Abstract:
A drug delivery device having a base member defining a skin-contacting surface, a syringe serving as a reservoir for the drug, and means for expelling drug from the syringe. The syringe is connected to the base member such that the longitudinal axis of the syringe is substantially parallel to the skin surface. A delivery needle is in communication with the syringe. The needle has an angled bend which directs the tip of the needle substantially perpendicular to the skin-contacting surface. In use, the tip of the needle is adapted to penetrate the skin of the subject.

Description:
RELATED APPLICATIONS 
     This application claims priority under 35 U.S.C. §119(e) of provisional patent application Ser. No. 60/093,062 having a filing date of Jun. 24, 1997 which in turn was converted from a utility patent application Ser. No. 08/881,542 filed on Jun. 24, 1997 which in turn claims priority under 35 U.S.C. §119(a)-(d) of Irish Patent Application No. 970445 filed on Jun. 16, 1997. 
    
    
     TECHNICAL FIELD 
     This invention relates to pre-filled drug delivery devices, and in particular to devices for attachment to the skin of a subject having a needle for penetration of the skin of the subject. 
     BACKGROUND OF THE INVENTION 
     WO 97/21457, which is incorporated herein by reference, discloses a liquid drug delivery device having a base member defining a skin-contacting surface for application to the skin of a subject. A columnar cartridge serving as a reservoir for the drug is connected to the base member such that in use the longitudinal axis of the cartridge is disposed substantially parallel to the skin-contacting surface. A delivery needle communicates in use with the interior of the cartridge and is adapted to penetrate the skin of the subject, and there is provided means for expelling a drug out of the interior of the cartridge and through the skin of the subject via the delivery needle. 
     It has been found that adapting conventional cartridges (such as cartridges for pen-type insulin injectors, or other drug cartridges well known in the art) so as to enable an expelling means to expel the drug therefrom, and so as to enable communication with a delivery needle forming part of such a device, increases the costs of the cartridge considerably, and this in turn adds to the cost of the overall device and hence its attractiveness to consumers. The main reason for this is that conventional drug cartridges are relatively inexpensive, but redesigning such a component and changing the manufacturing process, or individually modifying such components drives costs up considerably. 
     Nevertheless, in technical terms, the devices of WO 97/21457 have undoubted advantages over the prior art due to the fact that the disposition of the cartridge parallel to the skin enables the device to be applied to the skin and worn unobtrusively during drug delivery. Both application of the device and delivery of the drug can be accomplished in a single step requiring little or no manual dexterity. 
     A further problem associated with the devices of WO 97/21457 is in relation to the delivery needle which effectively extends at right angles to the axis of the cartridge. This may be accomplished by using a conduit arrangement leading from the cartridge to a conventional needle, or by means of a right-angled needle which extends from an end of the cartridge co-axially with the axis of the cartridge and then bends through a right angle to penetrate the skin. The latter arrangement is preferred since it reduces the number of parts and the complexity of the device. However, it may prove difficult to bend a needle while maintaining sterility (which is of course essential), since the sterility of the needle is assured by a protective sheath which extends the entire length of the needle and which may be damaged in the bending process. 
     For devices which employ a needle to penetrate the skin there is a danger that after use the device may accidentally infect the patient or others if not properly disposed of Our WO 95/13838 discloses an intradermal device of this type having a displaceable cover which is moved between a first position in which the needle is retracted before use and a second position in which the needle is exposed during use. Removal of the device from the skin causes the cover to return to the first position in which the needle is again retracted before disposal. 
     The present invention aims to decrease the possibilities that the needle could become exposed by accident before or after use for example by a child playing with the device if not properly disposed of. Clearly given the risks associated with infectious diseases, particularly those carried by blood, any possibility of accidental infection must be minimised to the utmost and preferably eliminated entirely. Some of the features of devices according to the invention which address these problems are set out below, and further advantages will become apparent from the following description. 
     In devices of the present invention, a conventional syringe barrel is mounted relative to a base member defining a skin-contacting surface, with the longitudinal axis of the needle substantially parallel to the skin-contacting surface in use. 
     SUMMARY OF THE INVENTION 
     The invention provides a base member defining a skin-contacting surface for application to the skin of a subject; 
     a syringe serving as a reservoir for the drug and which is connected to the base member such that in use the longitudinal axis of the syringe is disposed substantially parallel to the skin-contacting surface; 
     a delivery needle in communication with the syringe, the needle having an angled bend which directs the tip of the needle substantially perpendicular to the skin-contacting surface such that in use the tip of the needle is adapted to penetrate the skin of the subject; and 
     means for expelling a drug out of the interior of the syringe. 
