is curved towards the channel. The sealing of the opening is improved by a valve element with this shape, since due to a curved valve element its stability is enhanced. 
         [0035]    In a preferred embodiment, the valve element is pre-stressed, such that the valve element returns into the closed state if the pressure in the medium drops below a threshold. The pre-stressed state can be achieved by forming the valve element, in particular a valve element made of metal, in such a way, that a spring-like force acts in the direction of the opening, as it is done with leaf springs, for example. On the one hand the sealing is made safer in this way, since the valve element presses against the opening, and on the other hand the valve element closes automatically, when the pressure in the medium drops below a threshold. This threshold is defined by the point, where the force due to the pressure of the medium drops below the counteracting force of the pre-stressed valve element. A pre-stress can also account for faster closing times, since the valve element, does not need to be closed manually or by an external impulse. 
         [0036]    In a preferred embodiment, the valve element shows hysteresis during its opening and closing. That means that the relation between force or pressure on the valve element and its displacement is not only dependent on the current force but also on the internal state of the valve element or on the way the valve element came into the current state. By providing a valve element like this, the threshold for opening the valve element can be higher than the threshold for closing the valve element, for example. If there is no hysteresis, these thresholds are substantially the same. 
         [0037]    Since the pressure in the medium may drop as soon as the valve element is brought in an open state, it is especially advantageous to provide a valve element, which shows hysteresis to prevent the valve element  300  from an uncontrolled opening and closing movement. 
         [0038]    Such a hysteresis can be implemented either by the choice of the material of the valve element or by a treatment of the valve element like forming operations providing a pre-stress, for example. 
         [0039]    In an example embodiment, the valve element has a meta-stable open state. A meta-stable state is understood as a state of the valve element, into which the valve element can be brought and where only a small force is needed to bring the valve element out of said state. Such a meta-stable state could be provided by a metal plate, which can flip back and forth between a convex and a concave state, for example. Depending on the pre-stress, the valve element either remains in said meta-stable open state, even if the pressure of the medium inside the channel drops again, for example to ambient pressure, or the valve element is automatically brought out of the meta-stable state into the closed state again. In either way the meta-stable state provides a better controlled open state, which is less dependent on the pressure of the medium. 
         [0040]    If the valve element is configured such that it remains in the open state, even if the pressure in said medium drops, pressure variations do not change the degree to which the valve is opened. This can be achieved, if the pre-stress is low enough, for example. With a significant hysteresis the force or pressure necessary to open the valve element can be designed higher than the force or pressure necessary to keep the valve element open. In case a meta-stable open state is provided, the valve element can also be brought back into the closed state by an external mechanical impulse, for example. 
         [0041]    In a further embodiment the valve element is configured such that it switches back from said open state into said closed state if the pressure in said medium drops below a second threshold. This can be achieved by choosing a pre-stress, which is high enough, to bring the valve element out of the open state, for example. This results in very fast closing and response times, since the valve is closed as soon as the pressure of the medium in the channel drops below a certain threshold. 
         [0042]    It is also possible to provide a valve element with a hysteresis, in order to provide a first threshold for opening the valve element and a second threshold for closing the valve element. The second threshold can especially be lower than the first threshold. It is also possible to design the open state as a meta-stable state. 
         [0043]    It is preferred when the valve element has a convex shape in its closed position and a concave shape in its open position. In this way, it is possible to easily produce a valve element, which provides the necessary amount of flexibility. The embodiment is especially suitable to produce a meta-stable state, which would be the concave shape in this case. 
         [0044]    It is further preferred when the medium is a gas or a fluid, in particular a medicament. In particular gases and fluids transmit the pressure efficiently, yielding a uniform pressure in the channel. In this way, pressure can be applied to the gas or fluid in a distance place, for example in a reservoir, while at the same time the pressure rises at the valve. 
         [0045]    According to a last embodiment the medical device is a drug delivery device, a dispense interface for a drug delivery device or a needle hub. The use of a medical device according to the invention is especially useful for medical devices like these, since an effective sealing, a cost-saving production, an improved pressure control and an improved biocompatibility are desirable features for drug delivery devices and the like. 
