Abstract:
A system is provided for providing syringes filled with pharmaceuticals whose components must be stored separately, using a liquid such as water in a pharmaceutical vial, an active ingredient in a protosyringe such as a bottomless vial or a cartridge, and a combiner assembly which enables the content of the pharmaceutical vial to be transferred into the protosyringe and converts it into a ready-to-use syringe on activation. The combined assembly includes a tubular body having recesses at opposite ends for receiving capped ends of the vial and the protosyringe, and a hub and needle assembly between penetrable sheaths or shields which acts on activation of the assembly to enable the transfer and conversion referred to above. Components of the system may also be used to convert protosyringes and pharmaceutical vials containing pharmaceuticals into delivery systems.

Description:
REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of application Ser. No. 09/114,063, filed on Jul. 13th, 1998 now U.S. Pat. No. 6,149,623, which is a continuation-in-part of International Patent Application PCT/CA97/00017, filed on Jan. 10th, 1997, which is a continuation-in-part of application Ser. No. 08/584,049 filed Jan. 11, 1996 and now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to delivery systems for multiple component pharmaceutical preparations. 
     Many pharmaceutical preparations must be distributed as two or more separate components which can only be combined shortly before administration of the preparation, usually because the combined preparation is subject to rapid deterioration or otherwise unstable, and the components are only stable when stored separately. Typically at least one component of such a preparation is a liquid which acts as a solvent, diluent or carrier for the other component. 
     Traditionally such preparations have been prepared shortly before administration by taking one component packaged in a conventional pharmaceutical vial having a neck closed by a penetrable elastomeric stopper secured to a neck of the vial by a cap, taking a second liquid component in a hypodermic syringe, injecting the second component into the vial through the stopper, swilling the vial impaled on the syringe to dissolve, dilute or suspend the first component in the second component, and aspirating the combined components back into the syringe by withdrawing its plunger. This procedure requires a degree of dexterity, is subject to the errors commonly associated with manual on-site preparation of pharmaceuticals, and may compromise sterility. If a third component is used, the procedure must be repeated. 
     In endeavours to overcome these problems, many proposals have been made for systems to provide prepackaged two component pharmaceuticals, but these tend to suffer from one or more problems of their own such as complex and expensive structure requirements for specialized filling equipment, complex manipulation at the time of use, and often most serious of all, a heavy burden in time and expense in obtaining regulatory approval for a new product. 
     A further factor which may influence the practicability of a delivery system arises when one of the components of the system needs to be pure injectable water. Substantial difficulties arise in providing prefilled containers, including prefilled syringes, containing injectable water, due to a dearth of container material and structures within which such highly purified and sterile water can maintain its stability to a sufficient degree for the necessary regulatory approvals to be obtained. On the other hand, injectable water is available, with the necessary approvals, in conventional pharmaceutical vials. 
     U.S. Pat. No. 3,872,867 (Killinger) utilizes a tubular assembly incorporating a double ended cannula, into which two pharmaceutical vials are pressed in order to combine components in the two vials. The system requires that one of the vials is under vacuum or pressure, and merely results in a vial containing the combined product, which must still be transferred to a syringe for administration. 
     U.S. Pat. No. 3,563,373 (Paulson) discloses an arrangement utilizing two cartridges in tandem for packaging a two component pharmaceutical, utilizing an intermediate assembly incorporating a double ended needle, which penetrates the piston of one cartridge and neck stopper of the other. The arrangement cannot utilize a standard pharmaceutical vial. 
     U.S. Pat. No. 4,060,082 (Lindberg) also requires two syringes in tandem for combining a two component pharmaceutical, as well as specialized auxiliary pistons in the syringes. 
     U.S. Pat. No. 4,583,971 (Bocquet et al) discloses apparatus for transferring liquid through a cannula from a flexible container to dissolve a pharmaceutical, and returning the solution to the flexible container. The system is dependent upon manipulation of a frangible closure through the flexible container and could not be used to transfer liquid from a syringe to a pharmaceutical vial and back again. 
     U.S. Pat. No. 5,171,214 (Kolber et al) discloses a combination of a vial assembly, a syringe assembly, and an adapter for attaching the vial assembly to the syringe assembly so that a liquid constituent may be transferred from the syringe to the vial and the admixed compounds returned to the syringe. A special vial and special syringe are required, and indeed the system is predicated upon the use of a proprietary vial assembly. 
