IE970131A1 - Improved iontophoretic drug delivery device and method of manufacturing the same - Google Patents

Abstract

An iontophoretic drug delivery device (40) comprises a flexible reservoir (46) sandwiched between a flexible printed circuit board (41) and a pair of flexible electrodes (42,43). A rigid top cover is mounted on a spine on the reservoir by means of snap-fit connections. The rigid cover protects the device from damage while the flexible reservoir (46), circuit board (41) and electrodes (42,43) can conform to the skin of a subject. The configuration of the flexible elements (41-43,46) allows the manufacturing process to be simplified considerably, resulting in a less expensive device which is easier to make than prior art devices. <Fig. 5>

Description

^^^mproved iontophoretic drug delivery device and method of manufacturing the same This invention relates to iontophoretic drug delivery devices, and methods of manufacturing the same.

Iontophoretic (or electrophoretic) drug delivery involves using an electric current passing through the skin between an active electrode and a counter electrode to deliver an ionic drug from a reservoir through the skin.

A wide range of iontophoretic drug delivery devices are known. The present invention is directed to improving the comfort and performance of such devices and to simplifying the construction of such devices to assist in manufacture and thereby reduce costs.

US-A-5 314 502 discloses an iontophoretic delivery device comprising a flexible housing having a flexible printed circuit board (PCB) mounted therein, and a battery connected to the PCB. The PCB is connected to a pair of electrodes which each sit on top of a reservoir, the reservoirs being in contact with the skin, in use. The device of USA-5 314 502 is preferably flexible enough to conform to the contours of the body.

Certain problems are associated with the device of US-A-5 314 502, however. The flexible PCB carries a number of integrated circuit elements on its upper surfaces within a cavity in the flexible housing. However, the flexibility necessary to ensure conformity with the contours of the body means that the integrated circuits can be damaged by pressure exerted on the housing or by a shock occurring which could cause the integrated circuits to be crushed within the housing.

Furthermore, the battery, electrodes and connecting wiring are embedded within the housing making manufacture of the device difficult to achieve, which leads to the device being more expensive.

According to the present invention there is provided an iontophoretic drug delivery device comprising flexible reservoir means having opposed first and second surfaces, a flexible substantially flat delivery electrode carried on the first surface of the reservoir means, control means comprising an electrical circuit carried on a flexible circuit board mounted on the reservoir adjacent the second surface thereof, and a rigid protective cover mounted on the circuit board or on the reservoir means such that the circuit board is positioned between the reservoir means and the rigid protective cover.

The term “iontophoretic” as used herein encompasses iontophoretic, electrophoretic and electro-osmotic delivery (in which a non-ionic drug is assisted in diffusing across the skin transdermally by the application of an electric field, as opposed to being driven in ionic form by the current).

The present invention enables the flexibility of a flexible reservoir, electrode and flexible circuit board to be retained without the disadvantages of vulnerability arising from a flexible housing. The rigid cover serves to protect the sensitive components from shock or external applied pressure.

Furthermore, the use of a rigid cover allows a robust device to be produced without necessitating an enclosing housing, and this enables manufacture to be greatly simplified. One of the primary difficulties in the manufacture of the devices of US-A-5 314 502 is the assembly of delicate components such as integrated circuits, electrodes and reservoirs into the housing, since the components are embedded within the housing.

Preferably, the rigid protective cover is mounted on the reservoir means by mounting means, said mounting means being effective to hold the circuit board in position between the reservoir means and the cover.

It has been found that a particularly advantageous construction is to assemble the circuit board, reservoir means and delivery electrode as a flexible unit before finally adding the rigid cover. Again, because no housing per se is required, the assembly process is speeded up considerably.

In a preferred embodiment, the mounting means comprises complementary formations carried on the rigid cover and on the flexible reservoir means, respectively, said circuit board being shaped to accommodate the mounting means.

Particularly suitable examples of complementary formations include snap-fit components which engage securely with one another when pressed together. Such components allow a device to be assembled without welding or similar steps being required.

