AU3526199A - Device for transdermal administration of medicine by iontherapy - Google Patents

Description

WORLD PATENT INTERNATIONAL PATENT OFFICE WORLD ORGANIZATION FOR INTELLECTUAL PROPERTY International patent published on the basis of the Patent Cooperation Treaty INTERNATIONAL PUBLICATION NO. WO 99/56819 Al International Patent Classification 6 : A 61 N 1/32 International Patent Filing No.: PCT/FR99/01024 International Filing Date: April 29, 1999 International Publication Date: November 11, 1999 Priority Date: April 30, 1998 Country: FR No.: 98/05473 [Device for Transdermal Administration of Medicine by Iontherapy] Patent applicant (for all the contracting nations except USA): LABORATOIRE D'HYGIENE ET DE DIETETIQUE (L. H. D.) [FR/FR] 38, AVENUE Hoche, F-75008 Paris (FR) Inventors Inventors/Applicants (only for the United States): Michel, Ernest, Joseph Gicquel [FR/FR] 8, all6e du Petit Noyer F-21490 Orgeux (FR) Michel Lamoise [FR/FR] 10, rue d'Amont F-21 110 Bessey-les-Citeaux (FR) Philippe, Pierre, Marie Millot [FR/FR] 3, all6e de l'Ormerai F-21490 Orgeux (FR) 3 Representative: CABINET DE BOISSE ET COLAS; 37, AVENUE Franklin D. Roosevelt F-75008 (FR) Designated Contracting States: AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW, ARIPO Patent (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), Eurasian Patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European Patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI Patent (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG) 4 Published With international search report. This device for the transdermal administration of a drug by ionophoresis comprises an assembly (A) including at least an electrode attached to a reservoir (37) which is loaded with said drug and a counter electrode, an electronic circuit and an electric battery (35), said electronic circuit allowing the generation of a therapeutic electric current from the energy supplied by said battery, said current passing, between said two electrodes, through said reservoir and the patient's skin (41) against whom it is applied, and said electronic circuit comprising means to conform a temporary program of drug administration to the discharge versus time curve of said battery, from a fully loaded state of said battery to a state close to depletion. Application to disposable devices for transdermal administration. The present invention relates to a device for the transdermal administration of a drug by ionophoresis. This type of device, notably described in French Patent Application No. 96 04735 in the name of the applicant, allows the application to the patients of painless and perfectly dosed medical treatments. The latter characteristic is particularly important when the drugs used can be harmful to patient health in case of overdosage. The devices of the type described in the above mentioned document are designed to be reused a certain number of times. For this purpose, for example, the device described in the above mentioned document comprises a programmable electronic module, which can control, for a given drug, the treatment durations of varying length depending on patient needs. Moreover, in the cited example, this module can be separated from the assembly of electrodes containing a drug, and they can be adapted to another assembly of electrodes containing another drug.

In a certain number of standard treatments, for example, in local anesthesia, a single transdermal administration of a drug by ionophoresis is sufficient. The duration of the treatment, which is generally between 15 and 90 min, is fixed for a given drug. All the above mentioned possibilities of variable programming or of changing the drugs are then superfluous. For this type of treatment, a simpler device is thus sufficient. This, in combination with the unique and isolated character of the treatment, naturally leads to the consideration of a device which is intended to be discarded after use, such as, for example, a conventional dressing. In this context, it is important to manufacture this device at a lesser cost, and thus to simplify as much as possible, the means for the electronic control of the treatment and the structure of the device itself. In particular, it is essential to eliminate the complexity of the means currently used to trigger and stop the treatment. The purpose of the present invention is the construction of a device which integrates these constraints. This purpose of the invention is achieved, as are others which will become apparent after a reading of the following, using a device for the transdermal administration of a drug by ionophoresis, comprising an assembly including at least an electrode which is attached to a reservoir loaded with said drug and a counter electrode, an electronic circuit and an electric battery, said electronic circuit allowing the production of a therapeutic electric current from the energy supplied by said battery, said current flowing, between said two electrodes, through said reservoir and the patient's skin, against whom it is applied, said electric circuit comprising means to conform a temporary program for the administration of the drug to the discharge versus time curve of said battery, from a fully loaded state of said battery to a state close to depletion.

