Abstract:
A system is provided which permits syringe barrels of prefilled disposable syringes to be filled and capped on standard vial filling equipment, and which permits the syringe body and piston comprising the barrel to be simultaneously sterilized by a sterilizing gas. The system provides means for stabilizing syringe barrels so they can be conveyed upright on their bases without tipping through vial filling and capping equipment. Preferably, the stabilizing means comprises a cylindrical sleeve into which the lower end of the syringe body is inserted, thereby stably supporting it against tipping. The system also provides means by which the piston is retained in close proximity to the lower end of the syringe body, but slightly separated therefrom to permit access to all surfaces of the piston by a sterilizing gas. Preferably, the piston is retained directly below the lower end of the syringe body, and substantially centred therewith, to permit the piston to be inserted into the lower end of the body merely by pushing the body and piston together.

Description:
FIELD OF THE INVENTION  
         [0001]    The invention relates to the production of prefilled syringes for use in medical or veterinary treatment.  
         BACKGROUND OF THE INVENTION  
         [0002]    Prefilled disposable syringes have gained wide acceptance as a preferred dosage form for administration of medicaments, primarily for reasons of safety and convenience. Most importantly, prefilled syringes minimize handling of a medicament prior to administration, thereby reducing the chance of dosage errors or contamination of the medicament.  
           [0003]    Many different types of prefilled disposable syringes have been developed. Most known prefilled syringes include an elongate syringe “cartridge” or “barrel” comprising a cylindrical glass or plastic container into which the medicament or a component thereof is prefilled. In some types of prefilled syringe, the barrel forms the body of a syringe, having a mouth which permits attachment to an injection needle, and a movable bottom comprising an elastomeric piston which is acted upon by a plunger to administer the medicament.  
           [0004]    One common problem with prefilled disposable syringes is that a dedicated filling and capping line is usually required to fill the medicament into the syringe barrel. This problem has previously been addressed by the invention described in the applicant&#39;s European Patent No. 298,585, which describes a system for producing prefilled syringe barrels on ordinary equipment for filling and capping pharmaceutical vials This patent describes a system whereby the syringe barrel is made shorter and wider than a conventional barrel, so that it has the shape of a standard pharmaceutical vial, and is then filled and capped on standard machinery for filling and capping vials, through which the barrels are conveyed while standing on their bases. Since the pharmaceutical vial is a standardized container which is widely used in the pharmaceutical industry, most pharmaceutical companies have existing vial filling equipment. The equipment need only be modified by the addition of a station for insertion of the rubber piston into the body of the barrel. Therefore, the invention described in the applicant&#39;s prior patent eliminates the need for specialized filling equipment, thereby reducing cost.  
           [0005]    Despite the improvements described in the applicant&#39;s above-mentioned European patent, the further disadvantage exists that the relatively squat vial-shaped barrels cannot be used in all types of delivery systems. Some delivery systems, such as syringe pumps and two component systems, may require the use of conventional, elongate barrels which cannot be filled on standard vial-filling equipment. Therefore, it would be advantageous to provide a system which allows the preparation of conventional, elongate prefilled syringe barrels on standard equipment for filling and capping pharmaceutical vials.  
           [0006]    A further disadvantage exists in that it is not possible to adequately sterilize the assembled syringe barrel (i.e. with the piston completely inserted in the body) by conventional sterilizing agents, including gamma radiation and sterilizing gases such as ethylene oxide or steam. While gamma radiation would sterilize the assembled barrel, it destroys the elasticity of the rubber and therefore cannot be used. Sterilizing gases cannot adequately contact all surfaces of the piston once it is inserted in the body and therefore cannot be used. It would be desirable to supply a syringe barrel which is at least partially assembled and preferably pre-sterilized so as to allow maximum flexibility during the filling operation.  
         SUMMARY OF THE INVENTION  
         [0007]    The above-mentioned disadvantages of the prior art are overcome by the present invention, which provides a system for filling and assembling pharmaceutical delivery devices capable of accommodating barrels of various dimensions including elongate syringe barrels. The system according to the invention also provides for partial pre-assembly of the body and the piston, thereby permitting simultaneous sterilization of the body and piston by a sterilizing gas.  
           [0008]    In the system according to the invention, means are provided for stabilizing syringe barrels such that they can be conveyed upright without tipping through equipment for filling and capping pharmaceutical vials. Preferably, the stabilizing means comprises a cylindrical sleeve into which the rimmed end of the body (i.e. the end which receives the piston) is inserted, thereby stably supporting the body against tipping.  
           [0009]    The system according to the invention also provides means by which the piston is retained in close proximity to the rimmed end of the body, but slightly separated therefrom to permit access to all surfaces of the piston by a sterilizing gas. Preferably, the piston is retained directly below the rimmed end of the body, and substantially centred therewith, to permit the piston to be inserted into the rimmed end of the body merely by pushing the body and piston together.  
