WO2010150181A1

WO2010150181A1 - Device for monitoring transdermal delivery of a drug

Info

Publication number: WO2010150181A1
Application number: PCT/IB2010/052809
Authority: WO
Inventors: Giovanni Nisato; Roelf Kassies
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2009-06-25
Filing date: 2010-06-22
Publication date: 2010-12-29

Abstract

The invention relates to a device (102) for transdermally delivering a solvent of a drug (104) in a fluid to a mammal via an ejection mechanism. The device (102) monitors whether or not the solvent of the drug (104) has actually penetrated the mammal's skin. For that purpose, the device (102) comprises electrodes (126, 128) installable in a vicinity of a penetration region (124) of the solvent of the drug in the mammal and a sensor arrangement (132) for applying a frequency dependent voltage across the electrodes and for generating a measurement signal (136) indicative of a capacitance between the electrodes. The device furthermore comprises a comparator arrangement (140) for generating a penetration signal (146) indicative of a penetration of the solvent of the drug in fluid based on comparing the measurement signal with a nominal level (138).

Description

Device for monitoring transdermal delivery of a drug

FIELD OF THE INVENTION

The invention relates to a device for transdermally delivering a solvent of a drug in a fluid to a mammal via an ejection mechanism.

BACKGROUND OF THE INVENTION

WO 2007/149514 A2 discloses a device for microjet drug delivery, comprising a drug reservoir, a nozzle in fluid communication with the drug reservoir, an actuator and a power supply. The actuator is capable of acting on a dispensing member causing it to dispense a drug in liquid form from the drug reservoir via the nozzle at a velocity sufficient to penetrate the skin.

A problem of the device according to WO 2007/149514 A2 is that there is no guarantee for clinical efficacy. Namely, the morphological and mechanical properties of the tissue underneath stratum corneum differ for each and every patient, and are dependent on the anatomical location at hand. Hence, the velocity at which the liquid drug is dispensed may be too small to actually penetrate the skin.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a device according to the opening paragraph with improved real time monitoring of the device's therapeutic efficacy. This object is achieved by the device according to the invention. The device according to the invention comprises electrodes installable in a vicinity of a penetration region of the solvent of the drug in the mammal, a sensor arrangement for applying a frequency dependent voltage across the electrodes and for generating a measurement signal indicative of a capacitance between the electrodes, and a comparator arrangement for generating a penetration signal indicative of a penetration of the solvent of the drug based on comparing the measurement signal with a nominal level.

In case the electrodes have been installed on the patient's skin and more specifically the stratum corneum, the capacitance between the electrodes is proportional to the dielectric constant of the stratum corneum and the skin layers underneath the stratum corneum, i.e. the epidermis, the dermis and the hypodermis. The dielectric constant in its turn is proportional to the fluid contents of the stratum corneum and the skin layers underneath the stratum corneum. In the penetration region, the aforementioned fluid contents are modified by transdermal delivery of the solvent of the drug in the fluid. Given a known concentration of the drug in said solvent, the fluid contents are indicative for an amount of drug transdermally delivered. Therefore, by registering a change in the capacitance between the electrodes, the device according to the invention is capable of distinguishing successfully penetrating the stratum corneum and subsequently delivering the drug from unsuccessfully penetrating the stratum corneum. A comparator arrangement is configured for generating a penetration signal indicative for the penetration of the stratum corneum by the solvent of the drug. The latter signal is based on comparing the measurement signal with a nominal level.

In this document, transdermal implies all layers comprised in a mammal's skin underneath the stratum corneum which performs as the interface with the outside world. In order of increasing depth with regard to the stratum corneum, these layers are the dermis, the epidermis and the hypodermis, wherein the latter layer is also referred to as the subcutis or subcutaneous fat.

In this document, the penetration region is defined as the region in which the solvent of the drug penetrates the dermis and the epidermis via the stratum corneum by application of the ejection mechanism. In this document the feature that the electrodes are installable in the vicinity of the penetration region is interpreted such that a distance between the penetration region and the electrodes ranges from zero up to a value in the order of magnitude of 100 mm.

