WO2007116049A1

WO2007116049A1 - Application of ultrasound to the nails

Info

Publication number: WO2007116049A1
Application number: PCT/EP2007/053447
Authority: WO
Inventors: William Pilgrim
Original assignee: Galderma Research & Development
Priority date: 2006-04-10
Filing date: 2007-04-10
Publication date: 2007-10-18
Also published as: FR2899487A1

Abstract

The invention relates to the use of an ultrasound emitter for the manufacture of a therapeutic device for use in treating a nail disease, in particular onychomycosis and nail psoriasis. The device promotes in particular the release of a therapeutically active agent in or through the nail.

Description

APPLICATION OF ULTRASOUNDS TO NAILS

The invention relates to the treatment of nail diseases, in particular onychomycosis and nail psoriasis. The present invention relates more particularly to the use of ultrasound in the treatment of nail diseases, in particular onychomycosis and nail psoriasis.

Onychomycosis is a mycotic nail infection that results in opaque, white, thick, brittle and fragile nails. It usually affects more than one nail. Onychomycosis reaches 2 to 13% of the population and increases to about 15-20% in people aged 40 to 60 years.

The treatments of onychomycosis commonly used fall into three categories:

- systemic and local treatments of antifungals; - surgical procedures to remove the infected nail in whole or in part followed by topical treatment for the exposed tissues; or

- topical applications of creams, lotions, gels or solutions on the infected nail.

These different approaches have many disadvantages.

The systemic (oral) administration of antifungal agents for the treatment of onychomycosis gives a therapeutic effect only in the long term. For example, oral treatment with the antifungal compound Ketoconazole typically requires the administration of 200 to 400 mg daily for six months before significant therapeutic benefit is obtained. However, these antifungal agents can in the long term cause significant undesirable side effects.

Surgical removal of the nail also has a number of disadvantages, including pain and discomfort associated with the surgical procedure and unsightly appearance of the nail. In the case of usual topical treatments with creams, lotions, gels or solutions, the diffusion of the active ingredient through the surface of the nail is very low and the duration of treatment is particularly long. In addition, these topical dosage forms do not allow to keep the active ingredient in contact with the nail for an extended period of time and therefore bandages must be used.

Another known topical form is nail polish (Murdan et al., International Journal of Pharmaceutics, 236 (2002), 1-26). Loceryl® is an example of varnish composed of amorolfine (5%), Eudragit RL 100, glycerol triacetate, butyl acetate, ethyl acetate and ethanol. The varnish is applied to the fingernail plate and dried for a few minutes to evaporate the solvents and leave a waterproof polymer film on the surface of the fingernail. The active ingredient is then released from the film and diffuses through the horny plate of the nail.

Locéryl® is applied once or twice a week for six months on the nails of the hands and nine to twelve months for the nails of the feet. The duration of treatment depends essentially on the intensity, the location of the infection and the surface of the nail reached.

The treatment of nails with a varnish is thus relatively restrictive because it is repetitive, requires maintenance of the nail before each application and requires special attention to avoid contamination of the nails not reached.

Another proposed topical form is a patch containing an antifungal agent, in particular a patch containing amorolfine (WO2005 / 092299), which avoids most of the disadvantages mentioned above, but whose effectiveness remains conditioned by good penetration of the antifungal agent through the nail.

The problem shared by all topical antifungal agents used to treat onychomycosis, and the reason for their low efficacy, is the very low penetration of the active ingredients through the nail to reach the reservoir of the infectious agent, the bed of the nail. Regarding nail psoriasis, it is an inflammatory disease that can affect the matrix, the body or the bed of the nail or the skin at the base of the nail. The damage to the nail can be more or less severe and can go as far as the loss of the latter. Currently, the methods of treating nail psoriasis consist of the topical application of corticosteroids or retinoids, or local administration of glucocorticoids by local injection. However, these methods of treatment are not very effective.

The inventors of the present invention propose to solve the problems related to the techniques of the prior art for treating nail diseases, using ultrasound.

The medical use of ultrasound has been extensively described elsewhere. For example, ultrasound is used in medical imaging, particularly to observe the structure of the human nail plate and to measure the thickness of the nail.