According to a characteristic of the invention, said means comprise a current generator, supplied by a cutting power supply, and controlled by a voltage proportional to the voltage measured at the terminals of said battery. Thanks to these characteristics, it becomes possible to manufacture, at lesser cost, a device for transdermal administration by ionophoresis intended to be used a single time. Other characteristics and advantages of the present invention will become apparent after reading the following description and examination of the drawings in the appendix, which are only given as examples, and in which: - Figure 1 is a top view of the assembly of electrodes of the device according to the invention; - Figure 2 is a bottom view of this assembly of electrodes; - Figure 3 is a top view of an adhesive support intended to fix the assembly of electrodes to the patient's skin; - Figure 4 is a top view of the assembly of electrodes, positioned in the adhesive support, in the unfolded position and according to a first embodiment variant of the treatment triggering device; - Figure 5 is a side view of the device represented in Figure 4, placed on a patient's skin; - Figure 6 is a top view of the assembly of electrodes, positioned in the adhesive support, in the folded position and according to a second embodiment variant of the treatment triggering device; - Figure 7 is a side view of the device represented in Figure 6; - Figure 8 is a diagram describing the operation of the electronic surface of the device according to the invention; 7 - Figure 9 represents a characteristic discharge curve of a battery which can supply power to the electronic circuit of the device according to the claim; - Figure 10 represents the variation over time of the current applied to the patient's skin. In these figures, identical numerical references represent identical or similar devices or elements. Figures 1 and 2 show an assembly of electrodes A, which is intended to equip the device according to the invention. The body of this assembly consists of a sheet of flexible material, such as, for example, Bendflex or Kapton (registered trade names), cut so as to essentially form a strip 1 comprising a first rounded extremity 2 and a second rounded extremity 3. This strip comprises a folding line 4 which is transverse with respect to its length, located at the juncture of the first rounded part 2 with the remainder of the strip. According to a first embodiment variant of a treatment triggering means, the strip comprises, in addition, a slit 5 which is transverse with respect to its length, located at the juncture of the second end 3 with the remainder of the strip, and represented in a broken line in Figures 1 and 2. The use of this slit 5 will become apparent in the remainder of the description. Strip 1 is provided with a two-sided printed circuit 6, manufactured, for example, by photoengraving. On an essentially rectangular part of a face A of the strip, opposite to the one, A2, which is intended to come in contact with the patient's skin, the circuit 6 comprises a plurality of contact blocks 7 intended to receive electronic components, the printed circuit 6 and the assembly of these components forming the electronic circuit of the device according to the invention. The contact blocks 7 are connected to each other by conducting tracks of which some, 8, are located on the face Al of the strip, and the others, 9, are located on the face A2 of the strip.

