Abstract:
The invention faces the technical problem of reducing the manufacturing costs of medical devices while at the same time a secure, quick and easy reception of a needle by said medical device is guaranteed. The technical problem is solved by a needle guide configured to receive a needle in a first opening in an axial direction of the needle guide, comprising a guide area comprising the first opening and a second opening, a flange area and a connection area, wherein said connection area is configured to non-detachably connect said needle guide to a medical device and wherein said needle guide is made of metal. The technical problem is further solved by a method to produce a needle guide, wherein said needle guide comprises a guide area, a flange area and a connection area, comprising the steps of deep drawing a metal sheet to produce the guide area.

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/EP2012/058269 filed May 4, 2012, which claims priority to European Patent Application No. 11165131.1 filed May 6, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application. 
     
    
     FIELD OF DISCLOSURE 
       [0002]    The present patent application relates to medical devices for delivering a drug from a reservoir. It also relates to a device 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 automatically or manually by the user. 
         [0003]    The drug agents may be contained in one 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 
       [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). 
         [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. 
       SUMMARY 
       [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]    Especially for the production of aforementioned medical devices, for example the delivery device, the dose dispenser and in particular the dispense interface, it is important to provide devices which can be produced economically in mass production. 
         [0018]    The dispense interface for example should not be used on different delivery devices and might need to be exchanged regularly even for a single delivery device in order to meet the hygienic standards. This makes such medical devices a mass product, where a simple and effective production needs to be achieved. 
         [0019]    For hygienic reasons as well, a dose dispenser, such as a double-ended needle assembly, should be exchanged for every ejection process into the desired injection site, yielding in different exchanging frequencies for a dose dispenser and a dispense interface, for example. These different exchanging frequencies and the desire for flexibly attaching different dose dispensers, needles of different sizes for example, generate the need to produce corresponding modules, for example cartridge holder, dispense interface and dose dispenser, as separate attachable modules. 
         [0020]    Especially the production of medical devices which need to receive a needle is comparatively expensive, since openings which are able to receive the needle securely need to be designed yielding in more complex structures for the receiving opening compared to the rest of the device. 
         [0021]    The invention faces the technical problem of reducing the manufacturing costs of medical devices while at the same time a secure, quick and easy reception of a needle by said medical device is guaranteed. 
         [0022]    The technical problem is solved by a needle guide configured to receive a needle in a first opening in an axial direction of the needle guide, comprising a guide area comprising the first opening and a second opening, a flange area and a connection area, wherein said connection area is configured to non-detachably connect said needle guide to a medical device and wherein said needle guide is made of metal. 
         [0023]    By providing a needle guide the production of the needle guide can be separated from the production of the medical device to which the needle guide can be attached. This separation facilitates a very economic production of each element, the medical device and the needle guide. Here, needle is understood to mean any kind of needle or cannula. 
         [0024]    The medical device can preferably be produced as a plastic part, for example by injection moulding. The production of said medical device can now take place without the need of producing the medical device and the needle guide directly as an integral part. By doing so, the production of the medical device is made simpler and more economical, since the comparatively complex geometry of a needle guide is especially disadvantageous for production methods like injection moulding. 
         [0025]    By providing a guide area, the needle guide allows for a secure and easy guiding of the needle. The needle can preferably be inserted into the first opening or receiving opening of the guide area of the needle guide in the axial direction and the needle is then guided at least towards and preferably through the second opening of the guide area of the needle guide. The design of the guide area of the needle guide can precisely dictated the position of the needle, while the needle is being moved through the needle guide. This makes the handling easy and allows for a quick insertion of the needle into the needle guide. A precise positioning of the needle is important, since the dead volume of medical devices is often kept as small as possible resulting in small fluidic channels into which the needle needs to be inserted. The precise positioning can this way prevent the needle from not hitting the channel, which would result in not being able to establish a fluidic connection at all. Moreover the precise positioning can prevent the needle from colliding with the fluidic channels and causing leaks due to damaged channels. 
         [0026]    The flange area is particularly advantageous for the connection of the needle guide to the medical device. By providing a flange area, preferably adjacent to the first opening of the guide area, the connection of the needle guide to the medical device is facilitated, because a force can be applied to the flange area of the needle guide and the needle guide can thus be pressed against the medical device to efficiently produce a connection without affecting the shape of the guide area, for example. It is also possible to non-detachably connect the needle guide to the medical device during the production process of the medical device. For example, during injection moulding the connection area of the medical device can be brought into the injection mould before the injection process. 
