Abstract:
A method of manufacturing a container containing propellant includes 
     i) sealing a first sheet of rupturable material to a second sheet of rupturable material to form a lower seal and two side seals;
 
ii) placing a propellant dispensing apparatus in fluid communication with a central volume defined by said lower seal, the two side seals and a seal between the propellant dispensing apparatus and the first and second sheets;
 
iii) depositing propellant in the central volume using the propellant dispensing apparatus; and
 
iv) sealing the first sheet to the second sheet to form an upper seal to form a container where the propellant is contained between the upper seal, the lower seal, and the two side seals.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a US national phase under 35 USC §371 of International Application No. PCT/GB2013/051512, filed Jun. 7, 2013, which claims priority to United Kingdom patent application GB 1210082.2, filed Jun. 7, 2012. Priority application GB 1210082.2 is hereby incorporated by reference. 
     
    
     FIELD OF THE DISCLOSURE 
       [0002]    This invention relates to a syringe, and in particular, to a syringe propellable by a propellant that boils at a predetermined temperature, where the syringe is capable of venting propellant therefrom. 
       BACKGROUND 
       [0003]    It is known to power syringes using a gas pressure to move a stopper. In such known devices, a gas spring may provide the gas pressure required to move a stopper in the syringe and deliver a dose of medicament to a patient. When the dose of medicament has been delivered, the syringe still contains the pressurized gas that may present a hazard to the user. 
         [0004]    In order to minimize this problem, some gas powered devices include a mechanism for venting the pressurized gas after delivery of medicament is complete. 
         [0005]    However, in some prior art devices, tolerance stack up means that the configuration required for venting to occur may not be realized and may result in venting not taking place or taking place less effectively than desired. Additionally, in some prior art devices, tolerance stack up may also be responsible for an incomplete dose of medicament being delivered where there may be variation in the final position of the stopper relative to the forward end of the syringe barrel. 
         [0006]    It is an object of at least one embodiment of the present invention to provide an means for venting vapor pressure from a vapor powered syringe that overcomes some of the limitations associated with the prior art. In certain embodiments, it is an object of the present invention to minimize any potential after use risk presented by a syringe powered by a vapor pressure. 
       BRIEF SUMMARY OF THE DISCLOSURE 
       [0007]    In accordance with the present invention there is provided a syringe propellable by a propellant that boils at a predetermined temperature, the syringe comprising:
       a barrel having an outlet at a front end;   a stopper axially moveable in the barrel; and   a third chamber for containing propellant;   wherein the stopper defines and separates a first chamber and a second chamber, the first chamber being axially forwards of the stopper and being configured for containing a medicament, and the second chamber being axially rearwards of the stopper and being configured to receive propellant for acting on the stopper to move the stopper axially forwardly in the barrel to expel medicament through the outlet upon actuation of the syringe;   the syringe being configured such that, in use, upon actuation of the syringe, liquid propellant is released from the third chamber and boils outside of the third chamber at or above the predetermined temperature to provide an increasing vapor pressure in the second chamber that causes the stopper to move axially forwardly and begin to expel medicament from the first chamber through the outlet;   wherein during forward axial movement of the stopper in the barrel, propellant vents away from the second chamber through a vent hole.       
 
         [0014]    In one preferable embodiment, the stopper is axially moveable in the barrel between:
       a first position in which the vent hole is not in fluid communication with the first chamber or the second chamber; and   a second position axially forward of the first position in which the vent hole is in fluid communication with the second chamber thereby permitting venting of propellant from the second chamber.       
 
         [0017]    Further preferably, the stopper is additionally axially moveable in the barrel to a third position that is axially forward of the second position. The third position may be the forwardmost possible position of the stopper in the barrel in which the first chamber has substantially zero volume and substantially all medicament has been expelled from the first chamber. In either case, when in the second position, the syringe preferably contains liquid propeallent. Further preferably, when in the second position, the syringe contains sufficient liquid propellant for the stopper to reach the third position. 
         [0018]    In a further or alternatively preferable embodiment, in the first position the stopper blocks fluid communication between the vent hole and the first chamber and between the vent hole and the second chamber, and in the second position the stopper is axially forward of at least part of the vent hole such that the vent hole is in fluid communication with the second chamber. 
         [0019]    The stopper may comprise a bung and a piston extending axially rearwardly from the bung, wherein each of the bung and the piston seals to the barrel, the piston being configured to be acted upon by vapor pressure in the second chamber so as to cause the stopper to move axially in the barrel. 
         [0020]    Alternatively, the stopper may include a rearwardly axially extending rod that, in the first position, extends through the vent hole and seals to the vent hole so as to block fluid communication between the vent hole and the first chamber and between the vent hole and the second chamber, and, in the second position, the rod does not extend through the vent hole so that the vent hole is in fluid communication with the second chamber. The vent hole may comprise a seal for sealing against the rod. 
