WO2006003305A1

WO2006003305A1 - Ultrasonic wave transducer for making surface layers of the epidermis permeable

Info

Publication number: WO2006003305A1
Application number: PCT/FR2005/001409
Authority: WO
Inventors: Matthias Lebertre; Alain Boucaud
Original assignee: Transderma Systems
Priority date: 2004-06-08
Filing date: 2005-06-08
Publication date: 2006-01-12
Also published as: FR2871064B1; FR2871064A1

Abstract

The invention relates to the field of wave transducers for medical or cosmetic use. More particularly the invention concerns an ultrasonic wave transducer for fast permeabilization of the skin to enable variable-weight active molecules to be transdermally administered. Such use of ultrasounds for transdermal administration of active molecules is called sonophoresis. The invention also concerns a device for making permeable biological membranes comprising at least one transducer (1, 2, 12), characterized in that said transducer is capable of generating a specific ultrasonic wave corresponding to the frequency modulation of a first low-frequency ultrasonic wave and of a second low-frequency ultrasonic wave.

Description

ULTRASONIC WAVE TRANSDUCER FOR THE PERMEABILIZATION OF THE SURFACE LAYERS OF THE EPIDERM

The present invention relates to the field of wave transducers for medical or cosmetic use.

The present invention relates more particularly to an ultrasonic wave transducer permitting rapid permeabilization of the skin to allow transdermal administration of active molecules of variable weight. This use of ultrasound for the transdermal delivery of active molecules is known as sonophoresis.

The major problem, related to sonophoresis, is the control of the degree of cutaneous permeabilization. In fact, the intrinsic physiological differences in the cutaneous zones subjected to ultrasound, the type and size of the molecules to be administered and in particular the efficiency of the ultrasound waves result in poor reproducibility of the cutaneous permeabilization and consequently of the administered dose. Since the positive results obtained with low-frequency ultrasound, it is established that the effectiveness of ultrasonic waves, and therefore of sonophoresis, is directly related to cavitation. This physical phenomenon describes the formation, oscillation and implosion of gas bubbles under the effect of a mechanical wave and in particular acoustics. Cavitation occurs more easily at low frequency and for high acoustic power. However, cavitation is very difficult to control because it is dependent on several parameters related to ultrasound and the environment in which they propagate. Thus, several methods have been proposed to control cavitation to obtain better permeabilization and thus improve sonophoresis. The patent US6620123 (Mitragotri et al.) For example has a specific transducer for obtaining a homogeneous cavitation on the surface of the skin by the application of a single-frequency ultrasonic wave. Similarly, in US Patent 6491657, Rowe et al. Propose different types of ultrasonic waveguides with the objective of concentrating the cavitational activity locally on the skin.

We will show, from an acoustic point of view, the different signals that are obtained by the different ultrasonic devices of the prior art.

We will recall the characteristics of a transfer function. Either a system as shown in Figure 13. x (t) is the input signal that can be electrical, acoustic, light, electromagnetic ... The system is a system that will transform, thanks to its physical characteristics, the signal of input to an output signal y (t).

To illustrate our purpose, some simple examples are illustrated in figure 14. The system is characterized in the time domain by its impulse response noted s (t). The output signal y (t) is then expressed as a function of the input signal x (t) and the system impulse response s (t) by the convolution product.

y (t) = s (t) ®x (t) = fs (u) x (t-u) of

oo

In the frequency domain, that is to say after Fourier transform (TF) of each element,

this convolution product turns into a simple product:

Y (f) = S (f) xX (f)

The transfer function of the system is called S (jf).

A piezoelectric ceramic operates naturally at a natural frequency called resonance frequency, called f ₀ , and at multiple frequencies of Jf ₀ called harmonic. This resonance frequency depends mainly on the dimensions of the material used. For example, for a thickness mode and a material of 2 mm thickness, the resonance frequency will be 1 MHz. For a thickness of 1 mm, the resonance frequency will be 2 MHz. The frequency representation of such a phenomenon is illustrated in FIG.

