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EP0968029A1 - Method for measuring the cutaneous electric resistance of a patient subjected to transdermal administration of medicine - Google Patents

Method for measuring the cutaneous electric resistance of a patient subjected to transdermal administration of medicine

Info

Publication number
EP0968029A1
EP0968029A1 EP97947082A EP97947082A EP0968029A1 EP 0968029 A1 EP0968029 A1 EP 0968029A1 EP 97947082 A EP97947082 A EP 97947082A EP 97947082 A EP97947082 A EP 97947082A EP 0968029 A1 EP0968029 A1 EP 0968029A1
Authority
EP
European Patent Office
Prior art keywords
skin
patient
current
administration
measurement
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97947082A
Other languages
German (de)
French (fr)
Inventor
Philippe Millot
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Iomed LLC
Original Assignee
Laboratoires dHygiene et de Dietetique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires dHygiene et de Dietetique SA filed Critical Laboratoires dHygiene et de Dietetique SA
Publication of EP0968029A1 publication Critical patent/EP0968029A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0531—Measuring skin impedance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

Definitions

  • the present invention relates to a method for measuring the electrical cutaneous resistance of a patient and, more particularly, to such a method implemented on a patient subjected to a transdermal administration of medicaments assisted by an iontophoretic current.
  • This monitoring is commonly carried out via that of the electrical resistance of the patient's skin, it being noted that a modification of the structure thereof, due to the imminent appearance of a lesion, manifests itself by a variation of said cutaneous electrical resistance.
  • the electrical voltage present between the electrodes pressed against the patient's skin is noted at the time of the measurement.
  • These electrodes are part of a device for transdermal administration assisted by iontophoresis, which comprises means for adjusting the iontophoretic current.
  • this tension measurement also makes it possible to diagnose the occurrence of defective functioning of the device, such as for example a short circuit of the skin by sweat spread over this skin, insufficient hydration of a reservoir of active ingredient attached to an electrode, etc, etc, ...
  • the object of the present invention is precisely to provide a method for measuring the cutaneous electrical resistance of a patient subjected to a transdermal administration of drug assisted by iontophoresis, which makes it possible to safely diagnose the imminence of the appearance of such a lesion.
  • the present invention also aims to provide such a method which also makes it possible to diagnose the occurrence or the existence of malfunctions of the device used for ensuring the transdermal administration of the drug assisted by iontophoresis.
  • a value corresponding to a substantially zero flow of the drug through the patient's skin is chosen for said predetermined value of the iontophoretic current.
  • - Figure 2 is a flowchart illustrating an embodiment of the measurement method according to the invention
  • - Figure 3 is a flowchart illustrating the use made of the measurements obtained by the method according to the invention.
  • FIG. 1 of the appended drawing in which it appears that the current / voltage characteristic of the skin of a human being has a rectilinear part OA on the side of the origin 0, and a curvilinear part AB, the threshold A separating these parts typically corresponding to a current intensity of 200 ⁇ A, measured between two neighboring electrodes with a surface area of 4 cm 2 each, which corresponds to a current density of 50 ⁇ A / cm 2 .
  • this observation is used to make the tension measurement aimed at achieving the cutaneous resistance of the skin independent of the non-linearity of the part AB.
  • the iontophoretic current is adjusted to a value I m situated in the range of variation corresponding to the rectilinear part OA, ie in the range O-200 ⁇ A.
  • I m situated in the range of variation corresponding to the rectilinear part OA, ie in the range O-200 ⁇ A.
  • the difference ⁇ V of the voltages measured on these two curves is exactly representative of the only variation in slope of the right part of the characteristic, this slope corresponding precisely to the desired resistance of the skin in the intensity range O-200 ⁇ A, i.e. 0-50 ⁇ A / cm 2 . This would not be the case if we had placed sacred in the non-linear part of the characteristic.
  • the slope variation is measured with reference to the slope of the OA segment of the OAB characteristic corresponding to healthy skin.
  • the measured voltage variation is perfectly representative of the change in the structure of the skin over time, resulting from the application of an iontophoretic current to initially healthy skin. It is thus possible to detect the imminence of a state of degradation of the skin, edema, burning or the like, which one does not wish to reach, and to stop the transdermal treatment before the occurrence of this state. This prevents both an unbearable deterioration of the patient's skin and a prolongation of the treatment on degraded skin, not allowing a correct execution of this treatment.
  • the execution of this process can take place before the start of a treatment, to verify that the condition of the patient's skin and that of the transdermal delivery device used are suitable to such administration, as will be explained below in connection with FIG. 3.
  • the execution of the method can also take place during the duration of the treatment, for example at regular intervals, so as to monitor these same states and to decide to continuation or cessation of treatment depending on the diagnosed conditions.
  • the electronics of the administration device is programmed to reduce the intensity XmA of the iontophoretic current which it delivers (for example 500 ⁇ A) at the level I m indicated above, located in the rectilinear part OA of the characteristic of FIG. 1, this level being sufficiently low to create no sensitive ionophoretic flux liable to disturb the measurement to be carried out.
  • this intensity level I m or "measurement current” can thus be fixed at 50 ⁇ A (or 12.5 uA / cm 2 ) for example (step a, FIG. 2).
  • the device After having established and maintained this current for a certain time, for example 3 seconds, to allow stabilization of the measurement to be operated and possible depolarization of the skin, the device reads (step b) the voltage V skin prevailing between the applied electrodes on the patient's skin and calculates (step c) the cutaneous resistance R cut by applying Ohm's law:
  • the iontophoretic or "therapeutic" current is gradually restored between the electrodes up to the previous XmA level.