     Preferably, the syringe is a pre-filled syringe. 
     By employing a conventional syringe, preferably a pre-filled syringe, the devices of the present invention avoid the need for custom-designed components for which it may be difficult to obtain regulatory approval and manufacturing validation from bodies such as the U.S. Food and Drug Administration (F.D.A.) and similar other national bodies. 
     It has been found that while conventional drug-containing components such as cartridges and pre-filled syringes are relatively inexpensive, redesigning such components and changing the manufacturing process, or individually modifying such components drives costs up considerably for the device as a whole, which decreases the attractiveness of such devices to customers. Thus, devices of the present invention which employ widely available syringe bodies will be advantageous over corresponding devices which include a non-standard drug chamber. 
     Preferably, a mounting member is mounted along the length of the exterior of the needle at the angled portion. Such a mounting member serves two purposes: firstly it acts as a mounting point for a seal or sheath to ensure sterility of the portion of the needle which will contact or penetrate the skin, and secondly it may assist in the correct bending of the needle during the manufacturing process. 
     Preferably, the mounting member is permanently affixed to the needle. 
     Further, preferably, a sealing sheath is mounted on the mounting member. 
     The sheath is preferably removably mounted on the mounting member. 
     Preferably, means are provided for driving a piston along the interior of the syringe barrel, and these means are also mounted relative to the skin-contacting surface. Preferably, both the syringe barrel and the driving means are mounted within a housing. 
     In preferred embodiments, the driving means is disposed alongside the syringe barrel rather than at the end thereof, as this arrangement may lead to a more ergonomic design, as well as to advantages in the manner in which the driving means may be actuated as will be explained below in greater detail. 
     Preferably, the driving means is a gas generator. 
     Suitably, a tube provides communication between the gas generator and a piston in the syringe. 
     In one embodiment, the needle extends from the neck of the syringe barrel parallel to the longitudinal axis of the syringe and then bends to a substantially right angle, such that the tip of the needle points perpendicularly to the longitudinal axis of the syringe. 
     Preferably, the sealing sheath is provided with a flexible pull tab which extends through a release liner. 
     Further, preferably, when the pull tab is pulled away from the base member, the release liner is pulled away from a lower surface of the base member and the sealing sheath is detached from the mounting member to reveal the needle tip. 
     In one embodiment, the base member is pivotally mounted to a housing of the device. 
     Preferably, the device is provided with a removable locking member such as a semi-rigid safety tab which prevents relative movement of the base member towards the housing following removal of the sealing sheath and the release liner, thereby retaining the needle within the housing until skin penetration is required. 
     Further, preferably, relative motion of the housing towards the base member causes activation of the gas generator while optionally simultaneously causing the needle tip to penetrate the skin. 
     Preferably, the base member is displaceable relative to the housing between a first position in which the needle is concealed from the exterior of the device and a second position in which the delivery needle protrudes from the device for penetration of the skin, the device further comprising means for locking the device in the first position after a single reciprocation of the device from the first position to the second position and back to the first position. 
     In this embodiment preferably the locking means comprises a mechanical latch which is brought into operation by said reciprocation. 
     In an especially preferred embodiment said latch comprises a pair of elements mounted on the base member and the housing respectively, said elements being shaped such that they can have two relative configurations when the base member is in said first position relative to the housing, namely a movable configuration in which the elements are mutually movable, and a locked configuration in which the elements are prevented from mutual movement, and wherein reciprocation of the base member and the housing causes the elements to pass from the first movable configuration, through an intermediate configuration when the base member is in said second position relative to the housing, and then to said locked configuration, thereby preventing any further movement of the base member relative to the housing. 
     Also preferably one of said elements is provided with a recess which is adapted to receive a projection on the other of said elements, the recess and the projection being spaced apart from one another in the movable configuration, and being in engagement with one another in the locked configuration. 
     Further, preferably, movement of the base member relative to the housing is initially prevented by said removable locking member. 
     Still further, preferably, the presence of said removable locking member also prevents the means for providing a gas from being actuated. 
     The removable locking member preferably comprises a laminar member inserted between said base member and said housing. 
     In a preferred embodiment following delivery of drug through the needle, any residual gas is vented through a release valve. 
     In one embodiment means are provided for enabling a user to determine that delivery of drug has been completed. 
     In a further embodiment, the syringe barrel is provided with an end piston in addition to an internal piston so as to allow for mixing of a drug in a lyophilised form with a diluent, said internal piston initially dividing the interior of the syringe barrel into a diluent compartment and a drug compartment. 
