Abstract:
The present invention is directed to an automatic reconstitution drug delivery device. The inventive device effects simple and automatic reconstitution of a dry drug. To effect reconstitution, a user displaces a release button which causes first and second chambers of a drug cartridge to communicate, resulting in automatic mixing of a diluent and dry drug to effect reconstitution of the dry drug. The user then simply sets the dose volume using a dose-setting mechanism, and administers the injection in a manner typical of self-injection drug delivery devices. Whole or partial automatic priming can be also achieved by the device.

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of U.S. application Ser. No. 11/791,600, filed May 24, 2007, now allowed, which is a National Stage Application under §371 of PCT Appl. No. PCT/US2005/042426, filed Nov. 22, 2005, which claims priority to U.S. Provisional Appl. No. 60/630,947, filed Nov. 24, 2004, the entireties of which are incorporated by reference herein. 
     
    
     FIELD OF THE INVENTION 
       [0002]    This invention relates to self-injection drug delivery devices that automatically reconstitute a dry drug into liquid form. 
       BACKGROUND OF THE INVENTION 
       [0003]    Medication delivery pens have been developed to facilitate the administration of medication, particularly the self-administration of medication. Such medication delivery pens may be referred to herein as an injector device, a self-injection drug delivery device, a pen style drug delivery device, a pen, and other variations thereof. Such pens may be disposable, containing a single dose of a drug, or reusable, containing a single dose or more of a drug. The pen typically includes a vial or drug cartridge containing a drug and a dose setting mechanism which allows both for selecting a dose of medication to be delivered by the pen and for urging a plunger of the vial in a distal direction for a distance corresponding to the selected dose, thereby allowing the dose to be administered. 
         [0004]    Certain drugs or medicaments (those terms being used interchangeably herein) are preferably provided in powder or dry form (sometimes referred to a lyophilized form), and require reconstitution prior to administration. Lyophilized drugs, for example, typically are supplied in a freeze-dried form that needs to be mixed with a diluent to reconstitute the substance into a form that is suitable for injection. Medicaments may also be provided in other powder form that require reconstitution. 
         [0005]    Prior art devices have been developed that provide the diluent and lyophilized substance in separate chambers of a common container. Such devices permit manual reconstitution of the drug prior to administration. U.S. Pat. No. 4,874,381 to Vetter and U.S. Pat. No. 4,968,299 to Ahlstrand et al. are examples of manually activated devices which require a user to physically move one or more components to perform a reconstitution process. U.S. Pat. No. 6,793,646 to Giambattista et al. shows a device which allows for automated reconstitution. Specifically, to activate the device and effect reconstitution of the dry drug, the user manually causes certain components to move relative to one another axially to obtain reconstitution of a medication. The device of U.S. Pat. No. 6,793,646, however, is a single dose device which is disposable, not reusable. In addition, the device has limited variation in deliverable dosage amounts, based on a fixed arrangement of parts. 
         [0006]    Certain drugs, once reconstituted, may have a shelf-life of several days or months. For example, human growth hormone (HGH) may have a shelf-life of up to thirty (30) days once reconstituted. For such drugs, it may be desirable to have a device which enables the user to administer repeated dosing of varying volumes of reconstituted drugs or medicaments, thus allowing for multiple doses to be administered over time. 
       SUMMARY OF THE INVENTION 
       [0007]    The present invention is directed to an automatic reconstitution drug delivery device. The inventive device effects simple and automatic reconstitution of a dry drug. To effect reconstitution, a user displaces a release button which causes first and second chambers of a drug cartridge to communicate, resulting in automatic mixing of a diluent and dry drug to effect reconstitution of the dry drug. The user then simply sets the dose volume using a dose-setting mechanism, and administers the injection in a manner typical of self-injection drug delivery devices. Whole or partial automatic priming can be also achieved by the device. 
         [0008]    In a further aspect of the subject invention, an injector device for automatic reconstitution of a substance is provided herein having a dose-setting mechanism with a cartridge engagement surface extending therefrom. The dose-setting mechanism is adjustable to set a dose for the injector device. The injector device further includes a housing cooperatively engaging the dose-setting mechanism, and a biasing means for selectively moving the dose-setting mechanism from a first position to a second position relative to the housing. The cartridge engagement surface moves a predetermined distance relative to the housing with the dose-setting mechanism moving from the first position to the second position. Advantageously, the subject invention allows for the dose-setting mechanism to be moved relative to the housing to cause automatic reconstitution of a drug substance. The force of movement of the cartridge engagement surface is translated to a multi-chambered drug cartridge which, in turn, may utilize the force of movement to cause reconstitution of the contents of the drug cartridge using any known technique. 
         [0009]    Various dose-setting mechanisms can be used with the subject invention. In addition, various features can be optionally used with the injector device, such as, a releasable attachment for the drug cartridge, and a releasable retainer for maintaining the dose-setting mechanism in the first position against the biasing means. 
         [0010]    The injector device may also be included as part of a kit which further includes a mandrel for setting the dose-setting mechanism to the first position from the second position. 