By providing the circuit board with a shape which accommodates the mounting means, further steps to secure the circuit board to the cover or reservoir are unnecessary. Where snap-fit formations are provided on the cover and reservoir means, in the form of a stud and socket, for example, the circuit board can be provided with an aperture through which the stud or socket passes, such that when the stud and socket are pressed together the circuit board is automatically retained with the mounting means passing through the aperture on the circuit board. The mounting means can be designed to fit together leaving a gap between the cover and reservoir sufficient to just accommodate the circuit board in position.

Suitably, the flexible reservoir means is provided with a substantially rigid section which engages the formations forming part of the mounting means.

Preferably, the substantially rigid section is disposed along a central line separating two or more flexible sections, each of the flexible sections being a separate reservoir forming part of the flexible reservoir means.

For example, a rigid spine can be provided between two halves of a reservoir body. The spine provides the strength to hold the reservoir (and thus possibly also the circuit board and delivery electrode) in position relative to the cover, while the remainder of the reservoir body provides the requisite flexibility to conform to the contours of the body.

In a particularly preferred embodiment, the circuit board and the delivery electrode form part of a single flexible structure which is provided with means for accommodating the reservoir means between the circuit board and the delivery electrode.

It has been found that the use of a single flexible body is particularly advantageous because it allows the “electrical” (or electrochemical) elements of the device to be manufactured together as part of a single process, prior to assembling this flexible component in place on the reservoir means.

Suitably, the single flexible structure comprises a flexible member which serves as both the flexible circuit board and the flexible delivery electrode.

For example, a polymeric film can be used as an inert substrate. Part of the substrate can be converted into a flexible circuit board by known means (such as printing electronic circuitry using conductive inks) and part can be converted into an electrode by depositing a conductive layer (such as a silver layer which forms a particularly effective electrode in combination with a silver chloride counterelectrode). The combined flexible circuit board/flexible electrode is then assembled in place on the flexible reservoir. In the prior art, it was necessary to fabricate a circuit board, electrode, and reservoir separately, and then incorporate each of these elements, together with electrical connections, in a housing. If all of the elements are flexible, this task can be substantially more difficult than if rigid elements are used, since it is generally easier to manipulate and manoeuvre rigid elements relative to one another in restricted spaces than to do the same with flexible elements - with rigid elements the problem of the elements bending or deforming during the assembly process does not occur, making the task more suitable for automation.

Preferably, the reservoir means is sandwiched between the circuit board and the delivery electrode, the means for accommodating the reservoir means comprising a portion of said single flexible structure which connects the circuit board and delivery electrode across the thickness of the reservoir means.

This “sandwich” construction leads to the signal flexible unit referred to above on which the cover can be conveniently mounted in the final stage of assembly.

Suitably, there is provided a flexible counter electrode disposed on the first surface of the reservoir means adjacent the active electrode, each of the electrodes being provided as a flexible conductive member. Suitably, the flexible conductive member is porous.

Preferably, each electrode is in the form of a polymeric film coated with electrically conductive material.

Suitably, the control means comprises means for detecting the application of the device to the skin and means for commencing delivery of drug from the reservoir upon said detection of application to the skin.

Preferably, said detecting means comprises a skin contact sensor connected to a power source, and wherein said means for commencing delivery comprises a switch forming part of said electrical circuit which is activated upon detection of skin contact by the skin contact sensor.

In a preferred embodiment the control means comprises means for gradually increasing the current flowing through said electric circuit from an initial value of zero before commencement of delivery I l J fib CS I V to a first value which is higher than the steady state value required, maintaining said first value for a predetermined period of time, and then reducing the current to a steady state value and maintaining said steady state current throughout the duration of delivery.

The provision of a higher initial current is advantageous in that it serves to quickly build up levels of the drug after application of the device. In the case where the drug is an analgesic, for example, the patient may require rapid pain relief, and with many other classes of drug it may also be preferable to achieve therapeutic levels as quickly as possible.

Preferably, the time taken to increase the current from zero to the first, higher value is from 2 minutes to thirty minutes, more preferably from 5 minutes to fifteen minutes, and preferably the current is maintained at this value for between ten minutes and three hours, more preferably for between thirty minutes and two hours.

A further preferred feature is that the first, higher value is between 1.5 times and 10 times the steady state value, more preferably between 1.5 times and 4 times the steady state value.