         [0021]    In one preferable embodiment, the syringe further comprises a blocking member that is moveable between a blocking position in which fluid communication between the vent hole and the second chamber is blocked by the blocking member, and a non-blocking position in which the vent hole is in fluid communication with the second chamber; 
         [0022]    wherein the blocking member is moveable between the blocking position and the non-blocking position by the stopper such that in the first position the blocking member is in the blocking position and in the second position the blocking member is in the non-blocking position. 
         [0023]    The stopper may be selectively engageable with the blocking member such that when the stopper is not engaged with the blocking member, the stopper is forwardly axially moveable relative to the blocking member, and when the stopper is engaged with the blocking member forward axial movement of the stopper causes forward axial movement of the blocking member towards the non-blocking position. 
         [0024]    The stopper may include a rearwardly axially extending rod extending through blocking member where the rod includes a radial projection at a rear end thereof, wherein the stopper is able to move relative to the blocking member until the projection contacts the blocking member to engage the stopper to the blocking member. 
         [0025]    Alternatively, the stopper may include a bung and an extendible member that is connected to the blocking member and the bung, wherein the extendible member is able to extend in axial length and permit forward axial movement of the bung relative to the blocking member until the extendible member reaches a maximum axial extension due to the relative axial distance between the bung and the blocking member causing the stopper to engage with the blocking member. 
         [0026]    In one embodiment, the extendible member may be a coil. In an alterantive embodiment, the extendible member may be a flexible tether which may comprise string. 
         [0027]    In one preferable embodiment, upon actuation of the syringe the vent hole is in fluid communication with the second chamber such that propellant may vent from the second chamber, where the rate of venting through the vent hole is such that the vapor pressure in the second chamber may still rise sufficiently to cause the stopper to move axially forwardly in the barrel. 
         [0028]    The stopper may include an occlusion member that, in at least one axial position of the stopper in the barrel, occludes the vent hole so as to limit the rate of venting therethrough without preventing venting entirely. 
         [0029]    In one embodiment, the occlusion member may not occlude the vent hole when the stopper is in its forwardmost possible position in the syringe barrel in which the first chamber has substantially zero volume and substantially all medicament has been expelled from the first chamber. 
         [0030]    The vent hole may be elongate such that the occlusion member may occlude the vent hole along the elongate length of the vent hole. 
         [0031]    The third chamber may initially contain a sufficient volume of propellant to move the stopper to its forwardmost possible position in the barrel in which the first chamber has substantially zero volume and substantially all medicament has been expelled from the first chamber. 
         [0032]    In any embodiment, the vent hole may be formed in the barrel. Alternatively, the syringe may further comprise a propellant housing sealed to the barrel, and the vent hole may be formed in the propellant housing. 
         [0033]    The propellant may include a hydrofluoroalkane (HFA), which may be HFA 134a. 
         [0034]    In some preferable embodiments, the vent hole has an axial length and the axial distance between the stopper in the second position and the stopper in the third position is greater than the axial length of the vent hole. The axial distance between the stopper in the second position and the stopper in the third position may be at least two times greater than the axial length of the vent hole. 
         [0035]    In certain embodiments, the propellant may vent away from the second chamber to the outside environment through the vent hole. In alternative embodiments, the propellant may vent away to a further chamber from the second chamber through the vent hole, where the further chamber has a lower pressure than the second chamber. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0036]    Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which: 
           [0037]      FIG. 1A  shows a partial cross section of a syringe in accordance with an embodiment of the present invention that includes a vent hole, where, in  FIG. 1A , the vent hole is closed; 
           [0038]      FIG. 1B  shows the syringe of  FIG. 1A  with the vent hole partially open; 
           [0039]      FIG. 1C  shows the axial position of the stopper that corresponds to the configuration shown in  FIG. 1B ; 
           [0040]      FIG. 1D  shows the syringe of  FIGS. 1A and 1B  with the vent hole fully open; 
           [0041]      FIG. 1E  shows the axial position of the stopper that corresponds to the configuration shown in  FIG. 1D ; 
           [0042]      FIG. 2  shows a plot of leak magnitude versus time for the syringe shown in  FIGS. 1A to 1E ; 