     Preferably, the pressure resulting from the gas generator is transmitted through the diluent compartment so as to push the internal piston into the drug compartment allowing for ingress of diluent into said drug compartment. 
     In a further preferred embodiment a travel limiting mechanism is provided to limit the maximum amount of travel of the internal piston along the length of the syringe barrel so that the dose of drug can be adjusted to suit individual user needs. 
     It will be appreciated that the locking means described herein is capable of having a broad application in drug delivery devices having a drug delivery needle. 
     Thus in a further embodiment the invention provides a drug delivery device comprising: 
     a housing having an internal drug reservoir; 
     a drug delivery needle extending from the housing for penetration of the skin of a subject, the needle having an outlet for drug delivery; 
     a base member defining a skin-contacting surface for application to the skin of a subject, said base member being displaceable relative to the housing between a first position in which the needle is concealed from the exterior of the device and a second position in which the delivery needle protrudes from the device for penetration of the skin, the device further comprising means for locking the device in the first position after a single reciprocation of the device from the first position to the second position and back to the first position. 
     Preferably, the base member is pivotally mounted to the housing. 
     Preferably, the locking means comprises a mechanical latch which is brought into operation by said reciprocation. 
     Also preferably, said latch comprises a pair of elements mounted on the base member and the housing respectively, said elements being shaped such that they can have two relative configurations when the base member is in said first position relative to the housing, namely a movable configuration in which the elements are mutually movable, and a locked configuration in which the elements are prevented from mutual movement, and wherein reciprocation of the base member and the housing causes the elements to pass from the first movable configuration, through an intermediate configuration when the base member is in said second position relative to the housing, and then to said locked configuration, thereby preventing any further movement of the base member relative to the housing. 
     Further, preferably, one of said elements is provided with a recess which is adapted to receive a projection on the other of said elements, the recess and the projection being spaced apart from one another in the movable configuration, and being in engagement with one another in the locked configuration. 
     Still further, preferably, movement of the base member relative to the housing is initially prevented by said removable locking member. 
     The invention also includes a method of manufacturing and filling drug delivery devices in which a syringe barrel is filled with a drug under sterile conditions, with the fluid path and the skin-contacting and—penetrating portion of the needle also sealed or sheathed under sterile conditions. After this is completed, the remainder of the manufacturing and assembly steps can be carried out in a clean area (as opposed to a sterile area) since the sealed pre-filled syringe barrel remains sterile. 
     Thus, the invention provides a method for manufacturing and filling a drug delivery device comprising: 
     providing a base member having a skin-contacting surface; a syringe having drug therein and which is connected to the base member such that in use the longitudinal axis of the syringe is disposed substantially parallel to the skin-contacting surface; a delivery needle in communication with the syringe, the needle having an angled bend which directs the tip of the needle substantially perpendicular to the skin-contacting surface such that in use the tip of the needle is adapted to penetrate the skin of the subject; and means for expelling a drug out of the interior of the syringe, filling the syringe barrel with the drug under sterile conditions with the drug delivery path and the skin-contacting and skin-penetrating portions of the needle under sterile conditions and carrying out the remainder of the manufacturing and assembly steps in a clean area. 
     The term “clean area” denotes an area of high cleanliness as would be expected for manufacturing medical devices. The term “sterile area” denotes a higher standard of cleanliness (i.e. sterility) such as is required for areas in which syringes are pre-filled. While medical devices must be assembled in clean areas according to well defined standards, the level of cleanliness is not as stringent as for a filling suite in which parenteral drug containers are filled. By pre-filling and sealing all parts of the fluid path, one obtains a component which can be assembled with other components under normal clean area conditions. 
     Preferably, the sterility of the drug delivery path and the skin-contacting and skin-penetrating portions of the needle is achieved by securely affixing a mounting member along the exterior length of the needle under sterile conditions. 
     Further, preferably, the drug delivery path and the skin-contacting and skin-penetrating portions of the needle are sealed by means of a sheath mounted on the mounting member. 
     Preferably, the external mounting member is used as a bending point when a right-angled needle is required. 
     The sterility of portion of the needle adjacent the needle tip may be assured by securely affixing a mounting member along the exterior length of the needle and ensuring that the mounting member and needle are sterile, following which a sheath or seal is mounted on the mounting member. Subsequent steps of manufacture can then be carried out on the needle without compromising sterility. For example, the external mounting member can be used as a bending point if a right-angled needle is required. 