In a presently preferred embodiment described in detail below, the first, higher value is 0.75-1.0 mA, the steady state value is 0.250.50 mA, the time taken to reach the first, higher value is 8-12 minutes, and the first, higher value is maintained for 45-60 minutes before the current drops to the steady state value.

A further preferred feature is that the control means comprises means for controlling the current through a programmed routine, and means for detecting the removal of the device from the skin and for recommencing said programmed routine at the point at which it was interrupted by the removal of the device from the skin.

This feature allows a user to remove the device and reposition it if for any reason it is placed in an unsuitable location (e.g. it may be physically uncomfortable or the skin on which it is placed may be unusually sensitive), without interfering with the cycle. It also allows a user to remove a device which has a twenty-four hour delivery cycle, for example, to be removed from the skin during short periods such as when bathing or playing sports, before being returned to the skin to complete the cycle of delivery.

Preferably, the means for detecting removal and recommencing the routine at the point of interruption remains inoperative, in use, for an initial period of up to 10 minutes, 5 minutes or 3 minutes.

The reason for waiting for a brief period before starting delivery is that the possibility exists that a current may exist briefly before the device is applied to the skin. If the circuit includes means for detecting the application of the device to the skin and means for commencing delivery of drug from the reservoir upon said detection of application to the skin, then a false indication of current flowing through the circuit will start operation of the device and drain the battery.

For example, when a device is in storage, a strong electromagnetic field such as might occur during a thunderstorm could be interpreted as a current flowing through the skin detection means, especially if the current sensor is particularly sensitive, as is the preferred case. Alternatively, the delivery circuit could be accidentally actuated if the device is removed from packaging and the electrodes are touched briefly before it is intended to apply the device to the skin. By providing the “latch” circuit which requires continuous detection for a period of time of 3, 5 or 10 minutes, these false indications of application to the skin are avoided.

In another aspect of the invention, there is provided a method of manufacturing an iontophoretic drug delivery device, comprising the steps of; (a) interposing a flexible circuit board between a rigid cover and a flexible reservoir means, the rigid cover and the flexible reservoir means being provided with complementary formations for attachment together and said flexible circuit board being provided with means for accommodating said complementary formations; (b) joining the complementary formations together such that the means for accommodation holds the circuit board in place between the rigid cover and the reservoir means; and (c) providing a flexible, substantially flat delivery electrode on the surface of the reservoir means distal from the circuit board.

This method of manufacture is, as explained above, significantly faster and less complicated than assembling a plurality of flexible elements in the interior of a flexible housing, as well as providing a product which combines the advantages of flexibility and rigidity referred to above.

Even a small increase in the speed or ease of assembly provides a significant commercial advantage, and doing away with the need for any housing, as in the device and method of the present invention provides a significant decrease in the complexity of the manufacturing operation.

The speed, ease and lack of complexity of the assembly process enable the device to be made quicker, cheaper and with a better overall quality. Moreover the improved assembly process will decrease the likelihood of any contamination or desterilisation that may occur in the medicament reservoir.

Preferably, step (c) comprises adhering the delivery electrode to the reservoir by means of an electrically conductive adhesive.

It should be noted that step (c) is not necessarily carried out after steps (a) and (b). Indeed it may be preferable to assemble the flexible components together before attaching the rigid cover.

For example, in a preferred method, the flexible circuit board and the delivery electrode are provided as a single flexible structure, and wherein steps (a) and (c) involve sandwiching the reservoir means between the circuit board and electrode elements of the single flexible structure.

Suitably, the method includes the additional step of covering the exposed surface of the reservoir means and/or delivery electrode distal from the circuit board with adhesive means for adhering the device to the skin of a subject, in use.

The method according to the invention may further comprise the step of covering said adhesive means with a release liner which is adapted to be peeled away before use of the device, so as to expose said delivery electrode and said adhesive means for application thereof to the skin of a subject.

Suitably, the method according to the invention further comprises the step of filling the reservoir means with a drug to be delivered.

Further, suitably, the reservoir means comprises a plurality of reservoirs and the filling step involves filling different reservoirs with different drugs.