           [0043]      FIG. 3A  show a syringe in accordance with an embodiment of the present invention that includes a vent hole; 
           [0044]      FIG. 3B  shows a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole; 
           [0045]      FIGS. 4A and 4B  show a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole, where in  FIG. 4A  the vent hole is closed, and in  FIG. 4B  the vent hole is open; 
           [0046]      FIG. 5  shows a plot of leak magnitude versus time for the syringe shown in  FIGS. 4A and 4B ; 
           [0047]      FIGS. 6A and 6B  show a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole, where in  FIG. 6A  the vent hole is closed, and in  FIG. 6B  the vent hole is open; 
           [0048]      FIGS. 6C and 6D  show a syringe in accordance with an alternative embodiment of the present invention, wherein in  FIG. 6C  the vent hole is partially open, and in  FIG. 6D  the vent hole is entirely open; 
           [0049]      FIG. 7  shows a plot of leak magnitude versus time for the syringe shown in  FIGS. 6A and 6B ; 
           [0050]      FIGS. 8A and 8B  show a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole, where in  FIG. 8A  the vent hole is closed, and in  FIG. 8B  the vent hole is open; 
           [0051]      FIG. 8C  shows a detailed view of part of the syringe of  FIGS. 8A and 8B ; 
           [0052]      FIGS. 8D to 8F  show a syringe in accordance with an alternative embodiment of the present invention that, where in  FIG. 8D  the vent hole is closed, in  FIG. 8E  the vent hole is open and the stopper is not in its forwardmost position in the barrel, and in  FIG. 8F  the vent hole is open and the stopper is in its forwardmost position in the barrel; 
           [0053]      FIG. 9  shows a plot of leak magnitude versus time for the syringe shown in  FIGS. 8A and 8B ; 
           [0054]      FIGS. 10A and 10B  show a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole, where in  FIG. 10A  the vent hole is occluded, and in  FIG. 10B  the vent hole is not occluded and is open; 
           [0055]      FIG. 11  shows a plot of leak magnitude versus time for the syringe shown in  FIGS. 10A and 10B ; 
           [0056]      FIGS. 12A and 12B  show a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole, where in  FIG. 12A  the vent hole is occluded, and in  FIG. 12B  the vent hole is still occluded and the stopper is at its forwardmost axial position in the syringe barrel; 
           [0057]      FIGS. 12C and 12D  show a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole, where in  FIG. 12C  the vent hole is not occluded and the stopper is not in its forwardmost position in the barrel, and in  FIG. 12D  the vent hole is not occluded and the stopper is in its forwardmost position in the barrel; 
           [0058]      FIG. 13  shows a plot of leak magnitude versus time for the syringe shown in  FIGS. 12A and 12B ; 
           [0059]      FIGS. 14A and 14B  show a syringe in accordance with an alternative embodiment of the present invention that includes a vent hole, where in  FIG. 14A  the vent hole is closed, and in  FIG. 14B  the vent hole is open; 
           [0060]      FIG. 15  shows pressure plots of a syringe with venting and without venting, and a plot of the mass of gaseous propellant in the second chamber of the vented syringe, where the propellant is a liquefied gas; 
           [0061]      FIG. 16  shows pressure plots of a syringe with venting and without venting, and a plot of the mass of gaseous propellant in the second chamber of the vented syringe, where the propellant is a compressed gas. 
       
    
    
     DETAILED DESCRIPTION 
       [0062]    An embodiment of the present invention is shown in  FIGS. 6A and 6B  which show a syringe comprising a barrel  12  having an outlet  14  at a front end and a stopper  16  disposed in the barrel. In the particular embodiment shown in  FIGS. 6A to 6D , the stopper  16  includes a bung  645  at a forward end and a rod  644  extending axially rearwardly from the bung  645  parallel to the length of the syringe barrel  12 . The rod  644  extends out of the syringe barrel  12  and into a propellant housing  634  that is disposed at a rear end of the syringe barrel  12  and is sealed thereto. A rear end of the rod  644  is sealed with a piston seal  650  against an inside surface of the propellant housing  634 . The propellant housing  634  effectively provides an extension of the syringe barrel  12  and in certain embodiments may not be present if the syringe barrel  12  is sufficiently long in an axial direction. The stopper  16  (taken as a whole, i.e. including the bung  645 , rod  644  and piston seal  650 ) defines and separates a first chamber  18  and a second chamber  20 . The first chamber  18  is axially forwards of the stopper  16  and is configured for containing a medicament. The second chamber  20  is axially rearwards of the stopper  16  and is configured to receive propellant for acting on the stopper  16  to move the stopper axially forwardly in the barrel  12  to expel medicament through the outlet  14  upon actuation of the syringe. The syringe includes a third chamber  628  that acts as a propellant source containing a propellant that boils at a predetermined temperature. Suitable propellants are liquefied gases that include hydrofluoroalkanes (HFA), and a particularly suitable propellant is HFA 134a. 