     An object of the present invention is to provide a delivery system for two component pharmaceuticals which is economical to manufacture, easy to manipulate, and can minimize regulatory burdens. 
     SUMMARY OF THE INVENTION 
     According to the invention, there is provided an activation assembly for preparing a prefilled syringe from separately prepackaged components of a multicomponent pharmaceutical preparation, the assembly comprising a two part tubular body; the body defining in a first part a first cylindrical recess at one end of a diameter to receive, as a sliding fit, a discharge end of cylindrical body of a protosyringe at which end is located a closure, broachable on activation of the protosyringe, the recess also receiving a substantial portion of the cylindrical body of the protosyringe, which contains a first, liquid component of the pharmaceutical preparation and which is provided at its opposite end with a piston displaceable longitudinally of the cylindrical body and forming a hermetic seal therewith; a second cylindrical recess defined in the other end of the tubular body by a second detachable part to receive a cap securing a penetrable closure at the neck of the pharmaceutical vial containing a second component of the pharmaceutical preparation; the tubular body defining in said first part a passage connecting the cylindrical recesses; a hub movable longitudinally of the tubular body within the passage; 
     a cannula extending longitudinally of the tubular body from said hub to a distal end directed towards the second recess; a penetrable shield member covering the distal end of the cannula and located to contact a penetrable closure of a pharmaceutical vial inserted in the cylindrical recess, and a hollow cylindrical overcap concentric with the hub assembly and located within the tubular body in the first cylindrical recess, the overcap being connected to the hub to limit movement of the latter into the passage; the depth of the cylindrical recesses, the length of the passage connecting the recesses, the extent of the cannula from the hub, and the location of the overcap i the first cylindrical recess being such that upon a protosyringe received in the first cylindrical recess and a vial received in the second recess being displaced towards each other, the overcap is displaced onto the discharge end of the protosyringe and the hub moves longitudinally so that the cannula penetrates the penetrable shield member and the penetrable closure of the vial to place the cap of the protosyringe and the vial in fluid communication through the cannula; 
     wherein the protosyringe and the vial can be driven directly towards each other to effect penetration of the shield member and the penetrable closure of the vial, wherein a portion of the hub supporting the cannula is separately formed and detachable from the hub assembly, the hub assembly having a luer on which said separately formed portion is releasably lodged, and wherein means is provided within the detachable part of the tubular assembly to detain, within the tubular assembly, said one end of the cannula when the cannula is driven into a position into a position penetrating the cap of the pharmaceutical vial. 
     Two terms used in the preceding paragraph and elsewhere in this specification and the appended claims require mention. A ‘protosyringe’ is an assembly intended to form the basis of a prefilled syringe but requiring the addition of components to form a complete syringe. At minimum, it includes a cylindrical body containing at least a component of a pharmaceutical product, the body being closed at one end by a broachable closure and being at an opposite end with a piston connected to or provided with means for connection to an activating plunger so that the latter may be used to displace the contents of the body. Protosyringes include bottomless vials as described in my U.S. Pat. No 5,364,369; cartridges; and prefilled syringes requiring at least addition of an overcap as defined below and introduction of a further component of the pharmaceutical product to provide a ready to use syringe. An ‘overcap’ is a cap adapted to be lodged on the cap of a protosyringe and providing means for supporting a needle or other instrumentality through which contents of a syringe formed from the protosyringe may be discharged. In some instances, a complete prefilled syringe itself may be used as a protosyringe if it has a luer connection closed by a cap of penetrable material over which an overcap may be received. 
     The invention also extends to the combination of such an assembly with a protosyringe and/or pharmaceutical vials already engaged in their associated cylindrical recesses. If the protosyringe is already engaged in the first cylindrical recess, its free end may be covered by a removable cap to prevent accidental projection into the cylindrical bottom resulting in premature actuation of the assembly. When a protosyringe or vial is preengaged in its cylindrical recess, the associated sealing member in the assembly is in resilient contact with the penetrable closure of the vial in areas concentric with the cannula so as to help maintain sterility of areas of the sealing members and closures intended to be penetrated by the cannula. 
