RU2809801C2 - Device for electroporation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: electroporation device is designed to inject a product into the ciliary muscle of the eye. The device contains the following: a support having a spherical contact surface of the support extending along an imaginary sphere (S) with a radius of 10 to 15 mm, a first electrode containing an invasive electrode needle, a second electrode having an electrically conductive contact surface of the electrode, an injection needle, wherein the first electrode and/or the injection needle includes a guide rod extending parallel to the electrode needle(s) and/or to the injection needle, and the support includes a corresponding guide for rod insertion.

EFFECT: use of the invention will ensure precise and stable placement of the electrodes; will limit the risk of damage; will create an effective and strong electric field.

19 cl, 6 dwg

Description

TECHNICAL FIELD

The present invention relates to a device for electroporating a product into the eye, in particular into the ciliary muscle of the eye.

BACKGROUND OF THE ART

WO2006/123248 describes a device for applying a product by electroporation.

WO00/07530, WO2007/052730 and WO2006/052557 describe injection devices.

The object of the present invention is to provide a new electroporation device that allows:

- precise and stable location of electrodes;

- limiting the risk of damage;

- creating an effective and strong electric field.

DISCLOSURE OF INVENTION

To this end, the present invention provides an electroporation device for injecting a product into the eye, in particular the ciliary muscle of the eye, the device comprising:

a support having a support contact surface extending along an imaginary sphere of radius 10 to 15 mm so as to conform to the limb of the eye

- a first electrode (10) containing an invasive electrode needle,

- a second electrode having an electrically conductive electrode contact surface,

- optional injection needle,

According to the first main embodiment of the invention, the support comprises an insertion guide allowing directed sliding movement of the electrode needle and/or injection needle along the corresponding axis of the insertion, such that the angle ω between said insertion axis and the plane P _S tangential to the imaginary sphere at the insertion point , less than 40º, preferably less than 35º, preferably less than 30º, preferably less than 28º, and/or more than 10º, preferably more than 15º, preferably more than 20º, wherein the insertion point is the point at which said insertion axis intersects said imaginary sphere.

The inventors have found that this configuration allows for very precise and efficient electroporation of the product administered to the ciliary muscle of the eye. In particular, it allows the electrode needle to pass in front of the electrode contact surface, substantially parallel to the electrode contact surface.

Preferably, the angle ω for the insertion axis of the injection needle is less than 25º, preferably less than 23º.

Preferably, the angle ω for the insertion axis of the at least one electrode needle is greater than 25º. In a preferred embodiment of the invention, the angle ω is substantially the same for all electrode needles.

Preferably, the angle between said axis of the insert and a plane tangential to said electrode contact surface, preferably at least a plane perpendicular to the major axis of the electrode contact surface, preferably any plane tangential to the electrode contact surface, preferably the major plane of the electrode contact surface, is less than 20º , preferably less than 15º, preferably less than 10º or less than 5º. Thus, the axis of the insert is substantially parallel to the contact surface of the electrode.

Preferably, the support contains at least two, and more precisely three, four, five or more guides for inserting electrodes, preferably parallel to each other, which extend in a common plane defining together with a plane tangential to the contact surface of the electrode, preferably at least the plane , perpendicular to the major axis of the electrode contact surface, preferably by any plane tangential to the electrode contact surface, an angle that is less than 20º, preferably less than 15º, preferably less than 10º or less than 5º. Thus, the electrode needles may form a grid, preferably a grid, extending in front of and substantially parallel to the electrode contact surface. The advantage is the uniformity of electroporation.

According to a second main embodiment of the invention, at least along part of its length the electrode needle is flattened and has:

- a width W ₁₄ ranging from 0.2 to 2 mm, and

- thickness T ₁₄ , such that

the ratio W ₁₄ / T ₁₄ is greater than 3.

According to a third main embodiment of the invention, the support comprises an insert guide allowing directed sliding movement of the electrode needle and/or injection needle along a corresponding axis of the insert, the support forming a circular rim, preferably an open circular rim, that is, forming part of a circle and having an axis X and a radius greater than 5 mm and less than 8 mm, so as to correspond to the limb of the eye, and the insertion axis defines, at the insertion point, an angle α less than 50º, preferably less than 45º, preferably less than 40º, with the plane P _Cy' tangential to the cylindrical plane Cy ' X axis containing the insertion point and having a circular base.

Preferably, the angle α for the insertion axis of the injection needle is less than 35º, preferably less than 30º, preferably less than 28º, and/or more than 10º, preferably more than 20º, preferably more than 25º.

Preferably, the angle α for the insertion axis of at least one electrode needle is less than 35º, preferably less than 33º, and/or more than 10º, preferably more than 20º, preferably more than 25º, preferably more than 30º.

Preferably, the angle α for the insertion axis of the at least one electrode needle is less than 38º and/or greater than 30º, preferably greater than 35º.

Preferably, the support contains at least two guides for inserting electrodes, preferably parallel to each other, which extend in a common plane defining an angle Ω with the plane of the rim that is greater than 40º, greater than 45º, preferably greater than 50º, and/or less than 80º, preferably less than 70º , preferably less than 60º, preferably less than 55º.

According to a fourth main embodiment of the invention, the first electrode and/or injection needle comprises a guide rod extending parallel to the electrode needle(s) and/or injection needle, and the support comprises corresponding guide(s) for inserting the rod.

Preferably, the insertion guide(s) are/are holes that do not intersect the imaginary sphere over which the support contact surface extends.

Preferably, the guide rod(s) of the first electrode and/or injection needle extends beyond the tip of the electrode needle(s) of the first electrode and/or injection needle to a distance that is preferably greater than 2 mm and less than 5 mm.

Preferably, the largest transverse dimension of the guide rod is greater than 0.5 mm, preferably greater than 0.8 mm, preferably greater than 0.9 mm, and/or less than 2 mm, preferably less than 1.5 mm, preferably less than 1.2 mm.

Preferably, the device includes a needle stop configured to limit the axial movement of the guide rod. Preferably, the needle stop prevents the guide rod from being completely withdrawn from the corresponding insertion guide, that is, prevents the guide rod from leaving the support.

The present inventors have discovered that features of these basic embodiments can improve the efficiency of electroporation.

Features of the various basic embodiments of the invention, whether optional or not, as well as the optional features set forth in the following description, may be combined with each other. For example, in the first basic embodiment, the first electrode may be a flattened electrode.