           [0010]    Accordingly, in one aspect, the present invention provides An assembly for forming a barrel of a pre-filled syringe, comprising: (a) a syringe body having a generally cylindrical side wall with an inner surface and an outersurface, the sidewall extending between a neck end and a rimmed end; (b) a generally cylindrical elastomeric piston having an upper surface, a side surface adapted to form a hermetic seal with the inner surface of the cylindrical side wall when inserted into the open rimmed end of the syringe body, and a lower surface opposite the upper surface; (c) a generally cylindrical sleeve having a base end and a top end, wherein said syringe body is received inside the top end of the sleeve in a close fit with the rimmed end of the syringe body located intermediate the top end and the base end of the sleeve; and (d) piston support means in contact with the sleeve, said piston support means having a support surface on which the piston is supported with its upper surface spaced from the rimmed end of the syringe body and substantially concentric therewith, such that a gap exists between the upper surface of the piston and the rimmed end of the syringe body, thereby permitting sterilization of the syringe body and the piston by a sterilizing gas.  
           [0011]    In another aspect, the present invention provides a method for producing a pre-filled syringe body for a pre-filled syringe, the syringe body comprising a barrel and a piston, the barrel having a generally cylindrical side wall with an inner surface and an outer surface, the side wall extending between a neck end and a rimmed end of the barrel, the piston being generally cylindrical and formed of an elastomeric material with an upper surface, a side surface adapted to form a hermetic seal with the inner surface of the barrel when inserted into the open rimmed end of the barrel, and a lower surface opposite the upper surface, the method comprising: (a) forming a first assembly comprising said elastomeric piston, a generally cylindrical sleeve having an inner surface, and outer surface, a base end and a top end, and piston support means in contact with the sleeve and having a piston support surface on which the piston is supported with its lower surface engaging the piston support surface, the piston support surface being spaced radially inwardly of the inner surface of the sleeve; (b) forming a second assembly by inserting the rimmed end of the barrel into the top end of the sleeve to a sufficient depth that the barrel is stably supported in the sleeve, and such that the rimmed end is located intermediate the top end and the base end of the sleeve with a gap between the upper surface of the piston and the rimmed end of the barrel; (c) sterilizing the second assembly with a sterilizing gas; (d) applying a force to the second assembly to cause relative movement of the barrel toward the base end of the sleeve, causing insertion of the piston into the barrel such that the side surface of the piston forms a hermetic seal with the inner surface of the barrel and seals the rimmed end of the barrel; (e) filling said barrel with a medicament or a component thereof through the neck end using equipment for filling and capping pharmaceutical vials; and (f) capping the neck end of the barrel using said equipment for filling and capping pharmaceutical vials; wherein, subsequent to insertion of the piston in step (d), said second assembly is conveyed through at least a portion of said equipment for filling and capping pharmaceutical vials while freestanding in an upright position. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0012]    The invention will now be described, by way of example only, by reference to the accompanying drawings in which:  
         [0013]    [0013]FIG. 1 schematically illustrates a method for preparing a prefilled syringe barrel according to a first preferred embodiment of the present invention;  
         [0014]    [0014]FIG. 2 illustrates the lower portion of the syringe barrel of FIG. 1 prior to insertion of the piston into the body;  
         [0015]    [0015]FIG. 3 illustrates the lower portion of the syringe barrel of FIG. 1 after insertion of the piston into the body;  
         [0016]    [0016]FIG. 4 schematically illustrates a variant of the method shown in FIG. 1 in which the syringe barrels are packaged in trays for sterilization;  
         [0017]    [0017]FIG. 5 schematically illustrates a variant of the method shown in FIG. 1 in which the body is filled with a powder;  
         [0018]    [0018]FIG. 6 schematically illustrates a variant of the method shown in FIG. 1 in which the body is filled with a freeze-dried medicament;  
         [0019]    [0019]FIG. 7 illustrates combination of the syringe barrel of the first preferred embodiment with other components to form a delivery device for a two component medicament;  
         [0020]    [0020]FIG. 8 schematically illustrates a method for preparing a prefilled syringe barrel according to a second preferred embodiment of the present invention;  
         [0021]    [0021]FIG. 9 schematically illustrates a variant of the second preferred embodiment in which a plurality of piston supports and sleeves are secured to a handling tray;  
         [0022]    [0022]FIG. 10 schematically illustrates another variant of the second preferred embodiment in which a plurality of piston supports are secured to a handling tray;  
         [0023]    [0023]FIG. 11 illustrates a variant of the syringe barrel according to the second preferred embodiment of the present invention;  
         [0024]    [0024]FIG. 12 illustrates a further variant of the syringe barrel according to the second preferred embodiment of the present invention;  
         [0025]    [0025]FIG. 13 illustrates a further variant of the syringe barrel according to the second preferred embodiment of the present invention; and  
         [0026]    [0026]FIG. 14 illustrates a variant of the syringe barrel according to the first preferred embodiment of the present invention. 
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0027]    A first preferred embodiment of the invention will now be discussed below in the context of a syringe barrel which is intended for use in a delivery device for a two component medicament. Such a delivery device is described in U.S. Pat. No. 6,149,623, issued on Nov. 21, 2000 and co-owned by the applicant of the present application, which is incorporated herein by reference in its entirety.  