  • step d we can, for example, set XmA / 4, then 2XmA / 4, 3XmA / 4, each time for 1 second, before returning to XmA.
  • other current growth patterns could be used in place of it, in since they prevent a sudden return to the XmA level from causing an unpleasant sensation to the patient, before returning to therapeutic treatment.
  • the measurement method described above can be implemented both during a time of application of the therapeutic current XmA and during times when this current is zero, which makes it possible to continuously monitor the state of the device and the skin. So sweating of this skin can then be detected as well as the short circuit of the electrodes that it can cause.
  • the measurements carried out when the therapeutic current is zero benefit from good precision, in particular when the measurement takes place at the end of such a period. Indeed, the measurement is then not disturbed by the polarization of the skin, a depolarization time of the latter having been provided before the measurement.
  • the execution of the measurement method according to the invention can be triggered and controlled automatically by the electronics of the transdermal application device used.
  • the measurement can be triggered at predetermined regular time intervals, for example.
  • the duration of the interval can be chosen in the 20s-15mn range. It is preferable to choose an interval of 3 min.
  • the electronics are programmed to compare (step e) the measured value R cu t of the skin resistance with a threshold value R m i n .
  • This threshold can be adjusted between 100 and 1000 ohms, typically 500 ohms, when operating with electrodes with a surface area of 4 cm 2 . If Rcut is smaller than R m in and the measurement of R cu t takes place before the start of treatment, a visual and / or audible alarm is issued (step b) to the patient to warn him of its existence probable of a short circuit between the electrodes of the device, likely to prevent correct administration of the treatment. The start of treatment is then prohibited (step c). If this situation is detected during treatment, it is stopped.
  • R cu t is greater than R m in
  • the electronics of the device compares R cut with another threshold value R m a x (step d) which can be chosen between 50 kohms and 300 kohms, typically 100 kohms.
  • R C ut is greater than R m a x this situation is signaled to the patient by an audible and / or visual alarm (step e) and the start or continuation of the treatment is prohibited (step f). Indeed, this situation can result from an alteration of the structure of the skin likely to lead, in an imminent manner, to a lesion of the type of those mentioned above. It can also result from a defect in the transdermal delivery device itself.
  • the thresholds R m i n and R m a can be adjusted at different levels for measurements occurring before treatment and during treatment, respectively, so that the detections of defects or lesions are then carried out with different sensitivities .
  • the invention is not limited to the administration of such major analgesics and extends, on the contrary, to others: morphine, bupremorphine and derivatives, or even to any active principle capable of being administered transdermally under iontophoretic assistance.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Physics & Mathematics (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Electrotherapy Devices (AREA)

Abstract

The intensity (I) of an electrophoresis current aiding the administration is temporarily adjusted to a predetermined value (Im) corresponding to a point of an original rectilinear part (OA) of the current/tension characteristic of the patient's skin, the voltage (Vpeau) then prevailing between two electrodes applying the electrophoresis current to the patient's skin is measured and the measurement (Rcut) of the cutaneous resistance is deduced from the measured voltage (Vpeau) and the predetermined value (Im) of the electrophoresis current.

Description

PROCEDE DE MESURE DE LA RESISTANCE ELECTRIQUE CUTANEE D'UN PATIENT SOUMIS A UNE ADMINISTRATION TRANSDERMIQUE DE MEDICAMENT .METHOD FOR MEASURING THE SKIN RESISTANCE OF A PATIENT SUBJECT TO TRANSDERMAL ADMINISTRATION OF MEDICINAL PRODUCT.
La présente invention est relative à un procédé de mesure de la résistance électrique cutanée d'un patient et, plus particulièrement, à un tel procédé mis en oeuvre sur un patient soumis à une administration transdermique de médicaments assistée par un courant ionophorétique.The present invention relates to a method for measuring the electrical cutaneous resistance of a patient and, more particularly, to such a method implemented on a patient subjected to a transdermal administration of medicaments assisted by an iontophoretic current.
De nombreux dispositifs ont été conçus pour pratiquer une telle administration ionophorétique de médicaments. A titre d'exemple, on peut citer celui décrit dans la demande de brevet français N° 96 04735 déposée le 16 avril 1996 par la demanderesse. On sait qu'une telle administration implique l'utilisation d'un principe actif prenant une forme ionique susceptible, sous l'action d'un champ électrique, de traverser la peau du patient. Le champ est établi entre deux électrodes adjacentes plaquées sur la peau du patient. L'administration du médicament se développe classiquement suivant un programme temporel comportant des périodes d'administration séparées éventuellement par des périodes de non-administration pendant lesquelles le courant ionophorétique, ou "thérapeutique", est coupé. Pendant les périodes d'administration, l'intensité de ce courant peut être fixée à des valeurs prédéterminées, 500 μA, 750 μA, par exemple, éventuellement différentes d'une période à l'autre. La durée totale d'un programme d'administration se compte couramment en heures, voire en jours.Many devices have been designed to practice such iontophoretic administration of drugs. By way of example, mention may be made of that described in French patent application No. 96 04735 filed on April 16, 1996 by the applicant. It is known that such administration involves the use of an active principle taking an ionic form capable, under the action of an electric field, of passing through the patient's skin. The field is established between two adjacent electrodes pressed against the patient's skin. The administration of the drug conventionally develops according to a time program comprising periods of administration optionally separated by periods of non-administration during which the iontophoretic current, or "therapeutic", is cut. During the periods of administration, the intensity of this current can be fixed at predetermined values, 500 μA, 750 μA, for example, possibly different from one period to another. The total duration of an administration program is commonly counted in hours or even days.