         [0063]    In use, upon actuation of the syringe, the third chamber  628  releases liquid propellant that boils outside of the third chamber  628  at or above the predetermined temperature to produce a vapor that is fluidly connected to the second chamber  20 . In some embodiments, the liquid propellant may be released directly from the third chamber  628  to the second chamber  20  where it boils to produce the vapor pressure. In alternative embodiments within the scope of the present invention, liquid propellant may be released into a fourth chamber where it may boil and provide a vapor pressure to the second chamber  20 . In any embodiment, the propellant must vaporize outside of the third chamber and provide a vapor pressure to the second chamber  20 . By ensuring that the third chamber  628  releases liquid propellant that vaporizes at or above the predetermined temperature, a more reliable, predictable and controllable pressure profile results improving the reliability and controllability of the syringe. Additionally, the resulting pressure profile is of such a magnitude that a dose of medicament may be delivered using a relatively small volume of propellant. This is in stark contrast to devices powered by compressed gas where a large volume of compressed gas is required to deliver a dose of medicament (in comparison with a liquefied gas propellant) and provides a very high starting pressure that compensates for the inherent pressure drop of the compressed gas as it expands and causes the stopper to move. 
         [0064]    Returning to the present invention, as the vapor pressure in the second chamber  20  rises, the stopper  16  begins to move axially forwardly and begins to expel medicament our of the outlet. In certain embodiments (as with that of  FIGS. 6A to 6D ), a needle may be attached to the outlet  14  for carrying expelled medicament to an injection site. 
         [0065]    In accordance with the present invention, during forward axial movement of the stopper  16  in the barrel  12 , propellant vents away from the second chamber  20  through a vent hole. The present invention therefore provides an automatic means for ensuring that the syringe is depressurized after use. This venting may be to the outside environment (“atmosphere”) or a further chamber having a lower pressure than the second chamber, and is described in more detail below with reference to several distinct embodiments within the scope of the present invention. 
         [0066]    In addition to improving safety, venting during axial movement of the stopper allows the pressure profile within the second chamber to be controlled and manipulated during delivery. The controlled pressure profile may be used to control the rate or force of delivery, or trigger a further action caused by the controlled vapor pressure. 
         [0067]    Certain advantages of using a liquefied gas as a propellant over a compressed gas are evident by comparing  FIGS. 15 and 16 .  FIG. 15  shows the pressure profiles of two syringe powered by a liquefied gas propellant, where in one syringe a vent hole opens at time T1. In both cases, the delivery is complete at time T2.  FIG. 14  additionally shows how the overall mass of vaporized propellant in the second chamber changes over time for the syringe with a vent hole. 
         [0068]    For the syringe with no vent hole, the pressure decreases slightly during delivery due to cooling of the propellant as it vaporizes. Then, after delivery is complete (T2), the pressure gradually rises as some of the remaining liquid propellant vaporizes due to heat from its surroundings until equilibrium and a saturated vapor pressure is attained. 
         [0069]    For the syringe with a vent hole, when the vent opens at T1 the pressure is initially approximately maintained as liquid propellant continues to vaporize and provide pressure the second chamber. Then prior to the end of delivery, the pressure begins to decrease. This is partly due to the temperature drop arising from an energy drop as the liquid propellant vaporizes and vents through the vent hole. The pressure then falls away to 0 bar relative to atmosphere. Considering the mass of vaporized propellant in the second chamber,  FIG. 15  shows that the mass begins decreasing steadily from when the vent hole is opened at T1. The reason that this is a gradual decrease and not a sharp instantaneous drop is that the liquid propellant still remaining in the syringe continues to vaporize and therefore provides new mass of vaporized propellant. After the initial decrease, the rate of decrease slows as a steady state is reached in which the liquid propellant vaporizes but such vaporized propellant merely vents and does not increase the pressure in the second chamber.  FIG. 15  also shows the critical pressure threshold P1 above which there is sufficient force to overcome the friction and stiction of the stopper in order to axially move the stopper in the barrel. Pressures below P1 are insufficient for axially moving the stopper in the barrel. As can be seen from  FIG. 15 , the pressure of the vented syringe remains notably higher than P1 at T2 therefore providing a device that is able to reliably deliver a complete dose of medicament. 
         [0070]    In contrast,  FIG. 16  shows the same scenario for a syringe powered by a compressed gas (outside the scope of the present invention).  FIG. 16  shows the pressure profile of a syringe powered by a compressed gas where there is no venting, and additionally shows the pressure profile of a syringe powered by a compressed gas where a vent hole opens at time T1.  FIG. 16  also shows the corresponding change in mass of gaseous propellant in the second chamber over time. In both vented and non-vented cases, delivery is complete at T2. As shown in  FIG. 16 , in both the vented and non-vented syringes, the pressure drops rapidly when delivery begins. For the non-vented syringe, a residual pressure remains following the rapid decrease which then slowly decreases until the end of delivery at T2. In contrast, for the vented syringe, the pressure drops rapidly once more when the vent is opened at T1 and decreases to substantially zero. The corresponding plot of mass shows that substantially all of the gaseous mass disappears from the second chamber when the vent hole is opened at T1. 