The equation of a frequency-modulated signal is as follows:

s _FM (t) ≈ A cos (2πf ₀ t) + 2τtk fm (u) of

In the case of a sinusoidal or in any case periodic modulating signal, one can write: We then have as an expression of the frequency-modulated signal:

where β is the modulation coefficient

Its temporal representation is then as illustrated in Figure 16. After Fourier series decomposition, the frequency spectrum is written:

with Jn Bessel function of the first order. The frequency representation of a frequency modulation is illustrated in Figure 17.

The prior art already knows, from US Pat. No. 6,565,520 (Orthosonics Ltd., Michael Young), an apparatus for therapeutic ultrasound treatment. The method and apparatus of this invention relate to the non-invasive surgical treatment of skeletal muscle injuries and the diagnosis of bone fractures, involving the application of two components of ultrasonic energy, to an outer surface of living tissue, where the two components are frequencies in the range 10 kHz to 4 MHz, and separate transducers, each of which is uniquely powered by an excitation signal at one of two frequencies, are directionally arranged for acoustic propagation on the same directional axis.

The invention which is described in this US patent relates to an ultrasonic system for performing heating in depths of biological tissue. To achieve this goal, the author uses a device operating with two separate ultrasonic sources.

First, the present invention differs from this US patent by the final application of the ultrasonic device. The present invention relates to an ultrasonic device for permeabilizing biological tissues that is to say a surface effect. In this US patent, it is clearly the

shown that the advantage of the device, compared to those operating at a single frequency, is to obtain heating in different depths of a fabric. Moreover, the surface effect of the fabric is considered "secondary and unwanted".

From the point of view of technology, the advantage of the device according to the present invention is to use the coupling between the low frequency ultrasound source and the high frequency ultrasound source to obtain, thanks to a mechanical and therefore acoustic interaction, a "new frequency modulated ultrasonic wave acting solely on the surface of the tissue. In US Pat. No. 6,565,520, the author clearly describes a device in which the two ultrasonic sources are acoustically isolated in order to avoid any interaction between the low and high frequencies and finally obtain only a summation of the two waves (as shown in Figure 1). This isolation is obtained by using different types of elements, placed between the low frequency source and the high frequency source. We find ourselves in the case where two ultrasonic waves are added to form the resulting wave. Here, the two transducers resonate at two very distinct frequencies. The resulting acoustic wave thus has the form illustrated in FIG.

The prior art also discloses, by US Pat. No. 5,722,397 (Alten Technologies Inc., Jonathan A. Eppstein), an improvement in transdermal surveillance applications with ultrasound and chemicals. A method for improving the permeability of skin or mucous membranes for a diagnosis using ultrasound or ultrasound plus a chemical. If desired, the ultrasonic wave can be modulated by means of an electrical signal modulated in frequency, amplitude, and / or combinations of these different modulations. Low to high frequency modulation develops a local pressure gradient directed to the outside of the body, allowing components to be analyzed in the body to pass through the skin, to be collected and measured outside the body. The concentration of such components to be analyzed in the body is preferably determined by increasing the permeability of the skin or other biological membrane, optionally by means of a chemical, optionally applying the ultrasound with modulation. of frequency, amplitude, phase or combinations of these different modulations, which induces a local pressure gradient outside the body to collect the components to be analyzed and calculate the concentration in the body and d use data relating to these components.

The invention described in this US Pat. No. 5,722,397 relates to an ultrasound system making it possible to permeabilize the skin and thus to migrate and dose the molecules contained in the cutaneous tissues.

In this US patent, the author describes an ultrasonic device operating with a single ultrasonic source in the high frequency range (5-10 MHz), and to which an amplitude or frequency modulated electrical signal is applied. This modulation consists of performing a scan (increasing and / or decreasing) around the resonance frequency of the ultrasound source. This scanning can be continuous, gradual or well done "step by step".

The present invention differs from this US patent on the one hand, by the use of two ultrasonic sources (one in the low frequencies and the other in the high frequencies), and by the absence of a frequency modulated electrical signal.

Particular attention should be paid to the notion of "frequency modulation". Indeed, in US Pat. No. 5,722,397, it is a frequency modulated electrical signal that supplies a single ultrasonic source. While in the present invention, it is the result of the interaction between two ultrasonic waves of different frequencies, as is clearly indicated in the description.