Many patents also describe the use of ultrasound to facilitate the penetration of active molecules into the skin. These techniques are directed to transdermal systemic delivery of drugs. For example, the application WO2006 / 003305 describes an ultrasonic wave transducer permeabilizing the skin to allow transdermal delivery of active molecules.

However, no document has so far described the effective use of ultrasound in the treatment of nail disease. In fact, the authors of the only document mentioning an ultrasound use test in the treatment of a nail disease, a dystrophy of the nail, conclude their study on the inability of ultrasound to treat this disease (Lauber et al., South Med J 81, (9) Suppl 4, 18, 1988).

The present invention now provides a method of treating a nail condition, including applying ultrasound to the nail of a patient in need of such treatment. The invention further relates to the use of an ultrasound emitter for the manufacture of a therapeutic device for treating nail disease.

According to a preferred embodiment of the invention, ultrasound is used to promote the penetration of a molecule, such as a therapeutically active agent.

Thus, the invention also provides a combination product comprising a therapeutically active agent and an ultrasound emitter. Such a product can be used in the treatment of nail diseases, particularly onychomycosis and nail psoriasis. This combination product can be used simultaneously, separately or spread over time, to treat such pathologies.

The present invention also relates to an assembly for the treatment of nail disease which comprises a therapeutically active agent and an ultrasound emitter.

The details of the invention will be set forth in the detailed description which follows.

Ultrasonic transmitter

Ultrasonic or ultrasonic wave means a wavelength wave in the range 10 kHz - 10 MHz. Low frequency ultrasound has a wavelength between 10 kHz and 200 kHz, preferably between 20 kHz and 200 kHz. High frequency ultrasound has a wavelength of between 2 and 10 MHz, preferably between 2 MHz and 5 MHz.

In a preferred embodiment of the invention, a high energy wave is used whose frequency is between 20 kHz and 1 MHz, preferably between 20 kHz and 100 kHz.

The type of ultrasonic waves that can be used in the context of the invention can be adapted according to the disease to be treated, the progress of this disease, the thickness of the nail and possibly the therapeutic agent used. The wave can thus be a wave of a single wavelength, a combination of several ultrasonic waves of different frequencies, frequency modulation, etc. Similarly, the wave can be pulsed or continuously applied.

In a particular embodiment, the ultrasound emitting device used in the invention generates an ultrasonic wave at an acoustic intensity of less than 20 W / cm ² .

Any type of ultrasound transmitter can be adapted to the use according to the invention.

According to a particular embodiment, the transducer described in the application WO2006 / 003305 can be used in the present invention. This is a device for permeabilizing 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 ultrasonic wave frequency and a second high frequency ultrasonic wave.

Such a device comprises a low frequency transducer of the 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 juxtaposed in opposition of polarization and fed in parallel. These piezoelectric elements are positioned between two metal plates. The first mass serves as a damper (or backing) and prevents ultrasound to propagate backwards by damping the waves. The second mass, placed at the front, serves as waveguide as well as acoustic impedance matching between the piezoelectric ceramics and the coupling medium.

The device described in WO2006 / 003305 further comprises a high frequency power transducer consisting of a piezoelectric element of relative thickness to the resonant frequency. The piezoelectric element is excited via a high-frequency high-frequency voltage. This piezo element For example, the electrical connection may be bonded to an acoustic impedance matching blade whose thickness is relative to the resonance frequency of the high frequency transducer. The high frequency wave is generated at the front of the transducer.

Nail treatment

The invention relates to the use of an ultrasound transmitter for the manufacture of a therapeutic device for treating nail disease.

By "treatment" is meant preventive, palliative or curative treatment, allowing stabilization or complete cure of the disease.

Preferably, the invention relates to the use of an ultrasonic transmitter, as described above for example, for the manufacture of a therapeutic device for the treatment of onychomycosis or nail psoriasis. All types of onychomycosis are targeted, including distal-subungual onychomycosis, white proximal-subungual onychomycosis, superficial white onychomycosis, and Candida-induced onychomycosis. All types of nail psoriasis are also targeted.

The treatment of the sick nail can be achieved by the sole application of ultrasound on this nail. In this embodiment, the ultrasound treatment device is disposed directly on the nail, using a contact gel. An ultrasonic wave is then applied. Without wishing to be bound by any theory, it is possible that the ultrasound has, in the case of treatment of onychomycosis, a direct biocidal effect due to sonication phenomena, cavitation or through a thermal effect, which could break the mycelial forms of infectious agents dermatophytes.