On sait aussi que l'application d'un courant électrique à un élément de surface de la peau d'un patient, pendant des périodes de temps aussi longues, peut provoquer une modification des caractéristiques de celles-ci, voir des lésions allant d'un oedème superficiel léger à une brûlure profonde, accidents qu'il convient évidemment de prévenir par une surveillance constante de l'état de l'élément de surface de peau soumis au courant ionophorétique.It is also known that the application of an electric current to a surface element of the skin of a patient, for such long periods of time, can cause a modification of the characteristics of these, see lesions ranging from a slight superficial edema with a deep burn, accidents which obviously should be prevented by constant monitoring of the condition of the skin surface element subjected to the iontophoretic current.
Cette surveillance s'opère couramment par l'intermédiaire de celle de la résistance électrique de la peau du patient, étant constaté qu'une modification de la structure de celle- ci, due à l'imminence de l'apparition d'une lésion, se manifeste par une variation de ladite résistance électrique cutanée . Classiquement, pour mesurer cette résistance électrique on relève, à l'instant de la mesure, la tension électrique présente entre les électrodes plaquées contre la peau du patient. Ces électrodes font partie d'un dispositif d'administration transdermique assistée par ionophorèse, qui comprend des moyens de réglage du courant ionophorétique.This monitoring is commonly carried out via that of the electrical resistance of the patient's skin, it being noted that a modification of the structure thereof, due to the imminent appearance of a lesion, manifests itself by a variation of said cutaneous electrical resistance. Conventionally, to measure this electrical resistance, the electrical voltage present between the electrodes pressed against the patient's skin is noted at the time of the measurement. These electrodes are part of a device for transdermal administration assisted by iontophoresis, which comprises means for adjusting the iontophoretic current.
Connaissant la tension existant entre les électrodes et ce courant, on peut en déduire une mesure de la résistance électrique du patient dans le tube de courant limité par les deux éléments de surface de sa peau couverts par ces électrodes, par simple application de la loi d'Ohm. Dans la suite, cette résistance électrique est appelée résistance "cutanée" du patient.Knowing the voltage existing between the electrodes and this current, we can deduce a measurement of the patient's electrical resistance in the current tube limited by the two surface elements of his skin covered by these electrodes, by simple application of the law of 'Ohm. In the following, this electrical resistance is called the "skin" resistance of the patient.
Incidemment, on notera que cette mesure de tension permet aussi de diagnostiquer l'occurrence de fonctionnements défectueux du dispositif, tels que par exemple un court- circuit de la peau par de la sueur répandue sur cette peau, une hydratation insuffisante d'un réservoir de principe actif accolé à une électrode, etc, etc, ...Incidentally, it will be noted that this tension measurement also makes it possible to diagnose the occurrence of defective functioning of the device, such as for example a short circuit of the skin by sweat spread over this skin, insufficient hydration of a reservoir of active ingredient attached to an electrode, etc, etc, ...
La mesure de tension évoquée plus haut ne permet cependant pas de tirer des conclusions sures de l'observation de variations dans les mesures réalisées car la caractéristique courant/tension de la peau n'est pas linéaire, comme le montre le graphe de cette caractéristique représenté à la figure 1 du dessin annexé. A l'examen de ce graphe, établi avec des électrodes présentant chacune une surface de 4 cm2 et à l'aide de mesures opérées sans qu'apparaissent des modifications sensibles de la structure de la peau, on comprend que suivant la valeur du courant ionophorétique I aux instants de mesure de la tension, la mesure de la résistance cutanée par ladite loi peut prendre des valeurs différentes alors même que la structure de la peau n'aura subi aucune altération d'une mesure à l'autre. Il apparait ainsi que les mesures de tensions évoquées ci-dessus ne permettent pas de diagnostiquer avec sûreté l'imminence de l'apparition d'une lésion dans l'élément de surface de peau soumis au courant ionophorétique.However, the tension measurement mentioned above does not allow reliable conclusions to be drawn from the observation of variations in the measurements carried out because the current / tension characteristic of the skin is not linear, as shown in the graph of this characteristic represented. in Figure 1 of the accompanying drawing. On examination of this graph, established with electrodes each having a surface of 4 cm 2 and using measurements carried out without any noticeable changes in the structure of the skin appearing, it is understood that depending on the value of the current iontophoretic I at the instants of measurement of the tension, the measurement of the cutaneous resistance by said law can take different values then even that the structure of the skin will not have undergone any alteration from one measurement to another. It thus appears that the tension measurements mentioned above do not allow a reliable diagnosis of the imminence of the appearance of a lesion in the skin surface element subjected to the iontophoretic current.
La présente invention a précisément pour but de fournir un procédé de mesure de la résistance électrique cutanée d'un patient soumis à une administration transdermique de médicament assistée par ionophorèse, qui permette de diagnostiquer avec sûreté l'imminence de l'apparition d'une telle lésion.The object of the present invention is precisely to provide a method for measuring the cutaneous electrical resistance of a patient subjected to a transdermal administration of drug assisted by iontophoresis, which makes it possible to safely diagnose the imminence of the appearance of such a lesion.