In this US Pat. No. 5,722,397, a frequency modulated signal drives a single-frequency transducer. If we reason in the frequency domain, we must multiply the transfer function of the transducer with the frequency modulation spectrum, as shown in Figure 18. The sound pressure is identical to that obtained when the transducer is excited at its frequency. resonance.

The prior art also discloses, by US Patent Application 2002/055702 (Anthony Atala et al.) The delivery of drugs by means of ultrasound. This document describes methods and devices for treating physiological problems and for providing transdermal treatments, such as sprains, erectile dysfunctions, or baldness, without requiring the use of needles or other invasive procedures. A therapeutic agent and ultrasound improve the transdermal penetration of the agent. The invention of this US patent application is particularly useful for the localized delivery of controlled doses of therapeutic agent to small blood vessels and capillaries under the skin.

The invention which is described in this application for US Patent 2002/055702 relates to an ultrasonic system for permeabilizing the skin and thus migrate molecules contained in the skin tissue.

In this US patent application US 2002/055702, the author describes an ultrasonic device that can operate with several ultrasonic sources operating at the same frequency and to which a frequency modulated electrical signal is applied. This modulation consists of scanning around the resonance frequency of the ultrasonic sources. These ultrasonic sources are all connected to a single function generator. Although the objective of the present invention is similar to that presented in this US patent application US 2002/055702, that of the present invention differs from that of this US patent application US 2002/055702 on the one hand, by the use of two ultrasonic sources, one in the low frequencies and one in the high frequencies, and the absence of frequency modulated electrical signal.

On the other hand, both in the present invention and in this US patent application US 2002/055702, reference is made to the creation of cavitation on the surface of the skin. However, in this US patent application, this cavitation is created from the interaction of the ultrasonic waves, which is nothing more than a summation of the amplitudes, when the transducers are arranged in a circle. While in the present invention, cavitation results from a coupling of a low frequency wave and a high frequency wave.

We have in this US patent application several transducers excited at the same time, by a single electric source. From the acoustic point of view, we obtain a pressure for each transducer taken independently which has the form of Figure 19. If we take several transducers the only difference will be the phase shift between the waves. The interaction between the waves will be constructive or destructive, i.e. the resulting wave will be the sum of the incident waves as can be seen in Figure 20.

US 6,565,520, US 5,722,397 and US 2002/055702 neither describe nor suggest a transducer comprising at least one means for generating a specific ultrasonic wave corresponding to the frequency modulation of a first low frequency ultrasonic wave. and a second high frequency ultrasonic wave. Modulation within the meaning of the present invention is a coupling of a low frequency wave and a high frequency wave.

The use of specific ultrasonic waves is also known from the prior art. Ultrasonic devices based on multi-frequency systems have already been proposed for medical applications for surgical purposes as in US Pat. No. 5,827,204 or for the treatment of skeletal muscle injuries and the diagnosis of bone fractures as in the European application EP 0925090. These transducers emit, at the same time, a low frequency ultrasonic wave and a high frequency ultrasonic wave. In these patents, the devices presented are made to obtain a strong acoustic isolation between the two types of waves generated. The resulting acoustic wave consists simply of a summation of the low-frequency ultrasonic wave and the high-frequency ultrasonic wave as in FIG. 1. The devices presented in these patents make it possible to combine the effects therapeutic ultrasound of short wavelengths and long wavelengths for subcutaneous treatments.

The disadvantage of such a low-frequency and high-frequency wave summation is in particular a lack of efficiency in surface cavitation on the surface of the skin.

The present invention intends to overcome the drawbacks of the prior art by proposing a new ultrasonic wave for sonophoresis resulting from the frequency modulation of a high frequency ultrasonic wave and a low frequency ultrasonic wave.

In particular, it allows rapid ultrasonic permeabilization (less than 5 minutes), localized, secure, reproducible and reversible skin without adding physical promoters (solid particles of silica for example) or chemical promoters (SLS for example), and to allow diffusion through the skin of molecular weight molecules ranging from 20 Da to 200 kDa.