         [0011]    These and other features of the invention will be better understood through a study of the following detailed description and accompanying drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIG. 1  is a perspective view of an automatic reconstitution injector device formed in accordance with the subject invention; 
           [0013]      FIG. 2  is an exploded view of a portion of the injector device of the subject invention; 
           [0014]      FIG. 3  is an exploded view of a dose-setting mechanism usable with the subject invention, along with a body adapter, release ring, plunger, and locking ring; 
           [0015]      FIG. 3   a  is an enlarged view showing a resilient tube usable in the dose-setting mechanism; 
           [0016]      FIG. 4   a  is a side elevational view of a body adapter; 
           [0017]      FIG. 4   b  is an end view of the body adapter as viewed along line  4   b - 4   b  of  FIG. 4   a;    
           [0018]      FIG. 5  is a cross-sectional view of a spring seat taken along line  5 - 5  of  FIG. 2 ; 
           [0019]      FIG. 6  is a cross-sectional view of a rear housing taken along line  6 - 6  of  FIG. 2 ; 
           [0020]      FIGS. 7   a  and  b  are respectively top and side views of a release ring; 
           [0021]      FIG. 8  is a bottom plan view of a release button; 
           [0022]      FIG. 9  is a schematic view showing interengagement of the release button and the release ring; 
           [0023]      FIG. 10  is a cross-sectional view of the injector device prior to activation with the dose-setting mechanism being in a first position; 
           [0024]      FIG. 11  is a cross-sectional view of the injector device after activation with the dose-setting mechanism being in a second position; 
           [0025]      FIG. 12  is a partial cross-sectional view showing a cartridge release button in a release position; 
           [0026]      FIGS. 13   a - g  are various views of a mandrel useable with the injector device of the subject invention to cause re-setting thereof; and, 
           [0027]      FIGS. 14-16  depict various stages of a re-setting process of the subject invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0028]    With reference to  FIG. 1 , an automatic reconstitution injector device  10  in accordance with an embodiment of the present invention is there depicted. The inventive injector device  10  may be used to administer one or more injections of a drug or a medicament. The injector device  10  generally includes a dose-setting mechanism  12 , a housing  14 , and a drug cartridge assembly  16 . 
         [0029]    As used herein, the term “proximal”, and derivatives thereof, refer to a direction towards the rear of the injector body and away from a patient, while the term “distal”, and derivatives thereof, refer to a direction towards the front of the injector device and closer to a patient. 
         [0030]    The drug cartridge assembly  16  includes a drug cartridge or vial  216  that may be formed of any known material, such as glass or plastic. By way of non-limiting example, and with reference to  FIGS. 10 and 11 , the drug cartridge  216  includes a distal end  18  with an opening  20  formed therein sealed by a pierceable septum  22 . As is known in the art, the septum  22  is pierceable by a needle cannula  23  and re-sealable upon removal of the needle cannula  23 . Typically, the needle cannula  23  will be double-ended with both ends being sharpened, a proximal end  25  for piercing the septum  22  and a distal end  27  for insertion into a patient. The drug cartridge  216  further includes a proximal end  24  which is open and sealable by a first stopper  26  that is movably disposed in the drug cartridge  216  to slide along the length thereof and maintain a seal with the wall of the drug cartridge  216 . The first stopper  26  is engageable by the dose-setting mechanism  12 , directly or indirectly, to force movement thereof. 
         [0031]    The drug cartridge  216  may be a multi-chambered cartridge including at least first and second chambers for containing a first and second liquid or dry substance. For example, a reconstitutable substance, e.g. a lyophilized substance, may be disposed in one chamber with a diluent suitable for reconstituting the reconstitutable substance being disposed in a separate, second chamber. Reconstitution is achieved with communication being allowed between the two chambers. Various configurations are known in the art to selectively permit communication. By way of non-limiting example, and again with reference to  FIG. 10 , a second stopper  28  may be disposed in the drug cartridge  216  spaced from the first stopper  26  in an initial state. Accordingly, a first chamber  30  is defined between the first and second stoppers  26 ,  28 , and a second chamber  32  is defined between the second stopper  28  and the septum  22  at the distal end  18  of the drug cartridge  216 . A dry, reconstitutable substance  34  may be disposed in the second chamber  32 , while a diluent  36  suitable for reconstituting the reconstitutable substance  34  may be disposed in the first chamber  30 . In the initial state, the second stopper  28  prevents communication between the first and second chambers  30 ,  32  during transportation and up to reconstitution, which, preferably occurs just before administration. With the exemplary configuration, to achieve reconstitution, the first stopper  26  is caused to be driven distally with the second stopper  28  moving in response to the force of movement of the first stopper  26 . The force of movement may be translated to the second stopper  28  via the diluent  36  with the diluent  36  being generally incompressible. One or more communication channels  38  may be formed in the wall of the drug cartridge  216  adapted to by-pass the second stopper  28  over a range of movement of the second stopper  28 . With the second stopper  28  moving a sufficient distance, the communication channel  38  establishes communication between the first and second chambers  30 ,  32 . The communication channel  38  has sufficient length to permit communication between the first and second chambers  30 ,  32  about the second stopper  28 . With the first and second chambers  30 ,  32  being in open communication, the diluent  36  is urged into the second chamber  32  with further distal movement of the first stopper  26 . With continued movement, the first stopper  26  collapses the first chamber  30  and comes into contact with the second stopper  28  ( FIG. 11 ). The reconstitution process is terminated with further movement of the second stopper  28 , under force of movement of the first stopper  26 , to a position where the second chamber  32 , and reconstituted substance  37 , is sealed from the communication channel  38 . With the needle cannula  23  extending through the septum  22  into communication with the second chamber  32 , additional movement of the first stopper  26  can urge the reconstituted substance  37  from the second chamber  32  and into the needle cannula  23  for administration. 
         [0032]    As will be recognized by those skilled in the art, various drug cartridges and container designs exist which allow for selective communication between initially-separate chambers in permitting reconstitution of a drug or medicament. Alternative communication passages and arrangements can be utilized with the subject invention including specially designed stoppers or valve mechanisms, such as those shown in U.S. Pat. Nos. 5,713,857 and 4,929,230, the disclosures of which are both incorporated by reference herein. In addition, more than two chambers may be used as shown in U.S. Pat. No. 5,865,798 depending on the particular substance to be reconstituted. As will be further appreciated by those skilled in the art, any reconstitutable substance may be used with subject invention, such as a drug or medicament in powdered form which is not lyophilized. 