The fluid in which the drug is solved will typically be water. Nonetheless, any fluid in which the drug is solvable is considered to be appropriate. It is to be noted that WO 2004/105602 Al discloses a device for measuring the water content of subcutaneous fat. The device disclosed in WO 2004/105602 Al comprises an electromagnetic probe to be placed on the skin, wherein the electromagnetic probe is operated at a frequency from 20 MHz to 500 MHz. The probe is provided with two electrodes wherein the distance between the electrodes is large, i.e. 10 to 50 mm. In WO 2004/105602 Al the water content of subcutaneous fat is measured to evaluate in a better way the effects of medical operations, treatments with drugs, physical treatments, exercises or weight loss. Herein, the water contents are modified indirectly due to the therapeutic effects of the drugs. Hence, the instantaneous modification of the water contents of e.g. subcutaneous fat as would be obtained by transdermal delivery of the drug is not being monitored by the device disclosed in WO 2004/105602 Al. On the contrary, the latter device is not arranged for real time monitoring. As a result, the device according to WO 2004/105602 Al is not capable of monitoring the efficacy of transdermal drug delivery.

In a preferred embodiment of the device according to the invention, the nominal level corresponds to a value attained by the measurement signal in response to an absence of the solvent of the drug. This embodiment advantageously allows for compensating disturbances on the nominal level such as variations due to the patient at hand and the anatomical location under consideration. Preferably, the nominal level is being measured by the sensor arrangement prior to the delivery of drugs. A further preferred embodiment of the device according to the invention comprises reference electrodes for generating the nominal level, wherein the reference electrodes are situated substantially remote from the entry region of the micro jet. This embodiment has the advantage that physiological or environmental changes can be compensated for by accordingly adjusting the nominal level. In a further preferred embodiment of the device according to the invention, the nominal level corresponds to a preceding value of the measurement signal. This embodiment has the advantage that it enables more accurately monitoring the penetration of subsequent drug deliveries by the ejection mechanism. Namely, this embodiment allows for updating the nominal level according to a preceding penetration of the drug. As a result, the contribution of said preceding penetration to the measurement signal can be accounted for.

A further preferred embodiment of the device according to the invention comprises a memory for storing values of the measurement signal. This embodiment has the advantage that it allows for monitoring the total amount of medication that has been delivered transdermally presuming the concentration of the drug in the solvent is known. Namely by employing the memory, the success rate for a plurality of drug deliveries is recordable.

Thereby the device is capable of monitoring the transdermal delivery of the fluid solvable drug in a cumulative manner. Preferably, in this embodiment the nominal level is updated regarding a preceding penetration of the solvent of the drug in the mammal's skin.

In a further preferred embodiment of the device according to the invention, the frequency dependent voltage has a frequency ranging from 0.2 MHz to 5 MHz. Since in this range of frequencies the dielectric constant of the stratum corneum is almost fully determined by its fluid contents, disturbing influences on the dielectric constant are effectively minimized. As a result this embodiment advantageously increases the accuracy of monitoring whether or not medication has penetrated the stratum corneum. In a further preferred embodiment of the device according to the invention, the frequency dependent voltage has a frequency ranging from 20 MHz to 50 MHz. Since in this range of frequencies the dielectric constants of the epidermis and the dermis are almost fully determined by their fluid contents, disturbing influences on the dielectric constant are effectively minimized. As a result this embodiment advantageously increases the accuracy of monitoring whether or not medication has been delivered in the epidermis and the dermis.

In a further preferred embodiment of the device according to the invention, the frequency dependent voltage has a frequency ranging from 50 MHz to 500 MHz. Since for this range of frequencies the dielectric constants of the deeper parts of the dermis, i.e. the part of the dermis close to the hypodermis, and the subcutaneous fat are almost fully determined by their fluid contents, disturbing influences on monitoring said dielectric constants are effectively minimized. Therefore, this embodiment has the advantage that it further increases an accuracy of monitoring whether or not medication has been delivered in the deeper parts of the dermis and in the hypodermis. Preferably, the electrical field has frequencies that are alternatingly in the range from 0.2 MHz to 5 MHz, in the range from 20 to 50 MHz and in the range from 100 MHz to 500 MHz. In this way penetration by the drug of the stratum corneum, the dermis and the epidermis can be monitored with large accuracy.