     The hub assembly and a modified overcap may also be utilized in conjunction with a protosyringe or pharmaceutical vial to provide alternative delivery systems for pharmaceuticals contained in the protosyringe or vial. 
     Further features of the invention will be apparent from the following description of embodiments of the invention. 
    
    
     IN THE DRAWINGS 
     FIG. 1 is an exploded view of the components of an assembly according to the invention, including both a protosyringe, in this case a bottomless vial, and a pharmaceutical vial; 
     FIG. 2 illustrates an assembly according to the invention, including a bottomless vial, as it might be shipped; 
     FIG. 3 illustrates a similar assembly, but further including a pharmaceutical vial, ready for activation; 
     FIG. 4 illustrates in part sectional view components of an assembly according to FIG. 3, but with upper components removed for clarity; 
     FIG. 5 is a similar view to FIG. 4, but showing the illustrated components in the relationship which they assume after activation of the assembly in order to prepare a completed prefilled syringe; 
     FIG. 6 is a view of the assembly corresponding to FIG. 3, after activation; 
     FIG. 7 is a view of the assembly after the plunger has been pressed upwardly to transfer liquid from the bottomless vial to the pharmaceutical vial; 
     FIG. 8 is a view showing a mixing step; 
     FIG. 9 shows upper portions of the assembly being removed, leaving a syringe ready for application of a needle or other discharge means; 
     FIG. 10 shows a partially exploded view of a modified embodiment of delivery system utilizing a different form of protosyringe; 
     FIGS. 11 and 12 are fragmentary sectional views of an alternative form of syringe socket and associated parts which permit elements of the delivery system to be used in further embodiments of delivery system in conjunction with prefilled protosyringes or pharmaceutical vials; 
     FIG. 13 shows in section a cap which may be applied to a luer on a hub portion of the embodiment of FIGS. 11 and 12 to enable the hub to be driven from the position to FIG. 11 to that of FIG. 12 to activate a prefilled protosyringe; 
     FIG. 14 shows in an exploded view parts of an alternative activation system for use with the embodiment of FIGS. 11 and 12 so as to activate a syringe or vial for use in conjunction with a standard flexible mini-bag; 
     FIG. 15 shows an assembled syringe ready for activation; 
     FIG. 16 shows an activated syringe applied to a mini-bag; 
     FIG. 17 is an exploded view illustrating components of a presently preferred modification of the embodiment of FIGS. 1-9; 
     FIG. 18 shows the parts shown in FIG. 17 assembled ready for use, less the plunger; 
     FIGS. 19 and 20 illustrate a presently preferred modification of the embodiment of FIGS. 11 and 12; 
     FIG. 21 illustrates the assembled components of a further embodiment of assembly according to the invention; 
     FIG. 22 is an exploded view of components of a hub assembly used in the embodiment of FIG. 21; 
     FIG. 23 illustrates a modification of the embodiment of FIG. 18, showing how the assembly of the invention may be used to activate pharmaceuticals having more than two components; 
     FIG. 24 illustrates an assembly in accordance with a further embodiment of the invention; 
     FIG. 25 is a flow diagram illustrating the preparation of assemblies in accordance with the embodiment of FIGS. 17 and 18; and 
     FIGS. 26 and 27 are exploded and assembled views of a further embodiment of the invention. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Referring first to FIGS. 1 to  3 , the parts are shown of an assembly for preparing a syringe containing a pharmaceutical preparation, components A and B of which are contained respectively in a pharmaceutical vial  2  and a protosyringe in the form of a bottomless vial  4  consisting of a cylindrical body  6 , open at one end and provided with a neck  8  at its other end, the neck being closed by an elastomeric closure  10  secured in place by a metal cap  12  crimped over the neck. A piston  14  is lodged in the open end of the body, the piston being provided with means  16  by which a detachable plunger  18  may be secured to the piston. The plunger will normally be shipped detached from the piston, both to reduce the overall length of the assembly, and to permit a removable cap  20  to be applied over a projecting end of the bottomless vial  4  as shown in FIG. 2 so as to prevent inadvertent premature activation of the assembly. 
     At least one of the components A and B is liquid; usually it will be convenient to locate a liquid component in the bottomless vial but it would be possible to locate a solid component in the bottomless vial provided that the latter also contains an air or gas volume sufficient to displace liquid contents of the vial  2 . 