         [0033]    The needle cannula  23  is preferably fixed relative to the housing  14 . In particular, the needle cannula  23  is fixed to the housing  14  so that there is no relative movement therebetween during the reconstitution process or otherwise. The needle cannula  23  may be fixed using any known manner, such as being threadedly mounted or being rigidly staked to the drug cartridge assembly  16 . Alternatively, or in addition to, the needle cannula  23  may be directly fixed to the housing  14 . It may be desired to have the needle cannula  23  be removably fixed to allow for replacement and multiple uses with the same drug cartridge  216 , or permanently fixed, such as where the injector device  10  is intended as a single-use device. 
         [0034]    With reference to  FIG. 2 , the housing  14  may include a front housing  40  and a rear housing  42  which are joinable using any known technique, including, but not limited to, an interference fit, bonding, and/or mechanical interaction of locking members. The front housing  40  defines an open distal end  44  of the injector device  10 , while the rear housing  42  defines an open proximal end  46  of the injector device  10 . The housing  14  is formed to accommodate the dose-setting mechanism  12  with a portion of the dose-setting mechanism  12  being accessible through the proximal end  46 . 
         [0035]    The dose-setting mechanism  12  may be of any known pen-type dose mechanism which is adjustable and preferably allows for repeated and consecutive setting of variable-volume doses and administration thereof. Preferably, the dose-setting mechanism  12  includes a cartridge engagement surface  57  extending therefrom ( FIG. 3 ). Preferably, the cartridge engagement surface  57  is defined on the distalmost portion of the dose-setting mechanism  12 , such as the distalmost portion of a leadscrew  56  extending from the dose-setting mechanism  12 . Leadscrew-type dose-setting mechanisms provide for highly accurate and repeatable dose setting and dose administration of varying volumes. 
         [0036]    It is preferred that the dose-setting mechanism  12  be a self-contained unit within the housing  14 . In this manner, an “off-the-shelf” dose-setting mechanism can be utilized. With reference to  FIG. 3 , an exemplary configuration of a dose-setting mechanism  12  is shown. This dose-setting mechanism is generally the same as that disclosed in U.S. Pat. No. 6,248,095, the disclosure of which is incorporated by reference herein. In addition to the leadscrew  56 , the dose-setting mechanism  12  may include a spinner  58 , a retract nut  60 , a body  62 , a lens  64 , a reset ring  66 , a dose set knob  68 , a driver  70 , and a thumb button  78 . The specific configuration and interaction of these elements is discussed in U.S. Pat. No. 6,248,095. 
         [0037]    The dose-setting mechanism  12  may additionally include a spring retainer  72 , a spring  74 , and a spring cap  76 . The spring  74  may act as a spacer to ensure that the cartridge engagement surface  57  is located to have sufficient distal movement to cause reconstitution and, optionally initial priming, as described below. In other words, the spring  74  locates the initial start position of the cartridge engagement surface  57  (e.g., by locating the initial start position of the leadscrew  56 ) and prevents excessive movement proximally of the cartridge engagement surface  57 . In addition, the spring  74  acts as a damper upon re-setting of the dose-setting mechanism  12  where the leadscrew  56  is forced proximally to the start position. The spring  74  cushions the return force. The spring retainer  72  and the spring cap  76  act to hold the spring  74  in place by providing end point contacts. As an alternative, the spring  74  can be replaced with a resilient tube  73 , such as a silicone tube, as shown in  FIG. 3   a . Proximal end  75  of the leadscrew  56  can be provided with a protruding finger  77  for holding one end of the resilient tube  73 , while a separate holder  79  can be provided for holding the other end of the resilient tube  73 . The spring cap  76  can be provided as support for the holder  79 . The resilient tube  73  provides the same functions as the spring  74  in cushioning the re-set force and acting as a dimensional spacer. 
         [0038]    As will be appreciated by those skilled in the art, other dose-setting mechanisms can be utilized with the subject invention, including various combinations of features of dose-setting mechanisms. For example, U.S. Patent Application Publication No. 2004/0199117 A1, which published on Oct. 7, 2004, shows a “dial-back” feature which allows the user to freely correct a dose without having to reset the dose-setting mechanism. In addition, U.S. Patent Application Publication No. 2004/0127858 A1, which published on Jul. 1, 2004, shows a device having a limiter which prevents setting a dose that is greater than the available medication. The disclosures of these two publications are incorporated by reference herein in their respective entireties. 
         [0039]    The dose-setting mechanism  12  is preferably formed to be re-usable (i.e., formed to be used consecutively with multiple drug cartridges or drug cartridge assemblies). It is, thus, preferred that the cartridge engagement surface  57  be re-settable to a start position after the dose-setting mechanism  12  has been used. It should be noted that all or a portion of the cartridge engagement surface  57  may be defined on a distal face of the spinner  58 . 
         [0040]    By way of non-limiting example, with the configuration of the dose-setting mechanism  12  described above, the leadscrew  56 , which defines the cartridge engagement surface  57 , extends through the retract nut  60 , and the retract nut  60  interacts with the body  62  to preferably selectively permit rotation of the leadscrew  56 . With the leadscrew  56  being non-rotatably held by the retract nut  60  relative to the dose-setting mechanism  12 , the leadscrew  56  can be translated axially in a distal direction to allow for dose administration. With the retract nut  60  being rotatable, the leadscrew  56  is also rotatable and re-settable in a proximal direction to the start position. Alternatively, the dose-setting mechanism  12  may be a single-use device which is discarded with the completion of a single use, typically, coinciding with the completion of a single drug cartridge. Here, the leadscrew  56  need not be re-settable and can be non-rotatably held in the dose-setting mechanism  12  (e.g., by not permitting rotation of the retract nut  60 ). 
