Abstract:
A subcutaneous drug delivery device having a housing having an internal reservoir in communication with a drug delivery needle via a fluid path. An expandable chamber disposed adjacent to the reservoir forces drug from the reservoir to the needle when supplied with a gas. A flow regulating chamber, in communication with the fluid path, is capable of volumetric changes in response to temperature and/or pressure changes. An increase in the volume of the flow regulating chamber increases flow resistance to the needle and thereby counteracts the corresponding increase in delivery rate resulting from the expansion of the expandable chamber due to the same volumetric changes in response to temperature and/or pressure. 
     The device also includes an improved filling system that enables the reservoir within the device to be filled with drug from a source without regard to filling position and with a decreased risk of injury from needles. Moreover, the filling system provides an accurate measure of drug transferred into the device thus enabling patients to fill the devices and to ensure proper dosage upon delivery.

Description:
TECHNICAL FIELD 
     This invention relates to a subcutaneous drug delivery device having an improved filling system. 
     BACKGROUND OF THE INVENTION 
     A wide range of subcutaneous drug delivery devices are known in which a drug is stored in an expandable-contractible reservoir. In such devices, the drug is delivered from the reservoir by forcing the reservoir to contract. (The term “subcutaneous” as used herein includes subcutaneous, intradermal and intravenous.) 
     Such devices can be filled in the factory or can be filled by the pharmacist, physician or patient immediately prior to use. In the former case it may be difficult to provide the required drug stability in the device since the drug will be stored in the reservoir for a shelf life of from several months to a number of years. In the latter case, it is difficult to ensure that the drug has completely filed the reservoir, i.e. that the reservoir and fluid path do not contain any air bubbles. In general, this requires priming the device by filling it in a certain orientation which ensures that the air bubbles are pushed ahead of the drug, such as with the filling inlet at the bottom and the delivery outlet at the top (to allow the bubbles of air to rise during filling). 
     A further problem associated with subcutaneous drug delivery devices is that in many cases gas generation is used to compress the reservoir. While it may be possible to ensure a constant or a controllably varying rate of gas generation (for example by passing a constant current through an electrolytic cell), this does not ensure a constant rate of drug delivery. 
     The amount of compression of the reservoir (and thus the rate of delivery of drug) depends on the amount by which the volume of the gas generation chamber expands. The behaviour of an ideal gas is governed by the equation PV=nRT, in which the volume of gas, V, is proportional to the number of moles of gas, n, and the temperature, T, and inversely proportional to the pressure, P. 
     An electrolytic cell working at constant current will generate a constant number of moles of gas per unit time. However, changes in the temperature of the gas and in the atmospheric pressure exerted on the gas will cause the volume to vary. Even if the temperature of the device remains constant, the fact that atmospheric pressure drops by approximately 3% for every increase in altitude of 300 m means that the delivery rate will vary substantially between a location at sea level and a higher altitude location (for example, Denver, Colo. is approximately 5 miles or 8 km above sea level, so atmospheric pressure will be approximately 15% lower on average than at sea level). Similarly, normal changes in atmospheric pressure due to the weather cause the delivery rate of this type of device to vary. 
     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. However, this device does not include a locking mechanism in the assembly for locking the device prior to use to minimise accidental contact with the needle and/or accidental actuation of the device that may occur during shipping and/or storage. 
     When filling a drug delivery device, the conventional method is to use a syringe, which carries the risk of accidental injury. The present invention has as a further aim the improvement of safety when syringes are used. The present invention also 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. 
     Our International Application No. PCT/IE 96/00059 discloses a medicament delivery device having a filling mechanism integral within the housing which receives a cylindrical cartridge (or “vial”) sealed by a sliding stopper. When the cartridge is pushed into the filling mechanism, a hollow needle in the filling mechanism penetrates the stopper and establishes communication between the interior of the cartridge and the device&#39;s internal reservoir. 
     Continued movement of the cartridge into the filling mechanism causes the stopper to slide into the cartridge and act as a piston to pump the medicament from the cartridge into the reservoir. While this mechanism overcomes some of the disadvantages of using a syringe, it also makes the device bulkier. 
     Thus, there is a need to provide a subcutaneous drug delivery device having an improved filling mechanism which facilitates filling the device in an orientation-independent manner. 
     There is a further need to provide a filling system that is less bulky. 
     There is still a further need to provide a filling system that maintains the needles within the system in a recessed fashion so as to minimise the risk of injury associated with needles. 
     There is yet a further need to provide a device which operates at a substantially constant delivery rate independently of the ambient atmospheric pressure. 
     There is a further need to provide a drug delivery device in which the needle is retracted from the housing surface before and after use so as to minimise injury due to accidental contact with the needle. 
     There is yet a further need to provide a device having improved adhesion to the skin, i.e. for which there is less likelihood that the device will become detached during use. 
     SUMMARY OF THE INVENTION 
     The present invention overcomes these and other disadvantages associated with prior art drug delivery devices and filling systems. Stated generally, the present invention provides for a drug delivery device having a housing that has an internal reservoir and an expandable chamber disposed relative to the reservoir. The device also has a drug delivery needle extending from the housing for penetration of the skin of a subject. The needle has an outlet for drug delivery. The drug delivery device of the present invention further includes a fluid path defined between the delivery needle outlet and the reservoir and means for providing a gas at a controllable rate into the expandable chamber. The device also includes a flow regulating chamber, in communication with the fluid path, which is capable of volumetric changes in response to temperature and/or pressure changes. 
     By calibrating the degree of increase or decrease in flow resistance, it is possible to compensate for differences occurring in the rate of delivery which arise because of pressure- or temperature-induced differences in the volume of a given mass of gas in the expandable chamber. Thus, if the ambient atmospheric pressure drops, the gas in the expandable chamber will tend to expand and thereby force more drug from the reservoir. This will however be counteracted by the flow regulating chamber which will increase flow resistance along the fluid path and thereby counteract the increased flow rate arising from the effect of the tendency for the expandable chamber to expand. 
     Preferably, the expandable chamber causes contraction of the reservoir in use. Further, preferably, the flow regulating chamber alters the drug delivery rate by varying the flow resistance between the reservoir and the outlet. Preferably, the flow regulating chamber is associated with a blocking member which upon expansion of the flow regulating chamber moves within the fluid path so as to restrict the flow of drug. 
     Further, preferably, the blocking member comprises a formation provided on a displaceable member which at least partially bounds the flow regulating chamber, the formation being disposed adjacent to an inlet of a conduit forming part of the fluid path, such that restriction of the fluid path occurs when the blocking member is moved into the inlet of the conduit. By having a suitably shaped and sized formation relative to the inlet, it is possible to precisely vary the flow resistance of the conduit, and thereby precisely control the delivery rate notwithstanding changes in ambient temperature and/or pressure. 
     Suitably, the shape of the blocking member is adapted to cut off the fluid path completely with a predetermined degree of expansion of the flow regulating chamber. Alternatively, the formation can be shaped such that the fluid path is never entirely cut off. 
     In preferred embodiments of the invention, a displaceable cover is connected to the housing such that displacement of the housing relative to the cover when the cover has been applied to the skin of a subject causes the delivery needle to penetrate the skin of the subject. Such a displaceable cover is suitable for concealing the needle before and after application to the skin of a subject, which prevents injury and reduces the possibility of contamination of the needle. 
     In another aspect of the invention the expandable chamber is provided with a release valve operatively connected to the displaceable cover such that the movement of the housing relative to the cover controls the closing of the valve and thereby the sealing of the expandable chamber. This feature is not dependent on the existence of the flow regulating chamber. 