         [0046]    These as well as other advantages of various aspects of the present invention will become apparent to those of ordinary skill in the art by reading the following detailed description, with appropriate reference to the accompanying drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0047]      FIG. 1  illustrates a perspective view of a delivery device with an end cap of the device removed; 
           [0048]      FIG. 2  illustrates a perspective view of the delivery device distal end showing the cartridge; 
           [0049]      FIG. 3  illustrates a perspective view of the delivery device illustrated in  FIG. 1  or  2  with one cartridge retainer in an open position; 
           [0050]      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 ; 
           [0051]      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 ; 
           [0052]      FIG. 6  illustrates one arrangement of a needle assembly that may be mounted on a distal end of the delivery device; 
           [0053]      FIG. 7  illustrates a perspective view of the dispense interface illustrated in  FIG. 4 ; 
           [0054]      FIG. 8  illustrates another perspective view of the dispense interface illustrated in  FIG. 4 ; 
           [0055]      FIG. 9  illustrates a cross-sectional view of the dispense interface illustrated in  FIG. 4 ; 
           [0056]      FIG. 10  illustrates an exploded view of the dispense interface illustrated in  FIG. 4 ; 
           [0057]      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 ; 
           [0058]      FIG. 12   a  illustrates an exemplary embodiment of a valve element and a channel according to the invention with the valve element in a closed state in a perspective view; 
           [0059]      FIG. 12   b  illustrates the exemplary embodiment from  FIG. 12   a  in a side view; 
           [0060]      FIG. 13   a  illustrate an exemplary embodiment of a valve element and a channel according to the invention with the valve element in a closed state in a cross sectional view; 
           [0061]      FIG. 13   b  illustrate the exemplary embodiment from  FIG. 13   a  with the valve element in an open state in a cross sectional view; 
           [0062]      FIG. 14   a  illustrates another exemplary embodiment of a valve element and a channel according to the invention with the valve element in a closed state in a perspective view; 
           [0063]      FIG. 14   b  illustrates the exemplary embodiment from  FIG. 14   a  in a side view; 
           [0064]      FIG. 15  illustrates an exemplary embodiment of a valve element, a channel and a part of a medical device according to the invention in a cross sectional view. 
       
    
    
     DETAILED DESCRIPTION 
       [0065]    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. 
         [0066]    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. 
         [0067]    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. 
         [0068]    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 ). 
         [0069]    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. 
         [0070]    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 . 
         [0071]    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). 
         [0072]    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 . 
         [0073]    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 . 
         [0074]    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. 
         [0075]      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 . 
         [0076]    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). 
         [0077]    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 . 
         [0078]    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: 
         [0079]    a. a main outer body  210 , 
         [0080]    b. an first inner body  220 , 
         [0081]    c. a second inner body  230 , 
         [0082]    d. a first piercing needle  240 , 
         [0083]    e. a second piercing needle  250 , 
         [0084]    f. a valve seal  260 , and 
         [0085]    g. a septum  270 . 
         [0086]    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 . 
         [0087]    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. 
         [0088]    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. 
         [0089]    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. 
         [0090]    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 . 
         [0091]    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 . 
         [0092]    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. 
         [0093]    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 . 
         [0094]    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 . 
         [0095]    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. 
         [0096]    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. 
         [0097]    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. 
         [0098]      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. 
         [0099]    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 . 
         [0100]    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 . 
         [0101]      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 . 
         [0102]    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 . 
         [0103]    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 . 
         [0104]      FIG. 12   a  illustrates an exemplary embodiment of a valve element  300  and a channel  302  according to the invention with the valve element  300  in a closed state in a perspective view. The valve element  300  substantially comprises a rectangular metal sheet, which is raised by a convex curvature in its center. The valve element  300  is preferably fixed at one or more of the edges of the rectangle. The valve element  300  can of course be of any other geometric form or material. The valve element further comprises a sealing area  308 , which is in contact with a channel  302 . The channel  302  has two openings  304  and  306 . The opening  304  is sealed by the sealing area  308  of valve element  300 . 
         [0105]    In this case the channel  302  is a needle, which is preferably made of metal. In particular, the channel may comprise the needle  240  and/or  250  illustrated in  FIG. 9 . 
         [0106]      FIG. 12   b  illustrates the exemplary embodiment from  FIG. 12   a  in a side view. It can be seen that the sealing area  308  of the valve element  300  seals the opening  304  of the channel  302 . It is important to notice that the valve element  300  and the channel  302  and not connected with each other, but only in contact with each other. 
         [0107]      FIG. 13   a  illustrates an exemplary embodiment of a valve element  300  and a channel  302  according to the invention with the valve element  300  in a closed state in a cross sectional view. The illustrated embodiment is similar to the one illustrated in  FIG. 12 . The channel  302  guides a medium  310 , in particular a fluid, especially a medicament or a drug, though other mediums are possible as well. The medium  310  cannot exit the channel  302  through the opening  304  since it is sealed by the sealing area  308  of the valve element  300 . The fluid can have a pressure, which is too low to deform the flexible valve element  300 , for example a substantially ambient pressure. 