         [0028]    [0028]FIG. 1 illustrates a preferred sequence of steps to be followed during preparation of a prefilled syringe barrel  10  for use in a two component delivery device. The illustrations of the syringe barrel shown in FIG. 1 are somewhat schematic. Details of the lower portions of the syringe barrel  10  are more clearly shown in FIGS. 2 and 3.  
         [0029]    The barrel  10  comprises a body  12  preferably made of glass and having a generally cylindrical side wall  14  with an inner surface  16  and an outer surface  18 . At one end, the body  12  has a relatively narrow neck  20  with a neck flange  21  surrounding an open mouth  22 , and at the other end the body  12  has an open rimmed end  24 . Although the lower end of the body  12  is referred to herein as the “rimmed end”, it is to be appreciated that the body  12  may or may not have a perceptible inwardly or outwardly extending rim at its lower edge.  
         [0030]    The body  12  illustrated in FIG. 1 has a height to base ratio of approximately 4.5:1. It will be appreciated that the present invention can be utilized with barrels of various dimensions, including barrels having greater height to base ratios than that shown in FIG. 1, and barrels having lower height to base ratios, such as the vial-shaped barrels described above which generally have height to base ratios not exceeding 2.5:1.  
         [0031]    Barrel  10  further comprises a generally cylindrical elastomeric piston  26  having an upper surface  28  which forms the bottom wall of the barrel  10  in its assembled state, and an opposed lower surface  30  with an internally threaded bore (not shown). Piston  26  also has a side surface  32  connecting the upper and lower surfaces  28  and  30 , the side surface  32  being adapted to form a hermetic seal with the inner surface  16  of body  12 , and preferably being provided with one or more ribs  34  to improve the seal with the body  12 . Piston  26  is preferably made from an elastomeric material such as rubber.  
         [0032]    The open neck  20  of body  12  is sealed in a conventional manner by an elastomeric closure  36  with an overlying metal cap  38  crimped over the neck flange  21 .  
         [0033]    Barrel  10  is also provided with an activation cap  40  at its rimmed end  24 , the cap  40  performing a number of functions which are described below. As best seen in FIGS. 2 and 3, activation cap  40  comprises a generally cylindrical sleeve  42  having a base end  44  and a top end  46 , the rimmed end  24  of body  12  being received inside the top end  46  of sleeve  42  in a close fit with the rimmed end  24  being located intermediate the top end  46  and the base end  44  of the sleeve  42 .  
         [0034]    Preferably, the sleeve  42  has an inwardly projecting portion  48  extending radially inwardly from the inner wall of the sleeve  42  The inwardly projecting portion  48  shown in FIG. 1 comprises a detent of sufficient shape and size to retain the rimmed end  24  of the syringe body  12  intermediate the top end  46  and the base end  44  of the sleeve  42  in the absence of a force which pushes the rimmed end  24  of the body  12  and the base end  44  of the sleeve  42  toward one another, but which permits the rimmed end  24  to be pushed toward the base end  44  in response to a predetermined force, such as a downward force applied to the body  12  when the barrel  10  is standing upright on the base end  44  of the sleeve  42 . As defined herein, a detent includes any inward projection of the sleeve  42  which is effective to retain the rimmed end  24  of the body  12 , including a continuous circumferential lip or one or more protrusions, as shown in FIGS.  1  to  3 , on the inner surface of the sleeve  42 .  
         [0035]    The activation cap  40  further comprises piston support means  50  including a piston support surface  52  on which the piston  26  is supported such that its upper surface  28  is spaced from the rimmed end  24  of the body  12 , thereby providing a gap  54  between the piston and the body  12  which permits exposure of substantially the entire piston  26  and body  12  to a sterilizing gas as discussed below in greater detail Furthermore, the piston  26  is supported such that it is substantially concentric with the rimmed end  24  of the body  12 , ready for insertion into the rimmed end  24 .  
         [0036]    In the preferred embodiment of FIG. 1, the piston support means  50  is in contact with the sleeve  42  and is integrally formed therewith, both being components of the activation cap  40 . As shown in FIG. 1, the piston support surface  52  is positioned radially inwardly of the inner surface of the sleeve  42 . Preferably, the piston support surface  52  is spaced inwardly from the inner surface of the sleeve  42  by a distance which is substantially equal to the thickness of the body side wall, thereby forming an annular recess  56  between the piston support surface  52  and the inner surface of the sleeve  42  The annular recess  56  has a bottom wall  58  connecting the piston support means  50  and the sleeve  42  and located intermediate the piston support surface  52  and the lower surface of the base end  44  of the sleeve  42 , such that when a predetermined force is applied to push the rimmed end  24  of the body  12  into the annular recess  56  until the rimmed end  24  engages the bottom wall  58 , the piston  26  becomes fully inserted in the body  24  with its side surface  32  forming a hermetic seal with the inner surface  16  of the body  12 .  