Preferably, in any basic embodiment of the invention, the device comprises one or more of the following optionally preferred features:

- the axis of insertion of the electrode needle specifies an angle with a plane perpendicular to the main axis of the contact surface of the electrode, wherein said angle is less than 20º, preferably less than 10º, preferably less than 5º;

- preferably, all guides for inserting electrodes run parallel to each other in a common plane;

- the first electrode contains a plurality of parallel invasive electrode needles extending in a common plane, and the angle between said plane and the main plane in which the second electrode extends is less than 10º;

- the support forms a circular rim, preferably an open circular rim, having an X-axis and a radius of greater than 5 mm and less than 8 mm, so as to correspond to the limb of the eye, said rim being interrupted by at least one cutout, preferably located in a portion of the rim that extends along the corner sector less than 120º, centered on the median plane of the second electrode;

- in a close position, the portion of said electrode needle extending in front of the electrode contact surface is greater than 1 mm, preferably greater than 2 mm, preferably greater than 3 mm, preferably greater than 5 mm, preferably greater than 6 mm;

- the length of said electrode needle is set so that, in the front view of the second electrode, the inserted electrode needle faces the contact surface of the electrode and passes in a close position so as to completely intersect, that is, “split” the contact surface of the electrode formed by the second electrode;

- the area of the contact surface of the electrode is more than 6 mm ² and less than 20 mm ² ;

- the contact surface of the electrode is preferably a spherical contact surface, preferably passing along the same imaginary sphere as the contact surface of the support;

- preferably the complete contact surface formed by the contact surface of the support and the contact surface of the electrode has the shape of an open circular band;

- the support has a general open ring shape such that it has a gap between the first end and the second end, preferably

- the support is made of a plastically deformable material such that the support can be manually plastically deformed to change the distance between said first and second ends, and/or

- said gap is preferably substantially opposite the second electrode, and/or

- the support preferably comprises two retaining pins located at said ends of the support;

- the support contains a pre-positioning guide(s) designed to guide said electrode needle and/or said injection needle to a position in which said electrode needle and/or said injection needle is(are) in line with the axis of the insertion corresponding guide for insertion;

- the contact surface of the support and/or the contact surface of the electrode is made of a biocompatible material, which, in particular, can be brought into contact with the surface of the eye without causing harm;

- the contact surface of the support and/or the contact surface of the electrode is made of polycarbonate material, for example, sold by Bayer;

- the contact surface of the electrode is made of copper;

- the device contains:

- an injection needle, and

- a guide for inserting the electrode and a guide for inserting the injection needle, providing the possibility of directed sliding movement of the specified electrode needle and the injection needle along the corresponding axis of the electrode needle insertion and the axis of the injection needle insertion, and any plane perpendicular to the specified axis of the electrode needle insertion is parallel to any plane, perpendicular to said axis of insertion of the injection needle, and preferably parallel to the main axis of the contact surface of the electrode;

- in the close position of the injection needle, the maximum depth of the injection needle under the imaginary sphere is from 0.8 mm to 1 mm, and/or, in the close position of the electrode needle, preferably any electrode needle, the maximum depth of the electrode needle under the imaginary sphere is from 1.5 mm to 1.8 mm;

- the device contains a container containing the specified product, and an injection needle in fluid communication with the specified container, and the specified product is the desired therapeutic nucleic acid, preferably deoxyribonucleic acid molecules and ribonucleic acid molecules.

The present invention also relates to an electroporation method for injecting a product into the eye, in particular into the ciliary muscle of the eye, using a device according to the present invention, said method comprising the following steps:

a) place the contact surface of the electrode on the outer surface of the eye, preferably so that the rim of the support is pressed against the limbus of the specified eye (edge of the cornea),

b) inserting the electrode needle(s) of the first electrode into the corresponding insertion guide(s) in the support, preferably so that the ciliary muscle extends at least partially between the electrode needle(s) of the first electrode and the second electrode;

c) before or after step b), preferably after step b), inserting an injection needle into the eye, preferably by guiding it through a suitable insertion guide so that its tip preferably reaches the ciliary muscle of the eye;

d) injecting said product into the eye;

e) creating an electric field between the electrode needle(s) of the first electrode and the second electrode, the electric field facilitating the electroporation process.

DEFINITIONS

If the needle is movable and guided by a support, its position corresponding to full insertion is called the “close position.” In the present description, unless otherwise indicated, any position of the first electrode refers to a close position, and any position of the second electrode refers to a position of the second electrode in which it is attached to the support and ready for operation.

"Working position" corresponds to a configuration that allows the product to be electroporated, in particular into the ciliary muscle. In this case, the contact surface of the electrode and the contact surface of the support are pressed to the eye, and the first electrode is in its close position.

A “flattened” needle does not mean that the needle is necessarily flat, that is, it extends in any plane. This means that the needle is much thinner than it is wide, preferably at least 5 times thinner.

The "insertion point" of a needle is the point at which, in a close position, said needle intersects the imaginary sphere bearing the contact surface of the support. With the directed movement of the specified needle, the insertion point corresponds to the point at which the insertion axis intersects the imaginary sphere. Preferably, the insertion points correspond to the exit opening of the insertion guide.

"Spherical contact surface" means a substantially spherical contact surface, preferably corresponding to the shape of the anterior or posterior portion of the outer surface of the eye.

The "major axis" of a surface is the direction perpendicular to the specified surface and passing through its center.

"Quadrant of a hemisphere" refers to a quarter of the surface of that hemisphere, obtained by cuts in two perpendicular planes that intersect along the main axis of the hemisphere.

The terms “first” and “second”, or “top and bottom”, or “right” and “left” are used to distinguish the respective elements and are not intended to limit the legal protection of the invention.

In the present description, unless otherwise indicated, the term “comprising” should be understood as “comprising at least one”.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features and advantages of the present invention will become apparent upon reading the following non-limiting detailed description and the accompanying non-limiting drawings, in which the following are shown.

In fig. 1a and 1b show a perspective view along transverse plane P1 of a device according to a first preferred embodiment of the invention.

In fig. 2a shows a perspective view of a device according to a second preferred embodiment of the invention.

In fig. 2b and 2c along the X-axis show a top view of the device according to the second embodiment of the invention in FIG. 2a, as well as a corresponding modification of this second embodiment.

In fig. 3a and 3a' show a cross-section of a device according to a third preferred embodiment of the invention.

In fig. 4a - 4e, the device according to the fourth preferred embodiment of the invention is shown in various views.

In fig. 5a - 5f show the most preferred embodiment of the invention in front view, right view, left view, cross section AA, cross section BB and axonometric view, respectively.

In fig. 5g shows a preferred embodiment of the first electrode.

In fig. 6a - 6h show another most preferred embodiment of the invention, as shown on the right in FIG. 6b and 6d, as well as in various cross-sections in other figures.

In the embodiment of FIG. 3a, a side view of the electrode needle is obtained by viewing in a direction perpendicular to the plane in which, in a close position, the inserted portion of the electrode needle substantially extends and which is perpendicular to the rim 20.

Throughout the various drawings, the same reference numbers are used to denote identical or similar elements.

IMPLEMENTATION OF THE INVENTION

The drawings illustrate examples of devices according to the present invention.

Each of these devices includes a first electrode 10, a second electrode 12, and a support 16. The second electrode has an electrode contact surface 17 for contacting the surface of the eye.

Support

The support has a spherical support contact surface 18. This contact surface of the support extends along an imaginary sphere S corresponding to the outer surface of the eye O, so that in the operating position it can be pressed against the outer surface of the eye.

Preferably, the support 16 also forms a circular rim 20 having an X axis and partially defining the boundary of the contact surface 18 of the support.

General form

Preferably the support has the general shape of a ring around the X-axis, as shown in FIG. 2a, or ring parts as shown in FIG. 4 or FIG. 5.

As shown in FIG. 4, the support 16 has the general shape of a ring, which is interrupted by a gap 23 separating the first end 24a and the second end 24b. Said gap is preferably greater than 0.5 mm, preferably greater than 1 mm, and/or less than 8 mm, less than 6 mm, less than 5 mm, less than 4 mm.

Preferably, the ring is interrupted, as in the embodiment of FIG. 4, the support is made of a plastically deformable material such that the support can be manually plastically deformed to change the distance between said first and second ends. The advantage is that the support 16 can be deformed to accommodate different eye sizes.

The gap is preferably located substantially opposite the second electrode, which facilitates manipulation of the support.