         [0108]      FIG. 13   b  illustrates the exemplary embodiment from  FIG. 13   a  with the valve element  300  in an open state in a cross sectional view. When the pressure of the medium  310  in the channel  302  is increased, the medium can deform the valve element from a convex curvature into a concave curvature. This may be a meta-stable state. The concave curvature of the valve element  300  produces a circumferential opening or slit  312  between the sealing area  308  and the channel  302 , thorough which the medium  310  can exit the channel  302 , as shown by the arrows in  FIG. 13   b.    
         [0109]    If the pressure of the medium  310  in the channel  302  is decreased again, the force against the valve element  300 , in particular against the sealing area  308  is reduced, the valve element  300  may either remain in the open state or not, depending on whether the valve element  300  is pre-stressed such that this tension can bring the valve element  300  from the open state back into the closed, convex state. In case the valve element  300  remains in the open state, it may be closed again when a pressure outside the channel  302  increases that would press the fluid back into the channel  302 . 
         [0110]      FIG. 14   a  and  FIG. 14   b  illustrate another exemplary embodiment of a valve element  300 ′ and a channel  302  according to the invention with the valve element  300 ′ in a closed state in a perspective view and in a side view, respectively. In contrast to the embodiment illustrated in  FIG. 12  the valve element  300 ′ shown in  FIG. 14   a  is designed as a spring element. The sealing area  308 ′ is raised compared to the edge areas  314  and  316  of the valve element  300 ′. The edge areas  314 ,  316  are preferentially fixed. In this case due to the stable geometric form of the valve element  300 ′, it is not possible to bring the valve element  300 ′ in a meta-stable state, which is comparable to the state with the concave shape of the valve element  300 . Thus there is a constant force acting against the pressure of the medium  312 , even if the valve element  300 ′ is an open state. Thus a faster closing is possible while the pressure of the medium  312  decreases. The material of the valve element  300 ′ may be flexible, so that a pressure of a fluid in the channel  302  may slightly bend the sealing area  308 ′ downward. Thus, the fluid can be pressed out of the channel  302  through a slit or opening between the channel  302  and the sealing area  308 ′. When the pressure of the fluid in the channel  302  is reduced, the slit or opening will gradually become smaller and eventually close again, for example when the pressure of the fluid inside the channel  302  is substantially the same as the pressure outside the channel  302 . The degree of flexibility of the valve element  300 ′ may be determined by the material of the valve element  300 ′ as well as the geometric properties, for example the thickness of the valve element  300 ′, the height and angle of the flanges, the size of the sealing area  308 ′, and/or the like. 
         [0111]      FIG. 15  illustrates an exemplary embodiment of a valve element  300 , a channel  302  and a part  318  of a medical device according to the invention in a cross sectional view. The valve element  300  and the channel  302  are similar to the ones illustrated in  FIG. 12 . A medium  312  might be guided from a reservoir, for example, through the channel  302  in the direction of the arrows. In the closed state of the valve element  300  the medium  312  is stopped at the sealing area  308  of the valve element  300 . If the pressure is big enough the valve element  300  can switch to the open state, which state is illustrated by  FIG. 15   b . Now the medium  312  can pass the valve element  300  through a slit or opening between the channel  302  and the valve element  300  and enter the channel  320 . This channel can lead to another needle or a cannula in order to guide the fluid to an injection site, for example. The part  318  can specially be an arm of a y-channel, which is implemented in a medical device, as shown in  FIGS. 9 and 11 . The succeeding channel  320  can in particular be the fluid groove  264  or  266  and the medical device especially a dispense interface  200  or a drug delivery device  10 . 
         [0112]    The valves  262  and  268  as shown in  FIGS. 9 and 10  would be dispensable if a valve element according to the invention is used. It is also possible to implement valve elements  300 ,  300 ′ in the location of the valves  262  and  268 . 
         [0113]    The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
         [0114]    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, 
         [0115]    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, 
         [0116]    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, 
         [0117]    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. 
         [0118]    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. 
         [0119]    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. 
         [0120]    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. 
         [0121]    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), 
       [0122]    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, 
       [0123]    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; 
       [0124]    or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exedin-4 derivative. 
         [0125]    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. 
         [0126]    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. 
         [0127]    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. 
         [0128]    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. 
         [0129]    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. 
         [0130]    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. 
         [0131]    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. 
         [0132]    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. 
         [0133]    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). 
         [0134]    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. 
         [0135]    Pharmaceutically acceptable solvates are for example hydrates.