FR2562800A1 - Device for percutaneous administration of medicaments - Google Patents

Abstract

The invention relates to an improved device for administering pharmacologically active principles by percutaneous means. The percutaneous transfer is improved by a regulating plate 4 which may be coupled to an iontophoresis device (electrode 2). Various possibilities for precisely modulating the flow of the active principle. Application to chronopharmacology.

Description

Device for percutaneous administration of drugs
The invention relates to the technical sector of transcutaneous administration (also called percutaneous> of pharmacological active principles.

 A number of attempts have been made to resolve the particular problems posed by the implementation of this route of administration.

 We will cite the French patent no. 6733 M, French patent applications no. 2 437 830, no. 2 479 089 and no. 2 397 190 and the American patent no 3 996 934.

 A significant improvement was made by French patent application No. 82 - 17074 filed on October 12, 1982 in the name of the applicant. This document describes devices comprising a reservoir of active principle, communicating through an orifice of small dimensions with an intermediate percutaneous chamber whose lower wall is formed by the skin itself.

 The present invention relates to a similar device in which the percutaneous chamber is replaced by a "regulating plate", and which may include means for regulating and modulating the percutaneous flow and possibly stopping or even reversing it. These various operations will be grouped below, when they are not specified, under the term "control" of the percutaneous flow.

The invention allows the administration of the active principle (or active principles) by self-percutaneous as well as by iontophoresis, and allows
- to administer even molecules known to be difficult to percutaneous (in particular of molecular weight greater than 700),
- quickly reach the desired flow,
- to regulate this flow to a predetermined level and which remains substantially constant,
- to "control" this flow,
- and even to obtain a variable flow as a function of time according to a predetermined diagram and / or in response to the organism.

Other characteristics and advantages will be better understood on reading the description which follows and with reference to the appended drawings in which
FIG. I represents in section the principle of a preferred device according to the invention,
FIG. 2 represents another variant of the device according to the invention, with a regulating plate conducting electricity making it possible to "control" the flow,
FIG. 3 schematically represents the cardiac servo-control of the device represented in FIG. 5,
FIG. 4 represents another variant of the device according to the invention, with slaving to pulses,
FIG. 5 represents another variant of the device according to the invention, making it possible to cancel the flow,
FIG. 6 represents an example of mounting a device according to FIGS. 1, 2 or 5,
- Figure 7 shows. the general assembly diagram of the devices according to the invention,
FIGS. 8 a, b and c show variants of a regulating plate according to the invention,
FIG. 9 represents a device according to the invention with attached fibrous element,
FIG. 10 represents the preferred variant of the invention, applied to the skin,
- Figure 11 shows a preferred form of regulating plate and associated conductive plate (here, a grid).

1. Tank wall (especially plastic - aluminum complex).

2. Electrode (especially stainless steel) mounted on the tank.

3. Active principle (s) reservoir.

 4. Regulating plate (especially PVC or polyethylene).

 5. Plate holes.

 6. Double-sided adhesive.

 7. Protective cover (removed for application3.

 8. Single-sided adhesive.

 O9 Skin.

10. Conductive plate (metal or plastic, elastomer,
etc ... driver? perforated.

 11. Perforations of the plate (10).

 A, B. Electrocardiogram electrode.

 C. Neutral iontophoresis electrode.

 D. Device according to figure 2.

 E, I. Connection of electrodes A, B.

 F. Connection of the neutral electrode.

 G. Connection of the electrode (2).

 H. Control plate connection (10).

 M. "Monitoring" device (servo and control).

12. Part ensuring in low position an electrical contact with
the electrode 2.

 (GRT) Direct current generator with time delay.

 13. Gel containing the active ingredient (s).

 14. Electrical connection to the neutral electrode N (figure 6).

 15. Sheath.

 N. Neutral (or indifferent) electrode.

(MGR) Device ensuring the functions of "monitoring" and generator
current.

 16. Device according to the invention.

17. Connection only (conductive plate3 when the device
(16) is according to Figure 5.

18. Connection (electrode (2)) in conjunction with connection 17
when the device (16) is according to FIG. 1 or 2.

 R. Current regulator.

 CR. Power generator.

19. Generator verification circuit (switch (i) +
indicator light (t)).

20. Adjustment by variable resistance.

21. Inverter.

 El. #Indifferent electrode.

22. Percutaneous chamber under each orifice (5).

23. Micro orifices 24. Micro g percutaneous channels.

24. Micro channels 24a. Connection channels between the percutaneous micro-chambers.

25. Corrugated surface.

26. Fibrous block, possibly conductive.

27. Liquid containing the active ingredient (s).

28. Balancing chimney 29. Chimney opening.

30. Nesting area of (1) and (4).

h. High
b. Low in position on the skin.

The essential characteristic of the invention resides in
the presence of the regulating plate (4).

It is a plate perforated by a large number of orifices (5), each of these orifices ensuring a function of micro percutaneous chamber (22). Preferably, this plate will have the geometry shown in Figures 8a and 8b; one can also advantageously consider making the micro-channel structure shown in FIG. 8c, the lower surface 25 being corrugated, embossed, etc. so as to form, with the skin, chambers (22) of approximately 1 to 3 mm in diameter
Particularly sophisticated geometry is presented in Figure 11.