         [0027]    The connection between a connection area of the needle guide and the medical device can generally be realised by form-fit, force-fit or by bonding. It is, for example, possible to provide pins, snap locks, threads or any type of glue to connect the needle guide to the medical device. 
         [0028]    The connection area is preferably designed as a separate area and is preferably adjacent to the flange area and preferably provides connection means such as threads, hooks, or pins. But the connection area can also be the flange area itself, which is glued to the medical device, for example. 
         [0029]    Since the needle guide itself does generally not need to be exchanged separately from the medical device it is attached non-detachably to the medical device. Accordingly means for a non-detachable connection are used. 
         [0030]    The needle guide is furthermore made of metal, such as stainless steel, cold rolled steel or aluminium alloys, for example. This is especially advantageous, since needles can be guided effectively by metal surfaces due to the hardness of the material. Since needles are generally made of metal as well and comprising sharp edges, they cannot accidentally get stuck in the surface of a needle guide made of metal as it can happen in plastic needle guides. This further improves the handling of the medical device. 
         [0031]    Moreover a needle guide made of metal can be effectively and economically produced by mass production, for example by forming, moulding or deep drawing. 
         [0032]    It is especially advantageous, that the needle guide is made of metal, if the medical device at least in the area of the connection is made of plastic. This way the needle guide can effectively be fixed permanently. The connection elements can be in the form of a pin or of a barbed hook, which can be easily inserted into the plastic of the medical device by simply pushing it against the medical device. 
         [0033]    The medical device can generally be any device, to which a needle should be attached or into which a needle should be inserted, in particular a dispense interface, a cartridge hub, a needle hub, or any combination of them. 
         [0034]    It is a further advantage of the needle guide that it allows for more room in the medical device. A needle guide made of metal can achieve a better stability and rigidity than plastic with less material. Especially in connection with a dispense interface made from plastic, the use of unnecessary plastic material, which is resulting from production methods like injection moulding, in the area of the needle hub can be reduced by producing a metal needle guide. 
         [0035]    It is especially advantageous, if said guide area is produced by deep drawing a metal sheet. The process of deep drawing is effective to produce small metal parts like the needle guide economically in mass production. Producing the needle guide by deep drawing may also comprise cleaning steps beforehand or further treatments like metal finishing, cutting or forming. 
         [0036]    It is further preferred, if said guide area is substantially cylindrical in the axial direction and tapers at least in parts from the first opening of guide area to the second opening of the guide area. Substantially cylindrical in the axial direction means that the walls of the needle guide area are substantially cylindrical and the axis of the imaginary cylinder coincides with the axis of the axial direction. Due to the tapering the guide area is merely substantially cylindrical. That means that the first opening is larger than the second opening. The first opening of the guide area is preferably proximal to the flange area, while the second opening is distal to the flange area. The tapering allows for a very easy handling during the insertion of a needle into the needle guide area of the needle guide. The needle is forced to be inserted into the medical device at a defined point due to the tapering without needing the user to pay much attention to the process of insertion. 
         [0037]    The guide area preferably tapers conically, producing the shape of a cone with a cut cone end. The user only needs to insert the needle into the broader first opening and the needle is positioned automatically with further progress of the insertion in the smaller second opening. 
         [0038]    It is also advantageous, if the design of the tapering of the guide area is in a parabolic shape. The inner walls are shaped convex, while the curvature towards the second opening gets less. This may result in a smooth insertion of a needle into the guide area of the needle guide. Further, it may help the user, while inserting the needle into the needle guide, to gradually move the needle from a tilted position into a substantially parallel position relative to the axial direction and into a substantially concentric position relative to a fluidic channel, for example. 
         [0039]    According to another embodiment of the needle guide, the flange area is adjacent to the guide area, said flange area is substantially circular and said flange area is extending substantially perpendicular to the axial direction. By designing the flange area in that way, a connection of the needle guide to the medical device is especially simple, which saves production costs. The flange area serves as face via which a force can by applied to the needle guide in the axial direction and the needle guide can thus be pressed against the medical device to efficiently produce a connection without deforming the shape of the needle guide, especially the guide area. 
         [0040]    If said connection area extends substantially into the axial direction, an easy way of providing connection elements, which can engage the medical device in order to provide a connection by form fit, force fit or material bonding, is provided. Especially in connection with a flange area extending substantially perpendicular to the axial direction, connection elements in the connection area can engage the medical device easily. 
         [0041]    According to another embodiment of the needle guide, said connection area comprises a plurality of projections separated by recesses substantially projecting in the axial direction. Such projections can engage the medical device and provide a permanent connection between medical device and needle guide. In particularly if the medical device is made of plastic in the area of the connection, the projections can be easily inserted into the plastic of the medical device. The medical device does not need to be prepared and the projections engaging the plastic connect the medical device with the needle guide. 
