WO1999003531A1

WO1999003531A1 - Method for controlling a device for transdermal administering of medicine under an electric field

Info

Publication number: WO1999003531A1
Application number: PCT/FR1998/001525
Authority: WO
Inventors: Philippe Pierre Marie Millot; Estelle Louise Georgette Dumonet
Original assignee: Laboratoires D'hygiene Et De Dietetique (L.H.D.)
Priority date: 1997-07-15
Filing date: 1998-07-13
Publication date: 1999-01-28
Also published as: AU8735298A; FR2766093B1; FR2766093A1

Abstract

The invention concerns a device comprising a pair of electrodes applied on a patient's skin and powered by an electrical energy source, one at least of the electrodes being loaded with said medicine, and an electronic circuit for controlling the passage between said electrodes of an electric current derived from the source. The method consists, on switching on (1) the device, in passing an initial current pulse (4) between the electrodes, measuring the intensity of said current (6) and comparing it to a reference input value (7), repeating the process of passing pulses, measuring and comparing until the measured current finally reaches the reference input value (Ic), and triggering the operation of said device (12) in normal operating conditions. The invention is applicable to a device for transdermal administering of medicine by iontherapy.

Description

METHOD FOR CONTROLLING A DEVICE FOR TRANSDERMAL DELIVERY OF MEDICAMENT UNDER ELECTRICAL FIELD

The present invention relates to a method for controlling a transdermal drug delivery device under an electric field, comprising a pair of electrodes applied to the skin of a patient and selectively supplied, at least one of the electrodes being charged with said drug, a source of electrical energy and an electronic circuit for controlling the passage of a current from said source between said electrodes.

There is known a device, called "inonophoretic" of this type, in which the medicament is in ionic form and crosses the skin of the patient under the influence of a suitably oriented electric field. The amount of drug administered to the patient is then a function of the intensity of the current passing through the skin. The device ensuring programmed administration of the drugs, over periods of time ranging from a few hours to a few months for example, it is understood that it is necessary to monitor and control the temporal changes in the aforementioned current, known as "therapeutic".

It is also necessary to monitor the electrical voltage applied between the electrodes, in particular to prevent it from reaching unbearable values by the patient. For all these reasons, the iontophoretic methods of transdermal drug administration are implemented by devices, generally portable and powered by electric batteries, provided with means for monitoring and / or controlling the flow of current, its intensity and of the voltage established between the electrodes.

It is clear that one of the parameters on which the intensity of the therapeutic current depends is the electrical resistance of the patient's skin. Clinical studies have shown that the initial value thereof, before any treatment, varies greatly from one patient to another, for example from 25 to 250 kΩ. The passage of an electric current through the skin has the effect of causing this resistance to drop rapidly, up to 5 or 6 kΩ for example, after a current passing time of one or two minutes approximately, after which said resistance remains roughly constant.

If the source of electrical energy which supplies the transdermal drug delivery device delivers a constant voltage, at least at the start of treatment, as is the case when this source consists of electric batteries, it is understood that, by the game of Ohm's law, the decrease in "skin" resistance causes a correlative growth in current intensity, from 0.6 mA to 1.5 mA for example, ie in a range of higher intensities to that chosen for the actual treatment, fixed for example between 100 and 400 μA. If then the normal current monitoring and control means are activated as soon as the administration device is started, they immediately control the interruption of the current flow, because the current intensity is not equal to the set intensity selected for the treatment. It cannot then start.

A solution to this problem is proposed in international patent application WO 96/17651, a solution according to which the operation of said monitoring means is prevented during an initial time interval of predetermined duration, for example 100 seconds, measured from initiation of the passage of the therapeutic current, the duration of this time interval being chosen so as to allow sufficient time for the cutaneous resistance of the patient's skin to fall to its low value mentioned above. However, this solution has the drawback of unnecessarily delaying the start of the treatment under supervision, when the patient's skin resistance has fallen to this value before the complete expiration of the predetermined time interval mentioned above.