The plate (4) can be made of any plastic material chemically compatible with the formulation of the active principle and non-allergenic for the skin, for example
- polyethylene, PVC, silicone, nylon
Preferably, the face of the plate intended to come into contact with the skin will be slightly curved towards the skin (better contact).

 The presence of this Zp'laque effectively regulates the flow of active principle (s) and, in the case of substances which easily pass through the skin, no iontophoresis device is necessary: a self-percutaneous, the flow of which is rapidly established and then stabilizes at a substantially constant value (these two advantages are essential).

 In the reservoir (3), a known gel is placed containing the active ingredient (s). This gel also fills the orifices (5) of the plate and the chambers (22), until contact with the skin.

 According to a variant of the invention, the reservoir (3) may be filled with a supersaturated gel in principle (s) active (s) up to the plate (4), and brought into contact with a layer of saturated gel in the same active principle (s) filling the percutaneous microchambers. This variant will be used in the case of substance (s) which pass well in self-percutaneous treatment, to avoid any risk of plasma peak.

 According to another variant, it is possible to fill the reservoir (3) with an unsaturated, saturated or supersaturated liquid in the active ingredient (s) provided that the orifices (5) are covered by an element capable of preventing the liquid to flow too freely through the orifices (5) and to prevent the migration towards the skin of the crystals of the active principle (s). Such an element could for example consist of a fibrous or spongy pad (26; Figure 93.

 For active substances known for their difficult or impossible passage through the skin by self-percutaneous, the device with a regulating plate according to the invention will be supplemented by an iontophoresis device.

 Iontophoresis is a known method which consists in facilitating the passage of polar molecules through the skin by the establishment of an electric field.

 The general principle here will be to provide the wall (1) with an electrode (2) in contact with the gel (13) or the liquid (27), and to place the second electrode- (of opposite polarity) in another place appropriate body, after which an appropriate electrical voltage is established between the electrodes.

 The polarity of the first electrode depends on the polarity of the molecule. The polarity of the second electrode, opposite to that of the first electrode, will be "indifferent".

 According to a particularly advantageous variant, the regulating plate (4) is covered with a perforated plate (10) having the characteristic of being electrically conductive.

This plate (10) naturally has orifices (11) corresponding to those (5) of the plate (4). The plate (10) may in fact be constituted by a grid or a metal mesh (FIG. 11) or else by a metal plate (aluminum, stainless steel, etc.) or by a plate made of conductive plastic.

 The orifices (5) of the plate (4) advantageously have a diameter of 0.3 to about 2.5 mm.

 The area of the percutaneous chambers (22) will be equal to the area of the corresponding orifice (5) multiplied by the regulation factor.

 Thus, for a regulation factor equal to 4, the diameter of the chamber (22) will be substantially double that of the orifice (5).

 It will be recalled that the regulatory factor is defined as being the ratio of the variations in percutaneousness of the skin from one individual to another, and for the same individual over time. This ratio is determined experimentally.

 The thickness of the plates (4) and (10) will be of the order of 0.1 to a few millimeters.

 The devices according to the invention allow extremely varied applications, with flexibility and precision in the administration of the medicament absolutely unknown to date.

 It was specified above that the regulating plate (4) already alone brought a significant improvement to the phenomenon of self-percutaneous contact.

 It has also been specified that the combination of this plate with an iontophoresis device allows the controlled administration of molecules incapable of passing into self-percutaneous formation, for example molecules whose molecular weight is) 700, or molecules insufficiently percutaneous for produce a therapeutic effect.

 The variants shown in the accompanying drawing in fact allow total and precise control of the flow.

So for example, in the case of the devices of the figures
5 and 6 a drug molecule can be administered by iontophoresis
not self-percutaneous. The electrode 2 is supplied with a current
electric of suitable polarity thanks to the device of FIG. 7,
including a current regulator R which automatically corrects
variations in the electrical resistivity of the skin in addition to the
automatic correction of the trans cutaneous flow brought by the plate
regulating 4. Stopping the current supply to the electrode
2 produces an immediate cessation of the transcutaneous flow.

If the drug molecule is partially self
percutable, stopping the current supply to electrode 2
will not be enough to completely stop the transcutaneous flow. We
then supplies the conductive plate 10 with a polarity current
opposite to that of electrode 2. We can thus adjust the flux
transcutaneous to a predetermined value and even stop it.

In the case of cortico-dependent asthma, it is possible
to use hydrocortisone as a background treatment. In the event of a crisis,
we use prednisolone whose activity is 4 to 5 times higher
to that of hydrocortisone. Hydrocortisone is percutaneous
by applying a positive current to electrode 2 and prednisolone
is percutaneous by applying a negative current. Processing
therefore we will feed electrode 2 with a positive current and
to temporarily treat a crisis, it will suffice to reverse the
polarity of the current applied to the electrode 2.