     The valve enables the device to be supplied with the displaceable member positioned such that the volume of the (empty) reservoir is minimised and that of the expandable chamber maximised. Thus, the reservoir can be of substantially zero volume initially, with no entrapped air volume. The device can then be primed or loaded by filling the reservoir, for example using a syringe- or cartridge-based filling mechanism. As the reservoir is filled, the displaceable member moves to expand the reservoir and thereby contract the expandable chamber. The valve allows the air or other gas in the expandable chamber to be exhausted into the atmosphere. 
     The device can then be applied to the skin of the user. When the device is applied the housing moves relative to the cover which is applied to the skin, not only does the needle penetrate the skin, but also (because the valve is operatively connected to the cover) the valve is closed to seal the expandable chamber. If the valve remained open then gas supplied into the expandable chamber would be free to escape and delivery would not be effected. While it would be possible for the user to close the valve manually, this would clearly leave open the possibility of error. Instead, by connecting the valve operatively to the cover, it is possible to ensure that the valve is always closed when the device is applied to the skin. 
     Preferably the valve comprises two components one of which is connected to the cover and the other of which is connected to the expandable chamber, such that relative movement of the housing towards the cover causes the valve to close. 
     The invention includes a displaceable cover that 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. A further aspect of the present invention comprises 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. 
     The displaceable cover is an advantageous feature since it solves a problem unaddressed by prior art devices. Our prior art device has a locking mechanism to lock the housing in place after use and keep the needle concealed. However, there is no mechanism to prevent premature activation prior to intended use that may cause the needle to protrude accidentally thereby giving rise to injury. According to the present invention, however, the locking means engages automatically when the cover and housing are reciprocated relative to one another, i.e. the housing and cover are moved relative to one another to cause the needle to protrude when the device is applied to the skin. This relative movement is reversed when the device is removed thereby concealing the needle but also engaging the locking means to prevent the needle from being exposed again by accident. 
     In a preferred embodiment, the locking means comprises a mechanical latch which is brought into operation by the reciprocation. Further, it is preferred that the latch comprises a pair of elements mounted on the cover and the housing respectively. It is preferred that the elements be shaped such that they can have two relative configurations when the cover is in the first position relative to the housing. It is preferred the elements have a first movable configuration in which the elements are mutually movable, and a second locked configuration in which the elements are prevented from mutual movement. It is also preferred that the reciprocation of the cover and the housing causes the elements to pass from the first movable configuration, through an intermediate configuration when the cover is in the second position relative to the housing, and then to the second locked configuration, thereby preventing any further movement of the cover relative to the housing. 
     In preferred embodiments illustrated further below, one of the elements is provided with a recess which is adapted to receive a projection on the other of the 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. 
     These embodiments are preferred because while they are mechanically simple and easy to make, their very simplicity provides fewer opportunities for malfunction. 
     In a preferred embodiment of the present invention, movement of the cover relative to the housing is initially prevented by a removable locking member. This feature helps to prevent accidental injury occurring because the needle is only exposed when the housing is moved relative to the cover, i.e. only after the user has specifically removed the removable locking member. The presence of the removable locking member also prevents the means for providing a gas from being actuated. This prevents the device from being exhausted by accidental switching on at an incorrect time. In a preferred embodiment of the present invention, the removable locking member comprises a laminar member inserted between the cover and the housing. 
     In a further aspect of the invention, the surface of the housing from which the needle extends or the surface of the displaceable cover, if present, is of a concave cross-section. When the device has been applied to the skin of a subject, removal of the device is resisted because the cover conforms more closely to the skin. In prior art devices, it has been found that retention on the skin of the user is problematic because of adhesive failure, for example. Using a concave surface causes the device to be retained more effectively by adhesive means. 
     With prior art devices the lower surface tends to be peeled away from the skin more easily as the edges of the device can be detached relatively easily. Where a concave lower surface is used the edges tend to remain in contact with the skin and removing the device is thus more difficult. In effect a shear force is required rather than a simple peeling, and this assists in preventing accidental removal. This feature is not dependent on the existence of the other aspects of the invention. 
     In a modified device according to the invention, the needle extends from the lower surface of the housing is replaced by a tube extending from the housing. The tube is adapted for carrying a drug delivery needle. Such a device is preferred for intravenous delivery of a drug as the needle carried on the end of the tube can be accurately located in a suitable vein. The needle may be integral with the tube or supplied separately. 
     In a further preferred feature of the present invention, the drug reservoir is separated from the expandable chamber by a diaphragm. The diaphragm exhibits bistable behaviour such that in one stable state the reservoir is full and in the other stable state the reservoir is empty. The diaphragm is shaped to minimise the energy required in the transition between the stable states. In a preferred embodiment of the present invention, the diaphragm is in the form of a body having a peripheral lip connected to a substantially flat central section by a flexible annular section. The flexible annular section assumes a substantially frusta-conical cross-section in one of the states and assuming an arcuate curved cross-section in the other state. 
     Preferably, the means for providing a gas comprises an electrical circuit in which any transistors are bipolar transistors having a gain of not less than 500, such that the circuit can be irradiated by ionising radiation without destroying the circuit. 
     This type of transistor has been found to be advantageous as it enables the device to be sterilised using gamma radiation with the electronic components intact. While a certain loss of performance results from the irradiation, the high gain transistor still has an adequate gain after irradiation to operate reliably. It is preferred that the current gain of the or each transistor is not less than 750. For example, a transistor having a rated current gain of 800 has been found to give an excellent performance after irradiation, despite the fact that irradiation lowers the current gain characteristics of the transistor by a factor of ten or more. The initial high gain compensates for the subsequent reduction arising from irradiation. The fact that the effects of irradiation can be predicted means that the performance after irradiation is reliable. 
     It is also preferred that the circuit further include a reference component across which a fixed potential drop is measurable. The reference component is essentially unchanged by the ionising radiation. If a reference voltage is used which is not affected by the irradiation process, then the operation of the other components in the circuit may be determined by this reference voltage. For example, while the current gain of a group of transistors may vary individually when a batch is irradiated, each such transistor can be used to make an identically functioning amplifier if the output current of the amplifier is matched against a given reference component. 
     Light emitting diodes (LEDs) have been found to be affected less than other standard components when irradiated by gamma radiation. Thus, the reference component of the preferred embodiment comprises a light-emitting diode. Gallium arsenide (GaAs) LEDs are virtually unaffected by gamma rays. Thus, it is preferred that the light emitting diode employs gallium arsenide as a semiconductor. 
     In a further aspect, the present invention provides for a subcutaneous drug delivery kit including a drug delivery device as described above. The device is provided with a filling mechanism associated with the reservoir. The filling mechanism includes means for receiving a filling adapter. The filling adapter includes a body which is adapted to accommodate a drug cartridge. The body has means for engaging the adapter-receiving means of the drug delivery device at one end thereof, means for receiving a cartridge at the other end thereof, and transfer means for transferring a liquid from a cartridge to the filling mechanism of the device as the cartridge is emptied. The adapter-receiving means and the corresponding engaging means provided on the adapter together constitute a releasable locking mechanism which holds the adapter in place on the device once engaged. The locking mechanism is disengaged by the cartridge when the cartridge is emptied within the adapter. 
     The kit according to the invention is advantageous because it eliminates the need for a bulky filling mechanism which accommodates the cartridge within the device, and instead employs an adapter which is releasable from the device so as to enable the filled device to be less bulky than prior art cartridge-based devices. 
     Furthermore, the locking mechanism employed is only disengaged when the cartridge has been completely emptied, i.e., the rubber stopper within the cartridge is pushed to the bottom. If the cartridge used is of a type which will empty when the stopper is pushed to the bottom, this feature ensures accurate loading of the reservoir, i.e. it is not possible to easily remove the device before the reservoir is filled with the correct dose of medicament. 
