FR2616333A1 - IONOPHORESIS METHOD FOR ADMINISTERING A DISSOLVED OR PARTIALLY DISSOLVED SUBSTANCE, BY PERCUTANEOUS OR PERUNGUAL ROUTE AND CORRESPONDING DEVICE - Google Patents

Abstract

According to this method, said substance is placed, as active electrolyte, between the skin 5 or the nail of a patient and a first metal electrode 1, called the active electrode, a second electrode 2, called the indifferent electrode, having a potential of electrode different from the first and being electrically connected to it, said second metal electrode 2 being in contact with the skin 5 or the nail by means of a passive electrolyte 6, the contact zones of the two electrodes being suitably distant from the one from the other. The first electrode 1 has the more or less electropositive potential depending on whether the substance to be administered can penetrate into the skin or the nail in the form of positive ions or of negative ions.

Description

IONOPHORESIS METHOD FOR ADMINISTERING A SUBSTANCE

  HOLD OR PARTIALLY DISSOLVED, PERCUTANEOUSLY OR

  PERUNGUEAL AND CORRESPONDING DEVICE.

  The present invention relates, on the one hand, to an iontophoresis method, which allows administration, by

  percutaneous or perungual, of dissolved or partially

  partially dissolved, in particular medicinal, and, on the other hand, an integrated iontophoresis device for the

implementation of such a method.

  A drug substance can be administered by several routes: oral, parenteral, percutaneous or even perungual. The percutaneous route is particularly

  conducive to maintaining an effective concentration at the

  milk the first two routes which, if they allow rapid achievement of effective concentration, unfortunately lead to an abrupt drop as a function of time, which means that injections or

taking medication.

  Percutaneous absorption imposes restrictions in the choice of substances, in particular medicinal or cosmetic, to be penetrated through the skin, for example due to the fact that the horny layer of the skin plays a role of impermeable barrier. This layer does

  lets, in fact, penetrate the skin that only the

  stanzas with appropriate physicochemical properties: this means that a wide range of substances

must be dismissed.

  We have known for a few years, for example by document FR-A-2. 509.182, a process for percutaneous absorption, called iontophoresis, by which

  penetrate the skin electrophoretically, a sub-

  ionized stance. This process involves placing this sub-

  stance in ionic form under that of the terminals of a current generator, such as a battery, which has the same sign as the active ion, the other terminal of this generator being associated with an electroconductive fluid and placed on the skin to make an electrical contact. When the generator delivers current, the active ion enters the skin by electrostatic repulsion. If this process makes it possible to penetrate by percutaneous flight a large number of substances, it is nevertheless usable only by using a battery, which, even if it is light in weight, is

  bothersome for the user and for the cost of the application.

  The study conducted by MP JAMES, RM GRAHAM and J. ENGLISH, (Glinical and Experimental Dermatology (1986) 11, pages 54 to 61), shows that one can penetrate, by ionophoresis, a dissolved substance not only to treat diseases of the skin, but also of the nails:

  just place the electrode containing the substance

  hold on the skin or on the nail, respectively.

  We also know from the Japanese patent application published on October 14, 1985 under number -205,270, a method for administering liquid substances percutaneously, according to which this substance acts as the first active electrode after having been converted into a metal salt from a weakly ionizable metal, while a more easily ionizable metal is used to make a second metal electrode, these two electrodes being applied to the skin. Preferably, the substance to be administered percutaneously is in the form of a silver salt, while a more easily ionizable metal is a magnesium alloy, both

  electrodes being connected by an electroconductive wire.

  While this process has the particular advantage of avoiding the use of a battery, it nevertheless has major drawbacks: on the one hand, it does not allow

  penetrate dissolved substances in the form of positive ions

  tifs, since the penetrating substance is necessarily the anion of a metal salt, and on the other hand, the range of substances which can be thus applied is limited by the fact that these substances must be able to be converted into a metal salt of the least electropositive electrode; this metal being preferably silver, the method also has the drawback of blackening the skin at the right of

the active electrode.