     Because of the difficulties in manipulating axially unsymmetric components on a mass-production line, particularly where an unsymmetric part of the component protrudes sideways from an otherwise regular device (e.g. a syringe barrel with a bent needle extending perpendicularly for skin penetration) it is desirable to bend the needle as late as possible in the assembly process. 
     Conversely, because the sheath guarantees sterility, it is desirable to sheath the needle as early as possible in the manufacturing process (since remaining steps can be carried out in the less expensive clean area). 
     However, when a seal or sheath is mounted on the neck of the barrel to cover the needle, it is difficult to bend the needle without damaging the sheath and compromising sterility. Equally, it is difficult to mount a sheath on a bent needle since the manipulation may be difficult and the tip of the needle is likely to damage the sheath. Thus, the use of a sterile sheath and the requirement of a bent needle give rise to a conflict as to the most desirable method of manufacture. 
     The use of a mounting member solves this problem in two respects. Firstly, it enables the sheath to be applied at an early stage (during the filling of the syringe barrel, for example). The sterile barrel can then be removed from the sterile area for further manufacturing/assembly steps. Secondly, the needle can be bent with the sheath intact without having to contact the sheath and risk damage. The needle can be held by the mounting point and bent, and this step can be carried out in a clean environment without any risk to the sterility of the fluid path or the portion of the needle which penetrates or contacts the skin. 
     In a further aspect the invention provides a method of delivering drug to a subject comprising the steps of: 
     providing a drug delivery device having a skin-contacting surface, a syringe having drug therein, and which is connected to the base member such that in use the longitudinal axis of the syringe is disposed substantially parallel to the skin contacting surface, a delivery needle in communication with the syringe, the needle having an angled bend, and means for expelling a drug out of the interior of the syringe; 
     applying the device to the skin of the subject; and 
     activating the device. 
     Preferably, the tip of the delivery needle is substantially perpendicular to the skin contacting surface such that in use the tip of the needle is adapted to penetrate the skin of the subject. 
     Also preferably, the the means for expelling the drug comprises a gas generator. 
     Further, preferably, the syringe is prefilled. 
     Also preferably the device is activated by moving the housing towards the base member. 
     Preferably, the movement of the housing simultaneously causes the needle to penetrate the skin. 
     Further, preferably, the method comprises the step of causing the device to lock into position after use whereby the needle tip is recessed within the housing. 
     Other objects, features and advantages of the present invention will become apparent upon reading the following detailed description of the embodiments of the invention, when taken in conjunction with the drawings and appended claims. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The invention will be further illustrated by the following description of embodiments thereof, given by way of example only with reference to the accompanying drawings. 
     FIG. 1 is a sectional plan view of a drug delivery device according to the invention; 
     FIG. 2 is a sectional side view of the device of FIG. 1, shown after assembly; 
     FIGS. 3-5 are sectional side views of the device of FIG. 1, shown in successive stages of preparation and deployment for application to the skin of a subject; 
     FIGS. 6 and 7 are sectional side views of the device of FIG. 1, shown during and at the end of delivery, respectively; 
     FIGS. 8 and 9 are plan views of the device of FIG. 1, shown during and at the end of delivery, respectively; 
     FIG. 10 is a sectional side view of the device of FIG. 1, shown after the device has been removed from the skin; 
     FIGS. 11-13 are sectional side views of the device of FIG. 1 taken through the gas generator, at successive stages corresponding to FIGS.  4 , 5  and  10 , respectively; 
     FIGS. 14-18 are sectional side views components of the device of FIG. 1, shown during successive stages of manufacture; 
     FIG. 19 is a cross-sectional side view of the device of FIG. 1, taken through the needle thereof; 
     FIGS. 20-22 are sectional side views of an alternative embodiment of a device according to the invention, which enables a lyophilised drug to be reconstituted and delivered to a subject; 
     FIG. 23 is a sectional side view of a further variation on the device of FIG. 1; and 
     FIG. 24 is a sectional plan view of the device of FIG.  23 . 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In FIG. 1 there is indicated, generally at  10 , a drug delivery device according to the invention. The device  10  comprises a housing  11  in which a standard hypodermic syringe barrel  12  is mounted. A drug  13  is contained in the syringe barrel  12  and the drug is sealed by a conventional syringe piston  14 . 
     A gas generator  15  which will be described in greater detail below is mounted in the housing alongside syringe barrel  12 , and a tube  16  provides communication between gas generator  15  and piston  14 . 