     Suitably, the transfer means comprises a hollow double-ended needle, one end of which is associated with the engaging means such that it communicates with the filling mechanism when the adapter is engaged with the device, and the other end of which is associated with the cartridge receiving means such that it communicates with the interior of a cartridge having a penetrable stopper when such a cartridge is received by the adapter. 
     Such a hollow double ended needle can be replaced by a pair of needles which are connected by a conduit, such as a moulded conduit running through the body of the adapter and having a needle mounted at either end such that it is functionally equivalent to a double ended needle. Preferably, both ends of the needle are disposed within the body of the adapter such that they are recessed from the exterior of the body when the adapter is disengaged from the device. This arrangement is preferable for safety reasons, as it allows the adapter to be disposed of without fear of accidental injury occurring from casual handling of the adapter. 
     In a preferred embodiment, the releasable locking mechanism comprises a pair of locking members provided on the adapter receiving means and the corresponding engaging means, respectively. One of the locking members is movable between a locking position and a disengaging position. The movable locking member is disposed relative to the body such that, in use, when a cartridge is emptied within the body, the movable locking member is moved from the locking position to the disengaging position under the action of the cartridge. 
     Where a substantially cylindrical cartridge is employed, the body can receive the cartridge within a passage having a diameter sufficient to completely accommodate the cartridge. However, the end of the passage is of slightly narrower diameter on account of a projection provided on the movable locking member. Thus, when the cartridge completely emptied by pushing the stopper to the bottom, it contacts the movable locking member and pushes it out of the way, thereby disengaging the locking mechanism. 
     Suitably, the movable locking member is resiliently biased towards the locking position. Preferably, the movable locking member is a latch which automatically locks the adapter and device to one another when engaged together. It is preferred that the cartridge is emptied by moving the penetrable stopper against the adapter. 
     The present invention further provides a subcutaneous drug delivery kit including a device according to any preceding claim further comprising a filling mechanism associated with the reservoir, the filling mechanism comprising means for receiving a filling adapter as defined herein and a filling adapter. The filling adapter has a body adapted to receive a syringe. The body has means for engagement with the adapter-receiving means of the device at one end thereof, syringe-receiving means at the other end thereof and transfer means for transferring a liquid from the syringe to the filling mechanism of the device as the syringe is emptied. The transfer means includes a conduit associated with the syringe receiving means, the conduit leads to a needle which is associated with the engagement means and is disposed within the body of the filling adapter. 
     It is preferred that the needle disposed within the body of the filling adapter is recessed from the exterior of the body when the adapter is disengaged from the device. It is also preferred that the adapter receive the syringe without a needle. Since the needle on the adapter is recessed from the exterior of the adapter body and the syringe has no needle when filling, a conventional syringe (minus needle) can be used to fill the device without any risk of accidental injury. 
     A further aspect of the present invention provides a method of filling a drug delivery device. The method includes providing a drug delivery device having a drug reservoir. The reservoir is associated with a filling mechanism having filling adapter receiving means. The method further includes providing a filling adapter having a first end for engagement with the adapter receiving means, and a second end for receiving a syringe and causing the filling adapter receiving means to receive the filling adapter. The method further includes causing the second end of the filling adapter to receive a syringe having liquid stored therein and a needle, and providing a conduit for communication between the liquid stored within the syringe and the first end of the filling adapter. The method of filling further includes emptying the syringe and concurrently transferring the liquid from the syringe to the device via the conduit. In yet further aspects, the invention provides a filling adapter as defined above and a diaphragm as defined above. 
     Thus, it is an object of the present invention to provide a subcutaneous drug delivery device having an improved filling mechanism which facilitates filling the device in an orientation-independent manner. 
     It is a further object of the present invention to provide a filling system that is less bulky. 
     It is still a further object of the present invention to provide a filling system that maintains the needles within the system in a recessed fashion so as to minimise the risk of injury associated with needles. 
     It is yet a further object of the present invention to provide a device which operates at a substantially constant delivery rate independently of the ambient atmospheric pressure. 
     It is even yet a further object of the present invention to provide a drug delivery device in which the needle is retracted from the housing surface before and after use so as to minimise injury due to accidental contact with the needle. 
     It is yet a further object of the present invention to provide a device having improved adhesion to the skin, i.e. for which there is less likelihood that the device will become detached during use. 
     Other objects, features and advantages of the present invention will be apparent upon reading the following specification 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, in which: 
     FIG. 1 is a sectional side view of a first embodiment of drug delivery device according to the present invention; 
     FIG. 2 is an exploded perspective view of the flow regulating chamber and needle assembly of the first embodiment of the device of FIG. 1; 
     FIG. 3 is an enlarged sectional side view of the flow regulating chamber and needle assembly of the first embodiment of the device of FIG. 1; 
     FIGS. 4-6 are sectional side views of a second embodiment of drug delivery device according to the invention, shown before, during and after use, respectively; 
     FIGS. 7-9 are enlarged perspective views of the locking mechanism of the device of FIGS. 4-6, shown before, during and after use, respectively; 
     FIGS. 10A,  10 B and  10 C are schematic elevations of a first alternative embodiment of a locking mechanism, shown before, during and after use, respectively; 
     FIG. 10D is a perspective view of the locking mechanism as shown in FIG. 10A; 
     FIGS. 11A,  11 B and  11 C are schematic elevations of a second alternative embodiment of a locking mechanism, shown before, during and after use, respectively; 
     FIG. 11D is a perspective view of the locking mechanism as shown in FIG. 11A; 
     FIGS. 12A,  12 B and  12 C are schematic elevations of a third alternative embodiment of a locking mechanism, shown before, during and after use, respectively; 
     FIG. 12D is a perspective view of the locking mechanism as shown in FIG. 12A; 
     FIGS. 13A,  13 B and  13 C are schematic elevations of a fourth alternative embodiment of a locking mechanism, shown before, during and after use, respectively; 
     FIG. 13D is a side elevation of the locking mechanism as shown in FIG. 13A; 
     FIG. 13E is a perspective view of the locking mechanism as shown in FIG. 13A; 
     FIGS. 14 and 15 are sectional elevations of a third embodiment of drug delivery device according to the invention, shown before and during use, respectively; 
     FIG. 16 is a partially cut away perspective view of the lower part of the housing on the device of FIGS. 14 and 15, including various components housed therein; 
     FIG. 17 is an exploded perspective view of the electrolytic cell used in the embodiment of FIGS. 14 and 15; 
     FIG. 18 is a sectional side view of the electrolytic cell used in the embodiment of FIGS. 14 and 15; 
     FIGS. 19 and 20 are sectional side views of a fourth embodiment of drug delivery device according to the invention, shown before and during use, respectively; 
     FIG. 21 is a sectional plan view of a drug delivery kit comprising the first embodiment of FIG. 1, a filling adapter and a medicament cartridge; 
     FIG. 22 is a perspective view of a subassembly used in the adapter shown in FIG. 21; 
     FIGS. 23 and 24 are sectional side views of the drug delivery kit of FIG. 21, shown during and after filling of the device, respectively; 
     FIGS. 25 and 26 are sectional side views of fifth and sixth embodiments, respectively, of drug delivery device according to the invention; 
     FIGS. 27 and 28 are sectional side views of a diaphragm suitable for use in a device according to the invention; 
     FIG. 29 is a diagram of an electronic controller circuit suitable for use in a device according to the invention; and 
     FIGS. 30 and 31 are perspective views of the top side and underside, respectively, of a displaceable cover from a device according to the invention. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Referring now in more detail to the drawings, in which like numerals refer to like parts throughout the several view, FIG. 1 indicates a subcutaneous drug delivery device  10  according to the invention. A housing  11  defines a reservoir  12  which is partially bounded by an elastomeric diaphragm  13  which allows the reservoir to expand and contract. The diaphragm  13  also bounds an expandable chamber  14  such that expansion of the expandable chamber causes the reservoir  12  to contract and vice versa. In FIG. 1, the reservoir  12  is at full volume and contains a drug, while the expandable chamber  14  is at minimum volume. 