In a further preferred embodiment of the device according to the invention, the device comprises a first pair of electrodes and a second pair of electrodes, wherein the first pair of electrodes is provided with a first spacing, wherein the second pair of electrodes is provided with a second spacing and wherein the second spacing exceeds the first spacing. This embodiment is advantageous in that it is capable of varying the size of the probing volume and varying the probing depth.

In a further preferred embodiment of the device according to the invention, the first and second pairs of electrodes are actuated separately from one another during operation. This embodiment advantageously provides information relating to the presence of fluid solvable medication at specific depths.

In a further preferred embodiment of the device according to the invention, the first pair of electrodes is actuated prior to the second pair of electrodes during operation. This embodiment has the advantage that it enables monitoring a diffusion process of the fluid solvable drug in the tissue underneath the stratum corneum. Namely, the larger the mutual spacing, the larger the depth will be at which penetration of fluid medication is detectable by the device. A further preferred embodiment of the device according to the invention comprises at least three electrodes, wherein the sensor arrangement comprises a switch for shunting electrodes. This embodiment advantageously enables varying the size of the probing volume. The switch enables forcing the electric current to pass specific electrodes. By doing so the polarity of electrodes is effectively modified and thereby the cooperation between electrodes is interchanged. That is, through shunting a subset of electrodes, this subset is provided with substantially equal polarity. By exchanging the polarity of electrodes the mutual spacing for cooperating electrodes, i.e. electrodes having opposing polarities, will vary accordingly. A further preferred embodiment of the device according to the invention comprises a feedback control circuit for controlling an ejection velocity of the micro jet on the basis of the penetration signal. This embodiment advantageously increases a medical efficacy of the device. That is, in case the measurement signal exceeds the reference level, the fluid contents of the mammal's skin are increased and apparently, the medication has been delivered transdermally by the device. Consequently, there is no need to modify the ejection speed of the micro jet. In case the measurement signal is below the reference level, apparently the micro jet has not penetrate the mammal's skin and consequently, the ejection speed will be increased.

A further preferred embodiment of the device according to the invention comprises an antenna for communicating the measurement signal. This embodiment advantageously informs the patient about the medical efficacy of the device. Based upon this information, the patient may e.g. be required to move or replace the device. This embodiment furthermore advantageously informs a medical professional, e.g. a doctor in a hospital remote from the patient, about the medical efficacy of a therapy employing this embodiment. Based on the information provided by the device, the medical professional can substantiate his or her decision process regarding the therapy's parameters, e.g. the amount of medication that is to be delivered transdermally per unit of time.

In a further preferred embodiment of the device according to the invention, the device comprises a durable part and a disposable part, wherein the electrodes are situated in the disposable part. This embodiment advantageously increases the device's hygiene. Namely by incorporating the electrodes which are in contact with the mammal's skin in the disposable part of the device, the electrodes allow for easy and possibly regular replacement. In a further preferred embodiment of the device according to the invention, the electrodes are situated on opposite sides of the micro jet. This embodiment advantageously increases the robustness of detecting whether or not successful penetration of the stratum corneum is obtained, hence if a medication has been delivered transdermally indeed. Namely, by situating the electrodes on opposite sides of the microjet, at least a part of the penetration region is traversed by the electrical field that arises due to imposing the voltage across the electrodes. In other words, the probing volume in which the presence of a fluid solvable medication is measurable at least partially coincides with the penetration region. As a result, this embodiment will distinguish successful penetrations by the microjet from unsuccessful penetrations.

In a further preferred embodiment of the device according to the invention, the electrodes are situated in an arrangement, which arrangement is rotationally symmetric with regard to the micro jet. This embodiment is advantageous in that it further augments the accuracy of monitoring whether or not successful penetration of the stratum corneum is obtained, hence whether or not the drug has been delivered successfully to the mammal. Namely, by situating the electrodes in such an arrangement, a considerable part of the penetration region will be traversed by the electrical field between the electrodes, regardless the actual shape of the entry region.

SHORT DESCRIPTION OF THE FIGURES

Figure 1 schematically depicts an embodiment of the device according to the invention, comprising a pair of reference electrodes.