         [0042]    The projections can generally be provided by a deep drawing process, but they can also be crimped, for example after a deep drawing process. If the needle guide is produced from a metal sheet the projections can already be cut into the metal sheet before deep drawing the guide area. It is also possible to produce the projections by cutting the recesses into a crimped rim in the connection area, for example by laser cutting. 
         [0043]    It is further preferred if the recesses are tapering in the axial direction. This provides projections which are similar to a barbed hook, so that the projections can be easily inserted into the medical device, but provide a form-fit connection with the medical device in the engaged state. No further means for fixation need to be used, providing a very cost saving way of production. With an equidistant distribution of projections and recesses a uniform permanent connection can be provided. 
         [0044]    According to a further embodiment of the needle guide, said projections are angled compared to the axial direction. This further increases the strength of the connection between needle guide and medical device. This way the angled projections act like dowels. The angle can increase during the engagement of the angled projections with the medical device and prevent the needle guide from being removed form or falling off the medical device. 
         [0045]    It is in particular advantageous, if said projections are angled compared to the axial direction alternating towards the guide area and away from the guide area. This further increases the strength and thus the security of the connection between medical device and needle guide. 
         [0046]    The technical problem is also solved by an apparatus comprising a needle guide according to the invention, wherein said apparatus is a medical device configured to eject at least one medicament, or a dispense interface attachable to a medical device configured to eject at least one medicament. 
         [0047]    The technical problem is further solved by a method to produce a needle guide, wherein said needle guide comprises a guide area, a flange area and a connection area, comprising the steps of deep drawing a metal sheet to produce the guide area. By producing the needle guide by deep drawing a metal sheet, the production of the needle guide is decoupled from the production of medical devices for which the needle guide can be used for. Especially deep drawing provides an economic way for mass production processes and is cost saving compared to producing medical devices integral with the needle guide. By using a metal sheet for deep drawing a needle guide is provided which has an improved rigidity and stability compared to plastic needle guides. 
         [0048]    It is further advantageous, if said guide area, said flange area and said connection area are produced at least in part by said step of deep drawing said metal sheet. By producing the guide area, the flange area and the connection area by a deep drawing step the production of the needle guide is further facilitated due to a minimum of process steps. Though, further processing of the needle guide is possible. These processing steps can include crimping, mechanical cutting, laser cutting, and metal treatments before and/or after the deep drawing. Preferably said flange area and said connection area are produced completely by said step of deep drawing said metal sheet. 
         [0049]    According to another embodiment of the method, said method further comprises the step of pressing said needle guide into a medical device. By pressing the needle guide into the medical device a non-detachable connection between the needle guide and the medical device is established, without the need of glue or threads. The connection is achieved by form-fit and/or force-fit between the connection area of the needle guide and the medical device. It is especially advantageous, if the medical device, at least in the area of connection, is made from plastic. This facilitates the engagement of the connection area into the medical device. Connection elements according to the needle guide according to the invention can be used. 
         [0050]    According to another embodiment of the method, said medical device is a dispense interface, in particular a needle hub. It is particularly advantageous to attach a needle guide according to the invention to a dispense interface. Dispense interfaces are used, for example, to provide a single outlet for a device comprising two fluids, in particular medicaments. A dose dispenser comprises a needle, for example a double ended needle, which can be connected to the dispense interface. The dose dispenser needs to be exchanged regularly by the user, which makes it particularly advantageous to provide a needle guide, which provides an easy and reliable attachment of the dose dispenser to the dispense interface for the user, while at the same a cost saving method for the production of the needle guide and thus of the dispense interface is provided. 
         [0051]    For further designs and advantages of the method according to the invention, it is referred to the description of the needle guide according to the invention. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0052]    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: 
           [0053]      FIG. 1  illustrates a perspective view of the delivery device illustrated in Fig. la and lb with an end cap of the device removed; 
           [0054]      FIG. 2  illustrates a perspective view of the delivery device distal end showing the cartridge; 
           [0055]      FIG. 3  illustrates a perspective view of the cartridge holder illustrated in  FIG. 1  with one cartridge retainer in an open position; 
           [0056]      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 ; 
           [0057]      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 ; 
           [0058]      FIG. 6  illustrates one arrangement of the dose dispenser that may be mounted on a distal end of the delivery device; 
           [0059]      FIG. 7  illustrates a perspective view of the dispense interface illustrated in  FIG. 4 ; 
           [0060]      FIG. 8  illustrates another perspective view of the dispense interface illustrated in  FIG. 4 ; 
           [0061]      FIG. 9  illustrates a cross-sectional view of the dispense interface illustrated in  FIG. 4 ; 
           [0062]      FIG. 10  illustrates an exploded view of the dispense interface illustrated in  FIG. 4 ; 
           [0063]      FIG. 11  illustrates a cross-sectional perspective view of the dispense interface and dose dispenser mounted onto a drug delivery device, such as the device illustrated in  FIG. 1 ; 
           [0064]      FIG. 12  illustrates a cross sectional view of an embodiment of a needle guide according to the invention; 
           [0065]      FIG. 13  illustrates different embodiments of connection areas of an exemplary needle guide; 
           [0066]      FIG. 14  illustrates a cross sectional view of an embodiment of the needle guide attached to an exemplary needle hub of a dispense interface and an exemplary dose dispenser. 