The term “drug” as used herein includes but is not limited to conventional medicaments as well as cosmetic substances or other substances which may be advantageously applied to the skin of a subject. As far as medicaments are concerned, there is essentially no limitation on the type of drug which can be used with the invention other than to exclude those drugs which would be inappropriate to deliver to a subject iontophoretically, electrophoretically or electroIE 970131 ίο osmotically. Representative drugs include peptides or proteins, hormones, analgesics, anti-migraine agents, anti-coagulant agents, antiemetic agents, cardiovascular agents, anti-hypertensive agents, narcotic antagonists, chelating agents, anti-anginal agents, chemotherapy agents, sedatives, anti-neoplasties, prostaglandins and antidiuretic agents.

Typical drugs include peptides, proteins or hormones 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, somatostatin, 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 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 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, phenothiozines, and analogues thereof; narcotic antagonists such as naltrexone, naloxone, 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.

Other drugs include antiulcer agents, such as but not limited to cimetidine, and ranitidine; antibiotics; anticonvulsants; antiinflammatories; antifungals; antipsychotics; corticosteroids; immunosuppressants; electrolytes; nutritional agents and vitamins; general anesthetics; antianxiety agents, such as but not limited to compazine; and diagnostic agents.

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 an exploded, perspective view of an iontophoretic drug delivery device according to the invention: Fig. 2 is a perspective view of the device of Fig. 1; Fig. 3 is a plan view of the device of Fig. 1; Fig. 4 is a sectional view of the device of Fig. 1; Fig. 5 is an exploded view of an alternative embodiment of a drug delivery device according to the invention; and Fig. 6 is a block diagram of the electrical circuit of the devices of Figs. 1 and 5.

In Fig. 1 there is indicated, generally at 10, an iontophoretic drug delivery device according to the invention. The device 10 comprises a rigid cover 11, a flexible printed circuit board 12, three 3V lithium coin cell batteries 13,14,15 mounted on circuit board 12, reservoir means 16 in the form of an elastomeric body having two reservoir wells 17,18 and a rigid spine 19 separating the wells 17,18, and a pair of electrodes 20,21 which are adhered to reservoir means 16 by two adhesive patches 22,23, respectively. A further layer of adhesive 24 is positioned on the underside of reservoir means 16 around the electrodes 20,21. Finally, a release liner 25 protects electrodes 20,21 and adhesive 24 before use.

Rigid cover 11 is an injection moulded acrylonitrile-butadienestyrene polymer (ABS) component having a pair of snap-fit stud formations (not shown) on its underside which are received in corresponding snap-fit socket projections 26 located on spine 19.

Socket projections 26 pass through apertures 27 on flexible circuit board 12, such that when rigid cover 11 is snap-fitted to reservoir means 16, the mounting means comprising socket projections 26 and the corresponding stud projections on cover 11 hold the flexible circuit board 12 firmly in position. Thus, the circuit board 12 is protected between rigid cover 11 and reservoir 16. Reservoir 16 is made by injection moulding or vacuum forming an elastomer material sold by Shell Chemicals under the Trade Mark “Kraton G2705”, which is a thermosetting polymer compound with saturated rubber midblock.

This elastomeric reservoir cushions circuit board 12 from below, while rigid cover 11 protects circuit board 12 from above.

In the illustrated embodiment, reservoir well 17 contains an active formulation consisting of 0.5% methyl paraben (preservative), glycerol, agar, and the active ingredient which in this case is the analgesic hydromorphone. Reservoir well 18 contains a “counter” formulation which is used to ensure a good iontophoretic circuit. The counter formulation consists of glycerol, agar, water and sodium chloride.

The adhesive 22,23,24 used to attach electrodes 20,21 to the reservoir means 16 and to attach the underside of reservoir means 16 to the skin of the patient is an electrically conductive dermal adhesive available under the Trade Mark MA46 from Adhesives Research, Glen Rock, Pennsylvania, U.S.A. The resistance of the adhesive can be chosen by using a different adhesive or by varying the thickness of the adhesive, in order to obtain the desired current through the skin. it y/υ io i Electrode 20 is an active or delivery electrode comprising a layer of 0.15 mm polyester film on which a layer of silver ink is printed. A pure silver layer having a thickness of 16 microns is plated onto the ink.