         [0037]    In order to permit engagement of piston  26  by a plunger, the piston support surface  52  is annular with a central aperture  64 , and engages an outer edge of the lower surface  30  of the piston  26 . In the embodiment illustrated in FIGS.  1  to  3 , the piston is preferably provided with a threaded bore (not shown) open to its lower surface  30  which is adapted for connection to the threaded end of a plunger (shown in FIG. 4)  
         [0038]    As discussed above, the system of the invention is adapted to improve the stability of conventional, elongate syringe barrels, thereby permitting them to be conveyed standing upright through standard equipment for filling and capping pharmaceutical vials. This object is partly attained by provision of the sleeve  42 , which may lower the centre of gravity of the 
         [0039]    somewhat, thereby improving its stability. Stability can be further enhanced by increasing the thickness of the sleeve  42  throughout part or all of its height For example, as shown in FIG. 1, the sleeve  42  may preferably be provided with an outwardly projecting flange  66  at its base end  44 . The flange  66  has a diameter and a height so as to prevent interference such as would cause tipping when the 
         [0040]    is conveyed standing upright on the base end  44  through standard equipment for filling and capping pharmaceutical vials. Such interference typically comprises a phenomenon known as “shingling”, in which the flange of one barrel rides up over the flange of another barrel, resulting in tipping.  
         [0041]    Shingling can be prevented as shown in the preferred embodiment of FIG. 1, in which the flange  66  has a substantially flat radially outwardly facing wall sufficient height that the flanges  66  of adjacent  10  will not ride up over one another.  
         [0042]    [0042]FIG. 1 illustrates the steps involved in assembling and filling a barrel  10  with a liquid component of a medicament, which may comprise an active ingredient or a diluent to be combined with an active ingredient prior to administration.  
         [0043]    The first step of the method, illustrated In FIG. 1 a , comprises the formation of a first assembly  70  by inserting the piston  26  inside the sleeve  42  of activation cap  40  such that the lower surface  30  of piston  26  engages the piston support surface  52 .  
         [0044]    In the second step illustrated in FIG. 1 b , a second assembly  72  is formed by inserting the rimmed end  24  of body  12  into the top end  46  of sleeve  42  to a sufficient depth that the body  12  is stably supported in the sleeve  42 , and so that the rimmed end  24  is located intermediate the top end  46  and the base end  44  of the sleeve and gap  54  being formed between the upper surface  28  of piston  26  and the rimmed end  24  of the body  12 , thereby permitting sterilization of the body  12 , piston  26  and activation cap  40  by a sterilizing gas. A close-up cross-sectional view of the lower portion of second assembly  72  is shown in FIG. 2.  
         [0045]    The next step in the method, schematically illustrated in FIG. 1 d , comprises sterilization of the second assembly  72  by a sterilizing gas such as steam or ethylene oxide. FIG. 4 schematically illustrates a variant of the method of claim 1 in which the sterilization is performed while a plurality of assemblies  72  are packaged in trays  73  and covered with a plastic overwrap  75  so as to maintain sterility and keep them in place. A preferred plastic overwrap is sold under the trade-mark TYVEK™, which maintains sterility while allowing penetration of sterilizing gases such as ethylene oxide.  
         [0046]    After sterilization, a force is applied to the second assembly  72  to cause relative movement of the body  12  toward the base end  44  of the sleeve  42 , thereby causing insertion of the piston  26  into the body  12  such that the side surface  32  of the piston  26  forms a hermetic seal with the inner surface  16  of the body  12  and seals the rimmed end  24 . Preferably, the body  12  is pushed downward into sleeve  42  in the direction shown by the arrow in FIG. 1 d . This step may be performed while the assemblies  72  are packaged in trays  73  and covered with the overwrap  75 . Alternatively, the overwrap  75  may preferably be removed from the sterile assemblies  72  (preferably in a sterile environment) prior to pushing the body  12  into sleeve  42 , and the assemblies  72  may preferably also be removed from the tray  73  prior to performing this step.  
         [0047]    With the piston  26  fully inserted in the body  12  as shown in FIG. 1 e , and shown in greater detail in FIG. 3, the body  12  is now ready to be filled with a medicament, or a component thereof In this embodiment, the medicament is a liquid which is filled into the open mouth  22  of the body  12 . As discussed above, the body  12  is filled on standard equipment for filling and capping pharmaceutical vials, and is conveyed through at least part of said equipment freestanding on the base end  44  of sleeve  42 . The filled body  12  is illustrated in FIG. 1 f.    
         [0048]    The mouth  22  of the body  12  is then sealed in a conventional manner by application of an elastomeric closure  36  as shown in FIG. 1 g , followed by application of a metal cap  38  over the closure  36  as shown in FIG. 1 h , the cap  38  preferably being crimped over the neck flange  21  of the body  12 . This is also the most common method for sealing standard pharmaceutical vials and is therefore easily performed on standard equipment for filling and capping pharmaceutical vials.  