           [0067]      FIG. 15  illustrates a cross sectional view of a further embodiment of a needle guide attached to an exemplary needle hub of a dispense interface. 
       
    
    
     DETAILED DESCRIPTION 
       [0068]    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. 
         [0069]    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. 
         [0070]    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 ). 
         [0071]    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. 
         [0072]    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 . 
         [0073]    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). 
         [0074]    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 . 
         [0075]    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 . 
         [0076]    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. 
         [0077]      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 . 
         [0078]    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). 
         [0079]    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 . 
         [0080]    Referring now to  FIGS. 4 to 11 , one preferred arrangement of this interface  200  will now be discussed. In this one preferred arrangement, this interface  200  comprises:
       a. a main outer body  210 ,   b. an first inner body  220 ,   c. a second inner body  230 ,   d. a first piercing needle  240 ,   e. a second piercing needle  250 ,   f. a valve seal  260 , and   g. a septum  270 .       
 
         [0088]    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 . 
         [0089]    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. 
         [0090]    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. 
         [0091]    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. 
         [0092]    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 . 
         [0093]    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 . 
         [0094]    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. 
         [0095]    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 . 
         [0096]    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 . 
         [0097]    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. It is observable though, that the needle guide  292  takes up a comparably large part of the room of the outlet port  290  and the needle hub  216 . 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. 
         [0098]    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. 
         [0099]    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. 
         [0100]      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. 
         [0101]    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 . 
         [0102]    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 . 
         [0103]      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 . 
         [0104]    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 . 
         [0105]    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 . 
         [0106]      FIG. 12  illustrates a cross sectional perspective view of an embodiment of a needle guide  300  according to the invention. The needle guide  300  comprises a guide area  302 , a flange area  304  and a connection area  306 . As can be seen, the guide area extends in the axial direction, illustrated by the arrow  308 . The guide area further comprises a first opening  310  and a second opening  312 . The first opening  310  can receive a needle  406 . The guide area  302  then guides the needle to the second opening  312  during a movement of the needle  406  in the axial direction  308 . In case the needle  406  is not coaxially inserted into the needle guide  300 , the geometric shape of the guide area  302  guides the needle  406  to the second opening  312 , which has a similar diameter to the diameter of the needle  406 , bringing the axis of the needle  406  substantially in coincidence with the arrow  308 . The parabolic shape of the guide area  302  guides the needle  406  particularly smooth, other shapes, like conical, cylindrical, concave, convex or the like, are possible, too. 
         [0107]    As can be further seen from  FIG. 12 , the flange area  304  extends substantially perpendicular to the axial direction  308 . This way an area for pressing the needle guide  300  into a medical device is provided. 
         [0108]    The connection area  306  further provides a plurality of projections  314  extending in the axial direction  308 . The projections  314  are used as connection elements and can engage a medical device, like a dispense interface  200 , made from plastic, for example. The projections  314  are forced into the medical device when enough pressure is exerted onto the flange area  304 . The single projections  314  are separated by recesses  316 . The recesses reduce the force necessary to press the projections  314  of the needle guide  300  in the medical device. The recesses  316  taper in the axial direction  308  providing the recesses  316  with the shape of a barbed hook or a dowel, which positively affects the durability of the connection between needle guide  300  and medical device. Other shapes of projections  314 , like pins or blades, are possible as well. The needle guide  300  illustrated in  FIG. 12  can be produced especially economically by deep drawing a metal sheet. 
         [0109]      FIG. 13  illustrates different embodiments of connection areas  306  of an exemplary needle guide  300 .  FIG. 13   a  illustrates the enlarged connection area  306  illustrated in  FIG. 12  in a side view. The tapering of the recesses  316  between the projections  314  can be seen clearly. 