Electrode 21 is a passive or counter electrode comprising a layer of 0.15 mm polyester film on which a layer of silver ink is printed. A pure silver layer having a thickness of 8 microns is plated onto the ink and then the film is dipped into a ferric chloride solution to provide a silver/silver chloride outer layer.

A conductive strip 28 on delivery electrode 20 passes through an aperture 29 in reservoir means 16 to contact a terminal 30 of circuit board 12, thereby enabling power to be transmitted from the batteries 13,14,15 to electrode 20 via a control circuit which is printed on circuit board 12 (or can be in the form of an integrated circuit mounted on board 12). A similar conductive strip 31 contacts a terminal 32 on circuit board 12 to complete the return circuit (the circuit is closed when the device is applied to the skin).

The device is assembled by adhering the electrodes 20,21 to reservoir means 16, positioning circuit board 12 on reservoir means 16 (such that socket projections 26 protrude through apertures 27. and terminals 30,32 are in contact with conductive strips 28,31, respectively), and pressing rigid cover 11 downwards to snap the mounting means together. Adhesive layer 24 is applied to the underside of reservoir 16 and finally release liner 25 (sold as release liner 7010 by Adhesives Research) is applied to the underside of the device 10. The thus assembled device is illustrated in perspective view in Fig. 2 and in plan view in Fig. 3. In each of Figs. 2 and 3 cover 11, the periphery of reservoir means 16 and a tab 33 of release liner 25 can be seen.

Fig. 4 shows a sectional view of device 10, taken along the line IV-IV (see Fig. 3). Thus, cover 11 and reservoir means 16 can be seen sandwiching flexible circuit board 12 therebetween. Circuit board 12 rests on spine 19 and projections 34,35 which are formed on the upper surfaces of wells 17,18, respectively. Batteries 13,14 can be seen mounted on circuit board 12, and conductive strip 31 can be seen extending up to contact circuit board 12. The electrodes 20,21 on the underside of the device 10 can also be seen.

It can be seen from Fig. 4 that rigid cover 11 is connected to the remainder of the device only along the central spine 19, thereby allowing the device to flex and conform to the contours of the body to which it is applied, while still protecting the flexible circuit board from pressure or impact. Importantly, this is achieved by a construction which can be snap-fitted together which does not require a housing to contain all of the elements.

An alternative embodiment is illustrated, generally at 40, in Fig.

. Although the Fig. 5 embodiment is identical to that of Figs. 1-4 in many respects, the Fig. 5 embodiment employs a flexible circuit board 41 and electrodes 42,43 which form part of a single flexible structure, indicated generally at 44. A flexible connecting strip 45 between the circuit board 41 and electrodes 42,43 enables the structure 44 to be affixed to reservoir means 46 by sandwiching reservoir means 46 between circuit board 41 and electrodes 42,43.

This construction provides advantages in terms of ease of manufacturing, since it is not necessary to effect a connection between the circuit board 41 on one side of the reservoir means 46 and the electrodes 42,43 on the other side thereof (since the connection already exists as connecting strip 45, on which connecting circuitry is printed in conductive ink. Preferably, a single substrate forms the basis for structure 44, with circuit board 41 comprising a portion of the substrate on which controlling circuitry has been printed, and electrodes 42,43 comprising portions which have been treated (as described above in relation to Figs. 1-4) to become electrodes.

However, structure 44 can also be assembled initially from a flexible circuit board, flexible connecting strip and flexible electrodes which are bonded together to provide a single structure containing all of the electrical/electrochemical elements of the device, this structure then being assembled into place relative to the reservoir means.

The controlling circuitry is illustrated in block diagram format in Fig. 6. The circuit shown in the form of a block diagram in Fig. 6 is shown in detail in Fig. 7, in which all components and notations have their customary meaning within the art. The layout of the circuit in Fig. 7 follows the same general spatial configuration as the block diagram of Fig. 6.

The circuit, indicated generally at 50 in Fig. 6, comprises a programmer 51 which is provided with instructions for a given current profile. In the case of the hydromorphone delivery device described above, a suitable current profile is as follows: the current starts from zero at the beginning of the delivery regime (i.e. t=0), rising in 16 steps of 52μΑ over the first ten minutes (i.e. until t=10 min). The final current is stabilised at a levei of 0.83 mA, and is maintained at this first, higher level from t=10 min to t=60 min. The current then drops to a lower, steady state level for the remainder of the deliver period, in this case from t=60 min to t=30 hours. Although the device is designed to be a once-daily device, the extension of delivery to 30 hours rather than 24 hours takes account of the fact that delivery should be maintained even if the patient does not change the device at the same time every day.