8 Metal clad holes 10 make it possible to ensure the electric contact between the tracks located on the face Al and those located on the face A2. Two conducting tracks 11, 12 located on the face Al of the strip 1 connect two of the contact blocks 7 to two contact pads 13, 14, which themselves are connected, through the intermediary of two metal clad holes, to an electrode 15 and a counter electrode 16, respectively, which are located on the face A2 of the strip (see Figure 2). The electrode 15, which can have a circular contour, for example, is centered with respect to the first rounded end 2 of the strip. The counter electrode 16, which can have a rectangular contour, for example, is located between the part of the face A2 where the conducting tracks 9 are located and the second rounded end 3 of the strip. These two electrodes can be manufactured in the standard manner by deposition of a conducting material by serigraphy. A third conducting track 17, located along an edge 18 of the face Al of the strip 1, connects one of the contact blocks 7 to a metal clad hole 19 located at the juncture of the second rounded end 3 with the remainder of the strip. On the face A2 of the strip, a conducting track 20 connects the metal clad hole 19 to a contact block 25, which itself is connected through the intermediary of a metal clad hole to a contact pad 26 located on the face Al of the strip and centered with respect to the second rounded end 3. The distance dl between the contact pads 14 Metal clad holesJ0 make it possible to ensure the electric contact between the tracks located on the face Al and those located on the face A2. Two conducting tracks 11, 12 located on the face Al of the strip 1 connect two of the contact blocks 7 to two contact pads 13, 14, which themselves are connected, through the intermediary of two metal clad holes, to an electrode 15 and a counter electrode 16, respectively, which are located on the face A2 of the strip (see Figure 2). The electrode 15, which can have a circular contour, for example, is centered with respect to the first rounded end 2 of th strip. The counter electrode 16,'which can have a rectangular contour, for example, is located between the part of the face A2 where the conducting tracks 9 are located and the second rounded end 3 of the strip. These two electrodes can be manufactured in the standard manner by deposition of a conducting material by serigraphy. A third conducting track 17, located along an edge 18 of the face Al of the strip 1, connects one of the contact blocks 7 to a metal clad hole 19 located at the juncture of the second rounded end 3 with the remainder of the strip. On the face A2 of the strip, a conducting track 20 connects the metal clad hole 19, to a contact block 25, which itself is connected through the intermediary of a metal clad hole to a contact pad 26 located on the face Al of the strip and centered with respect to the second rounded end 3. The distance dl between the contact pads 14 and 26 is essentially equal to two times that of the pad 26 at the juncture of the second rounded end 3 with the remainder of the strip. Figure 3 shows an adhesive support B intended to fix the assembly of electrodes A to the patient's skin.

This adhesive support is cut from a standard adhesive material with simple medical face, so as to essentially form a strip 27 comprising a first rounded end 28 and a second rounded end 29. The width of the strip 27 is greater than that of the strip 1, and equal, for example, to twice the width of the strip 1. The length of the strip 27 is essentially equal to that of the strip 1. The strip 27 has a first transverse strip 30 and a second transverse strip 31, which are transverse with respect to its length, located essentially, and respectively, at the juncture of the second rounded end 28 with the remainder of the strip. The width of these slits is essentially equal to that of the strip 1, and the distance d2 which separates them is slightly smaller than that, d3, which separates the folding line 4 from the counter electrode 16. Moreover, one notes that the first slit 30 is connected to the edges of the strip 27 by a folding line 32. According to the first embodiment variant of the treatment triggering means, the strip 27 also comprises a third transverse slit 33, which is transverse with respect to its length, located on the second rounded edge 29, and having a width which is similar to that of the slit 5, formed in the strip 1. The distance d4 from the second slit 31 to the third slit 33 is essentially equal to half of dl. The slit 33 is represented in broken lines in Figure 3. The use of this slit 33 will become apparent in the continuation of the present invention. Figure 4, and Figure 5, in which the device of the invention is shown in place on the skin 41 of the patient, show how the assembly of electrodes A and the adhesive support B work in cooperation. These figures also show a certain number of devices which will have to be described. Electronic components 34 are implanted on the face Al of the assembly of electrodes, in the zone where the contact blocks 7 are located.