Figure 2 schematically depicts an arrangement of electrodes applicable in the embodiment depicted in Figure 1, wherein the electrodes are situated on opposite sides of the microjet.

Figure 3 schematically depicts an arrangement of electrodes applicable in the embodiment depicted in Figure 1 , wherein the electrodes are situated in a rotationally symmetrical arrangement.

Figure 4 schematically depicts an arrangement of electrodes applicable in the device according to the invention, wherein subsets of electrodes are shunted.

Figure 5 schematically depicts an embodiment of the device according to the invention, wherein the nominal level corresponds to a value attained by the measurement signal in response to a preceding penetration of the drug.

Figure 6 schematically depicts an arrangement of electrodes applicable in the embodiment depicted in Figure 5, wherein pairs of electrodes are actuated separately during operation depending on their mutual spacing. DETAILED DESCRIPTION OF THE EMBODIMENTS

Figure 1 schematically depicts a device 102 for transdermally delivering a solvent of a drug 104 to a mammal. The device 102 preferably comprises a durable part 106 and a disposable part 108, which disposable part 108 is reversibly mountable to the durable part 106. The durable part 106 comprises an actuator 112 for pressurizing a reservoir 110 via a connecting member 113, which is embodied by a membrane is this particular example. The reservoir 110 is situated in the disposable part for containing the solvent of the drug 104. The reservoir 110 is provided with an orifice 114, which orifice 114 is in fluid communication with a nozzle 116 for generating a micro jet 118. The nozzle 116 is situated in the disposable part 108. In this particular case, the actuator 112 is realized by a piezo-electric element. During operation, the microjet 118 is to penetrate the stratum corneum 120 and the layers 122 underneath the stratum corneum, which are jointly referred to in this example, in a penetration region 124. The device 102 furthermore comprises electrodes 126 and 128. In this specific example the electrodes 126 and 128 are comprised in the disposable part 108 of the device 102. In this particular example, the electrodes 126 and 128 are situated on opposite sides of the microjet 118, see also Figure 2 and Figure 3.

The durable part 106 is provided with a sensor arrangement 132 comprising an impedance meter 134 for measuring the capacitance between the electrodes 126 and 128 and for generating a measurement signal 136 indicative for said capacitance. In this text, an impedance meter is understood to be a measurement device for measuring impedance, wherein impedance is a resistance against the flow of a time dependent current i(t) due to a

time dependent voltage r(f). For a capacitor, the capacitance C performs as an impedance according to the following relation:

wherein t denotes time. For the purpose of measuring the capacitances

between the electrodes 126 and 128, the impedance meter 134 applies a frequency dependent voltage across the electrodes 126 and 128. Herein, the frequency dependent voltage is alternatingly applied at frequencies of 1.0 MHz, 30 MHz and 300 MHz in order to monitor the penetration of the drug 104 particularly in the stratum corneum 120, the epidermis and the upper dermis, and lower dermis and the hypodermis, respectively. As a result of applying said voltage, an electrical field 130 will emerge between the electrodes 126 and 128.

In case the electrodes 126 and 128 have been installed on the stratum corneum 120, the capacitance between the electrodes 126 and 128 is proportional to the dielectric constant of the stratum corneum 120 and the dermis 122. The dielectric constant in its turn is proportional to the fluid contents of the stratum corneum and the dermis. In the penetration region 124, the aforementioned fluid contents are modified by transdermal delivery of the solvent of the drug 104. Given a known concentration of the drug 104 in said solvent, the fluid contents of the stratum corneum 120 and the dermis 122 are indicative for an amount of drug transdermally delivered. Therefore, by registering a change in the capacitance between the electrodes 126 and 128, the device 102 makes the penetration of, and drug delivery in the stratum corneum 120 and the layers 122 underneath the stratum corneum 120 detectable. During operation, the measurement signal is 136 is compared to a nominal level 138 by a comparator arrangement 140, which comparator arrangement 140 is situated in the durable part of the device 102. The nominal level 138 corresponds to the value obtained by the measurement signal 136 in response to a minimum penetration of the drug 104 in the dermis 122 via the stratum corneum 120. A further impedance meter 139 is comprised for measuring the capacitance between reference electrodes 142 and 144 and for generating the nominal level 138 based on said capacitance. For that purpose, the further impedance meter 139 applies an equal frequency dependent voltage across the reference electrodes 142 and 144. As a result, an electrical field 145 will come into being.