         [0041]    As shown in  FIGS. 2 and 3 , a body adapter  48 , a release ring  50 , a plunger  52 , and, optionally, a locking ring  54  are mountable onto the dose-setting mechanism  12 . With reference to  FIGS. 4   a  and  b,  the body adapter  48  includes a shaft portion  80  defining a lumen  82  for accommodating the plunger  52 . Preferably, a slot  84  is formed in the wall of the shaft portion  80  which is generally straight and parallel to the longitudinal axis of the shaft portion  80 , and an angled guide member  86  ( FIG. 3 ) protrudes from the plunger  52  formed to extend into the slot  84  with the plunger  52  being disposed in the lumen  82 . The guide member  86  slides along the axial length of the slot  84  with movement of the plunger  52 , and the interengagement of the slot  84  and the guide member  86  prevents rotation of the plunger  52  relative to the shaft portion  80 . 
         [0042]    The body adapter  48  further includes a flange  88  which extends radially outwardly from the shaft portion  80 . A retaining wall  90  extends from the flange  88  opposite the shaft portion  80 . The retaining wall  90  is formed to be fixed to a distal end  92  of the body  62  ( FIG. 3 ) which also defines a distal end of the dose-setting mechanism  12 . The fixing may be of any known type, including an interference fit, bonding, and/or mechanical interaction of locking members. It is preferred that the body adapter  48  be fixed to the dose-setting mechanism  12  such that the two elements may move in concert during operation of the injector device  10 . It is further preferred that the body adapter  48  be attached to the dose-setting mechanism  12  so that there is no relative rotation therebetween. 
         [0043]    The lumen  82 , at the flange  88 , is formed to allow passage thereinto of the leadscrew  56  and, optionally, the spinner  58 . The leadscrew  56  engages the plunger  52  within the shaft portion  80 . The plunger  52  acts to translate force of movement applied thereto by the cartridge engagement surface  57  to the drug cartridge  216 . The plunger  52  can be formed of different lengths to accommodate various lengths of the dose-setting mechanism  12  and the drug cartridge  216 . With sufficient length of the plunger  52 , proper and full reconstitution can be achieved. In addition, proper initial priming can be achieved. As an alternative, the cartridge engagement surface  57  can directly engage the drug cartridge  216 , without the use of the plunger  52 . 
         [0044]    With reference to  FIG. 2 , a biasing means  94 , preferably a spring, is disposed in the housing  14  to urge the dose-setting mechanism  12  from an initial, first position to a second position relative to the housing  14 . It is preferred that the biasing means  94  be a coil spring which is sized to pass over the dose-setting mechanism  12  and to have a distal end  95  engage the flange  88  of the body adapter  48 . With this arrangement, buckling and other sideward displacement of the biasing means  94  may be limited. A proximal end  96  of the biasing means  94  may be disposed to act against the housing  14 . Alternatively, and with the preferred arrangement, a spring seat  98  is provided which is shaped and sized to be accommodated within the rear housing  42 . Preferably, the spring seat  98  is non-rotatably fixed in the rear housing  42 . The spring seat  98  includes a bearing surface  100  for engagement against the proximal end  96  of the biasing means  94 . 
         [0045]    A cut-out  102  may be formed in the spring seat  98  to match a cut-out  104  formed in the rear housing  42 . The cut-outs  102 ,  104  are axially alignable to permit a user to view the lens  64  of the dose-setting mechanism  12  in setting a dosage amount on the dose-setting mechanism  12 . The lens  64  permits visual inspection of the dose setting. Dose indicia may be provided on the dose set knob  68  which are viewable through the lens  64 . As shown in  FIG. 5 , the spring seat  98  is tubular and includes a passageway  110  therethrough sized to accommodate the dose-setting mechanism  12 . 
         [0046]    Preferably, the dose-setting mechanism  12  is retained in the first position against the force of the biasing means  94 . It addition, it is preferred that the dose-setting mechanism  12  be retained in the first position until released by a trigger. Although any known retaining arrangement and any known trigger configuration are usable with the subject invention, a representative arrangement is depicted and described herein. As shown in  FIG. 6 , a plurality of inwardly-extending ribs  112  may be disposed along a limited longitudinal length of the interior of the rear housing  42 . The flange  88  of the body adapter  48  defines a profile slidable through the interior of the rear housing  42  with slots  114  being formed on the flange  88  corresponding to the number, size and location of the ribs  112  ( FIG. 4   b ). As such, the flange  88  may slide through the rear housing  42  over the ribs  112 . Rotation of the flange  88  relative to the rear housing  42  is not desired and the slots  114  may be formed to limit such. 
         [0047]    With the dose-setting mechanism  12  being in the first position, the release ring  50  is interposed between the flange  88  and the ribs  112 . With reference to  FIG. 7   a , the release ring  50  includes a comparable profile to the flange  88 , with release slots  116  being formed that are comparably formed and arranged as the slots  114  of the flange  88 . In the first position of the dose-setting mechanism  12 , the release ring  50  is positioned to have the release slots  116  out of alignment with the ribs  112  of the rear housing  42 . With this arrangement, force of the biasing means  94  against the flange  88  is transmitted to the release ring  50 . However, the interengagement of the release ring  50  and the ribs  112  counteracts the force and prevents movement of the flange  88 . For activation, the release ring  50  is caused to rotate to align the release slots  116  with the ribs  112 . As such, the counteraction against the force of the biasing means  94  is removed and the biasing means  94  may urge the flange  88 , along with the body adapter  48  and the dose-setting mechanism  12 , from the first position. 