Preferably, the ring extends laterally to an angular sector α ₂₀ that is greater than 45º, preferably greater than 60º, preferably greater than 80º, preferably greater than 100º, preferably greater than 120º, preferably greater than 130º, preferably greater than 135º, and less than 180º, preferably less than 170º, preferably less 160º, preferably less than 150º, preferably less than 140º (see Fig. 5f).

The support preferably includes a holding pin, preferably at least two holding pins 25, preferably at least four holding pins 25, preferably located at the first and respectively second ends of the support. Retaining pins make the support easy to manipulate. Retaining pins 25 are located on the upper surface of the support, preferably on a portion of the outer surface opposite the support contact surface 18, and are preferably at least partially located in a portion of the support that is opposite the second electrode.

The support contact surface 18 preferably has one, preferably several, tenons 26 that project from said surface and are designed to limit sliding of the support over the eye. The support preferably contains more than 2, more than 5, more than 10, more than 20 tenons 26. The height of these tenons is preferably more than 0.1 mm and/or less than 0.5 mm or less than 0.3 mm.

In one embodiment of the invention, the support is configured to hold the eyelids open during the penetration phase of the electrode needle.

The support may also carry elastic means, such as a spring, for forcing the first electrode and/or injection needle into close position and/or pushing the second electrode onto the surface of the eye.

The support 16 is preferably made of a polymeric material. It is preferably made of a material that is not electrically conductive.

The support is preferably made of transparent material to provide the user with a better view.

The support can be used to manipulate the device. As shown in FIG. 5, the support may in particular comprise a handle 31 allowing the injection device to be grasped, for example, between the thumb and index finger of one hand. This greatly simplifies the process of manipulating the device.

Preferably, the handle extends along an axis ∆ ₃₁ inclined relative to the plane of the rim at an angle ω ₃₁ greater than 25º, preferably greater than 30º, and/or less than 45º, less than 40º, less than 35º.

If the first electrode 10 includes a plurality of coplanar electrode needles guided in respective coplanar electrode insertion guides, the handle preferably extends substantially along an axis ∆ ₃₁ substantially perpendicular to a plane containing said electrode insertion guides.

The length l ₃₁ of the handle 31 is preferably greater than 5 mm or 8 mm and preferably less than 50 mm, 30 mm, 20 mm, 15 mm.

Support contact surface

The width of the support contact surface 18 may be constant or variable. In the embodiment of FIG. 4, the width of the contact surface of the support is greater near the second electrode than near the two ends 24. The advantage is to limit the risk of eye damage.

The radius R of curvature of the support contact surface 18 is preferably in the range of 10 mm to 15 mm, preferably 11 mm to 14 mm, preferably 12 mm to 13 mm, and preferably 12.5 mm. The stability of the support on the user's eye is thereby significantly improved.

In one embodiment of the invention, the support contact surface 18 has a surface area greater than 50 mm ² , preferably greater than 100 mm ² , preferably greater than 120 mm ² , preferably greater than 140 mm ² , preferably greater than 150 mm ² , preferably greater than 160 mm ² , and/ or less than 200 mm ² , preferably less than 180 mm ² .

The contact surface 18 of the support may be continuous or may be locally interrupted by holes.

In one preferred embodiment, the contact surface 18 of the support is interrupted by an opening 19 for the introduction of a second electrode (see FIGS. 4 and 5).

Preferably, the contact surface 18 of the support does not extend more than a quadrant of the hemisphere.

In one preferred embodiment, the support contact surface 18 has the general shape of a circular band, preferably an open circular band.

When viewed from the front, the contact surface 18 of the support may have a substantially parallelepiped contour, for example a rectangular contour or a substantially trapezoidal contour.

The support contact surface 18 may have two large sides and two small sides. Large sides can in particular form rounded corners with small sides.

The length of the small sides may be greater than 3 mm, preferably greater than 4 mm, and/or less than 10 mm, preferably less than 8 mm, preferably less than 7 mm, preferably less than 6 mm. The length of the large sides may be greater than 10 mm, preferably greater than 12 mm, preferably greater than 14 mm and/or less than 20 mm, preferably less than 18 mm, preferably less than 16 mm.

Preferably, the support is configured such that when the support contact surface 18 is pressed against the eye surface, the support can contact the eye surface only through the support contact surface 18.

Headband

The rim 20 has the shape of an arc of a circle C ₂₀ (including a full circle) having an X axis and a radius R ₂₀ that is greater than 5 mm, preferably greater than 5.5 mm, preferably greater than 5.8 mm, and less than 8 mm, preferably less 7.5 mm, preferably less than 7 mm, preferably less than 6 mm. Such a rim has a shape essentially corresponding to the limbus L _i of the eye. It may be brought into contact with the limb so as to surround, at least partially, possibly completely, said limb.

The stability of the support is significantly improved if the rim 20 is designed to be pressed against the limb of the eye.

Preferably, the second electrode does not form, even partially, any rim. In a preferred embodiment, the rim configured to press against the limbus of the eye is formed only by a support.

The rim 20 may be shaped like a full circle, as shown in FIG. 2a. The advantage is to increase the stability of the device in the working position. However, preferably the rim 20 is open, that is, not closed, as shown in FIG. 4. Preferably, the rim 20 is wide open, as shown in FIG. 5, making it easier to handle.

The length of said circular arc is preferably greater than 5 mm, preferably greater than 10 mm, preferably greater than 12 mm, preferably greater than 13 mm, preferably greater than 14 mm, and/or preferably less than 45 mm, preferably less than 40 mm, preferably less than 35 mm, preferably less than 30 mm, preferably less than 25 mm, preferably less than 20 mm, preferably less than 17 mm, preferably less than 15 mm.

The support is preferably provided with a flexible skirt 22 extending along said rim (see FIG. 2a), the flexible skirt being preferably made from a material selected from the group consisting of silicone polymers, conductive porous material, in particular synthetic porous material, polyester, polyester, polyorthoether, polymethyl methacrylate, or any other elastic polymer for medical use.

Preferably, the rim is interrupted by at least one cutout 21, preferably by at least two cutouts, preferably by three cutouts. The cutouts 21 are designed so that the doctor can see the limbus of the eye through them when the support is placed on the eye. At least one cutout, preferably all of the cutouts, is located near the second electrode.

In fig. 4 and 5, the support contains two and, respectively, three cutouts 21, which interrupt the rim 20 near the second electrode. In fact, it is in this area that the location of the support is most critical.

Preferably, the cutout(s) is located on a portion of the rim that extends along an angular sector α ₂₁ of less than 120º, preferably less than 100º, the angular sector being preferably centered on the median plane M of the second electrode (see FIG. 4d).

The advantage is that the process of positioning the device on the eye is simplified and more accurate.

Electrodes

By definition, the first and second electrodes are configured to be electrically connected to the first and, respectively, second terminal of the electrical generator.

The first and second electrodes include first and second connectors, not shown in the drawings, for electrical connection to said first and second terminals, respectively. The electric generator is configured to have different polarizations of the first and second electrodes so as to create an electric field allowing electroporation to occur.

The device according to the invention may also contain such an electrical generator.

First electrode

The first electrode 10 may comprise one or more, preferably three, four or five, preferably parallel, preferably coplanar, preferably straight electrode needles 14. The electrode needles are preferably attached to each other so as to form a fork or ridge, as shown in FIG. 4a or 5g. The distance between the axis of two adjacent electrode needles is preferably greater than 0.5 mm, preferably greater than 0.6 mm, preferably greater than 0.7 mm, preferably greater than 0.8 mm, and/or less than 5 mm, preferably less than 3 mm, preferably less than 1 .5 mm, preferably less than 1.2 mm, preferably less than 1 mm, preferably less than 0.9 mm.