Finally, the inactivation of the monitoring means during said initial time interval prevents the detection of operating faults such as short-circuit or open-circuit faults, of the electrodes. When the electrodes of the device are put in place, depending on the condition of the patient's skin, these may in fact be short-circuited by sweat spread over the skin, or by a lesion such as a cut or burn of this skin. The device must then signal this short-circuit for it to be remedied. Also, the current circuit can be opened, for example by a defect in hydration of the electrode charged with the drug or by placing one of the electrodes on the skin without having rid it of an insulating film of protection, or on a skin area with excessive hair growth. Such faults must also be able to be detected and reported. The present invention therefore aims to provide a method for controlling a transdermal drug delivery device, of the type described in the preamble to this description for example, designed to start a treatment in normal regime as soon as the skin resistance of the patient's skin reaches a suitable value, and to suppress any unattended operation of the controlled delivery device.

The present invention also aims to provide such a method allowing in particular the detection of a short- circuit of the electrodes or the opening of the circuit between the electrodes.

Another object of the present invention is to provide such a method for controlling the transdermal delivery device, which ensures the tolerance of this device by the patient.

These objects of the invention are achieved, as well as others which will appear on reading the description which follows, with a method for controlling a transdermal drug delivery device under an electric field, this device comprising a pair electrodes applied to the skin of a patient, at least one of the electrodes being charged with medicament, a source of electrical energy and an electronic circuit for controlling the passage of an electric current from said source between said electrodes . According to the invention, when the device is switched on, an initial current pulse is passed between the electrodes, the intensity of said current is measured and compared with a current set value, this process of passing d is repeated. current, measurement and comparison pulse until the measured current reaches a final set value, and then operation in normal mode of said device is triggered. According to a first embodiment of the present invention, the current setpoint value is equal to said final setpoint value.

As will be seen below, the process according to one invention. allows the device to operate without delay under normal conditions, by eliminating any fixed time delay for this triggering.

According to another embodiment of the method according to the invention, the current reference value is incremented each time the measured current reaches said value, until the current setpoint reaches said final setpoint. By thus varying the setpoint value of the current, a more controlled reduction of the skin resistance of the patient is ensured, favorable from the physiological point of view and from the point of view of its tolerance by the patient.

Other characteristics and advantages of the present invention will appear on reading the description which follows and on examining the appended drawing in which: FIGS. 1 and 2 are complementary flow diagrams, connected to points A and B, illustrating the control method according to the invention, and - Figure 3 is a flow diagram of a variant of this method.

Transdermal drug delivery devices are well known. Reference may be made in this regard to French patent application No. 96 04735 filed on April 16, 1996 by the applicant, for more details concerning the structure and operation of such a device. In addition to the elements or organs thereof already mentioned above, such a device commonly comprises an electronic control circuit for this device organized around a microprocessor, and means for measuring the intensity of the electric current passing between the electrodes of the device, and of the voltage established between them, these measurements being supplied to the microprocessor. It is itself duly programmed to monitor and control the normal operation of the device, according to such or such predetermined time schedule for drug administration. All these means are well known and do not need to be described in more detail. Those skilled in the art will readily understand that these means and, in particular, adequate programming of the microprocessor, make it possible to implement the control method according to the invention, which will now be described in detail in conjunction with the figures in the appended drawing. To administer a medicament to a patient using an iontophoretic device of the portable type supplied with electric batteries for example, one begins by "hydrating" one of the electrodes of the device with a solution of the active ingredient to be administered. These electrodes are then placed on a member of the patient for example, the electrodes being held on this member with the electronic control circuit of the device, by means of a bracelet for example. The device is then switched on (see Figure 1, step 1). At the initiative of the patient, by action of the latter on a push button, or automatically, the treatment is initiated (step 2). The account of a counter forming part of the electronic circuit of the device is then consulted (step 3) and this account is compared with a predetermined account value, for example 30. If the count is less than 30, an electrical voltage is established between the electrodes to pass a current between them (step 4). We will explain later how the incrementation and resetting of the counter takes place. The intensity of the current depends, on the one hand on the applied voltage and, on the other hand, on the skin resistance of the patient during the passage of this current, resistance which varies considerably during the initial phase of the treatment, as is saw above. The current is maintained for a time interval of a predetermined duration, for example one second (step 5). We take this opportunity to measure its intensity (step 6) and compare this intensity to a predetermined setpoint I _c (step 7). This value is fixed at a sufficiently high value (for example 1 mA) so that the cutaneous resistance of the skin, under the action of the passage of the current, passes as quickly as possible to its substantially constant "regime" value from 5 to 6 kΩ for example, starting from an initial value lying in a wide range, from 25 to 250 kΩ for example depending on the patients, as we saw above in the preamble to this description. Because the initial skin resistance is high, the current measured in step 5 is most often lower than this set value and the process then continues with a stop of the therapeutic current