La présente invention a aussi pour but de fournir un tel procédé qui permette également de diagnostiquer l'occurrence ou l'existence de défauts de fonctionnement du dispositif utilisé pour assurer l'administration transdermique du médicament assistée par ionophorèse.The present invention also aims to provide such a method which also makes it possible to diagnose the occurrence or the existence of malfunctions of the device used for ensuring the transdermal administration of the drug assisted by iontophoresis.
On atteint ces buts de l'invention, ainsi que d'autres qui apparaîtront à la lecture de la description qui va suivre, avec un procédé du type décrit en préambule de la présente description, ce procédé étant remarquable en ce qu'on règle temporairement l'intensité du courant ionophorétique à une valeur prédéterminée correspondant à un point d'une partie d'origine rectiligne de la caractéristique courant/tension de la peau du patient, on mesure la tension régnant alors entre deux électrodes d'application du courant ionophorétique à la peau du patient et on tire la mesure de la résistance électrique cutanée de la tension mesurée et de la valeur prédéterminée du courant ionophorétique.These objects of the invention are achieved, as well as others which will appear on reading the description which follows, with a method of the type described in the preamble to the present description, this method being remarkable in that it is temporarily regulated the intensity of the iontophoretic current at a predetermined value corresponding to a point of a portion of rectilinear origin of the current / voltage characteristic of the patient's skin, the voltage prevailing between two electrodes for applying the iontophoretic current is measured at the patient's skin and the measurement of the cutaneous electrical resistance is taken from the measured voltage and from the predetermined value of the iontophoretic current.
Comme on le verra en plus de détails dans la suite, en fixant ainsi la valeur du courant à l'instant de la mesure de la tension, on s'affranchit de la non-linéarité de la caractéristique courant/tension de la peau susceptible de perturber le diagnostic de l'imminence de l'apparition d'une lésion sur la peau du patient.As will be seen in more detail below, by thus fixing the value of the current at the time of the voltage measurement, one overcomes the non-linearity of the current / voltage characteristic of the skin likely to disrupt the diagnosis of the imminent appearance of a lesion on the patient's skin.
Suivant une autre caractéristique du procédé selon l'invention on choisit, pour ladite valeur prédéterminée du courant ionophorétique, une valeur correspondant à un flux sensiblement nul du médicament à travers la peau du patient.According to another characteristic of the process according to the invention, a value corresponding to a substantially zero flow of the drug through the patient's skin is chosen for said predetermined value of the iontophoretic current.
D'autres caractéristiques et avantages de la présente invention apparaîtront à la lecture de la description qui va suivre et à l'examen du dessin annexé dans lequel : - la Figure 1 est un graphe de la caractéristique courant/tension de la peau, discuté en préambule de la présente description,Other characteristics and advantages of the present invention will appear on reading the description which follows and on examining the appended drawing in which: - Figure 1 is a graph of the current / tension characteristic of the skin, discussed in preamble to this description,
- la Figure 2 est un organigramme illustrant un mode de mis en oeuvre du procédé de mesure suivant l'invention, et - la Figure 3 est un organigramme illustrant l'exploitation qui est faite des mesures obtenues par le procédé selon l'invention.- Figure 2 is a flowchart illustrating an embodiment of the measurement method according to the invention, and - Figure 3 is a flowchart illustrating the use made of the measurements obtained by the method according to the invention.
On se réfère à la figure 1 du dessin annexé où il apparaît que la caractéristique courant/tension de la peau d'un être humain présente une partie rectiligne OA du côté de l'origine 0, et une partie curviligne AB, le seuil A séparant ces parties correspondant typiquement à une intensité de courant de 200 μA, mesurée entre deux électrodes voisines de 4 cm2 de surface chacune, ce qui correspond à une densité de courant de 50 μA/cm2.Reference is made to FIG. 1 of the appended drawing in which it appears that the current / voltage characteristic of the skin of a human being has a rectilinear part OA on the side of the origin 0, and a curvilinear part AB, the threshold A separating these parts typically corresponding to a current intensity of 200 μA, measured between two neighboring electrodes with a surface area of 4 cm 2 each, which corresponds to a current density of 50 μA / cm 2 .
Suivant une caractéristique de la présente invention, on exploite cette observation pour rendre la mesure de tension visant à atteindre la résistance cutanée de la peau indépendante de la non-linéarité de la partie AB. Pour ce faire, lors de la mesure de tension, on règle le courant ionophorétique à une valeur Im située dans le domaine de variation correspondant à la partie rectiligne OA, soit dans le domaine O-200 μA. On peut choisir, à titre d'exemple, de fixer ce courant à 50 μA, ce qui correspond à une densité de courant de 12,5 uA/cm2, densité faible qui correspond à un flux sensiblement nul du principe actif à travers la peau, flux alors non susceptible de perturber la mesure de résistance à laquelle on veut procéder.According to a characteristic of the present invention, this observation is used to make the tension measurement aimed at achieving the cutaneous resistance of the skin independent of the non-linearity of the part AB. To do this, during the voltage measurement, the iontophoretic current is adjusted to a value I m situated in the range of variation corresponding to the rectilinear part OA, ie in the range O-200 μA. We can choose, for example, to fix this current at 50 μA, which corresponds to a current density of 12.5 uA / cm 2 , low density which corresponds to a substantially zero flow of the active ingredient through the skin, flow then not likely to disturb the resistance measurement to be carried out.