Preferably, all electrode needles have the same structure. In the following description, only one electrode needle 14 is disclosed, however, one or more features thereof may be applied to any electrode needle of a first electrode comprising a plurality of electrode needles. In a preferred embodiment, all electrode needles have the same structure.

Preferably, the length l ₁₄ of the electrode needle 14 is greater than 8 mm, preferably greater than 10 mm, preferably greater than 11 mm, and/or less than 15 mm, preferably less than 14 mm, preferably less than 13 mm (see FIGS. 3a' and 4a).

Preferably, the length l _{14 i} of the insertion of the electrode needle, preferably any electrode needle, that is, extending into the imaginary sphere S in a close position, is greater than 5 mm, preferably greater than 7 mm, preferably greater than 8 mm, and/or less than 13 mm, preferably less 12 mm, preferably less than 11 mm (see Fig. 3a').

Preferably, the diameter of the electrode needle 14 is less than 0.5 mm, preferably less than 0.4 mm, preferably less than 0.35 mm. This feature is particularly advantageous when the electrode needle is inserted into the eye substantially tangentially to the surface of the eye, as in the embodiment of FIG. 4 or fig. 5.

Preferably, the diameter of the electrode needle 14 is greater than 0.2 mm, preferably greater than 0.3 mm. The advantage is that the electrode needle becomes sufficiently rigid to be inserted into the eye, and in particular substantially tangentially to the surface of the eye.

For the same reason, the tip 27 of the electrode needle 14 is preferably beveled to facilitate penetration of the electrode needle into the eye, as shown in FIG. 1a and 3a.

In one embodiment, any electrode needle 14 includes an insulated portion 14a, the outer surface of which is electrically insulated, and a non-insulated portion 14b, preferably extending from the insulated portion to the tip 27 of the electrode needle.

The insulated portion 14a may be insulated, for example, by an insulating coating, preferably such that the electrically insulated portion of said electrode needle can penetrate at least 0.4 mm, at least 0.6 mm, or at least 0.8 mm. mm into an imaginary sphere S in a close position.

As shown in FIG. 1, the electrode needle 14 may include a flattened portion, that is, such that its width to thickness ratio W ₁₄ /T ₁₄ is greater than 3, preferably greater than 5, greater than 7, greater than 10, greater than 15, greater than 20, and/or less than 30 or less than 25. Preferably, the width W ₁₄ has a value in the range from 0.15 to 2 mm, preferably greater than 0.2 mm and/or the thickness T ₁₄ has a value in the range from 0.15 to 0.5 mm, preferably greater than 0 .2 mm.

The flattened part preferably constitutes more than 50%, more than 60%, more than 70%, more than 80% or more than 90% of the length of the insertion part to be inserted into the eye, that is, which can protrude into the imaginary sphere S carrying the support contact surface 18.

Preferably, the flattened portion extends to the tip 27 of the inserted needle and/or along the entire length of the electrically conductive portion 14a, and even along the entire length of the inserted portion, and preferably along the entire length of the electrode needle.

The flattened portion preferably includes top and lower large edges 14 ₁ and 14 ₂ , and right and left side edges 14 ₃ and 14 ₄ defining the thickness of the flattened part, that is, the maximum distance between the two large edges.

The flattened portion may be curved along its length (see FIG. 1a), and/or along its width (see FIG. 1b).

The flattened portion 14 may be in the shape of a trough or part of a sphere.

In one preferred embodiment of the invention, the upper large edge 14 ₁ at least partially extends substantially parallel to the contact surface of the second electrode.

In particular, at least in the region facing the contact surface of the electrode, the upper large edge 14 ₁ may have the shape of a sphere having the same center as the imaginary sphere S. The advantage is to increase the uniformity of the electric field between the first and second electrodes, if the contact surface of the electrode passes along the indicated imaginary sphere. The upper large edge 14 ₁ may also have a length and/or width corresponding to the length and/or width of the second electrode.

The flattened portion 14 may have a constant or variable length and/or width and/or thickness. In particular, it may be beveled when looking at the electrode needle from the side and/or from above, that is, when looking perpendicular to the large edges.

Preferably, in the active region of the upper large face, that is, the region facing the second electrode at a close position, the thickness and/or width of the flattened portion is substantially constant.

Second electrode

In fig. 2b and 2c, the second electrode is shown in dotted lines.

The electrode contact surface 17 preferably extends along the same imaginary sphere S as the spherical contact surface 18 of the support. It corresponds to the outer surface of the eye O so that in the working position it is pressed against the outer surface of the said eye O.

It may be an electrically conductive layer covering at least a portion, preferably the entire surface of the support contact surface 18, as in the embodiments of FIGS. 2 and 3.

In the embodiments of the invention shown in FIGS. 4 and 5, the second electrode is not integral with the support, that is, it is a part that is initially independent of the support and is subsequently installed on the support.

Preferably, as shown in FIG. 4a, the second electrode can be removed, that is, disconnected from the support.

If the second electrode is to be mounted on a support (FIGS. 4 and 5), then the support, in particular the support handle, is preferably designed to guide this installation process. In particular, the support may form a tube (FIG. 4) or a groove (FIG. 5) into which the second electrode can slide until the assembled position is reached. Preferably, the support includes an elastic tongue 37 or blade configured to fix the second electrode on the support in an assembled position, possibly reversibly (see Fig. 5d).

The second electrode 12 is preferably a plate contact electrode made of an electrically conductive material.

The second electrode may also include a set of spikes, preferably extending perpendicular to its contact surface 17. These spikes may be similar to the spikes 26 on the support. Preferably, the second electrode does not contain any spikes. Preferably it is smooth.

The second electrode may form a circular rim 20. However, as shown in FIG. 4, the rim 20 is preferably formed by a support.

The electrode contact surface 17 is preferably substantially surrounded by the support contact surface 18.

Preferably, the distance d ₁₈ between the rim 20 and any point of the electrode contact surface 18 is greater than 2 mm, preferably greater than 2.5 mm, preferably greater than 3 mm, preferably greater than 3.5 mm, preferably greater than 4 mm, and/or less than 6 mm, preferably less than 5 mm, preferably less than 4.5 mm (see Fig. 6e).

Preferably, the contact surface of the electrode does not extend over more than one quadrant of the hemisphere.

Preferably, the second electrode extends within an angular sector α ₁₂ around the X-axis (see Fig. 2c) that is less than 90º, preferably less than 60º, preferably less than 50º, preferably less than 45º, preferably less than 35º, preferably less than 30º, and/or preferably more 10º, preferably more than 15º, preferably more than 20º.

The electrode contact surface area is preferably greater than 3 ^mm2 , greater than 4 ^mm2 , greater than 5 ^mm2 , greater than 6 ^mm2 , greater than 8 ^mm2 , greater than 10 ^mm2 , greater than 11 ^mm2 , greater than 12 ^mm2 , greater than 15 ^mm2 , more than 17 mm ² , and/or less than 90 mm ² , less than 60 mm ² , less than 30 mm ² , less than 20 mm ² .

In front view, the contact surface of the electrode preferably has a substantially rectangular shape. In the front view shown, the length l ₁₂ of the second electrode is preferably greater than 3 mm, greater than 4 mm, greater than 5 mm, and/or less than 8 mm, less than 7 mm. In the indicated front view, the width w ₁₂ of the second electrode is preferably greater than 1 mm, preferably greater than 2 mm, and/or less than 4 mm.

injection needle

Preferably, the device includes an injection needle 42.