In this specific embodiment, the reference electrodes 142 and 144 are situated in the disposable part 108. To prevent the capacitance between the reference electrodes 142 and 144 from being influenced by the penetration of the microjet 118 in the dermis 122, the reference electrodes are situated substantially remote from the microjet 118.

Based on the comparison of the measurement signal 136 and the nominal level 138 by the comparator arrangement 140, the comparator arrangement 140 generates a penetration signal 146 indicative for the penetration of the drug 104 in the dermis 122 via the stratum corneum 120. In this specific embodiment the actuator is 112 controlled by a feedback control circuit 148 on the basis of the signal 146. For that purpose the control circuit 148 comprises a controller 150, which is a Proportional Integral Derivative controller in this specific example. In case the signal 146 indicates that no penetration hence no transdermal delivery is accomplished by the device 102 for the drug 104, the actuator 112 is controlled by the control circuit 148 to exert a higher pressure on the reservoir 110 in order to generate a higher ejection velocity for the micro jet 118.

Figure 2 schematically depicts an arrangement of the electrodes 126 and 128, see Figure 1, wherein the electrodes 126 and 128 are situated on opposite sides of the nozzle 116. Consequently, the electrodes 126 and 128 are situated on opposite sides of a micro jet originating from the nozzle 116. In addition to that, the arrangement of the electrodes 126 and 128 is rotationally symmetric with regard to the micro jet. In this specific example, the electrodes 126 and 128 are rectangular. Typically, the mutual spacing S between the electrodes 126 and 128 amounts 10 mm. Figure 3 schematically depicts a further arrangement of the electrodes 126 and

128, see Figure 1, wherein the electrodes 126 and 128 are situated on opposite sides of the nozzle 116. Consequently, the electrodes 126 and 128 are situated on opposite side of a micro jet originating from the nozzle 116. In addition to that, the arrangement of the electrodes 126 and 128 is rotationally symmetric with regard to the micro jet. In this particular example, the arrangement of electrodes is circular except from the relatively small spacing between the electrodes 126 and 128 in order to cover the penetration of the drug 104 equally in each and every direction.

Figure 4 schematically depicts an arrangement of electrodes 402, 404, 406 and 408. Herein, the arrangement is rotationally symmetric with regard to a nozzle 410 hence with respect to a micro jet generated by the nozzle 410. The device (not shown) to which the electrodes are attached, comprises a switch known per se for shunting subsets of the electrodes 402, 404, 406 and 408. First, the electrodes 404 and 408 are shunted as to provide these electrodes with equal polarity. Second, the electrodes 404 and 406 are shunted in order to probe at a larger depth with respect to the stratum corneum. Namely, by shunting the electrodes 404 and 406, the electrodes 404 and 406 will perform as a compound of electrodes whereas the electrodes 402 and 408 will perform as a further compound of electrodes. Said compounds of electrodes increase the effective size of the electrodes involved therein. The increase of the electrodes' effective sizes materializes a larger probing volume. Hence by shunting subsets of the electrodes, probing at various depths with regard to the stratum corneum is effected.

Figure 5 schematically depicts a device 502 for transdermally delivering a drug 504 to a mammal. The device 502 comprises a reservoir 506 for containing the solvent of the drug 504, an actuator 508 for pressurizing the reservoir 506 via a connecting member 509 such as a mechanically flexible membrane, and a nozzle 510 in fluid communication with the reservoir 506 for generating a micro jet 512. During operation, the microjet 512 is to penetrate the stratum corneum 514 and the layers 516 underneath the stratum corneum, i.e. the epidermis, the dermis and the hypodermis, in a penetration region 518 in order to deliver the drug 504 transdermally. The device 502 furthermore comprises electrodes 530 and 534, and electrodes 520, 522, 524 526, 528 and 532, see Figures 6A and 6B.