(step 8) also maintained for a predetermined time, of 1 s for example (step 9). The counter is then incremented by one unit and the cycle of steps 3 to 7 is resumed by a comparison of the values 30 and 1 which triggers a new activation of the therapeutic current, for one second. The comparison established in step 7 between the new current measured in step 6 and the setpoint current I _c causes a new cessation of the therapeutic current because the skin resistance has only slightly decreased between the two measurements. This cyclic process is repeated a number of times before the measured current reaches the setpoint I _c . It is understood that, during the course of the successive loops defined by steps 3,4,5,6,7,8,9,10,3, etc ..., the electrodes see passing a series of square current pulses of period T = 2 seconds, with a duty cycle of 50%, in the example chosen.

These current pulses, lasting one second, are therefore separated by intervals without current of the same duration. The periodic current thus established is much better supported by the patient (no itching of the skin) than a direct current, as this has been demonstrated by numerous studies known to those skilled in the art.

However the passage of this periodic current causes in the long run (approximately one minute) a progressive lowering of the cutaneous resistance of the patient's skin and therefore, correlatively, an increase in the current measured in step 6. When this current reaches the value set point, this is significant that the cutaneous resistance of the skin has reached a value (of the order of 5 to 6 kΩ) low enough for the administration program in normal mode of the drug to start, with values of predetermined and programmed setpoint current I _cn , and under normal monitoring of the electrical parameters of the operation of the device, namely the current I passing between the electrodes and the voltage established between them (step

12).

On the other hand, if at the end of a predetermined time, chosen in the example described equal to 60 seconds (i.e. 30 x T), the current does not reach the set reference value, a processing stop (step 11) is ordered and the counter is reset. This stop can be canceled by a restart, automatic or manually controlled by the patient (step 2), of the cycle of steps 3 to 10. It is indeed considered that a skin preparation time of one minute is normal and sufficient for most patients. With some patients with particularly high initial skin resistance, one or more additional minutes of treatment may be necessary to achieve the desired skin resistance, for example 5 to 6 kΩ.

The normal operation of the administration device then begins, with a set intensity I _cn of the therapeutic current which may be lower (of the order of 100 to 400 uA for example) than that used in steps 3 to 10, while remaining suitable for maintaining the plasma dose of active principle administered to the patient at a predetermined value.

This operation takes place with monitoring of the therapeutic current I passing between the electrodes and of the cutaneous resistance Rc _Ut of the skin, where this current passes, as shown in the flow diagram of FIG. 2.

As seen above, transdermal administration of drug by iontophoresis makes it possible to execute an administration program extending over periods of time of variable length, possibly comprising breaks in the therapeutic current, or even variations in the intensity of this current between said cuts. The monitoring of this current (steps 13,14) is necessary for the regulation of its intensity, conventionally executed by the electronic circuit of the administration device. If, despite this regulation, the current deviates from the set point, this situation results from an incident in the operation of the device, an incident reported to the patient by the activation of an audible and / or visual alert (step 17) , followed by stopping treatment (step 11). This shutdown is used to control the installation of the device and its operation. Skin resistance is also monitored (steps 15 and 16), measured by dividing the voltage measured between the electrodes by the intensity of the current measured. The cutaneous resistance R _cut is compared to a low threshold Rmin, the exceeding of which is indicative of a state of short circuit of the electrodes, and to a high threshold Rm _ax defining the maximum cutaneous resistance compatible with the adjustment capabilities of the device. administration. All of these arrangements are well known to those skilled in the art and need not be discussed in more detail in the present invention. Such monitoring of the cutaneous resistance could also be implemented during the initial rise of the current occurring before step 12, to detect for example an incorrect placement of the electrodes. We return to the control method illustrated by the flow diagram of FIG. 1 and in particular to the characteristic of this method according to which the intensity of the current which passes between the electrodes is constantly monitored during the initial phase which precedes the operation in normal mode of the administration device (step 12).