         [0049]    The next step in the method is illustrated in FIG. 1 i  and comprises an optional terminal sterilization step, in which the sealed barrel  10  is subjected to sterilization, for example by exposure to high temperatures in an autoclave. This step is also part of the normal vial filling process and is performed on standard equipment for filling and capping pharmaceutical vials.  
         [0050]    As mentioned above, the barrel  10  of the first preferred embodiment comprises an activation and is therefore specifically directed to delivery devices for two component pharmaceuticals In the example described above, a liquid medicament, or a liquid component of a medicament, is contained in the barrel  10 . However, the first preferred embodiment is also adaptable to the situation where the barrel  10  contains a solid medicament or a solid component of a medicament, which is to be combined with a liquid, such as a diluent, prior to administration.  
         [0051]    A first preferred method for filling barrel  10  with a solid medicament is illustrated in FIG. 5. The steps followed in FIG. 5 are preferably the same as those described above with reference to FIGS.  1 , with the exception of step  5   f , in which a powdered substance is filled into body  12  through the mouth  22 . Powder filling is also performed on standard equipment for filling and capping pharmaceutical vials.  
         [0052]    A second preferred method for filling barrel  10  with a solid medicament is illustrated in FIG. 6. FIGS. 6 a  to  6   e  show preparation of the second assembly  72 , followed by sterilization and seating of the piston  26  in the barrel body  10 . These steps are identical to the steps followed in FIGS. 1 a  to  1   e , discussed above. Next, the body is filled in FIG. 6 f  with a liquid composition containing a medicament or a component thereof. This step is identical to that shown in FIG. 1 f . Next, a lyophilization stopper  74 , comprising a vented elastomeric closure, is partially inserted into the neck  20  of body  12  such that a vent space  76  is formed. The liquid contents of the body  12  are then lyophilized as shown in FIG. 6 g  such that only a solid remains in the body  12 . The stopper  74  is then completely inserted into neck  20  to close vent space  76  and seal the body, and a metal cap  38  is applied as in FIG. 1 h . Although not shown in FIG. 6, the sealed barrel may be subjected to terminal sterilization. The steps shown in FIGS. 6 f  to  6   i  are performed on standard equipment for filling, lyophilizing and capping pharmaceutical vials.  
         [0053]    As mentioned above, the barrel  10  according to the first preferred embodiment is specifically adapted for use in a two component delivery device, such as preferred delivery device  78  shown in FIG. 7 b . In order to assemble delivery device  78 , the 
         [0054]    is combined with a pre-assembly  80  of the type illustrated in FIG. 7 a , comprising a standard pharmaceutical vial  82  having a sealed neck  84 , a vial coupling  86  with a vial socket  88  into which the neck  84  of vial  82  is received, and a syringe socket  90  with a finger flange  91  into which the barrel  10  is received.  
         [0055]    The pre-assembly further comprises a rear needle  93  and a forward needle  94  housed in a luer lock assembly  96  which is secured to both the vial coupling  86  and the syringe socket  90 . When the delivery device  78  is assembled as in FIG. 7 b  with the finger flange  91  engaging the top end  46  of activation cap  40 , the ends of needles  93  and  94  do not penetrate the elastomeric closures of either the vial  82  or the barrel  10 . The device  78  is activated by pushing the syringe socket  90  and the activation cap  40  together such that the sleeve  42  of the cap  40  becomes received inside syringe 
         [0056]    . The socket  90  and cap  40  are pushed together until the finger flange  91  engages the flange  66  of activation cap  40 , at which point the ends of needles  93  and  94  penetrate the closures of the barrel  10  and the vial  82  respectively, allowing mixing of the respective contents of the vial  82  and barrel  10 , in this example by attaching plunger  98  to the piston  26  and aspirating the liquid contents of the vial  82  into the barrel  10 . The vial coupling  86  is then unthreaded from the luer  96 , also removing the forward needle  94  An injection needle (not shown) is then threaded onto the exposed luer  96  to provide a complete prefilled disposable syringe (not shown). The components of pre-assembly  80 , and the method for combining barrel  10  and pre-assembly  80  are described in greater detail in above-mentioned U.S. Pat. No. 6,149,623, which is incorporated herein by reference in its entirety. It will be appreciated that the activation cap  40  described herein functions in a manner similar to the driver described in the above-mentioned U.S. patent and identified by reference numeral  21  in FIGS. 17 and 18 thereof.  
         [0057]    Where the barrel  10  contains a liquid medicament or a component thereof, the vial  82  of pre-assembly  80  may comprise either a solid or a liquid. Where the vial  82  contains a solid, the medicament is formed by pushing the liquid contents of barrel  10  into the vial  82 , mixing the solid and liquid ingredients, followed by aspiration of the medicament suspension or solution into the barrel  10  prior to removal of the vial coupling  86 .  
         [0058]    A second preferred embodiment of the present invention is now described below with reference to FIG. 8, comprising preparation of a barrel  110  for use in the preparation of a prefilled disposable syringe for administration of a single component medicament A barrel similar to barrel  10  is shown in FIG. 13 of U.S. Pat. No. 5,137,511, issued on Aug. 11, 1992, commonly assigned to the assignee of the present invention, and incorporated herein by reference in its entirety.  