The device of Figure 2 is more particularly
suitable for self-percutaneous molecules, for example estradiol
used in the treatment of menopause. The transcutaneous flow is
regulated by plate 4 and the conductive plate 10 is electrically
isolated. For therapeutic reasons, it may be necessary to gradually reduce the transcutaneous flow before removing the device, or even to adjust it to a determined value. A current of suitable polarity is then applied to the conductive plate 10.

 Treatment for angina pectoris requires a continuous and regular flow of coronary vasodilator, for example trinitrine, dinitrate or disisorbide mononitrate. The regulating plate 4 of the device of FIG. 4 will ensure this regulation. But an angina attack requires a temporary overdose. The patient then places on electrode 2 the electrode 12 which is connected to a GRT current generator having a time delay in order to temporarily establish a current which will provide an additional dose of coronary vasodilator.

 Figure 3 shows schematically the enslavement of the transcutaneous flow to the heart rate using the device of Figure 5, for example for the administration of digitoxin. The heart rate is captured by electrodes A and B. Monitoring M regulates the current of 11 electrode 2 (connection G) according to the heart rate. As soon as the optimal heart rate is reached, the current is cut at 11 electrode 2 and a current of reverse polarity is applied to electrode 10 (connection H) in order to avoid an overdose of active principle.

 Finally, the invention is directly applicable to chronopharmacology, for example compliance with the nycthemeral cycle of hydrocortisone, which represents real progress in the treatment of addisonians.

Claims (15)

1. Device for percutaneous administration of medicament (s) comprising a reservoir (3) containing the medicament (s) in an appropriate form, a seal (7) for sealing this reservoir, easily detachable at the time of placing the device on the skin, and in particular adhesive means (6, 8) for fixing and holding the device in place on the skin, characterized in that the reservoir consists of a wall (1) forming the reservoir proper and a regulating plate (4) which closes the volume (3) defined by said wall, said regulating plate (4) being intended to come into direct and close contact with the skin and comprising several orifices (5) allowing the bringing the drug (s), being in the reservoir (3) in an appropriate form, into contact with the skin. 2. Device according to claim 1, characterized in that each orifice (5) formed in the plate is of substantially conical shape, the base of the cone being at the level of the face of the plate intended to come into contact with the skin. 3. Device according to claim 1, characterized in that each orifice (5) formed in the plate is formed of two cylindrical cavities, the first being the orifice itself and opening onto a coaxial cavity of greater diameter, itself opening onto the face of the plate intended to come into contact with the skin. 4. Device according to claim 1, characterized in that said plate is perforated by numerous micro channels and in that its face intended to come into contact with the skin is deformed to provide between narrow zones of contact with the skin of the chambers 22 where the micro channels open. 5. Device according to any one of claims 1 to 4, characterized in that the plate (4) is fitted into the wall (1). 6. Device according to any one of claims 1 to 5, characterized in that, on the side of the device intended to be placed in the high position on the patient, the plate (4) carries a chimney (28) open on one side on the reservoir (3) and having on the side opposite this opening an orifice (29) passing through the plate (4), and in that the percutaneous micro-chambers (5, 22) are connected to each other by channels (24a ). 7. Device according to any one of claims 1 to 6, characterized in that said plate is in particular made of polyethylene, PVC, silicone or nylon. 8. Device according to any one of claims 1 to 7, characterized in that an electrode (2) passes right through the wall (1) to come into contact with the interior of the tank (3). 9. Device according to any one of claims 1 to 8, characterized in that the face of said regulating plate (4) facing the interior of the tank (3) carries an electrically conductive coating, or is coated or covered by such a coating, this coating having at least one orifices (11) and facing the orifices (5) of the plate. 10. Device according to claim 9, characterized in that said coating consists of a metal mesh. 11. Device according to claim 9 characterized in that said coating consists of a perforated metal plate. 12. Device according to claim 9J characterized in that said coating consists of a sheet of perforated plastic material conducting electricity.  33. Device according to any one of claims 9 to 12, characterized in that said conductive coating is connected to an electrode (14) passing through the wall (1) right through. 14. Device according to any one of claims 1 to 13, characterized in that the reservoir (3) is filled with a gel (13) containing the drug (s) to be administered. 15. Device according to any one of claims 1 to 13, characterized in that the reservoir (3) is filled up to the plate (4) with a gel supersaturated with the drug (s) to be arlminiscrer, and in that the orifices of the plate (optionally coated with said conductive coating) are filled with a gel saturated with the same drug (s). 15. Device according to any one of claims 1 to 13, characterized in that the reservoir (3) is filled with a liquid containing the drug (s) to be administered and in that the plate (4) - optionally coated by said electrically conductive coating - is covered towards the inside of the tank (3) by an element (26), in particular a fibrous or spongy mattress, preventing too rapid flow of the liquid through the orifices (5 ) of the plate and / or a migration towards the skin of the active ingredient crystals 17. Device according to any one of claims 8 to 16, characterized in that one applies across the electrodes (2) and / or ( 14) appropriate electrical voltages making it possible to promote, modulate or stop the percutaneous treatment of all or part of the polar medication (s) contained in the reservoir (3), the electrodes (2) and / or (14) being for this purpose connected to generators and control devices preprogrammed and / or re acting on certain body functions.