     A circuit board  15  having an electrolytic cell  48  mounted thereon (explained in greater detail below) is mounted in the lower part  16  of the housing  11 . In use, the electrolytic cell  48  feeds a gas into the expandable chamber  14  via an aperture  17  in a supporting member  18 . 
     The reservoir  12  is provided with an inlet  19  which is in communication with a filling mechanism  20  (explained in greater detail below). A delivery needle  21  provided with an outlet  22  is in communication with the reservoir  12  via a fluid path  23  which is indicated by arrows. The fluid path  23  passes around an air-filled flow-regulating chamber  35  which comprises a top member  24 , annular member  25  and flow diaphragm  26 . The fluid path  23  also passes via a needle holder  27  to the needle  21 . The inlet  37  to the needle  21  is partially restricted by a projection  28  on the flow diaphragm  26 , such that any upward movement of the projection  28  reduces resistance to flow and any downward movement of the projection increases flow resistance. 
     Referring additionally to FIG. 2, the flow regulating chamber  35  can be seen in exploded view. Annular member  25  receives the flow diaphragm  26 , and top member  24  and the three components fit together to form an airtight chamber  36  which is positioned above the needle holder  27 . The inlet  37  in the needle holder  27  leading to the needle  21  can be clearly seen on the top surface of the needle holder. Projection of the flow diaphragm as shown in FIG. 37 extends into the inlet. 
     Further features of device  10  which can be seen in FIG. 1 are a displaceable cover  29  attached to the housing  11  by a hinge  30 . The movement of the displaceable cover  29  between the position shown in FIG. 1 (wherein the needle  21  protrudes through the displaceable cover) and a position in which the needle  21  is substantially concealed by the displaceable cover  29  (as shown in FIG.  4 ), is controlled by a locking mechanism indicated generally at  31  and explained in greater detail below. 
     In use, the displaceable cover  29  is affixed to the skin using an adhesive coating  29 ′ provided on the surface thereof distal from the housing (“the underside”). The displaceable cover  29  has a concave shape when viewed from the underside. This shape is advantageous because if a flat or convex surface is provided, the edges of the cover  29  will be more easily peeled away from the skin by accident, i.e. the use of a convex surface is less likely to have protruding edges, and the force required to peel the device away is a shear force rather than a simple peeling force. 
     The housing  11  is covered by a protective top cover  32  which can provide a more aesthetically pleasing appearance to the device, as well as one which is ergonomically more advantageous for the user. An aperture in protective top cover  32 , indicated at  33 , allows a transparent portion  34  of the housing  11  to be seen, thereby allowing the user to visually check the reservoir to see whether drug is present. The protective top cover  32  also protects the housing  11  and its component parts if the device  10  is mishandled or dropped 
     The flow regulating chamber  35  is shown in greater detail in FIG.  3  and comprises the top member  24 , the annular member  25 , and the flow diaphragm  26 , as explained above. The construction ensures that the airtight space  36  exists in the interior of the chamber  35 . A fluid path between the reservoir and the needle (FIG. 1) is shown with heavy arrows. As can be seen, projection  28  on the flow diaphragm  26  extends into the inlet  37  in the needle holder  27  leading to the needle  21 . The fluid has to push up on the flow diaphragm  26  in order to reach the needle  21 . Little force is required to do this, as the air in the chamber  35  is compressible. 
     However, if the ambient atmospheric pressure drops, for example due to an increase in altitude, the fixed mass of air in the chamber  35  tends to expand (since for ideal gases at fixed temperature the product of pressure and volume is a constant). This makes it more difficult for fluid to flow past the flow diaphragm  26  into needle holder  27  and would thus tend to cause a decrease in the rate of delivery of drug. 
     The fact that the drug is being driven by a gas-filled expandable chamber  14 , however, means that the expandable chamber tends also to increase in volume due to this increase in altitude, and the effect of an increase in expandable chamber volume is to speed up the rate of delivery. 
     Therefore, by calibrating the flow regulating chamber  35  correctly, barometric changes which would otherwise tend to increase or decrease the rate of delivery of drug are counteracted by the corresponding increase or decrease in the amount of flow resistance exerted by the flow regulating chamber, thereby allowing a constant delivery rate to be maintained. It will be appreciated that changes in temperature which would cause the gas in the expandable chamber to expand or contract are also counteracted in the same way. 
     A further feature of the device of FIGS. 1-3 is an o-ring  38  located on displaceable cover  29  (see FIG.  1 ). The o-ring  38  forms a seal with needle holder  27  and thereby assists in protecting the puncture point of the needle  21  into the skin of the user from contact with soap, water, perspiration or other contaminates. If water or other liquid contacts the needle  21 , the needle  21  may act as a switch and allow water to be drawn into the puncture. However, adhesive  29 ′ on the displaceable cover  29  prevents water from reaching the needle  21  via the underside of the cover, and the o-ring  38  prevents water from reaching the needle via the upper side of displaceable cover. 
     Top member  24 , annular member  25 , flow diaphragm  26  and needle holder  27  and all other parts in the fluid pathway are preferably made of a polycarbon material. Polycarbon materials are essentially inert and will not react with the liquid drug. Moreover, the polycarbon material withstands gamma radiation without degradation of any properties. 
     FIGS. 4,  5  and  6  show a device similar to that of FIG. 1 before, during and after use, respectively. The device, indicated generally at  50 , differs slightly from the FIG. 1 device and accordingly different reference numerals are used in relative to FIG.  1 . The device  50  is shown in FIG. 4 with the needle  51  concealed by the displaceable cover  52  because the displaceable cover  52  is displaced relative to the housing  53  about the hinge  54 . A removable tab  55  prevents the displaceable cover  52  from being moved towards housing  53 , as will be described further below. The underside  56  of the displaceable cover  52  is coated with a contact adhesive  56 , and during storage, the adhesive is protected by a release liner (not shown). 
     When the release liner is removed, the adhesive-coated underside  56  is pressed against the skin to ensure good adhesion (the concave surface assists in obtaining good adhesion) and the tab  55  is removed. The housing  53  is then pushed towards the skin and the needle  51  penetrates the skin as the displaceable cover  52  and housing  53  move together about hinge  54 , leading to the configuration shown in FIG.  5 . 
     A start button (not shown) is pressed to activate a gas generating electrolytic cell  57  (see FIG.  5 ). As gas is generated, a diaphragm  58  is pushed upwards to drive a liquid drug from the reservoir  59  (which was filled before use via inlet  60 ) and thereby force the drug through a fluid path  61  around the flow regulating chamber  62  (as explained above in relation to FIGS. 1-3) and to the patient via the delivery needle  51 . 
     When delivery has been completed, the diaphragm  58  will have moved up such that the space occupied by the reservoir  59  at the beginning of delivery (see FIGS. 4 and 5) is now occupied by the expandable chamber  60  (see FIG.  6 ), since the expansion of the expandable chamber causes contraction of the reservoir. 
     The device  50  is removed from the skin by pulling upwards on the upper protective cover  63  (FIG.  6 ). This causes the needle  51  to be retracted behind the displaceable cover  52  once again because the adhesive force holding the displaceable cover  52  against the skin is greater than the force exerted by the locking mechanism  64  (explained in greater detail below). Once the needle  51  is retracted in this way, the locking mechanism  64  holds the displaceable cover  52  permanently in the position shown in FIG. 6, i.e. away from the housing  53  with the needle  51  concealed. 