         [0059]    Barrel  110  comprises a body  112  preferably made of glass and having a generally cylindrical side wall  114  with an inner surface  116  and an outer surface  118 . At one end, the body  112  has a relatively narrow neck  120  with a neck flange  121  surrounding an open mouth  122 , and at the other end the body  112  has an open rimmed end  124 . Preferably. the rimmed end  124  is provided with an inwardly extending projection  125  which has a function to be described below. The dimensions of body  112  are similar to those of body  12  described above, although it will be appreciated that the dimensions of body  112  can be varied as discussed above in the context of the first preferred embodiment.  
         [0060]    Barrel  110  further comprises a generally cylindrical elastomeric piston  126  having an upper surface  128  which forms the bottom wall of barrel  110  in its assembled state, and an opposed lower surface  130 . Piston  126  also has a side surface  132  connecting the upper and lower surfaces  128  and  130 , the side surface  132  being adapted to form a hermetic seal with the inner surface  116  of body  112 , and preferably being provided with one or more ribs  134  to improve the seal with the body  112 . Piston  126  is preferably made from an elastomeric material such as rubber. The lower surface of piston  126  comprises an extension  139  for attachment to a plunger as described in greater detail in above-mentioned European Patent No. 298,585.  
         [0061]    The open neck  120  of body  112  is sealed in a conventional manner by an elastomeric closure  136  with an overlying metal cap  138  crimped over the neck flange  121 .  
         [0062]    The barrel  110  further comprises a stabilization cap  140  which has a number of functions. Firstly, stabilization cap  140  functions as a piston support means, having a cylindrical portion  142  with an upper end  144  and a lower end  146 , the upper end having a piston support surface  148 . The outer diameter of the cylindrical portion  142  is such that the cylindrical portion  142  can be received inside the body  112 . The stabilization cap  140  also has a radially projecting flange  150  at its lower end which functions as a finger flange during use of the syringe. Furthermore, the cylindrical portion  142  of cap  140  has a radially inwardly recessed band  152  which is adapted to form a snap fit with the inwardly projecting portion  125  of the body side wall  114 , thereby preventing removal of piston  126  from the body.  
         [0063]    [0063]FIG. 8 illustrates the steps involved in assembling and filling a barrel  110  with a liquid component of a medicament. The first step, illustrated in FIG. 8 a , comprises placement of the of the piston  126  on top of the piston support surface  148  of the stabilization cap, such that the extension  139  of piston  126  is received inside the cylindrical portion  142 , which is of sufficient height that the extension  139  does not contact the surface on which the stabilization cap  140  is supported.  
         [0064]    The next step comprises placement of a cylindrical sleeve  154  over the piston  126  and cap  140  as illustrated in FIG. 8 b . The cylindrical sleeve  154  performs a function similar to that of sleeve  42  of activation cap  40  described above, namely to add stability to the barrel  110  and to support the body  112  in spaced relation to the piston  126  during initial assembly of the barrel  110  In contrast to sleeve  42  of cap  40 , the cylindrical sleeve  154  does not form part of the barrel  110 , but rather is removed after filling and capping of the barrel  110  on standard equipment for filling and capping pharmaceutical vials. As with sleeve  42 , the cylindrical sleeve  154  can further enhance stability of the barrel  110  by being increased in thickness, by providing a flange similar to flange  66  of the cap  40 , and/or by forming the sleeve  154  from a relatively dense material, such as stainless steel. Since the sleeve  154  is removed from the barrel, preferably for re-use, forming the sleeve from a relatively thick and/or dense material does not add to the weight or cost of the barrel.  
         [0065]    As shown in FIG. 8, it may be preferred to form the sleeve with a partial recess  156  in its lower surface  158  to fit over the flange of the stabilization cap  140 , thereby substantially centring the piston  126  within the sleeve  154  and preventing relative movement between the sleeve  154  and the cap  140 .  
         [0066]    After combining the piston  126 , stabilization cap  140  and sleeve  154  to form a first assembly  160  as shown in FIG. 8 c , the body  112  is inserted into the top end of the sleeve  154  to form a second assembly  162 . with the body  112  being inserted into the sleeve  154  to a sufficient depth that the body  112  is stably supported therein and so that the rimmed end  124  of the body  112  is supported intermediate the top end of sleeve  154  and the flange  150  of the stabilization cap  140 .  
         [0067]    Preferably, the inner surface of the sleeve  154  is provided with a detent  164  which prevents premature insertion of the piston  126  into the body  112 , as discussed in detail with reference to the first preferred embodiment.  
         [0068]    The next step of the method, illustrated in FIG. 8 d , comprises sterilization of the second assembly  162  by a sterilizing gas. As in the first preferred embodiment, a plurality of assemblies  162  may preferably be packaged in trays with a plastic overwrap prior to sterilization. After sterilization, the piston  126  is inserted into the body  112  by pushing the body  112  downward relative to sleeve in the direction of the arrow shown in FIG. 8 e  until the inward projection  125  of body  112  snaps into the recess  152  of the stabilization cap.  