Ainsi, dans l'hypothèse où, au moment de la mesure, la caractéristique courant/tension de la peau n'est plus celle représentée en trait plein mais celle représentée en trait interrompu, par suite d'une altération de la structure de la peau consécutive au passage du courant ionophorétique, ou "thérapeutique", la différence ΔV des tensions mesurées sur ces deux courbes est exactement représentative de la seule variation de pente de la partie droite de la caractéristique, cette pente correspondant justement à la résistance recherchée de la peau dans le domaine d'intensité O-200 μA, soit 0-50 μA/cm2. Tel ne serait pas le cas si l'on s'était placé dans la partie non-linéaire de la caractéristique.Thus, in the hypothesis that, at the time of the measurement, the current / tension characteristic of the skin is no longer that represented in solid lines but that represented in broken lines, as a result of an alteration of the structure of the skin consecutive to the passage of the iontophoretic current, or "therapeutic", the difference ΔV of the voltages measured on these two curves is exactly representative of the only variation in slope of the right part of the characteristic, this slope corresponding precisely to the desired resistance of the skin in the intensity range O-200 μA, i.e. 0-50 μA / cm 2 . This would not be the case if we had placed ourselves in the non-linear part of the characteristic.
En outre, la variation de pente est mesurée en référence à la pente du segment OA de la caractéristique OAB correspondant à une peau saine. Ainsi la variation de tension mesurée est parfaitement représentative de l'altération dans le temps de la structure de la peau, résultant de l'application d'un courant ionophorétique à une peau initialement saine. On peut ainsi détecter l'imminence d'un état de dégradation de la peau, oedème, brûlure ou autre, que l'on ne souhaite pas atteindre, et arrêter le traitement transdermique avant la survenance de cet état. On prévient ainsi à la fois une dégradation insupportable de la peau du patient et une prolongation du traitement sur une peau dégradée, ne permettant pas une exécution correcte de ce traitement. On se réfère maintenant à la figure 2 du dessin annexé pour décrire en plus de détail un exemple de mise en oeuvre du procédé de mesure suivant l'invention. L'exécution de ce procédé peut intervenir avant le démarrage d'un traitement, pour vérifier que l'état de la peau du patient et celui du dispositif d'administration transdermique utilisé conviennent à une telle administration, comme on l'expliquera plus loin en liaison avec la figure 3. L'exécution du procédé peut aussi intervenir pendant la durée du traitement, par exemple à intervalles réguliers, de manière à surveiller ces mêmes états et à décider de la poursuite ou de l'arrêt du traitement en fonction des états diagnostiqués.In addition, the slope variation is measured with reference to the slope of the OA segment of the OAB characteristic corresponding to healthy skin. Thus the measured voltage variation is perfectly representative of the change in the structure of the skin over time, resulting from the application of an iontophoretic current to initially healthy skin. It is thus possible to detect the imminence of a state of degradation of the skin, edema, burning or the like, which one does not wish to reach, and to stop the transdermal treatment before the occurrence of this state. This prevents both an unbearable deterioration of the patient's skin and a prolongation of the treatment on degraded skin, not allowing a correct execution of this treatment. Referring now to Figure 2 of the accompanying drawing to describe in more detail an example of implementation of the measuring method according to the invention. The execution of this process can take place before the start of a treatment, to verify that the condition of the patient's skin and that of the transdermal delivery device used are suitable to such administration, as will be explained below in connection with FIG. 3. The execution of the method can also take place during the duration of the treatment, for example at regular intervals, so as to monitor these same states and to decide to continuation or cessation of treatment depending on the diagnosed conditions.
Dans le cas d'une mise en oeuvre en cours de traitement, l'électronique du dispositif d'administration, par exemple du type décrit dans la demande de brevet français précitée, est programmée pour réduire l'intensité XmA du courant ionophorétique qu'il délivre (par exemple 500 μA) au niveau Im indiqué plus haut, situé dans la partie rectiligne OA de la caractéristique de la figure 1, ce niveau étant suffisamment faible pour ne créer aucun flux ionophorétique sensible susceptible de perturber la mesure à réaliser. Comme indiqué plus haut, ce niveau d'intensité Im, ou "courant de mesure", peut ainsi être fixé à 50 μA (ou 12,5 uA/cm2) par exemple (étape a, figure 2).In the case of implementation during treatment, the electronics of the administration device, for example of the type described in the aforementioned French patent application, is programmed to reduce the intensity XmA of the iontophoretic current which it delivers (for example 500 μA) at the level I m indicated above, located in the rectilinear part OA of the characteristic of FIG. 1, this level being sufficiently low to create no sensitive ionophoretic flux liable to disturb the measurement to be carried out. As indicated above, this intensity level I m , or "measurement current", can thus be fixed at 50 μA (or 12.5 uA / cm 2 ) for example (step a, FIG. 2).
Après avoir établi et maintenu ce courant pendant un certain temps, par exemple 3 secondes, pour permettre une stabilisation de la mesure à opérer et une dépolarisation éventuelle de la peau, le dispositif relève (étape b) la tension Vpeau régnant entre les électrodes appliquées sur la peau du patient et calcule (étape c) la résistance cutanée Rcut par application de la loi d'Ohm :After having established and maintained this current for a certain time, for example 3 seconds, to allow stabilization of the measurement to be operated and possible depolarization of the skin, the device reads (step b) the voltage V skin prevailing between the applied electrodes on the patient's skin and calculates (step c) the cutaneous resistance R cut by applying Ohm's law:
" eau"water
Rcut = r -"•JI?Rcut = r - " • JI?