     FIG. 7 shows locking mechanism  64  in greater detail, with the protective top cover  63  removed for illustrative purposes. The locking mechanism  64  is illustrated before use, i.e. when the displaceable cover is positioned as shown in FIG.  4 . In other words, there is a gap between the housing  53  and the displaceable cover  52 , and the needle  51  (FIG. 4) is recessed in this gap and thereby concealed by the displaceable cover  52 . A projection  65  mounted on the front of housing  53  is positioned at the upper end of a slot  66 . The slot  66  has an enlarged portion  67  at the lower end and is provided with wedge projections  68 , 69  at the exterior surface of the upper portion thereof. The slot  66  is formed in a member  70  which is attached to displaceable cover  52  by connecting arms  72  which allow a slight degree of flexibility. A widened rib (not shown in FIG. 7) is provided on the projection  65 , and the width of this rib is greater than that of the upper portion of the slot  66 . The member  70  is biased slightly against this rib. 
     The removable tab  55  (see FIG. 4) is positioned so as to engage wings  71  and prevent them from moving towards the cover  52 . This effectively prevents the entire housing  53  from being moved towards the cover  52  and prevents the device from being activated prematurely. When the tab  55  is removed, as shown in FIG. 7, the displaceable cover  52  can be snapped towards the housing  53  by pressing down on the housing. This results in the locking mechanism adopting the configuration shown in FIG. 8, wherein the projection  65  has moved to the lower end of the slot  66 , allowing a lipped member  73  to pass through the enlarged portion  67  at the lower end of slot  66 . This allows a member  70 , which was biased in the direction of projection  65 , to relax. The sides of the lipped member  73  rest against the member  70   
     When delivery is complete and the housing  53  is lifted away from the displaceable cover  52 , this disengages the lips of the lipped member  73  from resting against member  70  and again moves the projection  65  to the upper end of the slot  66 . However, the lipped member  73  passes over the wedge projections  68 , 69 , as shown in FIG.  9 . When this happens, the wedge projections  68 , 69  catch the lipped member  73  and prevent it from moving back down. This effectively locks the locking mechanism  64  permanently in the configuration shown in FIG. 9, thereby concealing the needle  51  permanently from view and making the device  50  safe for disposal. 
     An additional feature of the device of FIGS. 4-8 relative to that of FIG. 1 can be seen with reference to FIGS. 4-6. A pair of projections  74  grip the flow regulating chamber  62  before use to block the path between the reservoir  59  and the needle  51  before use (FIG.  4 ). When gas generation begins, the pressure of liquid in the reservoir  59  forces the flow regulating chamber  62  downwards relative to the projections  74 . The projections  74  are resilient and move together when the flow regulating chamber  62  moves downwards. In this position the projections  74  hold flow regulating chamber  62  in a fixed position both during delivery (FIG.  5 ), and when the device is removed from the skin (FIG.  6 ). Thus, after delivery, accidental leakage of medicament from the needle  51  (e.g. due to gravity) is prevented by the fixed position of the flow regulating chamber  62 . 
     A further feature of the embodiment of FIGS. 4-6 is an annular elastomeric inwardly extending lip  75  which seals the skin at the point of entry of the needle  51  in the same manner as the o-ring  38  in the FIG. 1 embodiment. This feature reduces the danger of infection due to wicking by the needle of unwanted substances into the skin. 
     Four alternative embodiments of different locking mechanisms according to the invention are shown in FIGS. 10A-10D,  11 A- 11 D,  12 A- 12 D, and  13 A- 13 E. In each case the mechanism is shown schematically in “pre-use” (A), “in-use” (B) and “post-use” (C) configurations as well as in one or two perspective views (D/E). The mechanism can in each case be moved from position A to position B and from position B to position C with little difficulty (although generally some resistance is present to prevent spontaneous or accidental movement), but once in position C, the mechanism is effectively locked permanently and is no longer capable of operation. 
     The first alternative embodiment of a locking mechanism comprises a resilient arm and related assembly and is shown in FIGS. 10A-10D. In FIG. 10A the locking mechanism is indicated generally at  80  and comprises a biasing member  81  and a resilient strut  82  mounted on a housing  83 , and the resilient arm  84  and a post  85  mounted on a displaceable cover  86 . 
     The resilient arm  84  is flexibly hinged at the base thereof  87 . When the housing  83  is pushed towards the displaceable cover  86 , the biasing member  81  pushes the resilient arm  84  against the post  85 . The resilient arm  84  and post  85  are mutually shaped to allow the arm  84  to pass over the top of the post  85 , where it latches (see FIG. 10B) and is prevented from returning to the position shown in FIG.  10 A. 
     In passing over the top of the post  85 , the arm  84  acts against the resilient strut  82 , momentarily bending the strut  82  away from the biasing member  81 . Although when the arm  84  has passed fully over the top of the post  85  the strut  82  has returned to its relaxed (straight) position (FIG.  10 B). 
     When (after use) the housing  83  is pulled away from the displaceable cover  86 , this causes the strut  82  to again be bent away from biasing member  81  (because arm  84  which is now locked in place by post  85  impedes the path of strut  82 ). However, when the end  88  of strut  82  has cleared the arm  84 , it springs back into position, past a projection  89  on arm  84  (see FIG.  10 C). In fact, strut  82  latches behind projection  89 , preventing the strut from moving back to the position shown in FIG. 10B, and thereby permanently locking the mechanism  80  in the FIG. 10C configuration. 
     The perspective view in FIG. 10D shows the mechanism in the position illustrated in FIG.  10 A. An additional feature visible in FIG. 10D is a snap mechanism comprising an arm  90  depending from either side of the housing  83 . A raised protuberance  91  on the inner surface of each arm  90  acts against a sloped surface  92  on the displaceable cover  86  to provide resistance to movement. The effect of the snap mechanism is to add further resistance to any unintended relative movement between the housing  83  and the displaceable cover  86 . A further effect is that the movement of the housing  83  relative to the cover  86  between the configurations of FIGS. 10A and 10B, and the configurations of FIGS. 10B and 10C, is extremely rapid, causing the penetration of the needle into the skin and the removal of the needle from the skin to be quick and painless. 
     The second alternative embodiment of a locking mechanism of the present invention comprises an inverted V-shaped assembly and is shown in FIGS. 11A-11D. In FIG. 11A the locking mechanism is indicated generally at  100  and comprises a member  101  resiliently mounted on a housing  102 , and a pin  103  supported in a frame  104  mounted on a displaceable cover  105 . The member  101  has an inverted V-shape slot  106  therein. The slot  106  has an outer slot portion  107  connected at the upper end thereof to an inner slot portion  108 , and a dividing member  109  between the outer and inner slot portions  107 ,  108  below the upper ends. 
     In moving from the “pre-use” position to the “in-use” position, the (fixed) pin  103  moves up the outer slot  107 , acting against the dividing member  109  until it springs past the dividing member  109  at the top of the outer slot. In the position shown in FIG. 11B, the pin  103  is located above the top of the inner slot  108 . 
     When the housing  102  is subsequently pulled away from the displaceable cover  105  (moving from FIG. 11B to FIG. 11C, the pin moves down inner slot  108 , acting against the dividing member  109  to push the member  101  sideways. When the position shown in FIG. 11C is reached, the pin  103  locates a recess  110  (see FIG. 11B) in the lower end of inner slot  108 , which allows the member  101  to relax slightly but still keeping a certain degree of stress on the member  101  by holding it away from the equilibrium position relative to the housing  102 . In this way, the pin  103  latches into the recess  110  and locks the mechanism  100  permanently in the “post-use” configuration. In FIG. 11D, the mechanism  100  can be seen in the “pre-use” configuration, with the member  101 , housing  102 , pin  103 , frame  104 , and displaceable cover  105  visible. 