         [0069]    The steps followed for filling, capping and terminal sterilization of the sealed body  112  are shown in FIGS. 8 e  to  8   i  and are identical to the corresponding steps followed in FIGS. 1 e  to  1   i . As with the first preferred embodiment, these steps are performed on standard equipment for filling and capping pharmaceutical vials, with the sealed body  112  and the associated sleeve  154  being conveyed through at least a portion of this equipment while freestanding upright on the finger flange  150 .  
         [0070]    After removal of the sleeve  154 , the barrel  110  can be combined with a needle (not shown) and a plunger (not shown) to form a prefilled disposable syringe, as described in above-mentioned U.S. Pat. No 5,137,511.  
         [0071]    [0071]FIG. 9 and  10  illustrate variants of the second preferred embodiment of the invention in which components of the system are attached to trays. In the variant shown in FIG. 9, prefilled syringe barrels  168  are produced by combining a body  12  or  112  with a piston  126  having an extension  139 . The barrels  168  include neither an activation cap  40  or a stabilization cap  140  and are therefore similar to pharmaceutical vials, although they may preferably have a greater height to base ratio than standard pharmaceutical vials.  
         [0072]    In the variant shown in FIG. 9, a handling tray  170  is provided on which are arranged a plurality of support assemblies  172 , each of which comprises a generally cylindrical sleeve  174  having a base end and a top end, and piston support means  176  integrally formed with the sleeve  174  and having an annular piston support surface  178  adapted to support piston  126  by engaging the lower surface  130  thereof. A plan view of tray  170  with support assemblies  172  is shown in FIG. 9 d . As in the first embodiment shown in FIGS.  1  to  3 , piston support surface  178  is spaced from the inner surface of sleeve by a distance substantially equal to a thickness of the wall of the body  12  or  112  to form an annular gap  180  into which the rimmed end of the body  12  or  112  is received during insertion of the piston  126  into the body  12  or  112 .  
         [0073]    In order to assemble syringe barrels  168 , the pistons  126  are first inserted into support assemblies  172  as shown in FIG. 9 a  and supported on the piston support means  176 . Next, the bodies  12  or  112  are inserted into the sleeves  174  as shown in FIG. 9 b  and supported therein with their rimmed ends spaced above the upper surfaces  128  of the pistons  126 . In order to support the bodies  12  or  112  in the position shown in FIG. 9 c , the inner surface of each sleeve  174  is preferably provided with a detent (not shown) as described above in the context of sleeve  42  and  154 . After sterilization, the pistons  126  are then inserted into the bodies  12  or  112  by pushing the bodies  12  or  112  downward such that the rimmed ends thereof are pushed down into the gaps  180  (FIG. 9 c  and  9   e ), as described above in connection with the first preferred embodiment illustrated in FIG. 1.  
         [0074]    After insertion of the pistons  126 , the trays  170  and the barrels  168  are conveyed through equipment which is adapted for filling syringe barrels packaged in trays. After filling, the barrels  168  are sealed and capped as described above, preferably while standing on the trays  170 . The filled and capped barrels  168  may then be removed from trays  170  prior to shipment, with the trays being reused. Alternatively, the tray  170  and barrels  168  may be shipped as a unit to their final destination.  
         [0075]    illustrates a variant of the method of FIG. 9, in which trays  182  are provided with piston support means  184  attached thereto. A plan view of the tray is shown in FIG. 10 a . As shown in FIG. 10 b  and  10   c , pistons  139  are placed on the support means. The bodies  12  or  112  are inserted into an assembly  186  comprising a plurality of sleeves  188  joined together, the inner surface of each sleeve  188  having a detent (not shown) to support the rimmed end of the body as shown in FIG. 10 d . After insertion of bodies  12  or  112  into sleeves  188  as shown in FIG. 10 d , the assembly  186  is placed over the tray  182  so that a piston support means  184  and an associated piston is inserted into each sleeve  188  as shown in FIG. 10 e . After sterilization, the the pistons  126  are inserted into bodies  12  or  112  as shown in FIG. 10 e , thereby providing a tray of sterilized barrels shown in FIG. 10 f , ready for filling and capping as described above with reference to FIG. 9.  
         [0076]    [0076]FIG. 11 illustrates a variant of the second preferred embodiment in which a syringe barrel  192  is produced by combining a body  12  or  112  with a piston  26  having an internally threaded bore. As in the variant shown in FIGS  9  and  10 , the variant of FIG. 11 does not include an activation cap  40  or a stabilization cap  140 . in the variant of FIG. 11, the barrel  192  is stabilized on standard equipment for filling and capping vials by a stabilization means  194  comprising a sleeve  196  and an integrally formed piston support means  198  comprising an annular piston support surface  200  and having a raised central portion  201  to be received in the bore of the piston  26 , thereby centring the piston inside the sleeve  196 . The sleeve  196  is provided with a plurality of axially extending, circumferentially spaced support ribs  195 , best seen in FIG. 11 d , which is a cross-sectional plan view showing the stabilization means  194  in isolation, the cross-section being taken in a plane perpendicular to the axis of sleeve  196  and between the detents  202  and the piston support means  198 . As shown in FIG. 11 a , each rib  195  is provided with a detent  202  on its inner surface for supporting the body  12  or  112  above the upper surface  28  of the piston.  