In addition to rapid permeabilization of the skin, the use of the invention allows the skin to remain permeabilized longer than with conventional sonophoresis methods.

To do this, the present invention is of the type described above and is remarkable, in its broadest sense, in that it relates to a device for the permeabilization of biological membranes comprising at least one transducer, characterized in that said transducer comprises at least one means for generating a specific ultrasonic wave corresponding to the frequency modulation of a first low-frequency ultrasonic wave and a second high-frequency ultrasonic wave.

Preferably, it comprises at least a first portion for generating said low-frequency ultrasonic wave and at least a second portion for generating said high-frequency ultrasonic wave.

Advantageously, said first part is a transducer comprising at least one piezoelectric element.

In the same way, said second part is a transducer comprising at least one piezoelectric element.

According to one embodiment, said transducer comprises at least one broadband piezoelectric element powered by a frequency modulated electrical signal.

Preferably, said low-frequency ultrasonic wave corresponds to a frequency range from 10 kHz to 200 kHz.

Preferably, said high-frequency ultrasonic wave corresponds to a frequency range from 0.5 MHz to 10 MHz.

According to one embodiment, said specific wave results from the modulation of said low frequency ultrasonic wave by said high frequency ultrasonic wave. According to one embodiment, said specific wave results from the modulation of said high frequency ultrasonic wave by said low frequency ultrasonic wave.

Advantageously, said specific ultrasonic wave has an acoustic power of less than 20 W / cm ² .

Preferably, said first means is a composite transducer.

Preferably, said transducer comprises a probe nose.

Preferably, said piezoelectric element is powered by a low-frequency electrical source.

Preferably, said piezoelectric element is powered by a high-frequency electrical source.

The invention also relates to a method for permeabilizing biological membranes, characterized in that it comprises at least one step of generating a specific ultrasonic wave corresponding to the frequency modulation of a first low frequency ultrasonic wave and a second low-frequency ultrasonic wave and a step of applying said specific ultrasonic wave to at least one biological membrane.

Preferably, it comprises at least one step of generating a low frequency ultrasonic wave and a step of generating a high frequency ultrasonic wave.

The invention will be better understood by means of the description, given below for purely explanatory purposes, of an embodiment of the invention, with reference to the appended figures in which:

FIG. 1 illustrates the type of ultrasonic wave used according to the prior art; FIG. 2 illustrates an example of a low-frequency composite transducer of the Langevin type;

FIG. 3 illustrates a high-frequency power transducer;

FIG. 4 illustrates an exemplary transducer according to a first embodiment of the invention;

FIG. 5 illustrates an exemplary transducer according to a second embodiment of the invention;

FIG. 6 illustrates an example of the probe nose according to another embodiment of the invention; FIGS. ₁₈ and 9 illustrate another mode of arrangement of the elements of the transducer of the invention;

FIGS. 10 and 11 illustrate an example of a probe for insertion of the transducer according to the invention;

FIG. 12 illustrates the type of ultrasonic wave obtained thanks to the transducer according to the invention; Figures 13 and 14 show examples of systems;

FIG. 15 illustrates the transfer function of a piezoelectric ceramic; FIG. 16 illustrates the temporal representation of a frequency-modulated signal;

FIG. 17 illustrates the frequency representation of a frequency modulation;

FIG. 18 shows the multiplication of the transfer function of the transducer with the spectrum of frequency modulation in the frequency domain, as is the case for US Pat. No. 5,722,397 of the prior art; FIG. 19 illustrates the shape of the pressure for each transducer taken independently, as is the case for the US patent application US 2002/055702 of the prior art; and Fig. 20 shows that the resultant wave is the sum of the incident waves as is the case for the US patent application US 2002/055702 of the prior art.

Illustrated in Figure 2, the ultrasound source according to the invention consists first of a low-frequency transducer 100 of composite type, for example of the Langevin type. This type of transducer is well known for the production of high power and low frequency ultrasound. It consists for example of a sandwich of piezoelectric materials placed between two metal plates used to generate high intensity ultrasound. This type of transducer consists of 2n (n positive integer) piezoelectric elements 101 juxtaposed in opposition of polarization and fed in parallel. These piezoelectric elements are positioned between two metal masses. The first mass 102 serves as a damper (or backing) and prevents ultrasound to propagate backwards by damping the waves. The second mass 103, placed at the front, serves as waveguide as well as acoustic impedance matching between the piezoelectric ceramics and the coupling medium. It has a thread in its rear part.