  Consequently, one of the purposes of the present invention

  tion is to propose an iontophoresis process for

  administer percutaneously or perungually a sub-

  dissolved or partially dissolved stance, which allows

  penetrate a patient's skin or nail

  dissolved or partially dissolved stance formatted

  positive or negative ions.

  Another object of the present invention is to provide

  provide an integrated iontophoresis device for

  work of the process defined above.

  The invention is based on this unexpected observation.

  tense and surprising that penetration into the skin by a process of the type described in Japanese patent application 60-203.270 can very well be carried out, without the substance to be penetrated being formed in the form of a salt of the

  metal of the weakest ionizable electrode, i.e.

  say the least electropositive, and that said substance may as well be in the form of positive ions as in the form

negative ions.

  The subject of the invention is therefore a method of iontophoresis for administering a dissolved or partially dissolved substance by percutaneous or perungual route consisting in disposing this substance as active electrolyte. between the skin or the nail of a patient and a first

  metal electrode, called active electrode, a second electrode

  trode. said indifferent electrode, having a potential

  electrode different from the first one and being electro

  three-fold connected, this second metal electrode, being in contact with the skin or the nail by means of a passive electrolyte, the contact zones of the two electrodes being suitably distant from each other, process which is characterized , according to the present invention, in that the first electrode has the most or least electropositive potential depending on whether the substance to be administered can penetrate the skin or the nail in the form of positive ions

or negative.

  Preferably, the passive electrolyte is either an aqueous solution of a salt, not harmful to the skin or the nail, of the metal of the indifferent electrode, or else, by

example, physiological saline.

  Advantageously, the metal of the first electrode is chosen from the group formed by magnesium, aluminum and zinc, and that of the second electrode.

  is chosen from the group formed by silver and copper.

  The conductive means is constituted by a wire

  conductor connecting the two electrodes, possibly

  interrupted by a current generator, such as a photo-

  battery, electrically connected to each electrode.

  The present invention also relates to a provision

  integrated iontophoresis solution for administration by vbie

  percutaneous or perungual a dissolved or dispersed substance

  partially dissolved, comprising two metallic electrodes

  linked together by a conductive means, each elect

  trode being intended to be in contact with the skin or the nail of a patient, in zones suitably distant from each other, by means of an electrolyte pad, the two electrodes having potentials different electrode. this device being characterized by the fact that the dissolved or partially dissolved substance to be administered constitutes the electrolyte of the most or least electropositive electrode according to whether it forms an ion

positive or negative.

  Preferably, the electrolyte of the other electrode is either an aqueous solution of a salt, not harmful to the skin or the nail, of the metal constituting this electrode, or

  well, for example, physiological saline.

  Advantageously, the metal of one of the electrodes is chosen from the group formed by magnesium, aluminum and zinc, that of the other electrode being

  chosen from the group formed by silver and copper.

  The conductive means is constituted by a wire

  conductor connecting the two electrodes. This means can be

  interrupted by a current generator, such as a photo-

  battery, electrically connected to each electrode.

  The description, which will follow and which does not present

  not limiting in nature, will enable those skilled in the art to better understand the advantages of the present invention and should be read with reference to the appended figures, among which: - Figure 1 is a schematic representation of an iontophoresis device; - Figure 2 is a schematic representation of an iontophoresis device according to the invention, comprising a photocell; - Figure 3 shows the amount of cumulative product having passed through a rat abdominal skin for 24 hours with or without use of the device of the invention; FIG. 4 represents the quantity of product - accumulated having passed through a rat back skin for 24 hours with or without use of the device of the invention; and - Figure 5 shows the amount of accumulated histamine having passed through a rat back skin for 24 hours with or without use of the device according to the invention. As can be seen in FIG. 1, the integrated iontophoresis device comprises two electrodes 1 and 2 of different electrode potentials connected by a conductive means constituted by a metallic wire 3 (copper or silver): the electrode 1 is, in this example, the active electrode and is made of magnesium; electrode 2 therefore constitutes the indifferent electrode and is made of silver

or copper.