     Since a typical two component pharmaceutical for administration via a syringe comprises an active ingredient and a liquid solvent, diluent or carrier (hereinafter collectively referred to as diluent for convenience) which in the majority of cases will be one of only a few different types (most usually distilled water), it will usually be advantageous to place the active component in the vial  2 ; this is because in many, if not most cases, a suitable vial package of the active ingredient will already be certified by regulatory cylindrical recess  31  into which may be slid the body  6  of the bottomless vial  4 , although not initially to the full extent permitted by the depth of the recess. 
     The end portion  26  of the syringe socket includes a guide  52  with detents  53  for controlling longitudinal movement of a hub  34  having gapped longitudinal ribs  33 . The hub is formed at a front end with a liquid delivery conduit through a standard luer as utilized in the industry for coupling needles, or other delivery instrumentalities forming liquid delivery conduit extensions, to syringes and other sources of liquid pharmaceuticals. Such a luer comprises an internally threaded socket  36  for locking a needle in place, and a tapered central spigot  38  for establishing a seal with a complementary socket on the needle. In the present instance, a hollow transfer needle  40  has a socket  41  lodged on the central spigot, but is not provided with threads to engage those of the socket  36 , so the needle  40  may be pulled from the spigot  38 . A tapered shoulder  42  is formed on the transfer needle  40 . The hub  34  has a hollow needle or cannula  44  projecting from its end opposite the spigot  38  and in communication with a central passage in the spigot. A flexible needle sheath or shield  46  of thin rubber covers the needle  44 , having a portion  48  engaging a socket in the end of the hub  34 , and a flattened end  50  over the free end of the needle. Internally of the guide  52 , the end portion  26  of the syringe socket also contains an extension of the cylindrical recess  31  dimensioned to provide an overcap which is a press fit over the cap  12  of the bottomless vial  4 . 
     The vial coupling  22  has a passage extending from recess  30  which receives vial  2  to its internally threaded end, the passage being closed by a rubber stopper or shield  54 . Between the rubber stopper and the internally threaded end of coupling  22 , passage is formed internally with resilient pawls  56  which will detain the shoulder  42  of the needle  40  when the latter is pressed past the pawls. 
     The assembly just described may be shipped on its own with neither vial installed, in which case a removable cover (not shown) will be required to cover the cylindrical recess in the coupling  22  to maintain sterility, or with one or both vials installed (see FIGS.  2  and  3 ). When a vial  2  is installed, any removable central portion of a cap  60  covering a penetrable closure  58  of the vial is flipped off, so that the penetrable closure may contact a rib  64  on the stopper  54  to enclose an axial sterile zone of the two rubber parts  58  and  54 . Likewise, an axial zone of the closure  10 , similarly exposed, contacts the end  50  of the needle sheath  46  to provide protected zones on the contacting rubber parts. 
     In order to activate the assembly, after installation of the vials to provide the arrangement shown in FIG. 3, the bottomless vial is pressed into the syringe socket  24 , and the plunger  18  is attached to reach the condition shown in FIG.  6 . 
     Thereafter, the assembly is inverted and plunger  18  is activated to project the liquid content B from the bottomless vial into the pharmaceutical vial, (see FIG.  7 ), the assembly then being swilled as shown in FIG. 8 to dissolve, mix or suspend the contents of the vial  2  in the liquid, which is then aspirated back into the bottomless vial by withdrawing the plunger to reach a condition similar to that of FIG. 6, except that component A is now incorporated into component B to leave a product C in the bottomless vial. The vial  22  is now unscrewed from the syringe socket  24  and withdrawn, taking with it the transfer needle  40  which is pulled off the spigot  38  by the pawls  56 , thus leaving the luer of hub  34  ready to receive a needle or other fluid connection instrumentality, and providing a completed ready to use syringe, filled with the two component pharmaceutical (see FIG.  9 ). The hub  34  is retained on the cap  12  of the bottomless vial by the syringe socket  24 , with the needle providing a passage between the body  6  and the luer  36 ,  38 . 
     If the initial position of liquid and solid components is reversed, the step of FIG. 7 may be performed without inversion, with reciprocation of the syringe plunger being used to force air or gas from the vial  4  to the vial  2 , and liquid from the vial  2  to the vial  4 . 