The programmer 51 generates voltages which are fed to a current regulator 52 which translates the voltages generated by the programmer 51 into stabilised current levels, so as to supply a steady output independently of the battery voltage (which may fluctuate,) and independently of voltage drops between the two electrodes 53. Electrodes 53 serve to deliver the drug when applied to the skin.

A battery 54 is connected to programmer 51 and current regulator 52 across a transistor 55 (transistor Ql in Fig. 7). Transistor 55 is controlled by a skin contact sensor 56 which detects the closing of a circuit across electrodes 53. Before the device is applied to the skin, skin contact sensor 56 detects that the circuit between the electrodes 53 is open, and the power supply from battery 54 to programmer 51 and current regulator 52 is cut off by transistor 55. When skin contact sensor 56 detects the application of the electrodes 53 to the skin, it switches transistor 55 so as to connect battery 54 to programmer 51 and current regulator 52, thereby beginning delivery.

A latch circuit 57 is connected between programmer 51 and skin contact sensor 56. After a given period of time (e.g. 2.5 minutes) programmer 51 sends a signal to latch circuit 57. After this signal is received, if the device is removed from the skin the programmer will resume the delivery upon re-application from the point at which the cycle was interrupted. Thus, once the latch circuit is activated, the device can be removed for repositioning. If the skin contact sensor 56 detects omy a short (<2.5 min) current flow, the latch circuit 57 will not be operated and removal of the device from the skin will switch off the circuit, thereby preventing battery drainage occurring as a result of a briefly closed circuit or a strong electromagnetic field.

An over-current protector 58 continuously monitors the current provided by current regulator 52 and cuts off the current through the electrodes 53 if the current rises above a predetermined level (e.g. 1 mA) at which skin burning or excessive dosage levels might begin to occur.

A light emitting diode 59 is driven by an LED driver 60 which includes an oscillator. The LED 59 provides an indication of the proper functioning of the circuitry. During the first two minutes of delivery, LED 59 is continuously lit, and once the latch circuit 57 is activated, driver 60 causes the LED to flicker continuously throughout delivery.

Claims (30)

1. Claims: 1. An iontophoretic drug delivery device comprising flexible reservoir means having opposed first and second surfaces, a flexible substantially flat delivery electrode carried on the first surface of the reservoir means, control means comprising an electrical circuit carried on a flexible circuit board mounted on the reservoir adjacent the second surface thereof, and a rigid protective cover mounted on the circuit board or on the reservoir means such that the circuit board is positioned between the reservoir means and the rigid protective cover.

2. A device according to Claim 1, wherein the rigid protective cover is mounted on the reservoir means by mounting means, said mounting means being effective to hold the circuit board in position between the reservoir means and the cover.

3. A device according to Claim 2, wherein the mounting means comprises complementary formations carried on the rigid cover and on the flexible reservoir means, respectively, said circuit board being shaped to accommodate the mounting means.

4. A device according to Claim 3, wherein the flexible reservoir means is provided with a substantially rigid section which engages the formations forming part of the mounting means.

5. A device according to Claim 4, wherein the substantially rigid section is disposed along a central line separating two or more flexible sections, each of the flexible sections being a separate reservoir forming part of the flexible reservoir means.

6. A device according to any preceding claim, wherein the circuit board and the delivery electrode form part of a single flexible structure which is provided with means for accommodating the reservoir means between the circuit board and the delivery electrode.

7. A device according to Claim 6, wherein the single flexible structure comprises a flexible member which serves as both the flexible circuit board and the flexible delivery electrode.

8. A device according to Claim 6 or 7, wherein the reservoir means is sandwiched between the circuit board and the delivery electrode, the means for accommodating the reservoir means comprising a portion of said single flexible structure which connects the circuit board and delivery electrode across the thickness of the reservoir means.