         [0071]    Compressed gas powered devices are therefore not suitable for venting during movement of the stopper in the barrel due the rapid decrease in pressure in the second chamber. This would result in movement of the stopper arresting almost immediately. 
         [0072]    In accordance with embodiments of the present invention, venting whilst the stopper is axially moving as opposed to venting when the stopper is stationary permits reliable venting that occurs during delivery and accounts for possible variations in the dimensions of the components of the syringe due to tolerance (so-called tolerance stack up). If, for example, the stopper had to move entirely to the forward end of the syringe barrel before venting occurred, tolerance stack up may mean that due to the relative positions of components key to venting (e.g. the stopper and the vent hole) venting does not take place as effectively as desired or not at all. The present invention may ensure venting occurs in a configuration that is guaranteed to occur irrespective of tolerance stack up, and permit a full dose of medicament to be delivered. Again tolerance stack up in certain prior art syringes may result in an incomplete dose being delivered. 
         [0073]    One embodiment of the present invention is shown in  FIGS. 1A to 1E . In this embodiment, a propellant housing  634  is sealed by seals  636  to a rear end of the syringe barrel  12 . The propellant housing  634  has a vent hole  642  that may be any shape, size or configuration provided that it permits vaporized propellant to pass therethrough. In certain embodiments, the vent hole  642  is preferably small so as to limit the venting rate. Disposed in the syringe barrel  12  is a stopper  16  that includes a rod extending axially rearwardly through the propellant housing  634 . The propellant housing  634  has a narrowed forward portion  638 , however the narrowed forward portion has a diameter that is larger than the diameter of the rod  644  such that vaporized propellant may pass through the annulus between the rod  644  and the narrowed forward portion  638 . Disposed around the rod  644  is an axially moveable seal  640 . The axially moveable seal  640  is axially moveable relative to the rod  644  and seals against an inside surface of the propellant housing  634 . The axially moveable seal  640  does not seal to the rod  644  entirely (or not at all) and permits the passage of vaporized propellant across the axially moveable seal  640  (i.e. from axially rearward of the axially moveable seal  640  to axially forward of the axially moveable seal  640 ). 
         [0074]    In use, liquid propellant is provided from a propellant source to provide a vapor pressure in the second chamber  20  that extends between the propellant source and the stopper  16 . In the configuration shown in  FIG. 1A , the axially moveable seal  640  is sealing the vent hole  640  from the second chamber  20  such that propellant cannot escape from the second chamber  20  via the vent hole. In accordance with the present invention, the vapor pressure in the second chamber  20  rises as the liquid propellant boils and the stopper  16  begins to move axially forwardly to begin to expel medicament from the first chamber  18 . As the stopper  16  moves axially forwardly, the rod  644  slides axially through the axially moveable seal  640  that remains stationary, sealing the vent hole  640 . 
         [0075]    As shown in  FIG. 1B , a flange  646  projects from a rear end of the rod  644 . When the stopper  16  reaches an axial position in the syringe barrel  12  where the flange  646  contacts the axially moveable stopper  640 , further axially forwardly movement of the stopper  16  causes the flange  646  to move the axially moveable seal  640  axially forwardly and begin to open the vent hole  642 .  FIG. 22B  shows the vent hole  642  partially opened by the axially forwardly advancing axially moveable seal  640 . As the vent hole  642  opens, propellant in the second chamber  20  begins to escape and the vapor pressure in the second chamber  20  begins to decrease. The rate of the decrease in vapor pressure in the second chamber  20  will depend on the size of the vent hole  642 , the thermodynamics of the system (the temperature and pressure of the propellant in particular, and the speed at which the vent hole is opened (i.e. change from fully closed to fully open). 
         [0076]      FIG. 1C  shows the axial position of the stopper  16  corresponding to the configuration shown in  FIG. 1B . As can be seen in  FIG. 1C , the stopper  16  is not at its axially forwardmost position within the barrel  12 , and the first volume  18  still contains medicament. 
         [0077]    In the embodiment shown in  FIGS. 1A to 1E , the vent hole  642  is sized so that when the vent hole  642  is first opened, a sufficient amount of propellant remains for a long enough time in the second chamber  20  to move the stopper  16  to its forwardmost position in the syringe barrel  12 . 
         [0078]      FIG. 1D  shows the axially moveable seal  640  in an axial position that is entirely forward of the vent hole  642  such that the vent hole is fully open.  FIG. 1E  shows the axial position of the stopper  16  corresponding to the configuration shown in  FIG. 1D . 