     A presently preferred modification of the assembly described above is shown in FIGS. 17 and 18, in which the same reference numerals are used to designate similar parts, and only the differences are described. In this modification, the flange  35  of the hub  34  is extended to form the overcap, and the portion  26  of the syringe socket  24  acts to receive the forward portion of this overcap when the syringe body  6  is forced forward against and into the overcap during activation of the syringe. As best understood from FIG. 25, this rearrangement facilitates assembly. The cap  20  is replaced by a driver in the form of a tubular cylindrical element  21 , which snaps into the opening of the syringe socket  24  as shown in FIG. 18 in a position in which it covers the rear of the protosyringe, and from which position it can be driven forward to activate the assembly. The element  21  has a bottom aperture to accommodate the plunger  18 . The stopper  54  is replaced by a flexible sheath  54  similar to the shield  46 , since this is found to simplify assembly and provides complete coverage of the needle  40 . 
     It will be noted that the plunger  18  in the embodiment of FIGS. 17 and 18 is provided with ribs  18  at its distal end. This facilitates an alternative mode of activation of the assembly in which the plunger  18  is assembled to the piston  14  prior to activation, and activation is achieved by pressure on the plunger. This initially drives the hub forward so that the cannula  40  penetrates the closure of he vial  2 , then drives the cap  12  into the overcap  35  to penetrate the closure of the protosyringe so that the contents of the latter may be delivered into the vial. The ribs  18   a  abut the periphery of the opening in the bottom of the driver  21  as the plunger nears the end of its stroke, and presses forward the driver so that it snaps into the sleeve  24 , thus signaling the completion of activation. 
     Various modifications are possible within the scope of the invention, the above description being of a presently preferred example. For instance, the needle  40  could be permanently secured to the hub  34 , and the pawls in the vial omitted. Such an arrangement does not provide the user with any choice as to the needle to be used on the finished syringe, and needle length may be severely limited by the need to avoid excess needle extent into the vial  2 , which would make it difficult to aspirate its contents. 
     Likewise, the bottomless vial  4  may be replaced by other forms of protosyringe such as cartridges, or by a prefilled syringe provided with an elastomeric closure covering a luer connection, the front end of the syringe accepting an overcap providing such a needle connection and acting to retain the hub. Such an arrangement is exemplified in FIG. 10, which shows the bottomless vial replaced by a protosyringe which is a conventional prefilled syringe having a conventional luer nozzle  101  protected by a protective rubber sealing cap  100  over a front end of the syringe body, and the syringe socket  24  is modified in shape to receive the body  6  of the syringe, with longitudinal internal ribs  102  to grip the syringe body. As before, a cap  20  prevents the syringe body from being driven fully into the syringe socket  24  until activation is required, and the end  50  of the shield  46  rests against the cap  100  to help maintain sterility of the zones to be penetrated by the needle  44 . 
     Yet further forms of protosyringe may be employed. For example, a known form of diluent vial comprises a body  6  in the form of a glass tube with a piston at both ends. The piston at one end is similar to the piston  14  with an extension similar to the extension  16 . The piston at the other end fulfills the function of the neck  8 , stopper  10  and cap  12  of the bottomless vial shown in FIG.  1 . In conventional use, this other end of the vial is inserted into an open end of a sleeve which at its other end supports a luer or needle externally and an axial hollow pin projecting internally. The piston at the other end of the vial has an axial passage, through the piston and an outward extension of the piston, closed at its outer end by a bung which is displaced by the hollow pin on insertion of the vial into the sleeve, thus establishing communication between the needle or luer and the interior of the vial. Protosyringe from a vial into a syringe is completed by applying a plunger to the piston at the first end. This type of protosyringe can be substituted in the present invention for that shown in FIG. 1 or FIG.  17 . During activation, the overcap  16  or  35  will be driven into the extension of the piston at said other end of the vial so that the needle  44  penetrates the sheath  46  and displaces the bung. The bung may be replaced by an integral septum in the passage of the piston which is penetrated by the needle  44 . 
     The syringe socket itself may be made detachable from the completed syringe except for the overcap, or may be truncated in length as shown in FIGS. 11 and 12. It will be seen that the syringe socket  24  is shortened and reduced in diameter to receive the cap  12  of a bottomless vial, the syringe socket being pushed down over the cap  12  to engage the shoulder of the syringe body  6 . 