lU The two terminals of the battery 35 are in contact with the pad 14 and with the pad 26, respectively, thanks to the crimping of the second rounded end 3 of the strip I toward the interior of the face Al. The proximity of the conducting track 17 to the edge 18 of the strip 1 prevents it from coming in contact with the battery, thus eliminating any risk of short circuit. According to the first embodiment variant of the treatment triggering means, a blade made of an insulating material, 36, is inserted between the battery 35 and the contact pad 26. This blade projects to the outside through the slit 5 of the strip 1. Figures 4 and 5 also show the first reservoir 37 and the second reservoir 38, which are attached to the electrode 15 and to the counter electrode 16, respectively. These reservoirs consist, for example, of a layer of a material which is loaded with a substance: a solution containing the drug to be administered for the reservoir attached to the counter electrode, and a neutral solution, such as NaCl, for the reservoir attached to the electrode. These reservoirs are separated from the patient's skin 41 by permeable membranes 39, 40, and they are protected by shells (not shown) during storage. The assembly of electrodes A so equipped is inserted into the slits 30 and 31 of the adhesive support B, so that only the electronic components 34 appear on the side of the support B, which is not coated with adhesive. The folding lines 4 and 32 coincide, and, in the first embodiment variant of the treatment triggering means, the blade 36 traverses the slit 33 of the adhesive support B. Figure 5 demonstrates the fact that only the periphery of the adhesive support B is I I I II IU The two terminals of the battery 35 are in contact with the pad 14 and with the pad 26, respectively, thanks to the crimping of the second rounded end 3 of the strip 1 toward the interior of the face Al. The proximity of the conducting track 17 to the edge 18 of the strip 1 prevents it from coming in contact with the battery, thus eliminating any risk of short circuit. According to the first embodiment variant of the treatment triggering means, a blade made of an insulating material, 36, is inserted between the battery 35 and the contact pad 26. This blade projects to the outside through the slit 5 of the strip 1. Figures 4 and 5 also show the first reservoir 37 and the second reservoir 38, which are attached to the electrode 15 and to the counter electrode 16, respectively. These reservoirs consist, for example, of a layer of a material which is loaded with a substance: a solution containing the drug to be administered for the reservoir attached to the counter electrode, and a neutral solution, such as NaCl, for the reservoir attached to the electrode. These reservoirs are separated from the patient's skin 41 by permeable membranes 39, 40, and they are protected by shells (not shown) during storage. The assembly of electrodes A so equipped is inserted into the slits 30 and 31 of the adhesive support B, so that only the electronic components 34 appear on the side of the support B, which is not coated with adhesive. The folding lines 4 and 32 coincide, and, in the first embodiment variant of the treatment triggering means, the blade 36 traverses the slit 33 of the adhesive support B. Figure 5 demonstrates the fact that only the periphery of the adhesive support B is attached to the surface of the patient's skin 41, and, in addition, that this support is attached to the face Al of the first rounded end 2 and on the face A2 of the second rounded en 3. Figures 6 and 7 show the device according to the invention in the storage configuration.

11 The first rounded ends 2 and 28 of the assembly of electrodes A and of the adhesive support B, respectively, which are integrally connected by gluing, are folded back about the folding lines 4 and 32, respectively, against the face Al of the assembly of electrodes A. In this manner, the size of the device is reduced. Moreover, the components 34 of the electronic circuit are protected in this manner during storage and transport. According to the first embodiment variant of the treatment triggering means, not shown in Figures 6 and 7, the blade 36 points toward the outside, traversing the slits 5 and 33, as is apparent in Figures 4 and 5. According to a second embodiment variant of the treatment triggering means, represented in Figures 6 and 7, a blade made of insulating material, 45, interposed between the battery 35 and the contact pad 26, points in the direction of the electronic components 34. This blade is fixed to the adhesive face of the first rounded end 28 of the adhesive support B, so that the unfolding of this rounded end necessarily has the effect of moving the blade from its initial position, thus achieving electric contact between the battery 35 and the pad 26. Figure 8 is a diagram which makes it possible to understand the principle of operation of the electronic surface of the device according to the invention. The battery 35 supplies power to this circuit from the time when the blade 36 or 45 has been removed. The circuit essentially comprises a current generator 46, supplied with power by a cutting power supply, 47, and controlled by the middle point 48 of a divider bridge 49, consisting of the resistances 50 and 51. The cutting power supply, 47, and the bridge 49 both receive power from the voltage Vbatt delivered by the battery 35.