         [0079]      FIG. 2  shows the leak magnitude of the embodiment of  FIGS. 1A to 1E  as the axially moveable seal  640  moves axially and opens the vent hole  642 . 
         [0080]      FIGS. 3A and 3B  show examples corresponding to the embodiment of  FIGS. 1A to 1E . In  FIG. 3A , the propellant housing has an inlet  634   a  at a rear end, where the inlet  634   a  is fluidly connected to a propellant source  628 . In use the propellant source  628  provides liquid propellant to the second chamber  20 , which, in the embodiment of  FIG. 3A , is the volume between the propellant source  628  and the stopper  16 . In  FIG. 3B , the rear end of the propellant housing  634  is sealed and, instead, the propellant housing  634  has a side inlet  634   a . In any embodiment, there must be a fluidic flow path from the propellant source  628  that permits the vapor pressure in the second chamber  20  to act on and cause the stopper  16  to move. 
         [0081]    In the alternative embodiment shown in  FIGS. 4A and 4B , the propellant housing  634  has a vent hole  642  located at a rear end such that the rod  644  initially protrudes therethrough.  FIG. 4A  shows the device in an initial configuration prior to delivery of medicament. In this initial configuration, a rod seal  648  seals the propellant housing  634  to the rod  644  so as to block the vent hole  642 . 
         [0082]    In use, a propellant source  628  dispenses liquid propellant through an inlet  634   a  of the propellant housing  634  into the second chamber  20  where it may boil and cause the stopper  16  to move axially forwardly. The advancing stopper  16  causes the rod  644  to slide axially forwardly through the rod seal  648 . Throughout this movement, the combination of the rod seal  648  and the rod  644  continues to seal the vent hole. 
         [0083]    When the stopper  16  reaches its axially forwardmost position in the syringe barrel  12 , as shown in  FIG. 4B , the rear end of the rod  644  will have moved to an axial position where the vent hole  642  is no longer sealed by the combination of the rod seal  648  and the rod  644 , and venting of propellant from the second chamber  20  begins. The movement of the rod  644  may cause the vent hole  642  to be opened entirely, or it may create a restricted flow path. 
         [0084]      FIG. 5  shows the leak magnitude of the embodiment of  FIGS. 4A and 4B  as the rod  644  moves axially to open the vent hole  642 . In the embodiment of  FIGS. 4A and 4B , the size of the vent hole  642  is determined by the diameter of the rod  644  and is therefore larger than the smaller vent hole  642  of the embodiment of  FIGS. 1A to 1E ,  3 A and  3 B. Consequently, the leak magnitude shown in  FIG. 5  increases more rapidly than the leak magnitude shown in  FIG. 2 . 
         [0085]    As described above, a further alternative embodiment is shown in  FIGS. 6A and 6B  in which vapor pressure acting on the rod  644  (and piston seal  650 ) causes axial movement of the stopper  16  so as to expel medicament from the first chamber  18 . In this sense, the second chamber  20  is defined as the volume extending between a propellant source  628  and the rear end of the rod  644  (which forms part of the stopper  16 ) that is sealed against the syringe barrel  12 . The propellant housing  634  has an inlet  634   a  in fluid communication with the propellant housing  628  and further includes a vent hole  642  that is positioned so as to be in fluid communication with the second chamber  20  when the stopper  16  is in its forwardmost axial position in the syringe barrel  12  (i.e. at the end of delivery) as shown in  FIG. 2B , or, in alternative embodiments, when the stopper  16  is approaching its forwardmost axial position. 
         [0086]    In the configuration shown in  FIG. 6A  prior to medicament delivery, the vent hole  642  is not in fluid communication with the second chamber  20  and so propellant is not able to vent and, instead, causes axial movement of the stopper  16  (including rod  644 ). At the end of delivery, as shown in  FIG. 6B , the rod  644  and piston seal  650  have moved axially forwardly sufficiently for the vent hole  642  to open and permit venting of propellant from the second chamber  20 . 
         [0087]      FIGS. 6C and 6D  show a variation of the embodiment of  FIGS. 6A and 6B  according to an alternative embodiment of the present invention.  FIG. 6C  shows a configuration in which the vent hole  642  has just opened and the stopper  16  is not in its forwardmost axial position.  FIG. 6D  shows a configuration in which the vent hole  642  is fully open and the stopper  16  is in its forwardmost axial position. In order to ensure that the stopper  16  does not immediately stop moving axially forwardly as soon as the vent hole  642  opens, it is preferable for there to be liquid propellant remaining in the syringe which may vaporize to provide sufficient vapor pressure in the (now vented) second chamber  20  to continue moving the stopper  16 . Indeed, to ensure that the stopper  16  reaches its forwardmost axial position in the barrel  12  it is preferable for there initially to be enough liquid propellant in the syringe such that some liquid propellant remains in the syringe when the stopper  16  reaches its forwardmost axial position in the barrel  12  despite the vent hole  642  opening in the meantime. 