The injection needle may be part of the first electrode and/or the second electrode and/or support. In particular, it can be made of an electrically conductive material so as to form part of or constitute a part of the first and/or second electrodes. In particular, the electrode needle 144 of the first electrode may be an injection needle.

Alternatively and preferably, the injection needle can be configured independently of the first and second electrodes, as shown in FIG. 4 or 5.

Preferably, the injection needle is configured to penetrate the patient's eye only such that the maximum depth p ₄₂ of the injection needle under the outer surface of the eye is in the range of 0.6 mm to 1.3 mm, preferably greater than 0.7 mm, preferably greater than 0. 8 mm, preferably more than 0.85 mm, and/or less than 1.2 mm, preferably less than 1.1 mm, preferably less than 1 mm, preferably less than 0.95 mm.

The injection needle may in particular have one or more of the features of the injection needle described in WO2009/122030 or US12/921979, incorporated herein by reference.

Preferably, the insertion length of the injection needle is greater than 2 mm, preferably greater than 3 mm, preferably greater than 3.5 mm, preferably greater than 4 mm, and/or less than 7 mm, preferably less than 6 mm, preferably less than 5.5 mm.

Preferably, the ratio of the insertion length of the injection needle to the maximum insertion length of any electrode needle is in the range of 0.3 to 0.7, preferably in the range of 0.4 to 0.6, preferably 0.5.

Preferably, the insertion length of the injection needle and the position of the corresponding injection needle insertion guide are determined such that, in the proximity of the injection needle and the plurality of electrode needles, the tip of the injection needle is at the center of the lattice formed by the electrode needles within an imaginary sphere S as viewed along the major axis ∆ ₁₇ of the electrode contact surface 17 (see Fig. 6g).

The injection needle may include an injection channel 36 having one or more outlet openings 38.

One or more or all of the outlets 38 may open axially relative to the major axis of the injection needle, as shown in FIG. 3a. In particular, one or more or all of the outlets 38 may open on a large face (as shown in FIG. 1a) and/or on a side face of a flattened portion of the electrode needle.

The outlet openings are preferably evenly distributed on the large edge of the flattened portion.

As shown in FIG. 1a, the injection channel 36 can be fixed to the electrode needle 14, in particular, to the large edge of the flattened electrode needle.

The outlet(s) may open radially.

For a flattened needle electrode in particular, the injection channel 36 may be formed at least in part by a wall of a non-metallic material, in particular a polymer, for example selected from the group consisting of silicone polymers, polyester, polyorthoester, polymethyl methacrylate, or any another elastic polymer for medical use. The injection channel 36 is preferably formed by a wall made of silicone.

Preferably, according to the embodiment of the invention shown in FIG. 4, the device comprises only one injection needle 42, preferably equipped with a needle stop to restrict its insertion into the eye.

Needle direction

The support 16 may be equipped with one or more insertion guides 28.

Thus, the needle, that is, the electrode needle 14 or the injection needle 42, can be movable and guided between an extreme (ie, anvil-limited) proximal position and a distal position in which it can protrude inwardly from the support contact surface 18. The device may include a mechanism for automatically changing the position of the needle, and in particular the electrode needle 14, from a distant position to a close position.

The directional movement of the needle can occur by rotation and/or translation.

Preferably, the insertion guide 28 is designed such that it prevents any rotation of the corresponding needle about its longitudinal axis. As shown in FIG. 2a, the cross-section of the insertion guide 28 may be asymmetrical and complementary to the cross-section of the corresponding needle, for example rectangular, as shown in the drawing.

In one embodiment of the invention, guidance occurs due to contact between the inserted needle and the surface of the support hole into which the needle is inserted, as shown in FIG. 4.

The support preferably includes an electrode insertion guide 28a for guiding, by contact with an invasive electrode needle, insertion of the invasive electrode needle, and/or an injection needle insertion guide 28b for guiding, through contact with an injection needle, insertion of said injection needles.

The cross-section of the insertion guide 28a or 28b preferably corresponds to the cross-section of the corresponding electrode needle or injection needle.

Preferably, the insertion guide 28a or 28b is in the form of an opening that extends through the support, exiting at its contact and outer surfaces through a corresponding outlet opening 30 and an inlet opening 32, respectively.

The largest and/or smallest cross-sectional dimension(s) of the opening are preferably less than 0.5 mm, preferably less than 0.4 mm, preferably less than 0.35 mm, and/or preferably greater than 0.2 mm, preferably greater than 0.3 mm.

Preferably the opening is in the form of a tube, preferably having a constant cross-section along its length. The length of the insertion guide is preferably greater than 0.5 mm, preferably greater than 1 mm, preferably greater than 2 mm.

The cross section is preferably circular.

Alternatively or additionally, in one preferred embodiment of the invention, the first electrode and/or injection needle comprises at least one, preferably at least two, guide rods 39 extending parallel to the electrode needle(s) and/or injection needle, respectively, and the support contains a corresponding guide 28c for inserting the rod (see Fig. 5g).

The length l ₃₉ of the guide rod is preferably greater than 12 mm, preferably greater than 14 mm, and/or less than 20 mm, preferably less than 17 mm, preferably less than 16 mm.

Preferably, the rod insertion guides 28c are holes that do not penetrate the imaginary sphere S on which the support contact surface 18 extends. Thus, when the support contact surface 18 is pressed against the outer surface of the eye O, the guide rods cannot pass through the support contact surface 18, and therefore do not penetrate the eye. An advantage of this arrangement is that it is possible to increase the guide length, that is, the length of the insertion guide 28c.

Preferably, the guide rod or any guide rod is provided with a rod stop 40 configured to restrict the sliding movement of said guide rod 39 outside the corresponding rod insertion guide 28c, as shown in FIG. 6s. In this drawing, the rod stop 40 abuts the support 16, in particular, the bottom of the guide rail 41.

Preferably, only one guide rod is equipped with a rod stop 40.

Preferably, only one guide rod is provided for a set of all rod stops 40.

Preferably, the sliding of the stop rod 40 in the support is not guided.

Thus, the guide rod 39 is movable between a retracted position (FIGS. 6a and 6c) and an inserted position (FIGS. 6g and 6h), with the needle(s) being guided by the guide rod 39, i.e. four electrode needles in the embodiment fig. 6 is(are) outside the imaginary sphere S (see FIG. 6a) and, accordingly, at least partially inside the imaginary sphere S (see FIG. 6g).

In the retracted position, the contact surface of the support may be advantageously positioned to contact the eye prior to insertion of the directional needle(s), without any risk of injury to the eye.

The advantage is that the stop rod 40 prevents the corresponding guide rod 39 from leaving the support. Thus, in any position, and in particular in the retracted position, the guide rod is always at least partially located within the corresponding rod insertion guide. Therefore, in order to insert the guided needle(s) into the eye, there is no need for any prior insertion of the guide rod into the corresponding rod insertion guide. This makes the insertion of the guided needle(s) easier.

In addition, there is no risk that the tip of said directional needle(s) will come into contact with the support and possibly remove some of the support and insert it into the eye. Alternatively and additionally, for the same reason, the insertion guide, and in particular the injection needle insertion guide 28b, may be made of metal or ceramic material. A metal or ceramic coating may be provided on the support, or an insertion guide may be formed by a metal or ceramic tube or portion 43 (see FIG. 6g).