A clamping screw 104 passes through the ceramic / metal mass assembly in order to compress the ceramics, thus promoting the resonance of the assembly. This screw is insulated from ceramics thanks to a sheath 105 made of insulating materials. The low-frequency wave is generated at the front face 106 of the transducer and the diameter of the front face governs the ultrasound intensity emitted.

The dimensions (diameter and thickness) of the various constituents, as well as their physical characteristics (density, velocity ...) vary the resonance frequency of the whole.

This transducer principle is of known type and is found in all applications where power and low frequency are needed: sonar, ultrasonic welding, ultrasonic machining ...

Illustrated in FIG. 3, the ultrasonic source according to the invention also comprises a high-frequency power transducer 200 consisting of a piezoelectric element 201 of relative thickness to the resonant frequency. The piezoelectric element is excited via a high-frequency high-voltage alternating current. This piezoelectric element may for example be glued to an acoustic impedance matching blade 202 whose thickness is relative to the resonance frequency of the high frequency transducer. The high frequency wave is generated at the front face 203 of the transducer.

The electrical excitation of these different piezoelectric elements is carried out by separate generators. For low-frequency piezoelectric elements, the electrical signals are sinusoidal, triangular, rectangular or of any periodic shape, with a frequency of between 10 kHz and 200 kHz. For the high-frequency piezoelectric elements the

electrical signals are sinusoidal, triangular, rectangular or of any periodic form, with a frequency between 0.5 MHz and 10 MHz.

The power supply of the low frequency and high frequency piezoelectric elements is independent. The power of the electrical signals supplying the high-frequency and low-frequency piezoelectric elements is independently variable from zero watts to 100 watts electric. The power supply of the high-frequency and low-frequency piezoelectric elements can be carried out independently in continuous mode or in pulsed mode.

FIG. 4 represents an embodiment of a transducer generating a frequency modulated ultrasonic wave according to the invention. Two elements of piezoelectric materials 1 and 2, of annular shapes are juxtaposed in opposition to polarization and fed in parallel through three conductive metal electrodes 3 of very small thicknesses. Three electric wires 3 'are soldered or glued, with a conductive adhesive, to the metal electrodes 3 and convey the low-frequency power supply to the low-frequency piezoelectric elements 1 and 2. These piezoelectric elements 1 and 2 and the electrodes 3 are positioned between a counter-mass 4, high-density metal cylinder (steel, brass, etc.) for damping the ultrasonic waves propagating towards the rear, and on the other hand a horn 5 , cylinder of lower density materials (aluminum, magnesium, titanium ...) intended to transmit the ultrasonic vibrations to the insonification medium. The shape of the horn 5 can vary and influences the ultrasonic intensity provided by the the the

transducer. The horn 5 has a front end 6 and a rear portion 6 '. The flag 5 is pierced in its rear part 6 'of a threaded hole intended to receive a central screw 8 which passes through the counter-mass 4, the piezoelectric material elements 1 and 2 and the metal electrodes 3. This central screw 8 maintains in compression the assembly constituted by the elements of piezoelectric materials 1 and 2, the horn 5 and the counter-mass 4. This central screw 8 is electrically insulated from the rings made of piezoelectric materials 1 and 2 by the intermediate of a sheath 9 of insulating material such as PVC, PTFE or any other plastic material. The horn 5 is preferably of conical shape, with in particular an end diameter 6 smaller than the diameter of the rear portion 6 '. The front end 6 of the horn 5 is of reduced diameter and threaded to allow secure screwing, an intermediate ring 10. The inner / outer threaded intermediate ring 10 is made of insulating material and electrically insulates the horn 5 of the nose. probe 11. The probe nose 11 whose inner wall is threaded is screwed onto the intermediate ring 10. The probe nose 11 is made of material preferably identical to the material of the horn 5. The nose of the probe 11 is designed to receive a high-frequency piezoelectric element 12. This high-frequency piezoelectric element 12 is of relative thickness to its resonant frequency, this thickness is even lower than the resonant frequency is high. The high-frequency piezoelectric element 12 placed in the housing made in the probe nose 11 is held firmly in contact with the probe nose 11. This retention can be achieved with a special adhesive, conductive or insulating or any other holding system. The high-frequency piezoelectric element 12 is powered by a high-frequency electrical source via wires 13 and 13 'which crosses the entire transducer through the hole 7 made in the horn 5 and through the hole 7' made in the central screw 8. The electric supply wires 13 and 13 'are welded or glued together with glue In the rear of the high-frequency piezoelectric element 12, a cavity 15 is made to prevent the propagation of high-frequency waves backwards. This cavity 15 can be filled with a gas (air, ...) or with a liquid (water, oil, ...) or with a solid material (silicone, resin loaded or not, metal ...).