         [0088]    In some preferable embodiments (not limited to that described above in relation to  FIGS. 6C and 6D ), the vent hole has an axial length and the axial distance between the stopper when the vent hole first opens and the stopper in its final axial position (which is preferably at the forwardmost axial possible position in the barrel) is greater than the axial length of the vent hole. This axial distance may be at least two times greater than the axial length of the vent hole. In some embodiments, this axial distance may be greater than 1 mm. In alternative embodiments, this axial distance may be less than 1 mm. In a 1 ml long syringe, an axial distance of 1 mm corresponds to approximately 0.03 cc volume. 
         [0089]      FIG. 7  shows the leak magnitude of the embodiment of  FIGS. 6A and 6B  (or the embodiment of  FIGS. 6C and 6D ) as the rod  644  moves axially to open the vent hole  642 . As with the embodiment of  FIGS. 1A to 1E , the vent hole  642  may be sufficiently small so as to restrict venting and permit medicament delivery to continue for a time period following initial venting. 
         [0090]    Contrasting the embodiment of  FIGS. 6A and 6B  to that of  FIGS. 1A to 1E , the embodiment of  FIGS. 6A and 6B  will encounter higher frictional forces during medicament delivery due to the presence of the piston seal  650 . However, since the vapor pressure acts on the rod  644  and the piston seal  650  which are not limited by the diameter of the syringe barrel  12 , a larger surface area is permissible which allow greater delivery forces to be employed. 
         [0091]    The alternative embodiment shown in  FIGS. 8A to 8C  is very similar to that shown in  FIGS. 1A to 1E  but for the fact that the stopper  16  is connected to the axially moveable seal  640  by an extendible member  644 ′ rather than a rigid rod. As the stopper  16  moves axially forwardly in the syringe barrel  12 , the extendible member  644 ′ extends. As the stopper  16  approaches its axially forwardmost position in the syringe barrel  12 , the extendible member  644 ′ extends to its fullest extent and, due to tension, begins to cause axially forward movement of the axially moveable seal  640 . Consequently, the axially moveable seal  640  moves to an axial position where the vent hole  642  is opened and permits venting of propellant from the second chamber  20 . 
         [0092]      FIG. 8C  shows a detailed view of an example of a suitable extendible member  644 ′ that is in a coiled configuration. Axial movement of the stopper  16  causes the coil to unwind. Once the coil has fully unwound, the extendible member  644 ′ may apply a downward axial force on the axially moveable seal  640  to open the vent hole  642 . The extendible member  644 ′ may be any suitable member that is flexible so as to only apply a force to the axially moveable seal  640  sufficient to move the axially moveable seal  640  when the distance between the stopper  16  and the axially moveable seal  640  substantially equals the maximum length of extendible member  644 ′. A length of string or similar member may be a suitable extendible member  644 ′. 
         [0093]      FIGS. 8D to 8F  show a variation of the embodiment of  FIGS. 8A to 8C  within the scope of the present invention.  FIG. 8D  shows a configuration in which the vent hole  642  is blocked by the axially moveable seal  640 .  FIG. 8E  shows a configuration in which the vent hole  642  is open (i.e. is not fully blocked by the axially moveable seal  640 ) and the stopper  16  is not in its forwardmost axial position in the barrel  12 .  FIG. 8F  shows a configuration in which the vent hole  642  is fully open and the stopper  16  is in its forwardmost axial position in the barrel  12 . As described above in relation to  FIGS. 6C and 6D , it is preferable for there to be liquid propellant remaining in the syringe which may vaporize to provide sufficient vapor pressure in the (now vented) second chamber  20  to continue moving the stopper  16 . Indeed, to ensure that the stopper  16  reaches its forwardmost axial position in the barrel  12  it is preferable for there initially to be enough liquid propellant in the syringe such that some liquid propellant remains in the syringe when the stopper  16  reaches its forwardmost axial position in the barrel  12  despite the vent hole  642  opening in the meantime. Such an arrangement is not limited to the embodiment of  FIGS. 6C and 6D  or of  FIGS. 8D to 8F , but may be applicable to any embodiment within the scope of the present invention in which the vent hole opens when the stopper  16  is not at its forwardmost axial position in the barrel  12 . 
         [0094]      FIG. 9  shows the leak magnitude of the embodiment of  FIGS. 8A to 8C  (or the embodiment of  FIGS. 8D to 8F ) as the axially moveable seal  640  moves axially and opens the vent hole  642 . The leak magnitude shown in  FIG. 9  closely resembles that shown in  FIG. 2  due to the similarities in the embodiments of  FIGS. 1A to 1E  and  FIGS. 8A to 8C . 