Preferably, as shown in FIG. 6a, the tip 27 of the guide needle(s) is located within the support in the retracted position of the guide rod. Thus, the advantage of this arrangement is that the risk of injury to the eye is reduced.

Preferably, the guide rod(s) of the first electrode and/or injection needle extends under the tip of the electrode needle(s) of the first electrode and/or injection needle to a distance ∆ ₃₉ which is preferably greater than 1 mm, preferably greater than 2 mm , preferably more than 3 mm, and/or preferably less than 8 mm, preferably less than 7 mm, preferably less than 5 mm, preferably less than 4 mm.

The advantage is that the guide rods can be inserted into their respective rod insertion guides 28c before any penetration of the first electrode electrode needle and/or injection needle into the corresponding insertion guide 28a or 28b in the support. Thus, the tip of the inserted needle does not pierce the inner surface of said insertion guide 28a or 28b.

Preferably, the largest transverse dimension e ₃₉ of the guide rod 39, that is, in a cross section perpendicular to its length, is greater than 0.5 mm, preferably greater than 0.8 mm, preferably greater than 0.9 mm, and/or less than 2 mm, preferably less 1.5 mm, preferably less than 1.2 mm. The advantage of this arrangement is to increase the rigidity of the guide rod and improve directional movement.

Preferably, the device includes a needle stop, generally designated 29, and capable of limiting the movement of the electrode needle 14 (item 29a), and/or the injection needle (item 29b), and/or the guide rod 39 (item 29c), during time of the eye penetration stage.

In a close position to Fig. 3a, the needle stop 29 is adjacent to the support 16 so as to set the length of insertion of the needle into the eye O.

The guide rod stop 29c is preferably rigidly fixed to the guide rod(s) 39, as shown in FIG. 6s.

The length of the portion of the electrode needle and/or injection needle that can be inserted (insertion length) into the eye is determined such that the tip of said electrode needle and/or injection needle cannot reach a portion of an imaginary sphere located opposite the insertion point of said needle.

Preferably, the needle stop 29a (or 29c if the electrode needle is guided by a guide rod as shown in FIG. 6) is configured such that in a front view of the second electrode, that is, when viewing the second electrode along its major axis, the inserted electrode needle ( needles) passed (passed) in a close position so as to completely intersect the electrode contact surface formed by the second electrode (that is, pass in front of the electrode contact surface from at least one side to the opposite side of the electrode contact surface).

The needle stopper 29 preferably includes paddles 45 to facilitate manipulation of the needle stopper (see FIG. 6c).

The needle stop 29a preferably includes connectors 46 for electrical connection to the generator terminal. Connector 46 may include a screw for pressing a wire electrically connected to said terminal to a portion electrically connected to the electrode needle(s). It may also include a socket electrically connected to the electrode needle(s) and configured to interact with a corresponding plug of a wire electrically connected to said terminal, such as a micro plug.

The insertion guide and corresponding needle are preferably designed such that in a close position the needle can only penetrate to a maximum depth measured from the surface of an imaginary sphere.

Preferably, maximum depthR ₄₂ for any injection needle greater than 0.6 mm, preferably greater than 0.7 mm, preferably greater than 0.8 mm, and/or less than 1.2 mm, preferably less than 1.1 mm, preferably less than 1 mm (see Fig. 6e ).

Preferably, maximum depthR ₁₄ for an electrode needle, preferably for any electrode needle, greater than 1.3 mm, preferably greater than 1.4 mm, preferably greater than 1.5 mm, preferably greater than 1.6 mm, and/or less than 2.1 mm, preferably less than 1, 9 mm, preferably less than 1.8 mm, preferably less than 1.7 mm (see Fig. 6e).

In one embodiment of the invention, the support is designed such that, in a close position, the depth of the tip 27 of the electrode needle and/or injection needle under the imaginary sphere S forming the contact surface 18 of the support is the same, regardless of the guide 28a and/or 28b, respectively. for an insert into which said electrode needle and/or injection needle is inserted.

In one embodiment of the invention, the support is designed such that, in a close position, the position of the tip 27 of the electrode needle and/or injection needle and, in particular, the depth of insertion of the needle depends on the insert guide 28a and/or 28b, respectively, into which the said insert is inserted. igloo

Thus, it is an advantage that the support can be locally adapted to define different insertion lengths and/or different orientations of the insertion guides 28a or 28b, as shown in FIG. 3a'.

Multiple insertion guides may be used to provide different proximity positions for the needle and/or to provide a single proximity position for the first electrode or for injection devices containing multiple needles.

In particular, when the support includes multiple electrode insertion guides 28a, possibly with different lengths and orientations, the insertion of corresponding electrode needles allows for an optimal network of electrode needles to be provided.

If the electrode needle 14 is also an injection needle, the advantage of such a variety of different insertion guides is that it is possible to make multiple injections at different points so as to very precisely define the area into which the product will be injected. It also has the advantage of increasing the area of the eye that the injection needle can reach.

Finally, the advantage of such a variety of different insertion guides is that the same support can be used effectively for different applications or different products.

The insertion guides are preferably straight.

In one embodiment of the invention, the insertion guides 28a and/or 28b and/or 28c are parallel to each other.

In one non-preferred embodiment of the invention, when viewed along the X-axis, the insertion guide(s) 28, i.e. 28a and/or 28b and/or 28c, extend(s) substantially radially relative to said rim (in the plane , containing the X axis, see the middle guide in Fig. 2b) and, in particular, runs along the axis ∆ ₂₈ of the insert, which defines, together with the direction tangential to the specified rim and containing the intersection point of the axis of the insert and the rim 20, angle θ ₂₈ , which is more than 60º, more than 70º, and/or less than 110º, less than 100º. In particular, the insertion guide may extend substantially in a plane containing the center C of the imaginary sphere S and perpendicular to the circular rim 20, as shown in FIG. 3a.

Preferably, the angle θ ₂₈ is less than 45º, preferably less than 30º, preferably less than 20º, preferably less than 10º.

Preferably, the insertion guide, preferably any insertion guide, extends along an insertion axis ∆ ₂₈ defining an angle β that is less than 20º, less than 15º, less than 10º, less than 5º, less than 1º, with a plane P ₂₀ containing said rim.

Preferably, the insertion guide, preferably any insertion guide, extends parallel to the plane P ₂₀ .

Preferably, at least one electrode insertion guide 28a, preferably at least one electrode insertion guide 28a proximally located in the plane P ₂₀ of the rim 20, is shaped such that, in a proximate position, the electrode needle 14 inserted into said guide 28a for electrode insertion, extends at a distance d greater than 2 mm, preferably greater than 3 mm, preferably greater than 3.5 mm, preferably greater than 4 mm, and less than 6 mm, preferably less than 5 mm, less than 4.5 mm, from the plane P ₂₀ of the rim 20 (that is, the distance d applies to any point on the electrode needle (see Fig. 4e)).

Preferably, at least one, preferably any, electrode insertion guide 28a is shaped such that, in a close position, the electrode needle 14 inserted into said electrode insertion guide 28a extends entirely outside the imaginary X-axis sphere Cy adjacent to said rim. (see Fig. 3a').

Preferably, at least one, preferably any, electrode insertion guide 28a is shaped such that, in a proximate position, the bare portion 14b of the electrode needle 14 inserted into said electrode insertion guide 28a extends, as viewed along the X-axis, at least at least partially, preferably completely, within the area in front of the second electrode.