     A needle  17  is mounted in conventional manner at the neck  18  of syringe barrel  12  to provide a conduit for delivery of drug  13  from syringe barrel  12  under an applied pressure from piston  14 . 
     Referring to FIG. 2, the device  10  can be seen in sectional elevation with housing  11 , syringe barrel  12 , drug  13 , piston  14 , tube  16  and needle  17  visible. It will be seen that needle  17  extends from neck  18  of syringe barrel  12  parallel to the longitudinal axis of syringe barrel  12 , and that needle  17  then bends through a right angle such that the tip  19  points perpendicularly to the longitudinal axis of syringe barrel  12 . A plastics mounting member  20  is permanently affixed to needle  17 , and a protective sealing sheath  21  is removably mounted on mounting member  20 . Protective sealing sheath maintains the sterility of needle  17  below mounting member  20 , and in particular needle tip  19 . 
     Housing  11  has a base member  22  pivotally mounted thereon at a hinge  23 . The lower surface  24  of base member  22  is provided with a contact adhesive layer (not shown) and a release liner  25  covers the lower surface  24  before use. 
     Protective sealing sheath  21  is provided with a flexible plastics pull tab  26  which extends through release liner  25 . When pull tab  26  is pulled away from base member  22  (FIG.  3 ), release liner  25  is peeled away from lower surface  24  and sealing sheath  21  is detached from mounting member  20  to reveal needle tip  19 . Needle tip  19  is still somewhat concealed from full exposure by base member  22  which is hinged away from housing  11 . 
     Following the removal of sealing sheath  21  and release liner  25 , the lower surface  24  is applied to the skin to which it adheres. A semi-rigid safety tab  27  prevents relative movement of base member  22  towards housing  11  by passing above a first cylindrical post  28  integral with base member  22  and below a second cylindrical post  29  integral with housing  11 . Although first cylindrical post  28  is adapted to fit inside second cylindrical post  29  and thereby allow base member  22  to move towards housing  11  about hinge  23 , safety tab  27  prevents this when present. 
     FIG.,  4  shows device  10  when safety tab  27  has been removed. A snap action mechanism (not shown) holds the device  10  in the configuration shown in FIG. 4, but downward pressure on the upper surface  30  of housing  11  causes the housing  11  to snap towards base member  22  (mounted on the subject&#39;s skin) as shown in FIG.  5 . This causes needle tip  19  to shoot through an aperture  31  in base member  22  and thus through the subject&#39;s skin (not shown). 
     As will be further explained below, the relative motion of housing  11  towards base member  22  also causes the activation of gas generator  15  (not visible in FIGS.  2 - 5 ), and thus at the same moment that needle tip  19  penetrates the subject&#39;s skin, the gas generator  15  begins to generate gas, thereby increasing the pressure in tube  16  which in turn causes a driving force to be exerted on piston  14  to drive drug  13  through needle  17  for delivery to the subject. Such delivery is preferably subcutaneous, although it could also be intravenous, intramuscular or intradermal (i.e. to a point within the dermis below the epidermis), depending on the configuration of the needle and the positioning of the device on the skin of the subject. 
     FIGS. 6 and 7 show the device during delivery of the drug and when delivery has been completed, respectively. Thus, in FIG. 6, piston  14  has moved approximately half-way along the length of syringe barrel  12  (and delivered a corresponding fraction of the drug  13  to the subject). 
     In FIG. 7, the piston  14  has reached the end of syringe barrel  12  and can travel no further. At this point, the gas generator will still be generating a residual amount of gas, and a release valve  32  is provided to enable the escape of excess gas into the housing (and thus to the atmosphere) as indicated by the arrows in FIG.  7 . Release valve  32  is a simple mechanism comprising a cap  33  which seals a vent  34  under normal operating conditions and which allows gas to escape in the event of a predetermined overpressure within tube  16 . 
     Syringe barrel  12  is formed of a transparent material and a window  35  in upper surface  30  of housing  11  enables the user to see that delivery has been completed. FIGS. 8 and 9 show the upper surface  30  of housing  11  before delivery and when delivery is finished, respectively. Thus in FIG. 8, the user can see drug  13  and in FIG. 9, the user can see that the piston  14  has reached the end of its travel and thus that device  10  should be removed. 
     FIG. 10 shows the device  10  when it is removed. To remove the device  10  the user pulls housing  11  away from the skin. Before the adhesive force between the lower surface  24  and the subject&#39;s skin is overcome, the snap mechanism (which is designed to provide a lesser resistance to the tractive force exerted in pulling the housing from the skin) snaps to cause housing  11  to move away from base member  22 , such that when lower surface  24  is peeled from the skin the needle  17  is already recessed as shown in FIG.  10 . This helps avoid accidental injury or infection and makes the device safer to handle and to dispose of. 