         [0095]    A further alternative embodiment is shown in  FIGS. 10A and 10B . In this embodiment, the propellant housing  634  has a vent hole  642  that is open, to a certain extent, prior to propellant being released into the second chamber  20 . A flexible member  645  extends axially rearwardly from the stopper  16  and extends through the vent hole  642 . The presence of the flexible member  645  in the vent hole  642  does not prohibit propellant venting from the second chamber  20  therethough, however it does limit the rate at which propellant may vent. The absolute size of the vent hole  642  and the relative size of the vent hole  642  relative to the dimensions of the flexible member  645  will determine the rate at which propellant may vent from the second chamber  20 . Clearly, it is preferable for the leak rate to be low enough for the propellant remaining to deliver a full dose of medicament. 
         [0096]    At the end of medicament delivery when the stopper  16  is at its axially forwardmost position in the syringe barrel  12  as shown in  FIG. 10B , the flexible member  645  no longer occludes the vent hole  642  and so permits more rapid venting of any propellant remaining in the second chamber  20 . In alternative embodiments, the flexible member  645  may remain in an occluding position when the stopper  16  is in its axially forwardmost position. 
         [0097]      FIG. 11  shows the leak magnitude of the embodiment of  FIGS. 10A and 10B  as propellant vents from the second chamber  20  via the occluded vent hole  642 . 
         [0098]      FIGS. 12A and 312B  show an embodiment related to that shown in  FIGS. 10A and 10B . The embodiment of  FIGS. 12A and 12B  differs from that shown in  FIGS. 10A and 10B  in that the vent hole  642  extends axially to a greater extent in the embodiment of  FIGS. 12A and 12B . The presence of flexible member  645  in the vent hole  642  therefore provides an occlusion over a greater length and consequently limits venting therethrough to a greater extent compared to the embodiment of  FIGS. 10A and 10B . 
         [0099]    This slower leak rate is evident in  FIG. 13  where it can be seen that the leak magnitude increases more slowly compared with  FIG. 11 . 
         [0100]      FIGS. 12C and 12D  show a variation of the embodiment of  FIGS. 12A and 12B  within the scope of the present invention.  FIG. 12C  shows a configuration in which the flexible member  645  has just been fully withdrawn from the vent hole  642  thereby fully opening the vent hole  642 . In the configuration shown in  FIG. 12C , the stopper  16  is not in its forwardmost axial position in the barrel  12 .  FIG. 12D  shows a configuration in which the vent hole  642  is fully open and the stopper  16  is in its forwardmost axial position in the barrel  12 . It is preferable for there the be liquid propellant present in the syringe when the configuration shown in  FIG. 12C  is reached so that sufficient vapor pressure may be provided to the second chamber  20 , despite the venting, to cause the stopper  16  to move to its forwardmost axial position in the barrel  12  as shown in  FIG. 12D . It is further preferable to initially provide sufficient liquid propellant such that some still remains in the syringe when the stopper  16  reaches its forwardmost axial position in the barrel  12 . 
         [0101]    A further alternative embodiment is shown in  FIGS. 14A and 14B  which is similar to that described above in relation to  FIGS. 4A and 4B . The embodiment of  FIGS. 14A and 14B  differs from that of  FIGS. 4A and 4B  in that the rod  644  of  FIGS. 14A and 14B  is flexible so as to permit a reduction in the overall axial length of the device prior to actuation. As shown in  FIG. 14A , the part of the flexible rod  644  that is initially disposed outside of the syringe barrel  12  may bend so as remain compact and permit a more compact device. As the stopper  16  moves axially forwardly, the flexible rod  644  is drawn through the rod seal  648  and eventually moves to a position where it no longer prevents venting of propellant through the vent hole  642  as shown in  FIG. 14B . The rod  644  may be hollow to permit flexing. 
         [0102]    Throughout the present specification, the term “syringe” relates to and includes any medicament delivery device having a medicament container with an outlet and a moveable stopper for expelling medicament therefrom. As examples, the syringe may include a needle, a nozzle or a conduit attached to the outlet. In other embodiments, the syringe may not include any further components downstream of the outlet. The syringe of the present invention may be or form part of a subcutaneous delivery device, a nasal delivery device, an otic delivery device, an oral delivery device, an ocular delivery device, an infusion device or any other suitable medicament delivery device. 
         [0103]    Directions described herein as “axial” correspond to directions parallel to the longitudinal length of the syringe. 
         [0104]    Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. 
         [0105]    Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. 
         [0106]    The reader&#39;s attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.