12 The current generator 46 produces a "therapeutic" current Ith, intended to flow through the patient's skin between the electrode 15 and the counter electrode 16. The control voltage V of the current generator 46, which is proportional to the voltage Vbatt at the terminals of the battery, is compared to a reference voltage using a comparator 52. When the control voltage falls below the threshold voltage, the comparator commands the stopping of the current generator: the treatment is finished. Additionally, the comparator 52 with threshold can be connected to a signaling device comprising, for example, an electro-luminescent diode, which indicates when the treatment is finished. The control over time of the electronic circuit is ensured by the discharge of the battery 35, from a fully charged state to a state close to depletion. In standard practice, the voltage delivered by the battery 35 cannot exceed a few volts. However, the transdermal administration of a drug by ionophoresis requires a much higher voltage, often on the order of several tens of volts (typically on the order of 25-30 volt). It is the role of the cutting power supply, 47, to supply such a voltage to the current generator 46. The latter delivers the therapeutic current Ith whose intensity is essentially a linear function of the control voltage V. According to the present invention, this control voltage is supplied by the middle point 48 of the divider bridge 49, where this voltage V itself is a fraction of the voltage Vbatt delivered by the battery, defined by the ratio of division of the bridge 49. The voltage V then changes over time according to a function V(t) whose graph is essentially parallel and in conformity with that of the characteristic Vbatt(t) representing the variation over time of the voltage delivered by the battery, during continuous operation of the battery.

It follows that the intensity of the current Ith delivered by the generator of the current 46 itself evolves over time in a manner which conforms with the variation over time of the voltage Vbat delivered by the battery in continuous operation. Figure 9 allows a good understanding of this principle of operation. This figure represents the characteristic discharge curve of a battery of the GOULD 6C100 type, which is an example of a battery which can be used to supply power to the electronic circuit of the device according to the invention. The horizontal axis gives the time in h, and the vertical axes gives the voltage Vbat at the terminals of the battery, so that Figure 9 allows one to determine the time taken by Vbatt to reach a given value. As one can see, this curve comprises three clearly distinct parts. A first part 53 shows a drop in Vbatt of approximately 1 volt in 5 min: this corresponds to the passage of Vbazt from the electromotive force when depleted, to the voltage when charged. The second part 54 of the curve, which extends over approximately 3 h, has the shape of a plateau located at approximately 4.5 V. The third part 55 of the curve, where Vbatt decreases relatively rapidly, corresponds to the depletion of the pile. This shape of the discharge characteristic of the battery is also found in the variation over time of the therapeutic current Ith delivered by the current generator 46, as illustrated by the graph Ith(t) of Figure 10, where one observes that the latter comprises the parts 53', 54' and 55' which are analogous to the parts 53, 54 and 55, respectively, on the graph of Figure 9.

First, the initial excess intensity indicated by the part 53' of the curve allows a rapid decrease (within approximately 5 min) of the resistance of the patient's skin, and thus the preparation of a terrain favorable for the application of the ionophoretic treatment. Then, the part at plateau 54' corresponds to the application of the therapeutic current. Finally, the part 55' of the curve corresponds to the end of the treatment: the concomitant drop in Vbau effects, by a threshold device such as the comparator 52, the stoppage of the operation of the current generator 46. As can easily be understood, the effective duration of application of the therapeutic current to the patient can be perfectly predetermined, by choosing a drug/battery/threshold level combination which is adapted to each specific case. The procedure for using the device according to the invention is derived directly from the preceding description. First, the user removes the shells which protect the first reservoir 37 and the second reservoir 38; then he/she unfolds the first rounded end 28 of the rounded support 27; he/she then fixes the device according to the invention to the patient's skin by means of the adhesive strip 27; then, in the case of the first embodiment variant of the device according to the invention, he/she removes the blade 36 (in the second embodiment variant of the device according to the invention, the blade 45 was already removed during the opening of the first rounded end 28); finally, when the signal of end of treatment appears, the user detaches the entire device from the patient's skin, and discards it. One can now see that the above described invention makes it possible to manufacture a device for transdermal administration by ionophoresis, whose design is extremely simplified, and whose manufacturing cost is thus low, which makes it possible to discard it after use.