In a preferred embodiment, the ultrasound is used in combination with the nail application of a therapeutically active agent. Indeed, ultrasound has a pro-penetrating effect in the nail. "Generic effect" penetrating the nail "an effect of promoting the penetration of a molecule in or through the nail.

The invention therefore also relates to the use of an ultrasound emitting device for the manufacture of a therapeutic device for treating nail disease, wherein the device promotes the release of a therapeutically active agent in or through the nail.

This phenomenon of molecular transport through a membrane is called sonophoresis or phonophoresis.

Therapeutically active agents may be applied before or after ultrasound is delivered to the nail. Thus, in one embodiment, the user applies the active agent in one of the topical forms described below and then applies ultrasound to the nail coated with the active agent. In an alternative embodiment, ultrasound is first applied alone to the nail to prepare the nail for penetration of the active agent, and then the agent is applied to the nail thus prepared.

Advantageously, the therapeutically active agent may be present in the form of a base or of a free acid, not complexed in salt form.

By "therapeutically active agent" is meant a molecule effective against the nail disease to be treated.

In a particular embodiment, the therapeutically active agent is an antifungal agent effective in the treatment of onychomycosis.

Any antifungal agent known to those skilled in the art to be effective in the treatment of onychomycosis can be used in combination with the therapeutic device of the invention. In particular, the device is used to facilitate penetration into or through the fingernail of fluconazole, econazole, oxiconazole, itraconazole, naftifin, butenafine, terbinafine, clotrimazole, miconazole, ketoconazole and / or amorolfine. Preferably, the antifungal agent is amorolfine, more preferably amorolfine HCl, or terbinafine. Most preferably, the antifungal agent is terbinafine. The use of ultrasound may also be considered to promote penetration into or through the nail of drugs which are not currently used in the treatment of onychomycosis because of their low penetration into the nail.

In another particular embodiment, the therapeutically active agent is an effective compound in the treatment of nail psoriasis. These include corticosteroids (for example clobetasol, clobetasol propionate, hydrocortisone, dexamethasone), retinoids (for example adapalene, tazarotene) or compounds of the vitamin D family (for example colecalciferol, calcitriol, calcipotriol, tacalcitol, alphacalcidol, maxacalcitol).

It is furthermore possible that in addition to a pro-penetrating effect of the therapeutically active agents in the nail, the ultrasound has an effect on the passage of a fungus from a dormant form to a drug metabolizing form, making thus the fungus more sensitive to therapeutically active agents applied to the nail.

Advantageously, the therapeutically active agent may be applied to the nail in combination with an absorption promoter in the nail. The term "absorption promoter in the nail" means pharmaceutically acceptable compounds capable of increasing the permeability of a biological membrane such as the skin or the nail with respect to a therapeutic agent. active, so as to increase the kinetics of penetration of the therapeutically active agent or its derivatives across the membrane.

The term "absorption promoter in the nail" means pharmaceutically acceptable chemical compounds capable of increasing the permeability of a biological membrane such as the skin or nail with respect to a therapeutically active agent such as terbinafine. or its derivatives, so as to increase the kinetics of penetration of the therapeutically active agent or its derivatives across the membrane. This kinetics of penetration can be measured using techniques well known to those skilled in the art. Thus, a cell diffusion apparatus such as Franz cells described by Merrit et al. (Diffusion Apparatus for Skin Penetration, J. Controlled Release, 1984,1, 161-162) or the method described in Walters et al. (fate of substances delivered to follicles, ducts and nails, ASCC, 2005) or in Gupchup et al. Structural characteristics and permeability properties of the human nail: a review, J. Cosmet Sci., 1999, 50, 363-385). Another method is described in WO2005 / 011565.