     On activation of the syringe the hub  34  is driven downwardly relative to the end portion  26  of the socket  24  from the position shown in FIG. 11 to the position shown in FIG.  12 . In the position shown in FIG. 11, the end  50  of the rubber shield  46  rests against the closure  10  so as to provide a protected contact zone, which is penetrated by the needle  44  on the hub  34  as the hub is driven downwardly through the guide  52  until a flange  35  on the bottom of the hub  34  contacts the closure  10 . At this point the needle  44  establishes communication with the interior of the body  6  of the protosyringe. 
     FIG. 21 shows how the arrangement of FIGS. 11 and 12 (or FIGS. 19 and 20 considered below) may be used in an arrangement in which the assembly is activated by insertion of the vial  2 . As best seen in FIG. 22, the component  42  is lengthened and modified so that it, the penetrable shield  54  on the cannula  40 , and the cannula  40  itself, project into the vial socket  32 . On insertion of the vial  2 , the shield  54  is pressed into a recess in the arrangement  42  so that it is penetrated by the cannula, which also penetrates the closure of the vial  2 , and the vial closure presses on the component  42  so as to drive the cannula  44  through its sheath or shield and the penetrable closure of the protosyringe. If the modification of FIGS. 19 and 20 is used, with a hub  34  modified as shown in FIG. 22 so that the flange  35  provides the overcap, this driving action also drives the overcap  35  onto the cap of the protosyringe. If the arrangement of FIGS. 11 and 12 is used, the cap of the protosyringe is already lodged in the overcap. 
     FIG. 13 illustrates an alternative means of driving the hub  34 . The luer spigot  38  of the hub  34  is covered by a conventional moulded cover  104 , shown in section in FIG. 13, screwed into the socket  36  and providing a convenient driver for the hub which can be unscrewed and discarded preparatory to fitting a needle to the luer of the hub. 
     FIGS. 14 and 15 illustrate an alternative driver arrangement, making use of a known type of adapter used to couple syringes to flexible mini-bags so that the contents of the syringe may be discharged into the bag and mixed with the contents of the latter. The adapter  106  consists of a tube  108  which has an internally threaded socket  118  at one end for screwing in the present case on to complementary external threads on the portion  26  of a syringe socket  24 , and slots  110  at the other end to engage lugs on a nipple of the bag so that the nipple is guided into the adapter concentrically aligned with a needle  112  fitted to the spigot  38  of the hub  34 . A cap  114  covers the slotted end of the tube  108 , and has a concentric internal tubular extension  116  that sheathes the needle  112 , and extends the socket  36  of the hub  34  when the latter is in the position shown in FIG. 11, with the tube  108  extending only part way into the cap  114 . Pushing further on the cap will force the hub  34  from the position shown in FIG. 11 to the position shown in FIG. 12, thus activating the syringe. The cap  114  may then be removed, and the syringe applied to a mini-bag as shown in FIG.  16 . Alternatively the tube  10  may also be removed providing a ready to use syringe. 
     Instead of a protosyringe in the form of a bottomless vial, the arrangement of FIGS. 11,  12 ,  14  and  15  may also be used to activate a regular pharmaceutical vial so that its contents may be mixed with those of a mini-bag or other flexible bag. Liquid from the flexible bag may be caused to enter the activated vial through the needle, and the admixed contents of the vial then allowed to run back into the bag through the needle by suitable manipulation of the bag and the attached activated vial. 
     The arrangement shown in FIGS. 11 and 12 may also be modified as shown in FIGS. 19 and 20 by extending the flange  35  of the hub  34  to form the overcap (see also FIG.  22 ). In order to accommodate downward movement of the overcap while preventing inward movement of the protosyringe, the reduced diameter portion of the syringe socket is extended downward as at  27  to form a shoulder limiting insertion of the protosyringe. 
     FIG. 23 shows a modification of the embodiment of FIGS. 17 and 18 to allow preparation of a three component pharmaceutical. The vial socket  22  is bifurcated, as is the component  42 , so as to provide two vial sockets  30 , and two needles which are not seen since they are covered by sheaths  54 . On activation of the assembly by driving the driver  21  into the syringe socket  24 , the closures of the vials will be penetrated simultaneously, enabling liquid from the protosyringe body  6  to enter both vials  2  and dissolve or suspend their contents. On activation, latch members  56  engage the component  42  to retain it, as in previous embodiments. 