         [0048]    The release ring  50  may be caused to rotate in any known manner. For example, a displaceable release button  118  may be provided which is movably attached to the rear housing  42  ( FIG. 2 ). With reference to  FIG. 8 , the release button  118  is provided with an angled actuation surface  120 . In an initial state, the actuation surface  120  is positioned to be axially aligned, but preferably spaced from, an angled engagement surface  122  formed on the release ring  50  ( FIG. 7   b ). As shown in  FIG. 9 , with linear displacement of the actuation surface  120  and engagement with the engagement surface  122 , the engagement surface  122  is caused to move transversely and create a torque about the release ring  50 . This torque results in rotation of the release ring  50 . To ensure linear translation of the actuation surface  120 , the release button  118  is formed to slide along fixed button slot  124  formed through the rear housing  42 . Preferably, release button spring  126  is provided to urge the release button  118  to its initial state, with the actuation surface  120  being spaced from the engagement surface  122 . To facilitate handling, outer surface  128  of the release button  118  may be textured to enhance its gripability. As will be appreciated by those skilled in the art, the extent of rotation of the release ring  50  may be controlled by the extent of interengagement of the actuation surface  120  and the engagement surface  122  and the angles of the respective surfaces. The extent of rotation required to align the release slots  116  with the ribs  112  may be achieved by varying these factors. 
         [0049]    It is necessary to have the slots  114  of the flange  88  be axially aligned with the ribs  112  with the release ring  50  maintaining the dose-setting mechanism  12  in the first position. If the slots  114  are not axially aligned with the ribs  112 , the flange  88  may not pass through the rear housing  42  and proper movement of the dose-setting mechanism  12  may be prevented. Therefore, it is preferred that the spring seat  98  be formed with one or more channels  106  radially spaced about its interior ( FIG. 5 ). Preferably, two of the channels  106  are provided. The channels  106  are spaced and formed to accommodate positioning ribs  108  which extend from the periphery of the dose-setting mechanism  12 . As shown in  FIG. 3 , the positioning ribs  108  may protrude from the body  62 . The channels  106  and the positioning ribs  108  are located to interengage with the dose-setting mechanism  12  being in the first position. In addition, the channels  106  and the positioning ribs  108  are located to axially align the slots  114  with the ribs  112 . In this manner, with the release ring  50  permitting movement of the dose-setting mechanism  12 , as described above, the slots  114  are positioned to slide over the ribs  112 . The interengagement of the channels  106  and the positioning ribs  108  also prevents rotation of the dose-setting mechanism  12  with the housing  14 . It is further preferred that the channels  106  and the positioning ribs  108  have sufficient lengths to maintain interengagement with the slots  114  initially passing over the ribs  112 . As the flange  88  moves distally, the channels  106  and the positioning ribs  108  will disengage. 
         [0050]      FIGS. 10 and 11  illustrate operation of the injector device  10 . Initially, the drug cartridge assembly  16  is inserted through the distal end  44  and attached to the injector device  10 . Preferably, the first position of the dose-setting mechanism  12  corresponds to a position which allows the housing  14  to accommodate the drug cartridge  216  being in a full state. As shown in  FIG. 10 , with the drug cartridge  216  being in a full state, the first stopper  26  is located adjacent to the proximal end  24 . With the drug cartridge assembly  16  being secured to the housing  14 , distal end  130  of the plunger  52  is positioned to engage the first stopper  26 . To ensure a good connection therebetween, the distal end  130  may have a protrusion  132  formed for insertion into a recess  134  in the first stopper  26 . In addition, with the first position, the biasing means  94  is compressed and the release ring  50  is in a state of retaining the dose-setting mechanism  12 , as described above. As can be seen in  FIG. 10 , a substantial portion of the dose-setting mechanism  12  extends through the proximal end  46  of the injector device  10 . 
         [0051]    To cause activation, the release button  118  is displaced relative to the housing  14 , resulting in the first and second chambers  30 ,  32  coming into communication. With the preferred trigger arrangement, displacement of the release button  118  causes the release ring  50  to rotate as described above. This rotation may be achieved through displacement of the release button  118  to its actuation state. As shown in  FIG. 11 , with the release ring  50  permitting the dose-setting mechanism  12  to move from the first position, the biasing means  94  urges the dose-setting mechanism  12  distally into a second position. The second position is defined by a stop surface  136  within the housing  14 . During movement of the dose-setting mechanism  12  from the first position to the second position, the cartridge engagement surface  57  moves across a predetermined distance which, in turn, causes the first stopper  26  to move. The cartridge engagement surface  57 , however, does not move relative to the dose-setting mechanism  12  with the dose-setting mechanism  12  moving from the first position to the second position. Movement of the first stopper  26  can cause reconstitution of a drug substance (e.g., lyophilized substance  34 ) located in the drug cartridge  216 , as described above. It is preferred that the second position be defined so that the predetermined distance the cartridge engagement surface  57  traverses is sufficient to allow for reconstitution of the drug substance within the drug cartridge  216 . For example, the predetermined distance is sufficient to urge the second stopper  28  into a position sealing the second chamber  32  from the communication channel  38  at the end of the reconstitution process. The predetermined distance can be provided with additional length beyond that necessary for the reconstitution process to initiate, and even to complete, initial priming of the injector device  10 . Initial priming can also be achieved by manual operation of the dose-setting mechanism  12  after reconstitution. 
         [0052]    During the course of reconstitution, it is preferred that the needle cannula  23  be mounted to the drug cartridge assembly  16  and/or to the housing  14  to act as a vent and permit any trapped gases to escape from the second chamber  32 . The rate of venting will affect the rate of reconstitution. In particular, a smaller gauge needle cannula  23  will provide a higher level of resistance against movement of the dose-setting mechanism  12  during reconstitution, and, thus, will provide a slower rate of reconstitution than a larger gauge needle cannula. In addition, the spring constant of the biasing means  94  may be selected to affect the rate of reconstitution, as well as, adjustment of surface interfaces which generate frictional forces resisting the force applied to achieve reconstitution (e.g., frictional forces between the first stopper  26  and the drug cartridge  216  can be adjusted by selection of materials or providing lubricant therebetween). 