If the electrode contact surface is rectangular, the insertion axis of the insert guide, preferably any insert guide, is preferably substantially parallel to one of the sides, preferably the large side of the electrode contact surface.

In the case where the electrode needles are coplanar, the plane of the electrode insertion guides is preferably substantially parallel to the major and/or minor sides.

Preferably, the insertion guide 28, preferably any insertion guide 28, extends substantially parallel to the major plane P ₁₇ of the second electrode contact surface 17.

Preferably, the insertion axis ∆ ₂₈ of the insertion guide 28, preferably any insertion guide, is set at an angle with a plane perpendicular to the major axis ∆ ₁₇ of the electrode contact surface 17 that is less than 50º, less than 30º, less than 20º, less than 10º, less than 5º, preferably by essentially zero, as shown in FIG. 4e.

Preferably, if the electrode contact surface is spherical, at least the radius of said electrode contact surface 17 is inclined in a plane perpendicular to said insert axis. Preferably, said radius intersects said electrode contact surface relative to its center.

Preferably, the electrode insertion guides 28 are designed such that, in a close position, the distance δ between the invasive electrode needle 14, preferably any invasive electrode needle, and the electrode contact surface 17 is in the range of 2 to 1.3 mm, preferably 1.8 to 1.5 mm, preferably 1.7 mm to 1.6 mm, preferably about 1.65 mm, and preferably constant no matter what point of the electrode contact surface is considered, as seen in FIG. 1b or fig. 4e.

Preferably, at least two electrode insertion guides 28a extend in a common plane P _28a . In one preferred embodiment of the invention, all electrode insertion guides 28a extend in the same plane P _28a . Preferably, as shown in FIG. 4e, the plane P _28a defines with the plane P ₂₀ of the rim 20 an angle Ω that is greater than 40º, greater than 45º, preferably greater than 50º, and/or less than 80º, preferably less than 70º, preferably less than 60º, preferably less than 55º.

In one embodiment of the invention, the outlet openings 30 and/or the inlet openings 32 of the electrode insertion guides 28a do not extend at the same distance from the plane P ₂₀ of the rim 20, as shown in FIG. 3a or fig. 4e.

Preferably, the plane P _28a extends substantially parallel to the electrode contact surface which is intended to contact the outer surface of the eye. The angle between said plane P _28a and the principal plane in which the second electrode extends (the plane perpendicular to the principal axis of the second electrode) is preferably less than 20º, preferably less than 15º, preferably less than 10º, or less than 5º.

Preferably, all of the invasive electrode needles of the first electrode, preferably three, preferably four electrode needles, extend, in the operating position, in the plane P _28a . Preferably, at any point of the second electrode contact surface 17, the distance δ between the electrode contact surface 17 and the plane P _28a is in the range from 2 to 1.3 mm, preferably from 1.8 to 1.5 mm, preferably from 1.7 to 1.6 mm, and is essentially constant, regardless of which point of the electrode contact surface is considered (see Fig. 4e).

The injection needle insertion guide(s) may have one or more features of electrode insertion guide(s) 28a.

In one embodiment, the support includes at least one, preferably a plurality of electrode insertion guides 28a and at least one injection needle insertion guide 28b configured to guide insertion of the electrode needle(s) and injection needle(s) into the eye. along the corresponding axes of the insert, and the planes perpendicular to the specified corresponding axis of the insert define an angle greater than 3º, greater than 5º, and less than 10º. In other words, in a close position, the electrode and injection needles are not inserted parallel to each other. The advantage of this arrangement is that the contact surface 17 of the second electrode can be increased without any reduction in the mechanical strength of the support.

The support preferably comprises a pre-positioning guide(s) configured to guide one or more needles, i.e. electrode needle(s) and/or injection needle(s), to a position in which said electrode needle(s) ) and/or the injection needle(s) is(are) in line with the axis of the corresponding insertion guide.

The advantage is that the pre-positioning of the needle allows the needle to be aligned with the appropriate insertion guide so that during insertion the tip of the needle will not contact the support and, as a result, will not become blunt.

In particular, the support preferably has pre-positioning means that facilitate insertion of the needle(s) into the inlet(s) 32.

Preferably, as shown in FIG. 4e, the pre-positioning means comprise a tapered groove 33. Said groove 33 has a large hole 34 into which a needle can be easily inserted. The tapering part of the groove 33 guides the needle until it reaches the bottom of the groove 33. In this position, the tip of the needle faces the inlet 32 so that it can be inserted into the inlet without the risk of hitting the support when inserting it into the inlet 32 .

In the embodiment of FIG. 4e, however, it is necessary that the three electrode needles be pressed against the inclined surface 35 of the groove 33.

Similar insertion guides and prepositioning means may be provided for the electrode needle(s) and for the injection needle(s). In particular, as shown in FIG. 4b and 5b, the groove 44 may be configured such that the injection needle is aligned with the entry hole of the injection needle insertion guide 28b.

The embodiment of the invention shown in FIG. 5 does not contain a groove for electrode needles, due to the guidance by the guide rods 39 into the rod insertion guides 28c.

Medicine

The administered product may in particular be any of the medicinal products described in WO2013/024436, the contents of which are incorporated herein by reference, and in particular the desired therapeutic nucleic acid, preferably deoxyribonucleic acid (DNA) molecules (cDNA, gDNA , synthetic DNA, artificial DNA, recombination DNA, etc.), or ribonucleic acid (RNA) molecules (mRNA, tRNA, RNA interference, catalytic RNA, asRNA, viral RNA, etc.). In one embodiment, the preparation contains a cyclic portion of DNA.

In another particular embodiment of the invention, the electroporation device according to the present invention is particularly suitable for performing gene replacement. Accordingly, the nucleic acid may be responsible for a stable protein in order to replace a defective protein that is naturally expressed in the target tissue. Typically, defective genes that can be replaced include, but are not limited to, genes responsible for diseases disclosed in WO 2013/024436.

Set

Kits are also provided in accordance with the present invention. In particular, the device according to the present invention and the medicinal product according to the present invention, and optionally instructions for use, may be supplied together as a kit. Within a kit, components can be separately packaged or arranged.

Instructions may be in written, video, or audio form, and may be on paper, electronic media, or even a link to another source such as a website or reference manual.

The kit may also contain other components such as excipients, carriers, other drugs or drug excipients, instructions for the use of the active substances or drug, and the use of injection devices.

Way

The method according to the invention can be used for the treatment of an eye disease, the drug being preferably selected from among the drugs described above.

To use the electroporation device according to the first aspect of the invention, an operator may perform the following steps.

First, the operator fixes the second electrode on the support, connects the container filled with the drug to the injection needle, and electrically connects the first and second connectors to the two terminals of the electrical generator.

To position the device, the operator places the rim 20 on the limbus Li of eye O. The location of the rim 20 on the edge of the cornea and the pressing of the spherical contact surface 18 of the support against the sclera of the eyeball ensures good stability of the device and very accurate positioning. Stabilization is extremely important in this particular application since the angles between the electrode needles and/or injection needle on one side, and the spherical contact surface of the support on the other side, are very low at the insertion points, that is, the needles are inserted almost tangentially to the specified surface, which complicates the insertion process.

Next, the operator pushes the first electrode, preferably a comb of electrode needles initially in a remote position, into the insertion guides 28a.

In one embodiment, the guide rods 39 penetrate into corresponding rod insertion guides 28c. In another embodiment of the invention, the guide rods are slidably mounted on a support and held in the support by one or more rod stops, thereby eliminating the need to insert the guide rod 39 into a corresponding rod insertion guide.