     The operation of the gas generator  15  will now be described with reference to FIGS. 11-13, each of which is a sectional elevation taken on a line through the device  10  which passes through the centre of the gas generator  15  rather than along the axis of the syringe barrel  12 . Thus, with reference to FIG. 1, the elevations of FIGS. 2-7 and  10  are taken along the longitudinal axis of the syringe barrel  12 , whereas the elevations of FIGS. 11-13 are taken along a line which is parallel to the longitudinal axis of the device itself, passing through the centre of gas generator  15 . 
     FIG. 11 shows device  10  upon removal of the safety tab  27  but before the housing  11  is snapped towards base member  22  (i.e. at the same moment as is shown in FIG.  4 ). Gas generator  15  comprises an upper chamber  36  filled with citric acid solution  37  and sealed on its underside by a foil membrane  38  before use, and a lower chamber  39  containing a quantity of sodium bicarbonate  40  and means  41  for penetrating the foil membrane  38  when upper chamber  36  is pushed towards lower chamber  39 . 
     As shown in FIG. 12, when the housing  11  of device  10  is snapped towards base member  22  (i.e. at the moment illustrated in FIG.  5 ), the foil membrane  38  is penetrated by penetrating means  41 . This causes the citric acid  37  to mix with the sodium bicarbonate  40  to thereby generate gas and drive piston  14  (not shown in FIGS. 11-13) as previously described. 
     Because the gas generator  15  is situated alongside syringe barrel  12  rather than at the end thereof, it is further from the hinge  23  than would otherwise be the case. It may be preferred to move the gas generator  15  further from the hinge  23  than is shown in the present embodiment (see FIG.  1 ). This would mean that the action of pushing housing  11  towards base member  22  (i.e. pivoting housing  11  and base member  22  together about hinge  23 ) is more effective in causing the penetration of foil membrane  38 , since the further the distance a body is from the fulcrum of a lever, the greater the linear movement is for a given angular movement about the fulcrum. For this reason also, the needle  17  can penetrate the skin with a quick painless action because the needle travels in a predominantly vertical fashion which minimises penetration and thus any pain involved therein. If the needle were closer to the hinge, it would travel in a more circular pattern creating a larger pathway upon penetration and consequently cause more pain. A further advantage of moving gas generator  15  away from hinge  23  results from the fact that the citric acid  37  and sodium bicarbonate  40  are mixed to a greater extent (again due to the higher speed at which the foil membrane  38  is penetrated), and gas generation is thereby smoother. 
     FIG. 13 shows the device when the housing  11  has been retracted from the base member  22  and gas generation is completed (equivalent to the view in FIG.  10 ). 
     FIGS. 11-13 also illustrate a tamper-proof safety mechanism which ensures that device  10  is a single use device and that the needle  17  cannot be re-deployed after removal from the skin of a subject. 
     Thus, in FIG. 11 there is shown a sloped surface  42  integral with housing  11  and a post  43  connected to housing  11  in a resiliently flexible manner. A generally “F”-shaped member  44  is connected to base member  22  in a resiliently flexible manner, and a catch  45  adapted to receive and retain “F”-shaped member  44  is integral with base member  22 . 
     As shown in FIG. 12, when housing  11  is pushed towards base member  22 , sloped surface  42  engages “F”-shaped member  44  and pushes a projection  46  over catch  45 . Projection  46  deflects post  43  at the same time. When housing  11  is pulled away from base member  22  at the end of delivery (FIG.  13 ), post  43  clears the top of projection  46  (which is held in the FIG. 12 position by catch  45 ), and post  43  returns to the relaxed position as in FIG.  11 . At this stage, the device is locked and no further movement of housing  11  relative to base member  22  is possible because projection  46  prevents any downward movement of post  43 . Thus, the needle  17  can only be deployed on a single occasion, i.e. when the device is applied to the skin for the first time. 
     As previously indicated, the invention provides a method of manufacture which utilises a standard hypodermic syringe and which allows a sterile sheathed needle to be bent without risk of compromising the sterility. A method of manufacturing the device of FIGS. 1-13 will now be described to illustrate these advantages. 