         [0053]    As an alternative, the injector device  10  can be configured to cause reconstitution without the needle cannula  23  being mounted thereto. Here, the spring force of the biasing means  94  can be selected so as to provide sufficient force to compress any air trapped in the chambers  30 ,  32  and to force the diluent  36  into the second chamber  32 . Without venting, the reconstituted substance  37  will be pressurized in the second chamber  32 . Upon mounting the needle cannula  23 , the needle cannula  23  will vent the second chamber  32 , thereby releasing the trapped pressure and forcing the reconstituted substance  37  into the needle cannula  23 . This process may partially or completely achieve initial priming. Full priming can be manually achieved by manual operation of the dose-setting mechanism  12 . In addition, the elements of the injector device  10  can be selected and configured so that equilibrium between the pressurized reconstituted substance  37  and the spring force of the biasing means  94  can be achieved with the dose-setting mechanism  12  being in its second position. In this case, upon mounting the needle cannula  23  and venting the second chamber  32 , the pressure in the second chamber  32  will be released. The biasing means  94  may be configured to urge the dose-setting mechanism  12  to a third position. Movement to the third position may cause full and automatic initial priming. 
         [0054]    The drug cartridge assembly  16  may be initially provided with a removable cap  138  for covering the opening  20  during shipment. The cap  138  is removable to allow for mounting of the needle cannula  23 . 
         [0055]    With the dose-setting mechanism  12  being in the second position as shown in  FIG. 11 , and the reconstituted substance  37  being disposed in the second chamber  32 , the dose-setting mechanism  12  can be adjusted to select a desired dose of particular volume. With the desired dose being set, the dose-setting mechanism  12  may be actuated which results in the cartridge engagement surface  57  being moved distally relative to the dose-setting mechanism  12 , a distance corresponding to the volume of the desired dose. In turn, the first stopper  26  moves the corresponding distance. This movement results in the desired dose being expelled from the second chamber  32  via the needle cannula  23 . Dosing may be repeated as needed with varying volumes being provided. 
         [0056]    Upon depletion of the contents of the drug cartridge  216 , the drug cartridge assembly  16  may be separated from the housing  14  and discarded. If the injector device  10  is a single-use type, the injector device  10  may be discarded also with the drug cartridge assembly  16 . If the injector  10  is re-usable, the dose-setting mechanism  12  is returned to the first position, and the leadscrew  56  is reset to its initial position, as discussed below. 
         [0057]    Optionally, a releasable attachment may be provided for securing the drug cartridge assembly  16  to the housing  14 . In this manner, the injector device  10  may be re-usable with replacement of a spent drug cartridge  216 . For example, one or more cartridge release buttons  140  may be formed to be releasably attached to the drug cartridge assembly  16  to the housing  14 . It is preferred that two of the release buttons  140  be provided and located at diametrically opposed locations on the housing  14  to provide even holding force for the drug cartridge assembly  16 . With reference to  FIGS. 11 and 12 , the cartridge release buttons  140  are displaceable between release and locking positions. In a locking position ( FIG. 11 ), each of the cartridge release buttons  140  is positioned to interferingly engage a protrusion  144  extending from the drug cartridge assembly  16  upon distal movement of the drug cartridge assembly  16  relative to the housing  14 , thereby inhibiting separation of the drug cartridge assembly  16  from the housing  14 . In particular, a distal end  142  of the cartridge release button  140  is positioned to interferingly engage the protrusion  144 . The protrusions  144  may be formed with various configurations but are preferably cylindrical so that precise axial alignment of the protrusions  144  and the cartridge release buttons  140  may be avoided. Slots  141  may be provided to guide the protrusions  144  to the cartridge release buttons  140  and ensure sufficient axial alignment therebetween for locking engagement. The slots  141  extend from the distal end  44  of the front housing  40  ( FIG. 2 ). 
         [0058]    In a release position as shown in  FIG. 12 , each of the cartridge release buttons  140  does not interferingly engage the protrusion  144  upon distal movement of the drug cartridge assembly  16  relative to the housing  14 , thereby facilitating separation of the drug cartridge assembly  16  from the housing  14 . The distal ends  142  may be provided each with a shoulder  143  or other cut-out to provide an engaging surface against the protrusion  144 . Preferably, the shoulder  143  is disposed generally perpendicularly to the distal direction of movement of the drug cartridge assembly  16 . 
         [0059]    Preferably, each of the cartridge release buttons  142  is pivotally mounted to the front housing  40  to permit displacement. Two openings  148 ,  150  are defined on the sides of a cross-piece  146  in the front housing  40 . The cartridge release button  142  includes a notch  145  for pivotal engagement with the cross-piece  146 . The cartridge release button  142  is disposed interiorly of the rear housing  40  with the notch  145  being below the cross-piece  146 . The first opening  148  permits access to depress a proximal end  152  of the cartridge release button  142 . Upon being depressed, the cartridge release button  140  pivots about the cross-piece  146  with the distal end  142  moving away from the drug cartridge  16  to the release position. 