  The substance to be penetrated into the skin is norepinephrine, a vasoconstrictor which does not penetrate into the skin by topical application. A solution of noradrenaline hydrochloride is produced at a concentration of 2 mg / ml: in this solution, noradrenaline combines with the hydrogen ion to give a positive ion. This noradrenaline hydrochloride solution 4 is placed between the active electrode 1 and the skin 5 of a patient. Between the indifferent electrode 2 and the skin 5 of this patient is disposed a passive electrolyte 6, which can either be a solution of a metal salt (silver or copper) constituting

  the indifferent electrode 2, ie physiological saline.

  The two electrolytes 4 and 6 can be placed

  either inside a gel or a hydro-

  phile. We tested this system by placing it on the patient's forearm: the electrodes are separated

  from each other by at least 1 cm of dry skin and now

  bare in place using tape. It has been found that an electric current flows in the circuit thus formed, while an ion current is created in the skin of the patients. In Table I below, the observations made after an application time of 10 minutes are grouped, the physical characteristics of the device being measured by placing a voltmeter and an ammeter between the

two electrodes 1 and 2.

TABLE I

  Electrode Electrode Voltage Density Reaction Control

  active indifferent (volt) of pharmaco-

  current2 logic (___ A / cm) Mg Ag / Ag salt (AgSO4) 1.83 10 to 50 very clear negative whitening Mg Ag / physiological saline 1.62 10 to 50 Mg Cu / Cu salt (CuS04) 1, 45 10 to 30 Mg Cu / physiological saline 1.35 10 to 30 The bleaching observed on the skin, in line with electrode 1, indicates that the product, in this case norepinephrine, has effectively penetrated into the skin. As for the control, it consists of a deactivated device obtained by cutting the wire 3 between the electrodes 1 and 2. The variations in current density observed come from the variations in skin resistance that are observed between different zones. at the same

  -individual and between two same areas of skin in individuals

different videos.

  According to this table 1, it can be seen that the replacement

  Metal salts under the indifferent electrode with physiological saline lead to a slight decrease in the physical characteristics of the device. Nevertheless, it is

  better to use physiological saline as electro-

  indifferent lyte because it does not cause any inconvenience to

skin level.

  According to the embodiment shown in fig-

  ure 2, elements similar to those of Figure 1 bearing

  the same reference numbers increased by 10, the elect

  Trodes II and 12 are connected to a photocell 17. The positive pole of the photocell is connected to the most electropositive electrode: Mg. Although it only works in the presence of light rays, this solar cell 17 has the advantage of being easily integrated into a film or into a skin dressing comprising, moreover, the two electrodes.

11 and 12.

  The photocell reinforces the power of the system: for example, a photocell having a surface of 10 cm2 can generate a voltage of 10 volts and a current density of

  1 milliampere per square centimeter, through the skin.

  This device is particularly well suited to hand care for treating, for example, contact dermatoses, or to face care, for treating, for example,

acute acne rash.

  As a product which can be administered percutaneously or perungually according to the method of the invention and by means of a device according to the invention, there may be mentioned: - corticotdes such as derivatives of hydrocortisone, methylprednisolone, dexamethasone; - local anesthetics, such as lidocaine, procaine, cocaine, prilocaine; - anticancer substances such as

  methotrexate, cyclophosphamide, bleomycin, doxoru-

bicine;

  - nucleotides such as AMP (adenosine 5 'mono-

  phosphate), ADP, ATP, cyclic AMP, TMP (thymidine 5 'mono-

  phosphate), UDP (uridine 5 'diphosphate); - analgesic and anti-inflammatory products such as salicylic acid, mefenamic acid, indomethacin; - antiviral products such as idoxuridine, vidarabine, thymine arabinoside; - vitamins such as vitamins B1, B6, C; - antibiotics such as penicillin G, ampicillin, streptomycin, tetracyline;

  - antifungals like micona nitrate-

  zole, econazole nitrate, naftifine and terbinafine hydrochlorides: - vasodilator products such as histamine, methacholine; - vasoconstrictor products such as noradrenaline, adrenaline and their derivatives; and

  - peptides such as insulin, bra-

  dykinin, vasopressin, thyrotropin releasing hormone

(T.R.H.).