La mesure étant faite, le courant ionophorétique ou "thérapeutique" est rétabli progressivement entre les électrodes jusqu'au niveau XmA antérieur. Pour ce faire (étape d) on peut, par exemple, établir XmA/4, puis 2XmA/4, 3XmA/4, à chaque fois pendant 1 seconde, avant de revenir à XmA. Bien entendu d'autres schémas de croissance du courant pourraient être utilisés en lieu et place de celui-ci, dans la mesure où ils permettent d'éviter qu'un retour brutal au niveau XmA ne procure une sensation désagréable au patient, avant le retour au traitement thérapeutique.The measurement being made, the iontophoretic or "therapeutic" current is gradually restored between the electrodes up to the previous XmA level. To do this (step d) we can, for example, set XmA / 4, then 2XmA / 4, 3XmA / 4, each time for 1 second, before returning to XmA. Of course, other current growth patterns could be used in place of it, in since they prevent a sudden return to the XmA level from causing an unpleasant sensation to the patient, before returning to therapeutic treatment.
Le procédé de mesure décrit ci-dessus peut être mis en oeuvre aussi bien pendant un temps d'application du courant thérapeutique XmA que pendant des temps où ce courant est nul, ce qui permet de suivre en permanence l'état du dispositif et de la peau. Ainsi une sudation de cette peau peut alors être détectée ainsi que le court-circuit des électrodes qu'elle peut provoquer.The measurement method described above can be implemented both during a time of application of the therapeutic current XmA and during times when this current is zero, which makes it possible to continuously monitor the state of the device and the skin. So sweating of this skin can then be detected as well as the short circuit of the electrodes that it can cause.
On remarquera que les mesures opérées quand le courant thérapeutique est nul bénéficient d'une bonne précision, notamment lorsque la mesure intervient à la fin d'une telle période. En effet, la mesure n'est alors pas perturbée par la polarisation de la peau, un temps de dépolarisation de celle-ci ayant été ménagé avant la mesure.It will be noted that the measurements carried out when the therapeutic current is zero benefit from good precision, in particular when the measurement takes place at the end of such a period. Indeed, the measurement is then not disturbed by the polarization of the skin, a depolarization time of the latter having been provided before the measurement.
L'exécution du procédé de mesure suivant l'invention peut être déclenché et commandé automatiquement par l'électronique du dispositif d'application transdermique utilisé. En cours de traitement, la mesure peut être déclenchée à des intervalles de temps réguliers prédéterminés, par exemple. La durée de l'intervalle peut être choisie dans le domaine 20s-15mn. On peut choisir préférentiellement un intervalle de 3 mn. On se réfère maintenant à l'organigramme de la figure 3 pour décrire comment l'électronique du dispositif d'administration exploite les mesures de résistances cutanées réalisées, aussi bien avant le démarrage d'un traitement que pendant le déroulement de celui-ci. L'électronique est programmée pour comparer (étape e) la valeur mesurée Rcut de la résistance cutanée à une valeur de seuil Rmin. Ce seuil peut être réglé entre 100 et 1000 ohms, typiquement à 500 ohms, lorsqu'on opère avec des électrodes de 4 cm2 de surface. Si Rcut est plus petit que Rmin et que la mesure de Rcut intervienne avant le démarrage du traitement, une alarme visuelle et/ou sonore est émise (étape b) à l'intention du patient pour le prévenir de l'existence probable d'un court- circuit entre les électrodes du dispositif, propre à empêcher une administration correcte du traitement. Le démarrage du traitement est alors interdit (étape c) . Si cette situation est détectée en cours de traitement, celui- ci est arrêté. Si, au contraire, Rcut est plus grand que Rmin, l'électronique du dispositif compare ensuite Rcut à une autre valeur de seuil Rmax (étape d) que l'on peut choisir entre 50 kohms et 300 kohms, typiquement 100 kohms.The execution of the measurement method according to the invention can be triggered and controlled automatically by the electronics of the transdermal application device used. During processing, the measurement can be triggered at predetermined regular time intervals, for example. The duration of the interval can be chosen in the 20s-15mn range. It is preferable to choose an interval of 3 min. Reference is now made to the flow diagram of FIG. 3 to describe how the electronics of the administration device uses the skin resistance measurements carried out, both before the start of a treatment and during it. The electronics are programmed to compare (step e) the measured value R cu t of the skin resistance with a threshold value R m i n . This threshold can be adjusted between 100 and 1000 ohms, typically 500 ohms, when operating with electrodes with a surface area of 4 cm 2 . If Rcut is smaller than R m in and the measurement of R cu t takes place before the start of treatment, a visual and / or audible alarm is issued (step b) to the patient to warn him of its existence probable of a short circuit between the electrodes of the device, likely to prevent correct administration of the treatment. The start of treatment is then prohibited (step c). If this situation is detected during treatment, it is stopped. If, on the contrary, R cu t is greater than R m in, the electronics of the device then compares R cut with another threshold value R m a x (step d) which can be chosen between 50 kohms and 300 kohms, typically 100 kohms.
Si RCut est plus grand que Rmax cette situation est signalée au patient par une alarme sonore et/ou visuelle (étape e) et le démarrage ou la poursuite du traitement est interdit (étape f) . En effet cette situation peut résulter d'une altération de la structure de la peau susceptible de conduire, de manière imminente, à une lésion du type de celles évoquées ci-dessus. Elle peut aussi résulter d'un défaut du dispositif d'administration transdermique lui- même.If R C ut is greater than R m a x this situation is signaled to the patient by an audible and / or visual alarm (step e) and the start or continuation of the treatment is prohibited (step f). Indeed, this situation can result from an alteration of the structure of the skin likely to lead, in an imminent manner, to a lesion of the type of those mentioned above. It can also result from a defect in the transdermal delivery device itself.