         [0060]    Preferably, a deflectable spring  154  is provided to urge each of the cartridge release buttons  140  to its locking position. In particular, the spring  154  is positioned to bias the proximal end  152  of the cartridge release button  140  away from the drug cartridge assembly  16 . To facilitate mounting of the spring  154  within the housing  14 , a front housing shell  156  may be provided which is mountable into the front housing  40  and provides support for the springs  154 . The shell  156  is formed with an interior to accommodate the drug cartridge assembly  16 . Channels  158  are formed through the shell  156  to allow the cartridge release buttons  140  to extend therethrough and engage the drug cartridge assembly  16 . A stop arm  157  may extend from the cartridge release button  140  to engage a portion of the shell  156 . This engagement limits rotation of the cartridge release button  140  under force of the spring  154 . An internal stop surface (not shown) may also be provided on the shell  156  to limit proximal insertion of the drug cartridge  16  thereinto. In addition, the stop surface  136  may be defined on a proximal end  160  of the shell  156  to define the second position of the dose-setting mechanism  12 . The shell  156  is fixed to the first housing  40  using any known technique. 
         [0061]    It is further preferred that the distal end  142  be formed with a tapered or rounded end  162 . With proximal movement of the drug cartridge assembly  16  into the housing  14  during insertion thereof, the protrusion  144  engages the distal end  142  and may force the cartridge release button  140  in its release position, thus, allowing the protrusion  144  to pass thereby. With the protrusion  144  passing thereby, the cartridge release button  140  returns to its locking position. To allow a user visual inspection of the inserted drug cartridge, an aperture  164  may be formed through each of the cartridge release buttons  140 . Together with the opening  150  and the channel  158 , the aperture  164  provides visual access to the drug cartridge assembly  16  in an attached position. Locking means for preventing inadvertent detachment of the drug cartridge assembly  216  may be provided for the cartridge release buttons  140 . For example, the locking means may be required to be unlocked to permit detachment of the drug cartridge assembly  216 . 
         [0062]    As described above, and as a further optional feature, the injector device  10  may include a feature for selectively preventing rotation of the leadscrew  56 . With this feature, the leadscrew  56  may be prepared for actuation and be allowed to be re-set. With reference to the exemplary configuration of the dose-setting mechanism  12  described above, selective prevention of rotation of the leadscrew  56  can be achieved where the retract nut  60  is caused to be selectively non-rotatably fixed and released depending on circumstances. With the injector device  10 , one or more tabs  166  ( FIG. 3 ) may be formed in the body  62  to non-rotatably hold the retract nut  60 , as described in U.S. Pat. No. 6,248,095. The tabs  166 , however, require inward deflection to be activated. To achieve such inward deflection, the locking ring  54  is provided with an annular body  168  formed to slide onto the distal end  92  of the body  62  and over the tabs  166 , thereby causing inward deflection thereof. It is desired that the locking ring  54  cause inward deflection of the tabs  166  with the dose-setting mechanism  12  being in the second position. This allows for the retract nut  60  to be not rotatable in the second position of the dose-setting mechanism  12 , with the leadscrew  56  also not being rotatable and the leadscrew  56  being drivable distally to cause a dosage administration. 
         [0063]    It is also desired to have the annular body  168  be disengaged from the tabs  166  with the dose-setting mechanism  12  being in the first position. As such, this arrangement permits rotation of the leadscrew  56  and re-setting thereof to an initial position. This would also prevent use of the dose-setting mechanism  12  in the first position, prior to reconstitution. 
         [0064]    To allow for selective engagement and disengagement of the locking ring  54 , legs  170  are provided which extend from the annular body  168  and are formed to pass through passages  172  in the body adapter  48  ( FIG. 4   b ). The legs  170  have sufficient length to extend distally out from the flange  88  in an initial state, with the tabs  166  being not deflected ( FIG. 2 ). Stops  174 , corresponding to the legs  170  of the locking ring  54 , protrude from the distal end  160  of the shell  156 . The stops  174  are positioned to not obscure the stop surface  136 , but are positioned to axially engage the legs  170 . With movement of the dose-setting mechanism  12  from the first position to the second position, the stops  174  engage the legs  170  and cause the locking ring  54  to be held in a fixed position for the final length of the movement between the first and second positions. Accordingly, the annular body  168  is forced onto the moving dose-setting mechanism  12 , and, more particularly, onto the tabs  166 . With engagement of the tabs  166 , the dose-setting mechanism  12  can be actuated. 
         [0065]    For disengagement of the locking ring  54 , one or more extensions  176  extend from the spring seat  98  which are formed to hold the locking ring  54  in a fixed position upon proximal movement of the dose-setting mechanism  12  from the second position to the first position. The extensions  176  hold the locking ring  54  in a fixed position for the final length of the movement, thus, forcing the locking ring  54  off of the tabs  166  and returning the locking ring  54  to its initial position. The dose-setting mechanism  12  is then not actuatable. 
         [0066]    The injector device  10  can be re-set using various techniques, and possibly special tools. Re-setting may require not only moving the dose-setting mechanism  12  from the second position, but also re-setting the cartridge engagement surface  57  to its initial position. With reference to  FIGS. 13  a-g, a mandrel  178  is shown that may be inserted into the housing  14  to cause movement of the dose-setting mechanism  12  from the second position to the first position to re-set the injection device  10 , where preferably the retaining arrangement acts to hold the dose-setting mechanism  12  in the first position. The mandrel  178  may also force the leadscrew  56  to its initial position. The mandrel  178  may be further formed with various features which also permit rotation of the release ring  50  to an initial position with the engagement surface  122  being axially aligned with the actuation surface  120 . 
         [0067]    With reference to  FIGS. 13   a - g,  the mandrel  178  includes a base  180  and an upstanding shaft portion  182  extending therefrom. The base  180  is sized and shaped to provide the mandrel  178  with sufficient stability to stand vertically as shown in  FIGS. 13   a - e.  The shaft portion  182  is generally cylindrical and formed with an outer diameter smaller than the opening in the distal end  44  to permit insertion of the shaft portion  182  into the injector device  10 . Preferably, the base  180  is formed larger than the opening in the distal end  44  so as to act as a stop against excessive insertion. 