9. A device according to any preceding claim, further comprising a flexible counter electrode disposed on the first surface of the reservoir means adjacent the active electrode, each of the electrodes being provided as a flexible conductive member.

10. A device according to Claim 9, wherein each electrode is in the form of a polymeric film coated with electrically conductive material.

11. A device according to any preceding claim, wherein the control means comprises means for detecting the application of the device to the skin and means for commencing delivery of drug from the reservoir upon said detection of application to the skin.

12. A device according to Claim 11, wherein said detecting means comprises a skin contact sensor connected to a power source, and wherein said means for commencing delivery comprises a switch forming part of said electrical circuit which is activated upon detection of skin contact by the skin contact sensor.

13. A device according to any preceding claim, wherein the control means comprises means for gradually increasing the current flowing through said electric circuit from an initial value of zero before commencement of delivery to a first value which is higher than the steady state value required, maintaining said first value for a predetermined period of time, and then reducing the current to a steady state value and maintaining said steady state current throughout the duration of delivery.

14. A device according to Claim 13, wherein the time taken to increase the current from zero to the first, higher value is from 2 minutes to thirty minutes, and wherein the current is maintained at this value for between ten minutes and three hours.

15. A device according to Claim 14, wherein the time taken to increase the current from zero to the first, higher value is from 5 minutes to fifteen minutes, and wherein the current is maintained at this value for between thirty minutes and two hours. 16. A device according to any one of Claims 12-14, wherein the first, higher value is between 1.5 times and 10 times the steady state value.

16. A device according to Claim 15, wherein the first, higher value is between 1.5 times and 4 times the steady state value.

17. A device according to any one of Claims 12-16, wherein the first, higher value is 0.75-1.0 mA, the steady state value is 0.250.50 mA, wherein the time taken to reach the first, higher value is 8-12 minutes, and wherein the first, higher value is maintained for 45-60 minutes before the current drops to the steady state value.

18. A device according to any preceding claim, wherein the control means comprises means for controlling the current through a programmed routine, and means for detecting the removal of the device from the skin and for recommencing said programmed routine at the point at which it was interrupted by the removal of the device from the skin.

19. A device according to Claim 18, wherein the means for detecting removal and recommencing the programmed routine at the point of interruption remains inoperative, in use, for an initial period of up to 10 minutes.

20. A device according to Claim 19, wherein said initial period is 5 minutes or less.

21. A device according to Claim 20, wherein said initial period is 3 minutes or less.

22. A method of manufacturing an iontophoretic drug delivery device, comprising the steps of: (a) interposing a flexible circuit board between a rigid cover and a flexible reservoir means, the rigid cover and the flexible reservoir means being provided with complementary formations for attachment together and said flexible circuit board being provided with means for accommodating said complementary formations; (b) joining the complementary formations together such that the means for accommodation holds the circuit board in place between the rigid cover and the reservoir means; and (c) providing a flexible, substantially flat delivery electrode on the surface of the reservoir means distal from the circuit board.

23. A method according to Claim 22, wherein step (c) comprises adhering the delivery electrode to the reservoir by means of an electrically conductive adhesive.

24. A method according to Claim 22 or 23, wherein the flexible circuit board and the delivery electrode are provided as a single flexible structure, and wherein steps (a) and (c) involve sandwiching the reservoir means between the circuit board and electrode elements of the single flexible structure.

25. A method according to any one of Claims 22-24, further comprising the step of covering the exposed surface of the reservoir means and/or delivery electrode distal from the circuit board with adhesive means for adhering the device to the skin of a subject, in use. 5

26. A method according to Claim 25, further comprising the step of covering said adhesive means with a release liner which is adapted to be peeled away before use of the device, so as to expose said delivery electrode and said adhesive means for application thereof to the skin of a subject. 10

27. A method according to any one of Claims 22-26, further comprising the step of filling the reservoir means with a drug to be delivered.

28. A method according to Claim 27, wherein the reservoir means comprises a plurality of reservoirs and the filling step involves 15 filling different reservoirs with different drugs.

29. An iontophoretic drug delivery device, substantially as hereinbefore described with reference to and as illustrated in Figs. 1-4, 5 and 6 of the accompanying drawings.

30. A method of manufacturing an iontophoretic drug delivery 20 device, substantially as hereinbefore described.