Further, they can direct the movement of the first electrode to ensure that the electrode needles easily fit into their respective insertion guides 28a until the first electrode abuts the outer surface 26 of the support 16 and is thus in close position. In this case, the electrode needles form a grid that runs substantially parallel to the second electrode, along the entire length of the second electrode.

It has been noted by the present inventors that all human eyes have very similar sizes and shapes and, in particular, that the distance between the ciliary muscle and the edge of the cornea of the eye is essentially the same, regardless of which person is being considered. The shape and arrangement of the first electrode and the second electrode, the insertion guides 28, the pins 26, the rim 20 and the spherical contact surface are determined so that, in close proximity, it is ensured that the first and second electrodes are in an optimal position to create an electric field particularly effective for electroporation into the ciliary muscle.

The operator then inserts the injection needle into the appropriate insertion guide until it enters the appropriate close position. The previous insertion of the electrode needles ensures an extremely stable support position during insertion of the injection needle.

In one embodiment of the invention, the injection needle stopper, which determines its close position, causes the outlet(s) to open into the ciliary muscle, in front of the electrode needle array.

The operator can then administer the drug.

In a preferred embodiment of the invention, the injection needle is part of the syringe and the operator places the injection needle in the groove 44 so that it faces the entry hole of the injection needle insertion guide. Thereafter, the operator inserts an injection needle through the guide 28b for inserting the injection needle into the space between the first and second electrodes, injects the drug, and then removes the injection needle from the eye.

Increasing the number of injection points promotes drug penetration.

The device is then placed in the operating position and the operator sends a suitable electrical signal, for example suitable electrical pulses, using an electrical generator so as to create, within the injection zone, an electrical field that promotes electroporation. The device configuration disclosed above, particularly with a flattened shape for the electrode needle(s), increases the efficiency of electroporation.

In a particular embodiment of the present invention, an electric field created by one or more electrical pulses is used.

The field strength is preferably from 1 to 600 Volts; preferably from 1 to 400 Volts, most preferably from 1 to 200 Volts, preferably from about 10 to 100 Volts, or from 15 to 70 Volts.

The total duration of application of the electric field may be from 0.01 milliseconds to 1 second, preferably from 0.01 to 500 milliseconds, more preferably from 1 to 500 milliseconds, most preferably from greater than 1 or 10 milliseconds. In a preferred embodiment of the invention, the total duration of application of the electric field is in the range of 10 milliseconds to 100 milliseconds and is preferably 20 milliseconds.

The number of electrical pulses applied can be, for example, in the range from 1 to 100,000. Their frequency can be in the range from 0.1 to 1000 Hertz. It is preferably a regular frequency.

In addition, the electrical pulses can be applied irregularly relative to each other, the function describing the electric field strength as a function of time for one pulse being preferably variable.

The electrical pulses are preferably monopolar or bipolar wave pulses. They may be selected, for example, from the group consisting of square wave pulses, exponentially decreasing wave pulses, oscillating monopolar wave pulses of limited duration, oscillating bipolar wave pulses of limited duration, or other waveform shapes. Preferably, the electrical pulses comprise square wave pulses or oscillating bipolar wave pulses.

Once electroporation of the product is complete, the operator electrically disconnects the electrodes from the generator.

From the above it is clear that the device according to the present invention provides the ability to:

- precise and stable location of electrodes;

- precise direction of the invasive electrode needle during its penetration into the eye;

- precise injection into the eye relative to the limbus of the eye;

- creating an effective, uniform and strong electric field.

Of course, the present invention is not limited to the embodiments described and illustrated herein, which are provided by way of illustration only.

In particular, the various embodiments of the present invention may be combined with each other.

Claims (24)

1. An electroporation device for injecting a product into the ciliary muscle of the eye, the device comprising: - a support (16) having a spherical contact surface (18) of the support running along an imaginary sphere (S) with a radius of 10 to 15 mm, - a first electrode (10) containing an invasive electrode needle (14), - a second electrode (12) having an electrically conductive electrode contact surface (17), - injection needle (42), wherein the first electrode and/or injection needle includes a guide rod (39) extending parallel to the electrode needle and/or the injection needle, and the support (16) contains a corresponding guide (28c) for inserting the rod. 2. The electroporation device according to claim 1, wherein the guide for inserting the rod is a hole that does not intersect an imaginary sphere (S) along which the contact surface (18) of the support passes. 3. The electroporation device according to claim 1 or 2, wherein the guide rod of the first electrode and/or the guide rod of the injection needle extends beyond the tip (27) of the electrode needle (14) of the first electrode and/or the injection needle (42), respectively, at a distance (Δ39) that is greater than 1 mm. 4. The electroporation device according to claim 3, wherein said distance (Δ39) is greater than 2 mm. 5. Electroporation device according to any one of claims 1 to 4, wherein the largest transverse dimension of the guide rod (39) is greater than 0.5 mm. 6. Electroporation device according to claim 5, wherein said largest transverse dimension of the guide rod (39) is greater than 0.8 mm. 7. An electroporation device according to any one of claims 1 to 6, wherein the guide rod is equipped with a rod stop (40) configured to limit the sliding movement of said guide rod (39) beyond a corresponding rod insertion guide (28c). 8. Electroporation device according to claim 7, in which the rod stop (40) is configured to rest against the support (16). 9. Electroporation device according to any one of claims 7, 8, in which the sliding of the rod stop (40) in the support (16) is not guided. 10. Electroporation device according to any one of claims 7 to 9, wherein only one guide rod (39) is equipped with a rod stop (40). 11. Electroporation device according to any one of claims 7 to 10, in which the stop rod (40) is configured to prevent the corresponding guide rod (39) from leaving the support (16). 12. Electroporation device according to any one of claims 1 to 11, comprising a guide (28b) for inserting an injection needle made of metal or ceramic material. 13. Electroporation device according to any one of claims 1 to 12, comprising a needle stopper (29) configured to limit the movement of the electrode needle (14) and/or the injection needle and/or the guide rod (39) during the phase of penetration into the eye . 14. The electroporation device according to claim 13, wherein the needle stop (29) is configured to abut the support (16) so as to set the length of insertion of the needle into the eye in a close position. 15. The electroporation device according to claim 14, wherein the needle stop (29) is configured such that, in a front view of the second electrode, the inserted electrode needle extends at said close position so as to completely intersect the electrode contact surface formed by the second electrode. 16. The electroporation device according to any one of claims 1 to 15, wherein the support includes a pre-positioning guide configured to guide the electrode needle or injection needle to a position in which said electrode needle or injection needle is in line with the axis of the corresponding guide for insertion, so that during insertion the tip of the electrode needle or injection needle does not contact the support. 17. The electroporation device according to claim 16, wherein the prepositioning guide comprises a tapered groove (33), wherein the groove (33) includes a tapered portion for guiding the electrode needle or injection needle until it reaches the bottom of the groove (33) so that that in this position the tip of said electrode needle or injection needle faces the inlet (32) of the electrode insertion guide (28a) or the injection needle insertion guide, so that it can be inserted into said inlet hole without risk of hitting the support (16) when inserting it into the inlet (32). 18. An electroporation device according to any one of claims 1 to 17, comprising a container containing said product and an injection needle in fluid communication with said container, said product being the desired therapeutic nucleic acid. 19. The electroporation device according to claim 18, wherein said product is a deoxyribonucleic acid molecule or a ribonucleic acid molecule.

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