     The third alternative embodiment of a locking mechanism of the present invention comprises generally a rotatable pawl assembly and is shown in FIGS. 12A-12D. The mechanism, indicated generally at  120 , comprises a rotatable pawl  121  mounted on the displaceable cover  122  and which is rotated by an arm  123  in moving from the “pre-use” to “in-use” positions (FIGS. 12A and 12B, respectively). When the rotatable pawl  121  reaches the “in-use” position, a recess  124  (FIG. 12A) receives a projection  125  located on a resilient portion  126  of the displaceable cover  122 , providing a degree of resistance to further movement. 
     In moving from the FIGS. 12A to  12 B positions, the rotatable pawl  121  acts against a flexible strut  127  depending from the housing  128 . When the rotatable pawl  121  is in the FIG. 12B position, further clockwise rotation of the pawl is prevented by the arm  123 . 
     When the housing  128  is lifted (moving from FIGS. 12B to  12 C), the strut  127  acts against a projection  129  urging the rotatable member  121  in a clockwise direction, but the arm  123  prevents such rotation. As the housing reaches the FIG. 12C position, the strut  127  springs past the projection  129  to sit in a recess above the projection  129 , and the arm  123  clears the upper corner of the rotatable pawl  121 . When in this configuration, the arm  123  prevents any counter-clockwise rotation of the rotatable pawl  121 , while the strut  127  prevents any clockwise rotation thereby locking the rotatable pawl  121  in position and preventing any further downward movement of the housing  128  towards displaceable cover  122 . 
     The fourth alternative embodiment of a locking mechanism of the present invention comprises generally a flexible post assembly as shown in FIGS. 13A-13E. In FIG. 13A the locking mechanism is indicated generally at  130  and comprises a vertical flexible post  131  (see FIGS. 13D and 13E) mounted on the displaceable cover  132  and having a projection  133  extending therefrom towards a sloped surface  134  on the housing  135 . 
     A slot  136  in surface  134  connects two apertures, namely a lower aperture  137  (see FIG. 13B) which is of smaller diameter than the widest part of projection  133 , and an upper aperture  138  which is of larger diameter than the widest part of projection  133 . 
     In the “pre-use” position, projection  133  is positioned at the lower aperture. As the housing moves towards the “in-use” position (FIG. 13B) the flexible arm  131  is bent back until the projection  133  reaches the upper aperture  138  whereupon it springs back into position as the projection  133  moves through the upper aperture  138 . 
     In moving to the “post-use” position, the projection  133  is constrained by the slot  136  and the arm  131  is bent forward until the projection  133  reaches the lower aperture  137  which provides a recess for the projection  133  to spring back into (but not through). Because the arm  131  remains bent forward slightly, this effectively traps the projection  133  in the lower aperture  137  and thereby holds the mechanism permanently in the “post-use” configuration, as shown in FIG.  13 C. 
     In FIG. 14 there is another drug delivery device  140  according to the invention similar in many respects to the embodiments previously described. The device  140  has a protective upper cover  141 , a housing  142 , a displaceable cover  143 , a delivery needle  144 , a flow regulating chamber  145  and a three position locking mechanism  146 . 
     The internal space of the drug delivery device  140  of FIG. 14 defines an expandable chamber  147  when the diaphragm  148  is in the position shown or a reservoir when the diaphragm is in the position shown in dotted outline at  149 . The expandable chamber  147  is initially air filled (FIG. 14 shows the device in the pre-use configuration before medicament has been loaded). Thus, the reservoir is substantially of zero volume. The expandable chamber  147  communicates with the atmosphere via an open valve  150 . 
     When liquid drug is loaded into the reservoir via a fill port (not shown), the diaphragm  148  moves downwards to position  149 , with the reservoir filling with air and the expandable chamber  147  being emptied as the volume thereof decreases. Because the expandable chamber  147  is in communication with the atmosphere, the air initially filling the chamber  147  is exhausted into the atmosphere via the valve  150  without any necessity for action on the part of the user. 
     Furthermore, because the reservoir is initially of substantially zero volume, it does not require filling in any particular orientation. While prior art devices have required careful loading in order to ensure that all air bubbles are vented from the drug supply before delivery begins, the only air in the drug path of the device of FIG. 14 is in the short, narrow portion of the device between the reservoir and the needle  144 . Thus, when drug enters the reservoir it immediately pushes the small amount of air ahead of it through the narrow space towards the needle  144 , irrespective of the orientation of the device  140 . By filling with the drug until a drop of the drug appears on the end of the needle  144  one can be sure that no air remains in the fluid path. 
     When the device  140  has been filled with drug, the diaphragm  148  is at the position shown at  149 , and the valve  150  is open. However, when the displaceable cover  143  is applied to the skin, and the housing is pushed downwards, the valve  150  is closed and the closing of the valve actuates a switch  151  to begin generation of gas by an electrolytic cell  152  (described in more detail below). 
     The device  140  is then in the “in-use” position shown in FIG. 15, with reservoir  147  filled with drug, the diaphragm  148  in position  149 , valve  150  and switch  151  closed, and electrolytic cell  152  actuated to generate a gas and hence begin delivery of drug from reservoir to the patient through delivery needle  144 . 
     Valve  150  is closed by a connecting member  153  which is connected to displaceable cover  143 . When displaceable cover  154  moves towards housing  142 , connecting member  153  fits into a valve  150  and pushes it home to seal the expandable chamber  147  (the area below diaphragm  149 ) from the atmosphere. When a gas is generated by the electrolytic cell  152 , it pressurises the reservoir  147 . 
     A coloured plastic member  154  forming part of locking mechanism  146  protrudes through an aperture  155  in the protective upper cover  141  when the device  140  is in the position as shown in FIG.  15 . The coloured member  154  visually indicates that the device  140  has been actuated. 
     FIG. 16 is a detail view of the lower section  156  of the housing  142  (see FIG.  15 ). The lower section  156  houses a battery  157  and an electrolytic cell  158 , both mounted on a printed circuit board (PCB)  159 . The PCB  159  can be provided with controlling circuitry as required in order, for example, to vary the rate of delivery, stop delivery if the rate of gas generation is too high, or control the operation of the device  140  in any other way required. In the embodiment shown, the device  140  is a disposable single-rate device which does not require advanced controlling circuitry, but more sophisticated devices are of course within the scope of the invention. 
     A cylindrical outlet  160  is formed in section  156 , and this provides a valve seat for the valve  150 . When the valve  150  is pushed upwards into an outlet  160  it makes an airtight seal, as shown in FIG. 15. A recess  161  in the valve  150  tightly accommodates the connecting member  153  (FIG.  15 ), and the force used to push the housing  142  down onto displaceable cover  143  as described above is sufficient to jam the connecting member  153  into the valve  150 . This design enables the device  140  to be removed from the skin by pulling housing  142  away from displaceable cover  143  to the “post-use” position, causing the connecting member  153  (which is permanently mounted on displaceable cover  143  and at this stage jammed into valve  150  also) to pull the valve  150  down and out of outlet  160  so as to open the valve. Using this design, if the reservoir  147  is not empty when the device  140  is removed, and if gas generation continues, then the gas will escape through outlet  160  rather than driving further drug through the needle  144 . 