  "In vitro" tests were undertaken to determine the kinetics of penetration of radiolabelled noradrenaline on a piece of abdominal skin or back skin, taken from hairless rats. This experience has

26 1,633

  was carried out using six diffusion cells, three of which included an iontophoresis device according to the embodiment described above. These cells were mounted on an automatic sampling bench (1 ml / hour) for 24 hours. The isotopic solution included 10 mg / ml of unlabelled noradrenaline and 100 1 Ci / ml of labeled noradrenaline. A volume of 100! 1 is filed by

cell (1 mg / 100 l / 10 Ci / cell).

  In Figure 3, curve 20 represents the quan-

  cumulative amount of norepinephrine (mg / cm2) that passed through the hairless rat abdominal skin for 24 hours, using the iontophoresis device, curve 30 representing the cumulative amount of the same product that passed through the hairless rat abdominal skin for 24 hours without using the device according to the invention. We

  observe that the diffusion flow is multiplied by a fac-

  2.9 (from 0.28 to 0.811 r g / cm2 / h) when using a

  iontophoresis device according to the invention.

  In Figure 4, curve 21 represents the quan-

  cumulative amount of noradrenaline (mg / cm2) which has passed through the dorsal skin of hairless rats for 24 hours. using the iontophoresis device, the curve 31 representing the

  cumulative amount of this product that has passed through golden skin

  hairless rat room without using an iontophoresis device according to the invention. The diffusion flux is, in this case, multiplied by a factor 2.6 (from 0.244 to 0.636 g / cm2 / h). These "in vitro" tests therefore show that the use of an iontophoresis device makes it possible to penetrate a dissolved or partially dissolved substance through a skin. If, in the case of hairless rats, the

  noradrenaline penetrates, however, without the use of a device

  sitive according to the invention, but with fluxes much lower than those obtained with the device of the invention,

  this is due to the fineness of this skin subjected to the test.

  The same "in vitro" experiment was carried out with histamine on pieces of dorsal skin from hairless rats. The isotopic solution included, per cell, r Ci / 00 t 1/200 g. In FIG. 5, the curve 22 shows the cumulative amount (mg / cm2), which has passed through this back skin for 24 hours, using the iontophoresis device, curve 32 representing the cumulative amount having passed through this back skin without using a device iontophoresis according to the invention. The diffusion flux is, in this case, multiplied by a factor 24 (of

0.033 to 0.8 d g / cm2 / h).

Claims (5)

RESELL ICATIONS   1 - Iontophoresc device - for percutaneous or perungual administration of a dissolved or partially dissolved substance. comprising two] metallic ecotrodes (1, 2; 11, 12) interconnected by a mpyen   conductive, each electrode being intended to be in con-   tact with the skin (5, 15) or the nail of a patient in areas suitably distant from each other by   through an electrolyte buffer, the two elect   electrodes having different electrode potentials, characterized in that the substance to be administered constitutes the electrolyte (4, 14) of the most or least electropositive electrode (1, 11) depending on whether it forms a positive or negative ion.   2 - Device according to claim, characterized in that the electrolyte placed under the other electrode is an aqueous solution of a salt, not harmful to the skin or the nail, of the metal of this electrode, or physiological saline.   3 - Device according to one of claims 1 or   2, characterized in that the metal of one of the elect   trodes is chosen from the group formed by magnesium, aluminum and zinc.   4 - Device according to one of claims I to   3, characterized in that the metal of the other electrode   is chosen from the group formed by silver and copper.   - Device according to one of claims 1   4, characterized in that the conductive means is a   metallic wire (3) (silver or copper).   6 - Device according to one of claims to   , characterized in that the conductive means is interrupted by a photocell (17) connected to each electrode, the positive point of this photocell being connected to the electrode of the most electropositive metal.