         [0077]    To produce a prefilled syringe barrel  192 , the piston  26  is first inserted into the stabilization means as shown in FIG. 11 a . Next, the body  12  or  112  is inserted into the sleeve  196  as shown in FIG. 11 b  until the rimmed end engages the detents  202  on ribs  195  as shown in FIG. 11 c . It is to be noted that only the stabilization means  194  is shown in cross-section in FIGS. 11 a  to  11   c , with the other components being shown in elevation. The remaining steps are analogous to those shown in FIG. 8, with the exception that, after the barrel  192  is filled and capped, it is pulled out of engagement with the stabilization means  194 .  
         [0078]    [0078]FIG. 12 also illustrates a variant of the second preferred embodiment, and is similar to the variant of FIG. 11, with the exception that it is adapted for forming a syringe barrel comprising a body  12  or  112  and a piston  126  having an extension  139 . As in FIG. 11, the embodiment of FIG. 12 utilizes a stabilization means  190  comprising a sleeve  191  and a piston support means  193 , the sleeve  191  having a plurality of axially extending ribs  197 , each of which is provided with a detent  199 . FIG. 12 a  illustrates the subassembly of the piston  126  and the stabilization means  190  prior to insertion of body  12  or  112 , FIG. 12 b  illustrates body  12  or  112  having been inserted into sleeve  191  and being supported by detent  189 , such that a gap exists between the rimmed end of the body  12  and the upper surface of piston  126 . In FIGS. 12 a  and  12   b , only the stabilization means  190  is shown in cross section, with the other components being shown in elevation. FIG. 12 c  is a cross-sectional plan view showing the stabilization means in isolation, in a plane which is perpendicular to the axis of sleeve  191 , and which is between the detents  199  and piston support means  193 .  
         [0079]    [0079]FIG. 13 illustrates yet another variant of the second preferred embodiment, which is similar to that illustrated in FIG. 8 except that piston  126  is replaced by piston  26  having an internal bore, and sleeve  154  is replaced by sleeve  203 , having axially extending ribs  205 , each of which is provided with a detent  207 . As shown in FIG. 13 b , ribs  205  terminate immediately below detents  207 . FIG. 13 a  illustrates piston  26  being placed on stabilization cap  204 , comprising a cylindrical portion  206  with a flange  208  at the base end thereof, the flange  208  serving as a finger flange. Stabilization cap  204  also comprises a recessed band  210  adapted to snap into engagement with the inwardly projecting portion  125  at the rimmed end  124  of body  112  FIG. 13 b  illustrates the placement of the cylindrical sleeve  203  over the piston  26  and the stabilization means  204  to form the assembly  212  shown in FIG. 13 c . FIG. 13 c  also shows insertion of the insertion of body  112  into sleeve  203  to form the assembly  213  shown in FIG. 13 d , which is ready for sterilization and further processing according to the method described in connection with FIG. 8. FIGS. 13 a  to  13   d  illustrate the sleeve  203  in cross section and the other components in elevation FIG. 13 e  is a cross-sectional plan view showing the sleeve  203  in isolation, taken in a plane extending through ribs  205  and perpendicular to the axis of sleeve  203 .  
         [0080]    [0080]FIG. 14 illustrates a variant of the first preferred embodiment of the present invention, identical to that shown in FIGS.  1  to  3  except that syringe body  12  is replaced by body  214  having a rimmed edge  216  with slight outward projection  218  and a slight inward projection  220 . FIG. 14 a  is analogous to FIG. 2 and illustrates an assembly comprising the body  214 , plunger  26  and activation cap  40  prior to insertion of piston  26  into body  214  FIG. 14 b  is analogous to FIG. 3 and illustrates the assembly of FIG. 14 a  after the body  214  has been pushed down into activation cap  40 , and piston  26  is inserted into body  214 .  
         [0081]    It will be appreciated that the activation caps, stabilization caps, sleeves and handling trays described above will preferably be made from materials which are substantially unaffected by the conditions employed during sterilization. As sterilization is usually performed at elevated temperature, it is preferred that these components be made of heat-resistant materials. It is preferred that these components be formed from plastics, more preferably heat-resistant plastics.  
         [0082]    Furthermore, it may be preferred in some embodiments of the present invention to utilize syringe bodies and pistons which are siliconized. Siliconization is preferably performed during manufacture of the syringe body and the piston.  
         [0083]    Although the invention has been described with reference to certain preferred embodiments, it is not limited thereto. Rather, the invention includes all embodiments which may fall within the scope of the following claims