Claims (11)

1. Device for transdermal administration of a drug by ionophoresis, comprising an assembly (A) including at least an electrode (15) attached to a reservoir (37) loaded with said drug and a counter electrode (16), an electronic circuit and an electric battery (35), where said electronic circuit allows the production of a therapeutic electrical current (Ith) from the energy supplied by said battery, said current flowing, between said two electrodes, through said reservoir and the patient's skin (41), to whom it is applied, characterized in that said electronic circuit comprises means (46, 47, 49) to conform a temporal program of administration of the drug to the discharge versus time curve of said battery, from a fully loaded state of said battery to a state close to depletion.

2. Device according to Claim 1, characterized in that said means comprise a current generator (46) which is supplied with power from a cutting power supply (47) and controlled by a voltage (V) proportional to that (Vbatt) measured at the terminals of said battery (35).

3. Device according to Claim 2, characterized in that said electronic device comprises, in addition, a device with threshold (52) intended to stop the operation of said cutting power supply (47) when said control voltage (V) reaches a predetermined threshold value. 16

4. Device according to any one of the preceding claims, characterized in that said electronic circuit comprises a device for signaling the stoppage of the treatment.

5. Device according to any one of the preceding claims, characterized in that said assembly of electrodes (A) consists of a sheet of flexible material provided with a printed circuit (6) and intended to work in cooperation with an adhesive support (B) with simple face.

6. Device according to Claim 5, characterized in that said assembly of electrodes (A) and said adhesive support (B) are cut so as to form essentially a first strip (1) and a second strip (27), where the lengths of these two strips are essentially equal, and the width of said second strip (27) is greater than that of the second strip (1), in that said first strip (1) is inserted in two slits (30, 31) formed in said second strip (27), transversely with respect to its length, so that the part of said first strip (1) placed between said two slits (30, 31) is located on said second strip (27), which is not coated with adhesive, and so that the first part and the second part of said first strip (1), which are placed outside said two slits (30, 31), are located on the side of said second strip (27) which is coated with an adhesive.

7. Device according to Claim 6, characterized in that said part of said first strip (1) located between said two slits (30, 31) comprises, on a face (Al) opposite to the one, (A2), which is intended to come in contact with said skin (41) of the patient, a plurality of electronic components (34) connected to said printed circuit (6) by a plurality of contact blocks (7) to form said electronic circuit.

8. Device according to any one of Claims 6 and 7, characterized in that said first part and said second part of said first strip (1), placed on the exterior of said two slits (30, 31) comprise, on one face (A2) intended to come in contact with said patient's skin (41), said electrode (15) and said counter electrode (16). I /I

9. Device according to any one of Claims 7 and 8, characterized in that one of said first part and said second part of said first strip (1) placed outside of said two slits (30, 31) comprises an end (3) which is folded toward the interior of said face (Al) around said battery (35), so as to connect said battery to said electronic circuit by means of conducting tracks (12, 17, 20) and contact pads (14, 26).

10. Device according to Claim 9, characterized in that a blade made of an insulating material (36) is inserted between said battery (35) and said contact pad (26), and projects outward through the first slit (5) and the second slit (33) provided in said first strip (1) and second strip (27).

11. Device according to Claim 9, characterized in that a blade of insulating material (45) is inserted between said battery (35) and said contact pad (26), and in that it is fixed to said adhesive face of a folded end (28) of said second strip (27), so that the unfolding of said end results in the extraction of said blade and in contact between said battery and said contact pad [Insert Figures 1-8] Figure 8 Key 1 Battery 2 Cutting power supply 3 Current generator 4 Threshold 5 t (h) Figure 9 Key 1 t (h) Figure 10 Key 1 t (h)