On sait en effet que le ou les réservoirs de principe actif accolés aux électrodes sont couramment chargés, ou "hydratés", avant le traitement avec une solution ionique du principe actif à administrer. Si cette hydratation est incomplète, l'administration du principe actif ne peut être exécutée de manière satisfaisante et il faut alors interdire le démarrage ou la poursuite du traitement tout en excitant les alarmes disponibles pour alerter le patient sur la nécessité de procéder à une vérification de l'état d'hydratation du ou des réservoirs.It is in fact known that the reservoir or reservoirs of active principle attached to the electrodes are commonly charged, or "hydrated", before treatment with an ionic solution of the active principle to be administered. If this hydration is incomplete, the administration of the active principle cannot be carried out in a satisfactory manner and it is then necessary to prohibit the starting or the continuation of the treatment while activating the available alarms to alert the patient to the need to carry out a verification of the state of hydration of the tank (s).
Cette vérification est nécessaire en outre pour assurer la poursuite du traitement dans les conditions préprogrammées. En effet si on mesure R = 100 kohms par exemple, alors que le courant thérapeutique programmé est 1 = 1 mA, la tension à appliquer entre les électrodes serait de 100 volts, valeur beaucoup trop élevée pour être supportée sans brûlure par le patient. Si, après les étapes c) , d) il apparaît que R min < Rcut < Rma/ e traitement peut démarrer ou se poursuivre (étape g) .This verification is also necessary to ensure the continuation of the treatment under the preprogrammed conditions. Indeed if we measure R = 100 kohms by example, while the programmed therapeutic current is 1 = 1 mA, the voltage to be applied between the electrodes would be 100 volts, a value far too high to be supported by the patient without burning. If, after steps c), d) it appears that R m i n < R cut <R m a / e treatment can start or continue (step g).
Bien entendu les seuils Rmin et Rma peuvent être réglés à des niveaux différents pour des mesures intervenant avant traitement et pendant le traitement, respectivement, de manière que les détections de défauts ou de lésions s'opèrent alors avec des sensibilités différentes.Of course the thresholds R m i n and R m a can be adjusted at different levels for measurements occurring before treatment and during treatment, respectively, so that the detections of defects or lesions are then carried out with different sensitivities .
Pendant un traitement on pourra ainsi détecter l'imminence de l'apparition d'une lésion (oedème ou brûlure par exemple) et arrêter le traitement avant que cette lésion ne soit effective, ce qui assure la sécurité du patient, conformément au but essentiel poursuivi par la présente invention.During a treatment, it will thus be possible to detect the imminence of the appearance of a lesion (edema or burn for example) and to stop the treatment before this lesion is effective, which ensures patient safety, in accordance with the essential aim pursued. by the present invention.
Une telle sécurité est particulièrement nécessaire lorsqu'on administre des médicaments à très forte activité tels que certains antalgiques majeurs, le fentanyl et ses dérivés par exemple, qui peuvent être dangereux lorsqu'ils sont administrés à des doses qui s'écartent de celles précisément déterminées par des études pharmacologiques . Une altération non détectée de la peau du patient pourrait en effet conduire à une telle administration dangereuse du médicament.This security is particularly necessary when administering very high activity drugs such as certain major analgesics, fentanyl and its derivatives for example, which can be dangerous when administered in doses which deviate from those precisely determined. by pharmacological studies. An undetected alteration of the patient's skin could indeed lead to such a dangerous administration of the drug.
Bien entendu, l'invention n'est pas limitée à l'administration de tels antalgiques majeurs et s'étend au contraire à d'autres : morphine, buprémorphine et dérivés, voire à tout principe actif susceptible d'être administré par voie transdermique sous assistance ionophorétique. Of course, the invention is not limited to the administration of such major analgesics and extends, on the contrary, to others: morphine, bupremorphine and derivatives, or even to any active principle capable of being administered transdermally under iontophoretic assistance.

Claims

REVENDICATIONS
1. Procédé de mesure de la résistance électrique cutanée d'un patient soumis à une administration transdermique de médicament assistée par un courant ionophorétique, caractérisé en ce qu'on règle temporairement l'intensité (I) du courant ionophorétique à une valeur prédéterminée (Im) correspondant à un point d'une partie d'origine rectiligne (OA) de la caractéristique courant/tension de la peau du patient, on mesure la tension (Vpeau) régnant alors entre deux électrodes d'application du courant ionophorétique à la peau du patient et on tire la mesure (RCut) de la résistance cutanée, de la tension (Vpeau) mesurée et de la valeur prédéterminée (Im) du courant ionophorétique. 1. Method for measuring the cutaneous electrical resistance of a patient subjected to a transdermal administration of medicament assisted by an iontophoretic current, characterized in that the intensity (I) of the iontophoretic current is temporarily adjusted to a predetermined value (I m ) corresponding to a point of a part of rectilinear origin (OA) of the current / tension characteristic of the patient's skin, the tension (V skin) is then measured between two electrodes for applying iontophoretic current to the skin of the patient and the measurement (R C ut) of the cutaneous resistance, the tension (V skin ) measured and the predetermined value (I m ) of the iontophoretic current is obtained.
2. Procédé conforme à la revendication 1, caractérisé en ce qu'on choisit, pour ladite valeur prédéterminée (Im) , une valeur correspondant à un flux sensiblement nul du médicament à travers la peau du patient.2. Method according to claim 1, characterized in that one chooses, for said predetermined value (I m ), a value corresponding to a substantially zero flow of the drug through the patient's skin.