Absorption promoters are well known in the state of the art and may include, in particular, α-hydroxy acids, fatty acid esters and amides thereof, fatty alcohols, fatty acids and glycerol esters. especially 2- (2-ethoxyethoxy) ethanol, glycerolmonolaurate, propylene glycol, polyethylene glycols, polyglycosylated glycerides, unsaturated polyglycols (Labrafil M1944CS®, Gattefosse), saturated polyglycerides (Labrasol, Gattefosse), Labrafac HydroWL1219® (Gattefosse), decylmethylsulfoxide, pyrrolidones, salicylic acid, lactic acid, isopropyl myristate, dimethylformamide, dimethylacetamide, sodium dodecyl sulphate, phospholipids, Transcutol® (Gattefosse), mixtures of oleic acid and 2- (2-ethoxyethoxy) ethanol, oleic acid and Labrafil®, these oleic acid mixtures preferentially in a ratio of approximately 1: 1. Enzymatic compounds, such as that proteolytic enzymes that facilitate the penetration of the active ingredients through the keratinous tissues or through the nail, can also be used as absorption promoters. As non-limiting examples of fatty acids that can be used according to the invention, mention may be made of capric, auric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, petroselinic, oleic, linoleic and linolenic acids. .

Other known absorption promoters operate through hydrolysis, keratolysis, denaturation or other equivalent mechanism that destroy the nail or membrane. As examples of absorption promoters functioning in this manner, mention may be made of urea, amino acids containing sulphydryl groups, alkyl sulphoxides, and any equivalent compound which functions by destroying or denaturing the nail and / or the membrane thus allowing the pharmaceutical compound to penetrate the deep layers of the membrane.

As examples of absorption promoters, there may be mentioned in particular urea, exaltolide, N-acetylcysteine and lactic acid or a mixture thereof, urea associated with lactic acid or N-acetylcysteine, and exaltolide alone, being particularly preferred.

The amount of each absorption promoter can be determined by those skilled in the art depending, in particular, on the form of administration of the therapeutically active agent, the appearance of the nail and / or the advancement of the disease to be treated.

The therapeutically active agent, optionally combined with an absorption promoter, can be applied in the form of a cream, a lotion, a gel, a solution, a varnish, or in the form a patch or a bandage.

In a preferred embodiment, the active agent is applied to the nail through a package such as a patch or a dressing. Advantageously, the packaging is permeable only on the side in contact with the nail. In a particular embodiment, the packaging of the therapeutically active agent comprises an adhesive side to maintain said conditioning on the nail while ultrasound is applied. Advantageously, the therapeutically active agent may be present in the form of a base or of a free acid, not complexed in salt form, in such a packaging.

The doses of therapeutically active agent may be adapted by those skilled in the art depending on the patient and the pathology to be treated. The level of dosage chosen will depend on various factors including the activity of the particular compound used, the mode of administration, the duration of administration, the rate of excretion of the particular compound being used, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular therapeutically active agent used, age, sex, weight, condition, general health and medical history anterior patient who is treated and other factors well known in the medical profession. The skilled person can easily determine and prescribe the required amount of therapeutically active agent. For example, it may start with doses of therapeutically active agent at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In a particular embodiment, the nail is prepared prior to applying ultrasound or the pharmaceutical composition containing the therapeutically active agent. For example, the nail may be pre-conditioned by pretreatment with an absorption promoter or with an occlusive patch to hydrate it. Such an occlusive patch is described in patent FR 2 871 292.

Alternatively or in combination, the nail may also be prepared by abrasion with a nail file or with an abrasive chemical composition for the nail, such as that described in the US 2004 application. / 0197280.

Claims

A product comprising a therapeutically active agent and an ultrasound emitter as a combination product for simultaneous, separate or time-course use for treating nail disease.

2. Product according to claim 1, characterized in that the therapeutically active agent is in the form of base or free acid, not complexed in the form of salt.

3. Product according to claim 1 or 2, characterized in that the active agent is an antifungal agent selected from amorolfine, fluconazole, econazole, oxiconazole, itraconazole, naftifine, butenafine, terbinafine, clotrimazole, miconazole and ketoconazole.

4. Product according to claim 3, characterized in that the antifungal agent is terbinafine.

5. Product according to claim 1 or 2, characterized in that the active agent is a corticosteroid or a retinoid.

6. Product according to any one of claims 1 to 5, wherein the ultrasonic transmitter emits an ultrasonic wave frequency between 20 kHz and 1 MHz.

7. Product according to one of claims 1 to 6, characterized in that the ultrasonic transmitter emits an ultrasonic wave frequency between 20 kHz and 100 kHz.