     In FIG. 14 the syringe barrel  12  is shown prior to assembly in the device according to the invention. Thus, there is shown a standard hypodermic syringe barrel  12  with a standard piston  14  sealing a drug  13 , and with a needle  17  mounted thereon in conventional manner. The syringe barrel is filled with the drug and sealed with the piston in the manner currently used for filling pre-filled syringes. After attaching the needle  17  to the syringe barrel  12 , the mounting member  20  is permanently attached to the needle and this assembly is sterilised (such as by steam sterilisation or gamma irradiation), and a protective sterile sealing sheath  21  is mounted on the mounting member  20 . 
     The assembly shown in FIG. 14 can be safely removed to a clean room for all further manufacturing/assembly steps in the knowledge that the internal fluid path (i.e. the sealed interior of syringe barrel  12 ) and the internal bore of needle  17 ) is sterile, as is the portion of the needle from the tip  19  to the mounting member  20 . It is important to note that the needle  17  as shown in FIG. 14 is axially symmetric, i.e. it can be moved around a production line without difficulty (the same would not necessarily be true if the needle were already bent). 
     FIG. 15 shows the gas generator  15  and tube  16  (including valve  32 ) during manufacture. Tube  16  is straight initially which again assists in handling in a mass production environment. 
     Outside the sterile area, i.e. in a clean room, the tube  16  is mounted on the syringe barrel  12  (see FIG. 16) and the needle  17  is bent by manipulating the mounting member  20 , i.e. without manipulating sheath  21 . Mounting member  20  is shaped to ensure a smooth bend. 
     Referring next to FIG. 17, the assembly of gas generator  15 , tube  16  and syringe barrel  12  is mounted in housing  11  and safety tab  27  is fitted in position. Tube  16  may be completely flexible or it may be permanently bent into the required curved shape before being fitted to housing  11 . 
     FIG. 18 shows the device when base member  22  is connected to housing  11 . Base member  22  is fitted with release liner  25  already in position, so that it is only necessary to fit pull tab  26  through an aperture provided in release liner  25  for this purpose. Device  10  is then ready to be packaged, although it may be desired to fold pull tab  26  to lie against release liner  25  (as illustrated in FIG.  2 ). 
     It can be seen that the design of the device allows the majority of the manufacture and assembly to occur outside a sterile area while still ensuring that those parts of the device for which sterility is required remain sterile. 
     FIG. 19 shows a sectional view through needle  17 , mounting member  20 , protective sealing sheath  21  and pull tab  26  which illustrates the exact assembly of these components. 
     FIG. 20 shows a variant on the device already illustrated, in which like numerals are designated by like reference numerals, the only difference being that the syringe barrel  12  is of the type used for drugs which are provided in lyophilised form and mixed with diluent prior to use. Such syringe barrels are known in the art. 
     The barrel  50  is provided with an end piston  51  which is acted on by gas pressure from a gas generator as previously described. An internal piston  52  initially divides the interior of syringe barrel  50  into a diluent compartment  53  and a drug compartment  54 . The internal bore of the syringe barrel  50  is greater in the drug compartment  54  than in the diluent compartment  53 . Thus, while internal piston  52  makes a sealed sliding fit with the narrower bore, it becomes loose in the wider bore of the drug compartment. Alternatively, the barrel could be of a constant diameter with a channel along part of the interior surface providing a pathway for the diluent. A lyophilised drug  55  is provided in the drug compartment together with a quantity of entrapped air. Diluent compartment  53  is entirely filled with liquid diluent  56  suitable to reconstitute the drug  55 . 
     When gas generation begins, the pressure acting on end piston  51  is transmitted through the diluent  56  to push internal piston  52  towards drug compartment  54 . Continued gas generation pushes internal piston  52  entirely into drug compartment  54  (FIG. 21) and allows the ingress of diluent  56  into drug compartment  54  where the diluent reconstitutes the drug into solution. Continued pressure on end piston  51  forces the reconstituted drug solution out through the needle  17  to the subject for delivery as previously described. 
     Although a certain amount of air is pushed through needle  17  ahead of the drug solution, the amount involved will not have any adverse effect if delivery is subcutaneous. The design of the device can also be optimised to minimise or eliminate air from being delivered. Delivery of drug continues until the position shown in FIG. 22 is reached, wherein end piston  51  and internal piston  52  have travelled the maximum distance and substantially all drug has been delivered. 
     It should be noted that the barrel  50  and pistons  51 , 52  are shaped such that gas cannot be pumped to the patient after delivery of the drug is completed. 