     As described above, when the valve  150  is closed, it actuates a switch  151  (see FIG. 15) which comprises a fixed contact  162  and a rocking contact  163 . This completes a circuit to connect a battery  157  to an electrolytic cell  158 . When the valve  150  is pulled downwards as the device  140  is removed from the skin, the switch  151  should automatically disconnect because of the resilience of rocking contact  163  which pivots about a fulcrum  164 . Thus, the opening of the valve  150  is generally a redundant feature and is important as a safety feature if the switch  151  does not automatically disconnect (leading to an unwanted continuation of delivery or, if the reservoir  147  is already empty, to a build up of gas pressure inside the device  140 ). 
     The electrolytic cell  158  comprises (see also FIGS. 17 and 18) a body  165  defining an internal space  166  for an electrolyte and through which a pair of electrodes  167  pass, each electrode being connected to a terminal of battery  157  (FIG.  16 ). 
     The internal space  166  is enclosed above and below by a pair of hydrophobic filters  168 , 169 . These filters  168 , 169  retain the electrolyte but allow gas generated in the cell  158  to be released to the expandable chamber  147 . The top and bottom of the body  165  is provided with a seating  170 . The filters  168 ,  169  are placed in the seating  170  above and below the body  165  and are sealed in place. 
     The cell  158  is then sealed above and below by aluminium foil layers  171 , 172 . A connecting cell  174  sealed at both ends by foil layers  171 , 172  enables gas passing through the hydrophobic filters  168 , 169  to be released, once the top foil layer  171  has been pierced. A gap adjacent to the seating  170 , 171  enables gas escaping through hydrophobic filters  168 , 169  to reach the connecting cell  174 . The foil layer  171  is pierced by a spike  175  carried on rocking contact  164  (see FIG.  16 ). Thus, when the device  140  is actuated, the foil layer  171  is pierced to unseal the cell  158 . A hydrophobic filter  176  (see FIG. 17) is also carried in the body  165  to enable the cell  158  to be filled with electrolyte by injection. 
     In FIGS. 19 and 20, a further embodiment  180  of the invention is shown. This embodiment differs from the embodiment of FIGS. 14-18 only in that the valve member  181  is not held by the displaceable cover  182  when the device  180  is removed from the skin after use. However, the valve  181  nevertheless achieves the primary purpose of allowing the internal space  183  to be occupied entirely by the expandable chamber when received by the user, with the diaphragm  184  moving to the position shown at  185  when the device  180  is loaded with medicament. This means that no air bubbles can be entrapped in the reservoir during filling, and the reservoir can thus be filled quickly and easily. The valve  181  closes automatically when the housing  186  is pressed towards the displaceable cover  182  (see FIG.  20 ). 
     FIG. 21 shows a device  190  according to the invention which is identical to the device of FIG. 1, together with a filling adapter  191  and a drug-containing cartridge  192 . Cartridge  192  is cylindrical in shape, closed at one end  193  thereof and sealed at the other end  194  by an elastomeric stopper  195  which is fittably mounted in the cartridge  192 . Because the cartridge&#39;s liquid-filled internal space  196  is sealed, the stopper  195  is prevented by the incompressible nature of the liquid from moving in either direction. 
     The adapter  191  has a housing  197  in which a cannula subassembly  198  is mounted. The subassembly  198  (see FIG. 22) includes a plastic body  199  moulded in two halves  200 , 201 , which when assembled together clamp a double-ended hollow needle or cannula  202  in place. 
     A device  190  is provided with a socket  203  for receiving an adapter  191 . A cylindrical projection  204  on the end of the adapter  191  is designed to fit into the socket  203 , and also to conceal the cannula  202  to prevent injury before and after the adapter  191  is mounted on the device  190 . A self-sealing penetrable plug  205  mounted in the socket  203  leads to a conduit  206  and an inlet for the reservoir (see inlet  19  in FIG.  1 ). 
     A subassembly  198  is mounted in a channel  207  of the adapter  191  such that it can be pushed inward until a shoulder  208  meets the end of the structure  209  defining the channel  207 . At this point, the cannula  202  will penetrate the plug  205  enabling communication between the cannula  202  and the reservoir of device  190 . 
     In use, a cartridge  192  is pushed into the adapter  191 , whereby a stopper  195  causes the subassembly  198  to be pushed inwards and the cannula  202  to penetrate the plug  205 . Since the subassembly  198  can move no further inward, further pushing of the cartridge  192  into the adapter  191  causes cannula  202  to penetrate stopper  195 , thus putting drug-filled space  196  in indirect communication with the reservoir of device  190 . 
     The stopper  195  is then held by subassembly  198 , further pushing of the cartridge  192  inwards causes the stopper  195  (which remains stationary) to move relative to the cartridge  192  (which is progressively accommodated in the interior of adapter  191 ), with a consequent emptying of the contents of the cartridge  192  through the cannula  202  into the reservoir of device  190 . 
     This is illustrated best in FIG. 23, which shows a sectional view of the components shown in sectional plan view in FIG. 21, after the cartridge  192  has been pushed most of the way home into adapter  191 . It can be seen that at this point, the stopper  195  (penetrated by cannula  202  which also penetrates plug  205 ) has almost reached the end  203  of cartridge  192 . 
     The adapter  191  is not only held by the fit of the projection  204  into the socket  203 , but also by a releasable locking mechanism  210 . The releasable locking mechanism comprises an aperture  211  on the device  190  and a resilient catch  212  on the adapter  191  which is biased into the position shown in FIG. 23 so as to hold the adapter firmly in place on device. Preferably the adapter  191  and the device  190  are sold together in kit form, optionally with the adapter already mounted on the device. 
     When the cartridge  192  is pushed fully home it acts on a sloped section  213  of wall  214  of adapter  191  so as to push resilient catch  212 , which is an extension of wall  214 , downwards. This disengages the locking mechanism  210 , allowing the adapter  191  to be removed from the device  190 . 
     FIG. 24 shows the kit after the cartridge  192  has disengaged the catch  212  allowing it to be withdrawn from the aperture  211 . This permits the adapter  191  to be removed from the device  190  by pulling the projection  204  from the socket  203  whereupon the plug  205  seals itself and thereby isolates the reservoir of the device. 
     Because the catch  212  is only disengaged when the cartridge  192  is fully emptied (i.e. when the stopper is pushed to the closed end  193  of the cartridge  192 ), one can ensure that the reservoir is loaded with exactly the correct amount of drug every time, thereby eliminating human error and making the kit more suitable for home administration. 
     Furthermore, because both ends of the cannula  202  at all times are concealed, the adapter  191  can be safely disposed of without risk of injury. The adapter  191  allows the drug to be transferred to the reservoir with sterility ensured, since the user does not at any time handle any of the components in the fluid path. 
     FIG. 25 shows another alternative embodiment of the device according to the invention, indicated generally at  220 . This embodiment differs from previous ones in that instead of a needle extending directly from the housing  221 , a tube  222  extends from the housing  221  and carries a connector  223  thereon to which a needle may be affixed before use. This device  220  is particularly suitable for intravenous drug delivery because the tube  222  allows the needle to be accurately positioned in a vein. 
     FIG. 26 shows an alternative intravenous embodiment, indicated generally at  230 . In this embodiment the displaceable lower cover has been omitted and the device is actuated by a contact switch  231  positioned on the underside of the housing  232 . When the device is applied to the skin, the switch  231  is pressed inwards (to the position shown in FIG.  26 ), thereby closing an electrical circuit and actuating a gas generating electrolytic cell  233  in the manner previously described. As the snap action provided by previously described devices is not required to cause a needle to penetrate the skin, the cover can be omitted without interfering with other functions of the device. 