This design allows the high-frequency ultrasonic wave and the low-frequency ultrasonic wave to be created simultaneously on the front face 14 of the probe nose 11. The birth of the frequency modulated ultrasonic wave thus takes place on the front face 14.

According to another embodiment illustrated in FIG. 5, the probe nose may comprise a concave high-frequency piezoelectric element 12 in order to focus the high-frequency ultrasound beam.

Another embodiment of the probe nose may be shown in Figure 6. Here, the front face 14 of the probe nose 11 is convex to diverge the frequency-modulated ultrasound beam.

All shapes are conceivable for the probe nose 11, for its front face 14 and for the high-frequency piezoelectric element 12 to vary the shape of the ultrasonic wave and improve the efficiency of the transducer to permeabilize the skin . the

In addition, the manner of arranging the different elements of this transducer may vary. For example, in Figure 7, the end 6 of the horn 5 is pierced with a threaded hole to screw an intermediate ring 10, insulating material, threaded inner / outer. The intermediate ring 10 electrically isolates the horn 5 from the probe nose 11. The probe nose 11, the outer wall of which is threaded, is screwed inside the intermediate ring 10. The front face 14 of the probe nose 11 has a diameter equal to the outside diameter of the end 6 of the horn 5. A high-frequency piezoelectric element 12 is encapsulated inside the probe nose 11 and the assembly is held by a special glue, for example of the conductive epoxy type. or not. The high-frequency piezoelectric element 12 is fed by a high-frequency electrical source via electrical wires 13 and 13 'which passes through the entire transducer through the hole 7 made in the horn 5. The supply wires 13 and 13 'are welded or glued with conductive glue to the high-frequency piezoelectric element 12.

FIG. 8 represents another way of producing the transducer, by freeing itself from the probe nose 11 of FIG. 4. The end 6 of the horn 5 is pierced by a smooth hole in which is glued, with a special glue of the type conductive epoxy or not, an intermediate ring 10 of insulating material. This intermediate ring 10 electrically isolates the horn 5 of the high-frequency piezoelectric element 12 which is bonded to the intermediate ring 10 with a special glue of conductive or non-conductive epoxy type. A smooth hole 16 is drilled through the wall at the end 6 of the horn 5 to allow the passage of a high frequency power supply wire 13 '. Hole 16 is clogged with a silicone type product to prevent the infiltration of liquid, dust inside the cavity 15. The power supply son 13 and 13 'are welded or glued with conductive glue, to the high-frequency piezoelectric element 12. 6 end of the horn 5, the end of the intermediate ring 10 and the outer face of the high-frequency piezoelectric element 12 is in an identical plane that is called the front face 14 of the transducer. The frequency modulated ultrasonic wave originates on the front face 14.

Finally, illustrated in FIG. 9, in all the embodiments described above, it is possible to dispense with the insulating ring 10, for example by directly screwing the end 6 of the horn 5 at the inner part of the probe nose. 11.

Figures 10 and 11 show an example of a specific probe for cutaneous permeabilization with insertion of the transducer in this probe. This probe is an assembly that makes it possible to interface the ultrasonic source and the skin.