     FIG. 23 shows a further feature which may be incorporated into devices according to the invention. A travel limiting mechanism is provided to limit the maximum amount of travel of a piston  14  along the length of a syringe barrel  12 . The travel limiting mechanism comprises an adjustable length of fish line  60  connected at one end  61  thereof to the piston  14  and at the other end  62  thereof (FIG. 24) to length adjustment means in the form of a knurled wheel  63  which can be rotated to shorten or lengthen the line  60 . The line can provide from 100% travel down to 70% travel depending on the setting of the wheel  63 . The wheel may be adjustable by the patient or it may be designed to prevent patient tampering and to allow only a physician or pharmacist to make adjustments. 
     The advantage of this arrangement is that it converts the device of FIG. 1 from a single dose device to one in which the dose can be adjusted to suit individual patients. Many drugs are administered on a “body weight basis” (e.g. a certain number of milligrams of drug per kilogram body weight), and so the dosage must be varied to suit each patient. By providing a series of devices with complementary dosages, a manufacturer may be able to cater for a broad selection of patients. 
     For example in a series of two devices (sizes “A” and “B”), each being adjustable to deliver from 70% to 100% of the total pre-filled dose, size “A” may contain 100 units (arbitrary units). Thus, device “A” can deliver from 70 to 100 units by adjustment of suitable travel limiting means. If device “B” is pre-filled with 70 units, then it can deliver from 70% to 100% of this dose, i.e. from 49 to 70 units. Thus, with only two devices, doses from 100 units down to less than 50 units can be catered for, covering a wide range of patients on a mg/kg dosage basis. Adding third or fourth device sizes to the series extends the possible delivery amounts even further. 
     It is to be understood that the illustrated travel limiting means are intended only for illustrative purposes and that a wide variety of equivalent means to control the dosage delivered may be employed. 
     Furthermore, while the invention has been shown with a simple gas generator which delivers the drug at a rate determined by the mixing of an effervescent couple, the gas generator could also be a more sophisticated, controllable generator, such as an electrolytic cell which generates gas at a rate determined by a current which is electronically controlled. 
     As used herein, the term, “drug”, is meant to encompass any drug-containing fluid capable of being passed through a hollow needle in a controlled manner, such as a liquid, solution, gel or fine suspension. The term “drug” used herein includes but is not limited to peptides or proteins (and memetics thereof), antigens, vaccines, hormones, analgesics, anti-migraine agents, anti-coagulant agents, medications directed to the treatment of diseases and conditions of the central nervous system, narcotic antagonists, immunosuppressants, agents used in the treatment of AIDS, chelating agents, anti-anginal agents, chemotherapy agents, sedatives, anti-neoplastics, prostaglandins, antidiuretic agents and DNA or DNA/RNA molecules to support gene therapy. 
     Typical drugs include peptides, proteins or hormones (or any memetic or analogues of any thereof) such as insulin, calcitonin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoietin (EPO), interferons such as α, β or γ interferon, somatropin, somatotropin, somastostatin, insulin-like growth factor (somatomedins), luteinizing hormone releasing hormone (LHRH), tissue plasminogen activator (TPA), growth hormone releasing hormone (GHRH, oxytocin, estradiol, growth hormones, leuprolide acetate, factor VIII, interleukins such as interleukin-2, and analogues or antagonists thereof, such as IL-1ra; analgesics such as fentanyl, sufentanil, butorphanol, buprenorphine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclofenac, naproxen, paverin, and analogues thereof; anti-migraine agents such as sumatriptan, ergot alkaloids, and analogues thereof; anti-coagulant agents such as heparin, hirudin, and analogues thereof; anti-emetic agents such as scopolamine, ondansetron, domperidone, metoclopramide, and analogues thereof; cardiovascular agents, anti-hypertensive agents and vasodilators such as diltiazem, clonidine, nifedipine, verapamil, isosorbide-5-mononitrate, organic nitrates, agents used in treatment of heart disorders, and analogues thereof; sedatives such as benzodiazepines, phenothiazines, and analogues thereof; chelating agents such as deferoxamine, and analogues thereof; anti-diuretic agents such as desmopressin, vasopressin, and analogues thereof; anti-anginal agents such as nitroglycerine, and analogues thereof; anti-neoplastics such as fluorouracil, bleomycin, and analogues thereof; prostaglandins and analogues thereof; and chemotherapy agents such as vincristine, and analogues thereof, treatments for attention deficit disorder, methylphenidate, fluoxamine, Bisolperol, tactolimuls, sacrolimus and cyclosporin. 
     It will further be appreciated that many of the embodiments discussed above are preferred embodiments, falling within the scope of the invention, and that various alternative embodiments are contemplated.