     A further vial socket  30  and a further branch of the component  42  may be provided for each additional component to be handled. 
     Referring now to FIG. 24, the principles of the invention may also be utilized with protosyringes in the form of a shell vial (or as shown, the functional equivalent of a shell vial produced by reversing a bottomless vial  206  as described in U.S. Pat. No. 5,364,369A and applying a driver cap  220  to its cap end). Such shell vials are normally formed into a completed syringe by screwing a threaded extension  216  of a piston  214  into a free end of a plunger stem within a concentric syringe shell connected to the other end of the plunger. A double ended needle extends axially of the plunger stem and out of its other end. Screwing the extension  216  fully onto the plunger stem causes the needle to penetrate the piston so that the contents of the shell vial may be expelled through the needle by driving the vial onto the plunger stem. Such an arrangement is described in U.S. Pat. No. 5,171,214A already referenced above. In the present instance, a syringe socket  224  provides the shell, and the hub assembly utilized in the embodiment of FIGS. 1-10, modified as shown in FIGS. 17 and 18, is further modified by providing an elongated cannula  244  surrounded by a concentric plunger stem  218  positioned on the cannula by passing through a flange  245  and entering the overcap  35 . The length of the cannula  244  is such that it ends short of a penetrable septum (not shown) within the piston  21  with the components in the unactivated state shown in FIG. 24, with the piston extension  216  screwed into a threaded socket at the bottom of stem  218 . 
     The assembly is activated by driving the shell vial upwardly so that a reduced diameter portion  219  of the stem  228  enters the overcap  35 , permitting the cannula  244  to perforate the septum in the piston. Further upward movement causes the cannula supported at the upper end of the hub to penetrate the sheath  64  and the penetrable closure of the vial  2 , whereafter activation can proceed as previously described save that the shell vial  206  is manipulated in place of a conventional plunger. 
     Referring now to FIG. 25, there is shown a flow diagram of the preparation of an assembly in accordance with the invention, specifically the embodiment of FIGS. 17 and 18. 
     Starting at the top left, the parts  34 ,  35 ,  42 ,  46  and  64  are assembled to form the hub assembly  300 , which is then sterilized by gamma radiation (step 32°). Within a clean room  314  (top right) the parts  6 ,  12 ,  14 ,  16  are assembled and filled to provide a protosyringe  304  to the cap of which the overcap  35  is applied, but not far enough for the cannula within the overcap  35  to penetrate the shield or sheath  46 , to provide subassembly  306 , which then passes through an inspection station  316 . 
     In the meanwhile parts  21 ,  22  and  24  are assembled to provide a subassembly  302  and, together with the plunger  18 , sterilized by gamma radiation at  322 . The assembly  306  of protosyringe and hub assembly is inserted into the assembly  302  under a laminar flow hood to provide the assembly  308 , whereafter, in the same environment, a vial  2 , from which any protective metal disc on the cap has been flipped off, is inserted into the vial socket of the assembly  308 , which corresponds exactly to that of FIG.  18 . The contacting surface of the penetrable closure  58  (see FIG. 1) of the vial  2  and the surface  50  of the shield  64  are sterilized by a high intensity ultraviolet flash or an antiseptic spray  318  during this step, whereafter the resulting assembly  310  together with the plunger  18  is sealed into a plastic tray  312 . The tray is vacuum formed with a recess shaped to correspond to the profile of the assembly  310 . In particular, it is advantageous that this recess snugly embraces the narrower portion of the actuator  21  to avoid any possibility of inadvertent activation prior to use occasioned by shock or rough handling. 
     Variations are of course possible in this procedure. For example, the protosyringe  304  like the vial might be preproduced and terminally sterilized, and assembled to the hub assembly to produce the assembly  306  in a similar manner to combination of assemblies  302  and  308 . 
     In the embodiments described above, activation of the protosyringe involves penetration of the closure of the protosyringe by a second cannula on the hub, but the invention is also applicable to protosyringes activated by other means. In U.S. Pat. No. 3,967,759 (Baldwin), there is disclosed a protosyringe in which the closure at the capped end of the body of the protosyringe is a plug lodged in an end of a tubular body, which closure is breached by ejection of the plug into a hollow interior of the cap such that the contents of the syringe may bypass the plug within the cap. 