It consists of a plastic body or bio-compatible resin. The ultrasonic source is placed in this plastic body, the cohesion being made at a zero vibration node of the transducer. The end of the ultrasound source is not in direct contact with the patient's skin. It bathes in a coupling medium (water, oil, alcohol, gel ...) retained by a flexible bio-compatible membrane (plastic, rubber, latex, silicone, new material ...) acting as acoustic window.

The distance separating the end of the ultrasound source and the patient's skin is calculated according to frequencies and resulting wavelengths to obtain the maximum of acoustic energy on the surface of the skin. This distance is given by the wavelength of the specific frequency modulated ultrasonic wave in the coupling fluid divided by two. Respecting this distance allows optimization of the system. This is a known result for acoustic impedance adaptations in ultrasound probes.

Moreover, according to a variant of the method according to the invention, the transducer allowing the emission of the modulated ultrasonic wave consists only of a single piezoelectric element with a very large bandwidth (from a few kHz to several MHz ) powered by an electrical signal directly modulated in frequency.

We can finally note Figure 12 the type of ultrasonic wave obtained with the device according to the invention. This wave is the specific ultrasonic wave that allows permeabilization of the outer layers of the skin. The waveform is quite distinct from that of physiotherapy processes known as those of Figure 1 and corresponds to a modulation of a high-frequency wave by a low-frequency wave. This ultrasonic wave causes unstable cavitation on the surface of the skin for low acoustic powers.

It preferably has an acoustic intensity less than 20 W / cm ² , in order to produce an effective permeabilization, without ever reaching the cavitation thresholds that can cause superficial or deep skin lesions. Cavitation is then easily controlled by simultaneously playing on the power of the low-frequency waves. the

frequency and high-frequency waves as well as the frequency of these.

Note that the modulated wave can be the resultant of the low-frequency wave modulated by the high-frequency wave, as well as the resultant of the high-frequency wave modulated by the low-frequency wave.

The application of the transducer according to the invention is for example sonophoresis or any application requiring permeabilization of biological membranes. In particular, in an application at the level of the skin, the modulated acoustic wave produced then disorganises the stratum corneum, superficial layer of the epidermis, and opens pathways for active molecules. This system greatly improves existing systems for passing molecules through the skin.

The invention is described in the foregoing by way of example. It is understood that the skilled person is able to realize different variants of invention without departing from the scope of the patent.

Claims

1. Device for the permeabilization of biological membranes comprising at least one transducer, characterized in that said transducer comprises at least one means for generating a specific ultrasonic wave corresponding to the frequency modulation of a first low frequency ultrasonic wave and of a second high frequency ultrasound wave.

2. Device for permeabilization of biological membranes comprising at least one transducer according to claim 1, characterized in that said means consists of a first part for generating said low frequency ultrasonic wave and a second part for generating said wave high frequency ultrasound.

3. Device for permeabilization of biological membranes comprising at least one transducer according to claim 2, characterized in that said first part is a transducer comprising at least one piezoelectric element.

4. Device for permeabilization of biological membranes comprising at least one transducer according to claim 2, characterized in that said second part is a transducer comprising at least one piezoelectric element.

5. Device for permeabilization of biological membranes comprising at least one transducer according to claim 1, characterized in that said low-frequency ultrasonic wave corresponds to a frequency range from 10 kHz to 200 kHz.

6. Device for permeabilization of biological membranes comprising at least one transducer according to claim 1, characterized in that said high-frequency ultrasonic wave corresponds to a frequency range from 0.5 MHz to 10 MHz.

7. Device for permeabilization of biological membranes comprising at least one transducer according to claim I _1, characterized in that said specific ultrasonic wave has an acoustic intensity of less than 20 W / cm ² .

8. Device for permeabilization of biological membranes comprising at least one transducer according to claim 2 or 3, characterized in that said first part is a composite transducer.

9. Device for permeabilization of biological membranes comprising at least one transducer according to claim 1, characterized in that said transducer comprises a probe nose.

10. Device for permeabilization of biological membranes comprising at least one transducer according to claim 3, characterized in that said piezoelectric element is powered by a low-frequency electrical source.

11. Device for the permeabilization of biological membranes comprising at least one transducer according to claim 4, characterized in that said piezoelectric element is powered by a high frequency power source.