3. Procédé conforme à l'une quelconque des revendications 1 et 2, caractérisé en ce qu'on ramène progressivement, après la mesure, le courant ionophorétique de la valeur (Im) prédéterminée à sa valeur antérieure (XmA) .3. Method according to any one of claims 1 and 2, characterized in that gradually reduces, after the measurement, the iontophoretic current from the value (I m ) predetermined to its previous value (XmA).
4. Procédé conforme à l'une quelconque des revendications 1 à 3, caractérisé en ce qu'on compare la résistance cutanée mesurée (RCut) à un seuil (Rmin) et en ce qu'on interdit le démarrage ou la poursuite du traitement si4. Method according to any one of claims 1 to 3, characterized in that the measured skin resistance (R C ut) is compared to a threshold (R m i n ) and in that the starting is prohibited or further treatment if
Rcut < Rmin •Rcut <Rmin •
5. Procédé conformément à la revendication 4, caractérisé en ce qu'on déclenche une alarme sonore et/ou visuelle si Rcut < Rmin-5. Method according to claim 4, characterized in that an audible and / or visual alarm is triggered if R cut <Rmin-
6. Procédé conforme à l'une quelconque des revendications 4 et 5, caractérisé en ce qu'on choisit pour le seuil (Rmin) une valeur permettant la détection d'un court-circuit de la peau du patient. 6. Method according to any one of claims 4 and 5, characterized in that one chooses for the threshold (R m i n ) a value allowing the detection of a short circuit of the patient's skin.
7. Procédé conforme à l'une quelconque des revendications 1 à 3, caractérisé en ce qu'on compare la résistance mesurée (RCut) à un seuil (Rmax) et en ce qu'on interdit le démarrage ou la poursuite du traitement si Rcut ^ Rmax •7. Method according to any one of claims 1 to 3, characterized in that the measured resistance (R C ut) is compared to a threshold (R m a x ) and in that the starting or the continuation of treatment if Rcut ^ Rmax •
8. Procédé conforme à la revendication 7, caractérisé en qu'on déclenche une alarme sonore et/ou visuelle si8. Method according to claim 7, characterized in that an audible and / or visual alarm is triggered if
Rcut ^ Rmax •Rcut ^ Rmax •
9. Procédé conforme à l'une quelconque des revendications 7 et 8, caractérisé en ce qu'on choisit, pour le seuil (Rma ) une valeur permettant la détection d'une lésion ou de l'imminence de l'apparition d'une telle lésion sur la peau du patient, et/ou une hydratation insuffisante d'un réservoir de médicament accolé à une des électrodes. 9. A method according to any one of claims 7 and 8, characterized in that one chooses, for the threshold (R ma ) a value allowing the detection of a lesion or the imminence of the appearance of such a lesion on the patient's skin, and / or insufficient hydration of a reservoir of medicament attached to one of the electrodes.
10. Procédé conforme à l'ensemble des revendications 4 et 7, caractérisé en ce qu'on autorise le démarrage de l'administration du médicament, ou la poursuite de celui-ci,10. Process in accordance with all of claims 4 and 7, characterized in that the administration of the administration of the medicament is authorized, or the continuation thereof,
SI Rmin < Rcut < Rmax *IF Rmin <Rcut <Rmax *
11. Procédé conforme à l'une quelconque des revendications précitées, caractérisé en ce qu'on l'exécute avant le démarrage de l'administration du médicament.11. Method according to any one of the preceding claims, characterized in that it is carried out before the start of the administration of the medicament.
12. Procédé conforme à l'une quelconque des revendications précitées, caractérisé en ce qu'on l'exécute périodiquement pendant l'administration du médicament. 12. Method according to any one of the preceding claims, characterized in that it is carried out periodically during the administration of the medicament.
13. Procédé conforme à l'une quelconque des revendications précitées, caractérisé en ce qu'on choisit la densité du courant de mesure (Im) dans le domaine 0-50 μA/cm2 , ladite densité étant préférablement choisie égale à 12,5 μA/cm2 environ. 13. Method according to any one of the aforementioned claims, characterized in that the density of the measurement current (I m ) is chosen in the range 0-50 μA / cm 2 , said density preferably being chosen to be 12, 5 μA / cm 2 approximately.
EP97947082A 1996-11-19 1997-11-18 Method for measuring the cutaneous electric resistance of a patient subjected to transdermal administration of medicine Withdrawn EP0968029A1 (en)

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FR9614088 1996-11-19
FR9614088A FR2755842B1 (en) 1996-11-19 1996-11-19 METHOD FOR MEASURING THE SKIN RESISTANCE OF A PATIENT SUBJECT TO A TRANSDERMAL ADMINISTRATION OF MEDICAMENT
PCT/FR1997/002072 WO1998022182A1 (en) 1996-11-19 1997-11-18 Method for measuring the cutaneous electric resistance of a patient subjected to transdermal administration of medicine
US09/312,498 US6391015B1 (en) 1996-11-19 1999-05-17 Method for measuring the cutaneous electrical resistance of a patient subjected to transdermal administration of medicine

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JP2001505098A (en) 2001-04-17
FR2755842B1 (en) 1999-04-23
FR2755842A1 (en) 1998-05-22
WO1998022182A1 (en) 1998-05-28
AU5226098A (en) 1998-06-10
US6391015B1 (en) 2002-05-21

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