     Such a protosryinge is activated by application of fluid pressure to the plug by the application in turn of longitudinal pressure to the piston of the protosyringe by a plunger, and thus the second cannula and its associated sheath is not required. 
     This arrangement is exemplified in FIGS. 26 and 27, in which the same reference numerals are used to identify the same parts as in FIGS. 1-8 or  17 , and only the points of difference will be discussed in detail. The components shown in the left hand portions of FIG. 26, with the exception of a filter  400 , are essentially identical to the corresponding components of the embodiment of FIGS. 17 and 18, but the protosyringe shown in the right hand of FIG. 26 is essentially similar to that described with reference to FIGS. 1-4 of U.S. Pat. No. 3,967,759 (Baldwin), the text and drawings of which are incorporated herein by reference, except that the piston retainer  402  pressed into the rear of the body  6  is formed without the external flange  25  shown in the Baldwin patent, and the connector  37  of the Baldwin patent is replaced by a more conventional luer connector  36 ,  38  forming a hub integral with the cap  12 , which otherwise corresponds to the cap  31  of the Baldwin patent, and is secured to the body  6  by means of a flange  404  pressed onto the body. The plug  10  corresponds to the plug  51  of the Baldwin patent, and may be formed with ribs similar to the ribs  53  of Baldwin or other means to ensure that, once the plug moves forward from the body  6  into the cap  12 , the seal formed by the plug remains broached, and liquid can bypass the plug. There are other systems known using displaceable plugs generally similar to that disclosed in the Baldwin patent but differing in detail in the means used to ensure that the plug remains bypassed once broached, and these could also be utilized. 
     An adaptor  400  containing a filter may be provided secured to the connector  41  on the cannula  40 , the adaptor being a press fit on the luer  38 , such that when the cannula  40  is captured by the detents  56  and the portion  22  is removed, the adaptor  400  discarded with the cannula  40  and the portion  22 . This enables a filter, incorporated in the adaptor  400 , to be utilized during transfer of liquid between the vial  2  and the protosyringe during an activation process, so that any particulate may be removed from the reconstituted pharmaceutical as it is drawn back into the protosyringe. 
     The activation process is generally quite similar to that previously described. Referring to FIG. 27, pressing down on the activation cap  21  causes the latter to move into the open end of the socket  24  and press the piston retainer  402  at the rear end of the body  6  so as to move the cap  12  into the overcap  26 . This moves the hub assembly formed by the luer  34 , adaptor  400  and cannula  40  upwardly within the sleeve  22  until the cannula  40  pierces the closure of the vial  2 . The plunger  18  can then be attached to the piston  14 , and on applying pressure to the plunger, the plug  10  is moved forward to broach the closure of the protosyringe at its capped end, allowing the contents of the syringe to be discharged through the cannula  40  into the vial  2 . After admixture (See FIGS.  4 - 9 ), the dissolved pharmaceutical is withdrawn back into the protosyringe through the cannula  40  and the filter in adaptor  400 , and the filled syringe is removed as shown in FIG. 9, leaving behind the cannula  40  and the adaptor  400  containing the filter, and presenting the luer  34  for attachment of a hypodermic needle or other injection instrumentality. 
     In another possible variation, the portion of cap  12  beyond the body  6  has a smaller rather than larger internal diameter than the body  6 , and the plug  10  is initially lodged in that portion of the cap  12 . The  44  of the FIG. 1 or  17  embodiment is replaced by an activator rod, and the hub is made axially movable only readily ailable prepackaged in pharmaceutical vials. The solid component B is in this case located in the bottomless vial  4 , as set forth as a possibility above, and this in turn can be advantageous when this component is lyophilized, as by freeze drying,in which case the bottomless vial may be as set forth in claim 7 of my U.S. Pat. No. 5,137,511, the text and drawings of which are imported herein by reference. 
     Rather than the fluid coupling established between the protosyringe and the vial during activation being established through a luer within the transfer device, it may be formed between a luer and an adaptor within the protosyringe, as set forth in my International Patent Application PCT/CA0000699 filed on Jun. 9, 2000.