         [0110]      FIG. 13   b  illustrates another embodiment of a connection area  306  extending perpendicular from the flange area  304 . Here, the projections  314  have a rectangular shape and the recesses  316  are not tapered. It can be seen that the projections  314  are angled compared to the axial direction  308  alternating towards the guide area  302  and away from the guide area  302 . In  FIG. 13   c  the alternating angled projections  314  can be seen in a cross sectional view of the connection area  306  from  FIG. 13   b . The alternating projections  314  are particularly effective in securing the needle guide  300  from getting removed from the medical device. 
         [0111]      FIG. 14  illustrates a cross sectional view of an embodiment of the needle guide  300  attached to an exemplary needle hub  216  of a dispense interface  200  and an exemplary dose dispenser  400 . The dose dispenser  400  is similar to the one illustrated in  FIG. 6 . The dose dispenser  400  comprises a double ended needle  406 . The double ended needle or cannula  406  is fixedly mounted in the protrusion  402 . The dose dispenser  400  comprises a circular disk shaped element which has along its periphery a circumferential depending sleeve  403 . Along an inner wall of the dose dispenser  400 , a thread  404  is provided. This thread  404  allows the dose dispenser  400  to be screwed onto the needle hub  216  of the dispense interface  200  which, in one preferred arrangement, is provided with a corresponding outer thread along the needle hub  216 . The 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). 
         [0112]    The second end  407  of the needle or cannula  406  is guided by the needle guide  300  into the needle hub  216  of a drug delivery device, for example the dose dispenser  200  illustrated in  FIG. 7  or  8 . Of course, the needle guide  300  can also be used with a drug delivery device or a dispense interface, which is configured to eject a single medicament or liquid. It can be seen that the connection area  306  of the needle guide is non-detachably connected to the needle hub  216 . In case the needle  406  has an offset from the axis coinciding with the axial direction  308 , the needle  406  is guided by the guide area  302  so that the axis of the needle  406  and the axis coinciding with the axial direction  308  coincide. The needle  406  can then accurately pierce one or more septa  270 , which seal a holding chamber  280  in this case. The two septa are fixed by a clip  318 . 
         [0113]    Moreover, it can be seen that compared to the needle guide  292  illustrated in  FIG. 9  the needle guide  300  takes up less space. This allows for further elements to be implemented in the dispense interface  200  or a lighter and smaller design of the dispense interface  200 . 
         [0114]      FIG. 15  illustrates a cross sectional view of a further embodiment of a needle guide  300  attached to an exemplary needle hub  216  of a dispense interface  200 . The embodiment illustrated in  FIG. 15  differs from the embodiment illustrated in  FIG. 14  in that the septum  270  and the need to guide  300  are non-detachably attached to the dispense interface  200  in the area of the holding chamber  280  by the crimping clip  320 . The crimping clip  320  encompasses a part of the dispense interface  200 , the septum  270  and the needle guide  300 . The dispense interface  200  provides in this case adapted recesses with which the crimping clip  320  can engage in order to be fixedly mounted on the dispense interface  200 . The crimping of the crimping clip  320  can in principle not be reversed or only be reversed with great effort and/or with damaging certain components. 
         [0115]    The needle guide  300  illustrated in  FIG. 15  particularly differs from the needle guide  300  illustrated in  FIG. 12  in that the flange area  304  is at the same time the connection area  306 . The flange and connection area  304 ,  306  are located at the opposite end of the guide area  302  at the second opening  312 . Flange and connection area  304 ,  306  are connected to the guide area  302  by a cylindrical skirt  322 . 
         [0116]    After the crimping clip  320  has been crimped, the flange and connection area  304 ,  306  is tightly positioned between crimping clip and septum with a force and/or form fit and is thus non-detachably connected to the dispense interface  200 . 
         [0117]    The needle guide  300  in  FIG. 15  is also made of metal. Production of such a needle guide  300  can be facilitated particularly by producing the needle guide  300  by a deep drawing process. 
         [0118]    The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
         [0119]    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, 
         [0120]    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, 
         [0121]    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, 
         [0122]    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. 
         [0123]    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. 
         [0124]    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. 
         [0125]    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. 
         [0126]    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), 
       [0127]    wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; 
         [0128]    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,   
       [0129]    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(02)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(02)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(02)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;   
       [0130]    or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exedin-4 derivative. 
         [0131]    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. 
         [0132]    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. 
         [0133]    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. 
         [0134]    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. 
         [0135]    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. 
         [0136]    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. 
         [0137]    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. 
         [0138]    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. 
         [0139]    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&#39;)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). 
         [0140]    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. 
         [0141]    Pharmaceutically acceptable solvates are for example hydrates.