This constant monitoring allows, in addition to the comparison of the current measured with a set value (step 7), the comparison of this current with low values I _m i _n and high 1, -aχ. When the current measured exceeds I _m a _x or falls below I _m i _n o diagnoses a faulty operation of the equipment resulting either from a failure of the therapeutic current generator, or from an accidental opening of the electrode circuit (we have then 1 = 0). These situations are reported to the patient, or. to the personnel in charge of the treatment, so that it can be remedied. This eliminates any unattended operation of the drug delivery device, in accordance with one of the objects of the invention.

The control method illustrated by the flow diagram of FIG. 1 brings into play a reference current I _c fixed at a constant value. Thus, the "current" value of this setpoint current, during the execution of each of the loops formed by steps 3 to 10, remains constant from one loop to another.

The flow diagram of FIG. 3 illustrates a variant of this process, in which the current set value varies during the initial period of time during which the skin resistance decreases gradually, while the current applied increases to a value allowing the initiation of the drug administration program, under the supervision illustrated in FIG. 2. Steps 1 to 10, 11 are found in the flow diagram of FIG. and 12 of the flow diagram of FIG. 2. The flow diagram of FIG. 3 is distinguished by an additional loop made up of steps 18 and 19 which will be described later. The purpose of this additional loop is to gradually vary the "current" setpoint, so as to ensure controlled growth of the current passing between the electrodes. This is how the "current" setpoint is fixed, during the first loop, at a value I _c / X, I _c being the final setpoint which must be reached by the current measured to start the treatment under normal monitoring (step 12) and X being for example an integer progressively decremented up to X ≈ 1 (step 19). Thus, if X = 10 at the start, the setpoint taken into account progressively goes from I _c / 10 to I _c . When the measured current reaches the "current" setpoint I _c / X, the setpoint is automatically incremented to I _c / X-1 (steps 18, 19). The measured current value follows the same progression, starting from a low value, for example 100 mA, passing through intermediate values of 200 A, 300 mA, etc. to the final set value of 1 mA for example. When the measured current reaches this value (step 18), the normal monitoring of the processing, according to the flow diagram of FIG. 2, starts (step 12).

Such an increment of the current set value makes it possible to improve the patient's tolerance to the growth of the therapeutic current and ensures a controlled growth of this current, resulting from the decrease in the patient's skin resistance. The progressive growth of the current ensures a progressive habituation of the patient without any unpleasant sensation such as internal tingling.

Of course, the invention is not limited to the embodiments described and shown which have been given only by way of example.

Claims

1. Method for controlling a transdermal drug delivery device under an electric field, this device comprising a pair of electrodes applied to the skin of a patient, at least one of the electrodes being charged with said drug, a source of energy and an electronic circuit for controlling the passage of a current from said source between said electrodes, the method being characterized in that, when the device is switched on, an initial current pulse is passed between the electrodes , the intensity of said current is measured and compared with a current setpoint, this process of passing current pulse, measurement and comparison is repeated until the measured current reaches a final setpoint (I _c ), and the operation in normal mode of said device is then triggered.

2. Method according to claim 1, characterized in that said current set value is equal to said final set value.

3. Method according to claim 1, characterized in that the current setpoint value (I _c / X) is incremented each time the measured current reaches said value, until the current setpoint reaches said final set value (I _c ).

4. Method according to claim 1, characterized in that the current pulses are counted and in that the operation of the device is stopped when the count reaches a predetermined value.

5. Method according to any one of claims 1 to 4, characterized in that the current measured during a pulse is compared with predetermined maximum (Ima) and minimum (I _m _n) values and an operation is diagnosed. device defective when the measured current leaves the domain bounded by said values.

6. Method according to any one of the preceding claims, characterized in that the successive current pulses form a periodic current of square wave form at about 50% duty cycle and of period T = 2 seconds approximately.