The device 502 comprises a sensor arrangement 538 comprising a switch 540 for alternately shunting subsets of the electrodes 520, 522, 524 526, 528, 530, 532 and 534. The sensor arrangement 538 furthermore comprises an impedance meter 542 for measuring capacitances between the electrodes 520, 522, 524 526, 528, 530, 532 and 534, and for generating a measurement signal 544 indicative for said capacitances. For the purpose of measuring capacitances between the electrodes 520, 522, 524 526, 528, 530, 532 and 534, the impedance meter 542 applies frequency dependent voltages across subsets of the electrodes 520, 522, 524 526, 528, 530, 532 and 534. As a result of said voltages, electrical fields 536 will emerge across the penetration region 518. During operation, the measurement signal is 544 is compared to a nominal level 546 by a comparator arrangement 548. In this specific embodiment the nominal level 546 corresponds to the preceding value of the measurement signal 544 for the subset of electrodes in question, i.e. the subset that of electrodes that is being actuated, see also Figures 6A and 6B. Referring to Figure 5, the device 502 comprises a memory 550 operatively connected to the sensor arrangement 538 for storing said preceding value of the measurement signal 538. In that way, a previous penetration of the drug 504 in the drug can be accounted for by accordingly updating the nominal level 546. The memory 550 is additionally configured for storing an array of values of the measurement signal 544 in order to register a total amount of medication that has been delivered transdermally. Based on the comparison of the measurement signal 544 and the nominal level

546 by the comparator arrangement 548, the comparator arrangement 548 generates a signal 552 indicative for the presence of the drug 504 in the dermis 516 via the stratum corneum 514. The actuator is 508 controlled by a feedback control circuit 554 on the basis of the signal 552. For that purpose a controller 556 is comprised in the feedback control circuit 554. In case the signal 552 indicates that no penetration hence no transdermal delivery is accomplished by the device 502 for the drug 504, the actuator 508 is controlled by the feedback control circuit 554 to exert a higher pressure on the reservoir 506.

In this particular example, the device 502 furthermore comprises an antenna 558 operatively connected to the sensor arrangement 538 for communicating the measurement signal 544 to a e.g. a computer, which computer is configured for communicating the measurement signal to a medical professional remotely located from the patient employing the device 502. More specifically, the value of the measurement signal 538 and particularly the total amount of medication that has been delivered transdermally are of interest for said medical professional. Owing to that, for instance if the total amount of medication that has been delivered transdermally proves to be too small, the medical professional may timely take appropriate measures.

Figure 6A schematically depicts an arrangement of the electrodes 520, 522, 524 526, 528, 530, 532 and 534. Herein, the arrangement is rotationally symmetric with regard to a nozzle 602 hence with respect to a micro jet generated by the nozzle 602. The arrangement of the electrodes 520, 522, 524 526, 528, 530, 532 and 534 comprises an inner- arrangement of the electrodes 520, 522, 524 526 which is concentrically arranged with respect to an outer-arrangement of the electrodes 528, 530, 532 and 534. Obviously, the electrodes situated in the outer-arrangement are provided with a larger mutual spacing compared to the electrodes comprised in the inner-arrangement. As aforementioned, the device 502 comprises a switch 540 known per se for shunting subsets of the electrodes 520, 522, 524, 526, 528, 530, 532 and 534. In Figure 6A merely the electrodes situated in the inner-arrangement are actuated. Hence the electrodes 528, 530, 532 and 534 which are situated in the inner-arrangement are effectively connected to ground, which is indicated in Figure 6A by way of the dotted lines. In Figure 6A, initially the electrodes 522 and 526 are shunted i.e. provided with substantially equal polarity. Herein the difference in polarity between the subset of shunted electrodes and the subset of non-shunted electrodes is to exceed the polarity differences between the non-actuated electrodes and said subset of shunted electrodes on the one hand, and between the non-actuated electrodes and said subset of non-shunted electrodes on the other hand. Hereafter during operation the electrodes 520 and 524 in order to modify the probing volume. Here an equal consideration holds regarding the polarity differences between the various electrodes.