     FIG. 27 shows the elastomeric diaphragm  240  utilised in the above-described devices according to the invention. The diaphragm  240  can also be used in other drug delivery devices according to the invention. The diaphragm  240  is shown in FIG. 27 in its relaxed position, as it would be when the reservoir is empty (see FIG. 6, for example). In this configuration the diaphragm  240  substantially has the form of a truncated cone having a sloped portion  241  surrounding a flat portion  242 , with a lip  243  surrounding sloped portion  241  (lip  243  is used to attach diaphragm  240  to the housing of a drug delivery device). 
     FIG. 28 shows the diaphragm  240  in the configuration in which the reservoir is full (see FIG. 1, for example). In this configuration, the central portion  242  is still flat, and the surrounding portion  241  has an arcuate curved cross-section, in the form of a substantially inverted U shape. 
     The diaphragm  240  is bistable, such that it is stable in either the FIG. 27 or the FIG. 28 configuration. However, a particular advantage has been found to result from the fact that in moving from the reservoir full (FIG. 28) configuration to the reservoir empty (FIG. 27) configuration, very little energy is needed. 
     Unlike many bistable arrangements, only minimal force is required to move between the stable configurations. In many bistable arrangements a substantial amount of energy is required to move from one configuration to a midpoint, at which the amount of stored energy is relatively high, following which the stored energy is released to complete the transition. The diaphragm  240 , rather than flipping between configurations, makes a smooth transition. However, in contrast to a completely pliable body, which cannot be depended on to exert force uniformly, the diaphragm  240  will behave dependably since it is constrained in its movement between configurations. This means that a predictable manner of movement is combined with a minimal expenditure of energy in actually effecting the transition between bistable configurations. 
     The elastomeric diaphragm  240  (and others shown in alternative embodiments) and the flow diaphragm  26  of the flow regulating chamber  35  are elastomers. There are two preferred sources for this material. One is a bromobutyl compound made by Vernay Laboratories, Inc. of Yellow Springs, Ohio (material number: VL 911N7). The second is an ethyl propylene diene monomer (“EPDM”) material number Bryant 850-55, made by Bryant Rubber. 
     There are several advantages in using these two materials. First, the material has a low durometer, which enables the material to remain soft. Moreover, it enables the diaphragm to keep air out and deflect from one stable position to the other with little energy. In addition, these elastomers provide a long shelf life. Another advantage is the ability to withstand gamma radiation without degradation of properties. As stated above, gamma radiation is used in some sterilisation procedures. The ability of these materials to withstand gamma radiation is very important as these materials will be assembled in the device and sterilised. An additional advantage of using these materials is their lack of toxicity. 
     FIG. 29 shows a circuit diagram of a controlling circuit particularly useful or a drug delivery device according to the invention. In the circuit  250 , all symbols have their normal meanings within the art. The components shown are a battery B 1 , a switch S 1  (activated by applying the device to the body), fixed resistors R 1 -R 6  and R 9 -R 10 , variable resistors R 7  and R 8 , a capacitor C 1 , transistors Q 2 -Q 6 , measurement terminals TP 1  and TP 2 , a light emitting diode LED, and a load U 1  which represents the electrolytic cell or other gas generating means. Reference numeral  251  denotes a section of the circuit  250  which functions as a current driver, and reference numeral  252  denotes a section of the circuit  250  which functions as an error circuit. 
     The current through the electrolytic cell U 1  determines the potential drop across variable the resistance comprising resistors R 7  and R 8  (which may be adjusted to calibrate the device or set the delivery rate). This potential drop is compared by the error circuit with the potential drop across a reference resistor R 1 , which itself depends on the voltage drop across the LED. The value of resistor R 1  is chosen to provide a potential drop equal to the drop measured across the resistors R 7  and R 8  when the correct current is flowing through the cell U 1 . 
     If the potential drop across the resistors R 7  and R 8  is lower than the constant potential measured across the resistor R 1 , indicating that the current through the cell U 1  is too low (e.g. because of fading battery power, changes in the internal resistance of electrolytic cell U 1  as the reactants are consumed, etc.), the error circuit  252  forces the driver  251  to increase the current flow to the correct value. In practice, the error circuit  252  continually ensures that the current does not deviate from the correct value by constant feedback operation. 
     Each of the transistors in the circuit  250  is a silicon-based bipolar transistor. The advantage of using bipolar transistors in particular is that they have been discovered to surprisingly withstand gamma radiation to a far greater extent than other types of transistors. The use of silicon as semiconductor is not essential but this material is currently less expensive than many other semiconductors. It has been found that by employing a circuit in which the or each transistor is a bipolar transistor, the circuit and hence the entire device can be subjected to intense gamma irradiation as a means of sterilising the device after manufacture. Conventional integrated circuits are destroyed by the intense radiation required to sterilise a device quickly. 
     For example, a dose of 2.5 Mrad (25 kJ/kg) of gamma radiation may be required to sterilise a device. In trying to design a circuit which would withstand such harsh conditions we consulted data regarding the electronic components used in space missions, such as the U.S. Space Shuttle missions. It was found that the same degree of radiation resistance was not required because the absorbed dose measured on the Space Shuttle averages approximately 0.4-0.5 Mrad. 
     As a rule, all electronic components will undergo a degree of degradation when subjected to irradiation. However, by selecting components which are resistant to irradiation as far as possible and whose performance can be predicted after receiving a given dose of radiation, it is possible to design a circuit which will withstand intense gamma radiation and still function in a predictable manner. 
     In particular, by using a bipolar transistor with a high current gain (e.g. a current gain of at least 600 but preferably 800 or more) the drop in current gain exhibited after irradiation can be compensated for in advance. This drop in gain can be of the order of a tenfold drop or more, but can be predicted well in advance. Furthermore, by using current values which are sufficiently low, the drop in voltage at the silicon junction of the transistor occurring as a result of the irradiation only slightly affects performance. 
     A further advantage is gained using a circuit which employs a light emitting diode as a basis for the reference voltage used in the error correction circuit, since the LED reference source is not affected by the gamma radiation. The LED used is a gallium arsenide (GaAs) based LED which has been found to provide particularly good resistance to gamma radiation. 
     In summary, the components and circuit employed have been found to be suitable for gamma irradiation, following which they give a well predictable performance in use. This enables the manufacture to be completed more efficiently, with the assembled device sterilisable by gamma radiation. 
     FIG. 30 is a perspective view of the top side of a displaceable cover  160  forming part of a device according to the invention. FIG. 31 is a perspective view of the underside of cover  160 . Such a cover is described generally above in relation to the embodiment of FIGS. 4-8, for example. 
     The cover  160  is provided with formations  161  forming part of a locking mechanism as described above, with an aperture  162  through which a delivery needle protrudes in use. The cover  160  also has hinge formations  163  which enable the cover to be displaced relative to the housing between first and second positions as previously described. 
     The cover  160  is shaped to improve retention of the device against the skin: thus the top side  164  (FIG. 30) is convex, and the underside  165  (FIG. 31) from which the needle protrudes in use is concave. Accordingly, when the device has been applied to the skin of a subject removal of the device is resisted because the cover  160  conforms more closely to the skin. It is less likely that the device will peel from the skin without a conscious effort by the user since there is a lower likelihood of the periphery of the cover being detached from the skin. 
     It is further appreciated that the present invention may be used to deliver a number of drugs. 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 agnets, 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- 1 ra, thereof; 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 anlogues 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, varapmil, isosorbide-5-mononitrate, organic nitrates, agents used in treatment of heart disorders, and analogues thereof; sedatives such as benzodiazepines, phenothiozines, and analogues thereof; chelating agents such as deferoxamine, and anlogues thereof; anti-diuretic agents such as desmopressin, vasopressin, and anlogues 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 should be understood that the foregoing relates only to preferred embodiments of the present invention and that numerous modifications or alterations may be made therein without departing from the spirit and scope of the invention as set forth in the appended claims.