         [0068]    The shaft portion  182  includes at least one protruding locator pin  184 , preferably two diametrically opposed locator pins  184 , extending radially from the shaft portion  182 . The locator pins  184  are positioned and formed to slide into the slots  141  formed in the front housing  40 . To ensure proper alignment of the shaft portion  182  within the injector device  10 , the locator pins  184  are sized only to permit insertion with the locator pins  184  being in the slots  141  (i.e., insertion is prevented where the locator pins  184  are not aligned with the slots  141 ). 
         [0069]    At the free end of the shaft portion  182 , interrupted flange portions  186  extend radially outwardly having breaks  188  defined therebetween. The flange portions  186  each include a generally flat top portion  190  on which is formed teeth  192 . The teeth  192  are formed to shape matingly engage ratchet teeth  194  formed on the release ring  50  ( FIG. 7   a ) so that when engaged rotation of the mandrel  178  will result in rotation of the release ring  50 . As will be appreciated by those skilled in the art, any set of cooperating members can be used which will permit a clutching-type action and simultaneous rotation. 
         [0070]    One or more re-set channels  196  are formed on the side of the shaft portion  182 , each extending from one of the breaks  188 . Preferably, two of the re-set channels  196  are provided. The re-set channels  196  are each defined by spaced-apart straight guide wall  198  and configured guide wall  200 . With reference to  FIG. 13  d, the straight guide wall  198  is preferably aligned to extend from one end of the associated break  188  and is generally parallel to a longitudinal axis of the shaft portion  182 . The configured guide wall  200  includes a first, generally straight portion  202  and a second divergent portion  204 . The straight guide wall  198  and the second divergent portion  204  of the configured guide wall  200  define an enlarged pocket  206  of the re-set channel  196 . All of the enlarged pockets  206  formed about the shaft portion  182  are preferably aligned to radially extend in the same direction. In other words, with looking at the circumference of the shaft portion  182 , all of the enlarged pockets  206  preferably extend away from the associated straight guide wall  198  in the same angular direction (clockwise or counter-clockwise). 
         [0071]    The re-set channels  196  are formed to accommodate the stops  174  in sliding engagement. The stops  174  are preferably inwardly directed in extending from the shell  156 . The interengagement of the locator pins  184  and the slots  141  allows for axial alignment of the stops  174  and the re-set channels  196 . With insertion of the mandrel  178  into the injector device  10 , the stops  174  slide within the re-set channels  196 ; the straight guide wall  198  and the first straight portion  202  of the configured guide wall  200  prevent relative rotation between the mandrel  178  and the injector device  10  for a predetermined length of movement. Upon traversing the predetermined length of movement, the stops  174  reach the enlarged pockets  206 , where rotation between the mandrel  178  and the injector device  10  is permitted. 
         [0072]    It is also preferred that the shaft portion  182  define an inner lumen  208  sized to accept insertion of the shaft portion  80  of the body adapter  48  ( FIGS. 13   f  and  13   g ). The inner lumen  208  preferably extends the full length of the mandrel  178  and is open at both ends. An inwardly extending ridge  210  is formed at a mid-point of the inner lumen  208 . The ridge  210  is annular in shape and formed with a smaller diameter than the shaft portion  80  to bear against the plunger  52  (or the cartridge engagement surface  57  if the plunger  52  is not utilized). 
         [0073]    The shaft portion  182  is formed with sufficient length to forcibly urge the dose-setting mechanism  12  from the second position to the first position. In addition, the ridge  210  is located to urge the leadscrew  56  to a start position. As such, the injector device  10  is re-settable to permit a further automatic reconstitution and is re-settable to have the dose-setting mechanism  12  back to its start position. 
         [0074]    With reference to  FIGS. 14-16 , a re-setting process is depicted. With the drug cartridge assembly  16  not being present in the housing  14 , the mandrel  178  is inserted into the housing  14  with the locator pins  184  sliding along the slots  141 . With insertion, the shaft portion  80  of the body adapter  48  is received within the inner lumen  208  with the plunger  52  engaging the ridge  210 . Further insertion causes the dose-setting mechanism  12  to retract proximally against the force of the biasing means  94 . With the dose-setting mechanism  12  still being outside of the first position, the leadscrew  56  is non-rotatably fixed and, thus, is not movable proximally relative to the dose-setting mechanism  12 . Accordingly, the leadscrew  56  transmits the force applied to the plunger  52  to the dose-setting mechanism  12  until the dose-setting mechanism  12  is forced to the first position, as shown in  FIG. 15 . At this point, the leadscrew  56  is released and allowed to rotate, as described above, whereby further insertion of the mandrel  178  into the housing  14  causes the leadscrew  56  to move proximally to its start position, as shown in  FIG. 16 . The spring  74 /resilient tube  73  limits the proximal movement of the leadscrew  56  relative to the dose-setting mechanism  12 . 
         [0075]    With the dose-setting mechanism  12  and the leadscrew  56  having been urged to their respective start positions, the mandrel  178  is fully inserted into the housing. Here, the teeth  192  of the flange portions  186  engage the ratchet teeth  194  of the release ring  50 . The mandrel  178  is caused to rotate with the release ring  50  also rotating. As a result, the release slots  116  are taken out of alignment with the ribs  112 , and the dose-setting mechanism  12  is releasably retained, as described above. The configuration of the enlarged pockets  206  will only permit rotation in one direction, to ensure that the release ring  50  is properly situated for later actuation. The mandrel  178  is then removed, and the housing  14  is ready to receive a drug cartridge assembly  216 . 
         [0076]    While the invention has been described in relation to the preferred embodiments with several examples, it will be understood by those skilled in the art that various changes may be made without deviating from the spirit and scope of the invention as defined in the appended claims.