Subsequently, as indicated in Figure 6B, in order to further increase the probing volume merely the electrodes situated in the outer-arrangement are actuated. The electrodes 520, 522, 524 and 526 which are situated in the inner-arrangement are thereby effectively connected to earth, which is indicated by way of the dotted lines. First, the electrodes 528 and 532 are shunted, that is, provided with equal polarity. Herein the difference in polarity between the shunted electrodes and the non-shunted electrodes is to exceed polarity difference between the non-actuated electrodes and the shunted electrodes as well as the polarity difference between the non-actuated electrodes and the non-shunted electrodes on the other hand. Second, to even further enlarge the probing volume, the electrodes 528 and 530 are shunted in favor of the electrodes 532 and 534. With that the electrodes 528 and 530 are caused to perform as a compound of electrodes whereas the electrodes 532 and 534 are effected to perform as a further compound of electrodes. Herein, the guideline regarding polarity differences for the various electrodes equally holds.

While the invention has been illustrated and described in detail in the drawings and in the foregoing description, the illustrations and the description are to be considered illustrative or exemplary and not restrictive. It is noted that the apparatus according to the invention and all its components can be made by applying processes and materials known per se. In the set of claims and the description the word "comprising" does not exclude other elements and the indefinite article "a" or "an" does not exclude a plurality. Any reference signs in the claims should not be construed as limiting the scope. It is further noted that all possible combinations of features defined in the set of claims are part of the invention.

Claims

CLAIMS:

1. A device (102, 502) for transdermally delivering a solvent of a drug (104, 504) in a fluid to a mammal via an ejection mechanism, comprising: electrodes (126, 128, 402, 404, 406, 408, 520, 522, 524 526, 528, 530, 532, 534) installable in a vicinity of a penetration region (124) of the solvent of the drug in the mammal, a sensor arrangement (132, 538) for applying a frequency dependent voltage across the electrodes and for generating a measurement signal (136, 544) indicative of a capacitance between the electrodes, a comparator arrangement (140, 548) for generating a penetration signal (146, 552) indicative of a penetration of the solvent of the drug based on comparing the measurement signal with a nominal level (138, 546).

2. The device according to claim 1, wherein the nominal level corresponds to a value attained by the measurement signal in response to an absence of the solvent of the drug.

3. The device according to claim 2, comprising reference electrodes (142, 144) for generating the nominal level, wherein the reference electrodes are situated substantially remote from the penetration region of the micro jet.

4. The device according to claim 1, wherein the nominal level corresponds to a preceding value of the measurement signal.

5. The device according to claim 4, comprising a memory (550) for storing values of the measurement signal.

6. The device according to claim 1, wherein the frequency dependent voltage has a frequency ranging from 0.2 MHz to 5 MHz.

7. The device according to claim 1, wherein the frequency dependent voltage has a frequency ranging from 20 MHz to 50 MHz.

8. The device according to claim 1, wherein the frequency dependent voltage has a frequency ranging from 50 MHz to 500 MHz.

9. The device according to claim 1, comprising a first pair of electrodes and a second pair of electrodes, wherein the first pair of electrodes is provided with a first spacing, wherein the second pair of electrodes is provided with a second spacing and wherein the second spacing exceeds the first spacing.

10. The device according to claim 9, wherein the first and second pairs of electrodes are actuated separately from one another during operation.

11. The device according to claim 10, wherein the first pair of electrodes is actuated prior to the second pair of electrodes during operation.

12. The device according to claim 1, comprising at least three electrodes, wherein the sensor arrangement comprises a switch (540) for shunting electrodes.

13. The device according to claim 1, wherein the ejection mechanism comprises a reservoir (110, 506) for containing the drug, an actuator (112, 508) for pressurizing the reservoir, and a nozzle (116, 510) in fluid communication with the reservoir for generating a micro jet (118, 512).

14. The device according to claim 13, comprising a feedback control circuit (148, 554) for controlling an ejection velocity of the micro jet on the basis of the penetration signal (146, 552).

15. The device according to claim 1, comprising an antenna (558) for communicating the measurement signal.

16. The device according to claim 13, comprising a durable part (106) and a disposable part (108), wherein the electrodes are situated in the disposable part.

17. The device according to claim 13, wherein the electrodes are situated on opposite sides of the micro jet.

18. The device according to claim 13, wherein the electrodes are situated in an arrangement, which arrangement is rotationally symmetric with regard to the micro jet.

19. The device according to claim 1, wherein the electrodes are provided with a mutual spacing ranging from 1 mm to 50 mm.