EP2205228A2

EP2205228A2 - Patch for cutaneous application, which comprises a hydrophile powder

Info

Publication number: EP2205228A2
Application number: EP08839020A
Authority: EP
Inventors: Bertrand Dupont; Nathalie Donne
Original assignee: DBV Technologies SA
Current assignee: DBV Technologies SA
Priority date: 2007-10-01
Filing date: 2008-09-30
Publication date: 2010-07-14
Also published as: JP2010540603A; KR20100080778A; FR2921562A1; EA201070402A1; FR2921562B1; CA2700168A1; AU2008313589A1; BRPI0817539A2; US20100222753A1; WO2009050403A3; MX2010003297A; IL204587A0; WO2009050403A2; CN101938997A

Abstract

The invention relates to a patch (1) for skin application that comprises: a hydrophilic powder (2) acquiring an adhesive property in the presence of water; a substrate (4) having an application surface on which the hydrophilic powder (2) is provided.

Description

HYDROPHILIC ADHESIVE PATCH

The present invention generally relates to devices for cutaneous application. The invention more particularly relates to products and methods for better skin fixation of devices such as patches or transdermal patches, intended to interact with the skin to moisturize or facilitate the absorption of cutaneous biologically active substances. It also relates to a method for the manufacture of such devices, as well as their uses, in the therapeutic, diagnostic and / or cosmetic field, for example.

Cutaneous or percutaneous absorption is the transfer of a substance through the skin, typically from the outside to the blood. This absorption is generally defined as the sum of two phenomena: a penetration of the molecules into the layers of the skin, followed by resorption by the blood or lymphatic circulation from the papillary dermis and then the deep dermis. The penetration stage is physically a passive diffusion through each or some of the structures of the integument: the stratum corneum, the Malpighi epidermis, the dermis and the cutaneous appendages. Penetration, in the broadest sense, does not necessarily imply a diffusion through all the structures of the integument, especially the deep ones, but it must preferably allow an exposure of the substance to the immune or circulatory system. Once absorbed, the substance is usually distributed in the body and then, after being metabolized, it is eliminated. The steps following percutaneous absorption are normally similar to those encountered for any other route of administration.

The stratum corneum is the most effective barrier against the penetration of a substance: anatomically, the substance can penetrate in two ways: one through the intercellular spaces of the stratum corneum and through the horn cells themselves, other through the skin appendages. It has been mentioned that the passage of hydrophilic active principles into the stratum corneum is facilitated when these compounds are find in a humid atmosphere. In the case of a vaccine, once the stratum corneum is crossed, the substance (antigen, immunogen, adjuvant, etc.) is able to meet the immunologically competent cells and, in particular, the antigen-presenting cells such as the cells. of Langerhans whose role is essential in the immunological reaction of the body. Facilitating the initial passage of antigen through the stratum corneum is to make epicutaneous vaccination more effective. In the case of a patch intended for the administration of a molecule for systemic treatment, temporarily reducing the efficiency of the stratum corneum as a barrier, opens the way for transcutaneous administration of active principles to high molecular weights and, in general, improve the rate of administration of the active ingredients (proteins, peptides, chemical molecules, nucleic acids, etc.).

Different types of patch have been proposed in the literature for the cutaneous transfer of active substances. Generally, these patches are "adhesive", that is to say that they are provided with a glue or an adhesive, typically acrylic type, ensuring the narrow maintenance of the patch on the skin.

Thus, the document US2004 / 137004 relates to a transdermal patch that can comprise different formulations and an acrylic adhesive or in the form of a hydrogel. US2006 / 002949 relates to an unadjuvanted transcutaneous immunization method in which an antigen in powder form can be used. US2006 / 147509 relates to a device for transdermal delivery of an immunogen, comprising a saponin-sterol delivery system and an occlusive vehicle.

WO00 / 43058 relates to a method of transdermal administration of active ingredient in the form of accelerated particles. The method uses either an injection with the PowderJect ™ device or a patch held in place by an athletic band. WO02 / 07325 relates to a patch for transcutaneous immunization and the document

WO2006 / 007366 relates to fusion proteins for transcutaneous immunization. In these documents, the antigen may be used in the form of powder or liquid, alone or mixed with an adjuvant. If an adhesive can be used to maintain the patch, it is either a resin or an aqueous adhesive.

Patches are also known for moisturizing the skin. In such a case, the patch does not necessarily contain active substance, but its application, in particular of occlusive format, creates a zone of hydration in contact with the skin. Such patches are mainly intended for the field of cosmetics.

Patches of the prior art have disadvantages, particularly when the desired effect requires a strong adhesion of the patch, obtained by a conventional adhesive (acrylic for example). When removing the patch, the separation between the adhesive surface and the skin can indeed lead to irritation and a sensation of pain. Furthermore, the use of aqueous adhesives can lead to an alteration of the active ingredient on the patch and therefore a short shelf life. A compromise must therefore be found for the adhesive strength of the adhesive surface, in order to limit the sensation of pain during the withdrawal, while ensuring that the patch remains on the skin. This membership is relatively difficult to establish precisely because it can vary with the duration of storage of the patch before its application.

The invention aims to solve one or more of these disadvantages. The invention indeed provides a hydrophilic adhesive patch for cutaneous application, characterized in that the adhesion of the patch to the skin is provided by a hydrophilic powder acquiring adhesion in the presence of water. This characteristic of the invention ensures better adhesion of the device during its application, ease of storage, no loss of adhesiveness as a function of the storage duration, stability of the active ingredient (maintained in dry form), and better penetration into the skin of any active substance due to the hydration (natural or artificial) necessary prior to the skin to the transformation of the hydrophilic powder into adhesive gel .. The advantages of this adhesive powder are: Compared to the use of a hydrogel: the patches using the hydrogel require that a large amount of hydrogel is deposited on the patch, generally over the entire surface of the patch, which makes its manipulation imprecise ; such a patch can not be worn on the skin as a conventional transdermal patch, under clothing, for example; in addition, the preservation of the hydrogel, wet by definition, in its packaging before installation, is limited (limited storage time); Finally, the use of hydrogel prevents the active ingredient, if any, from being presented in dry form, as some require to be preserved because the water contained in the hydrogel then moistens the skin. active ingredient.

Compared to the use of an acrylic or silicone adhesive: Some devices for cutaneous administration, require, to obtain locally under the device hyperhydration in depth of the skin (for example to facilitate the passage of the asset) or better dissolution of the dry active ingredient disposed on the inner face (facing the skin) of the device, which is wetted the skin beforehand; the use, in this case, of a hydrophilic powder acquiring adhesiveness in the presence of water, allows the immediate adhesion of the device to the wet skin, which does not allow an acrylic or silicone type adhesive.

A particular object of the invention thus relates to a patch for cutaneous application, comprising:

a hydrophilic powder acquiring an adhesion power in the presence of water; and

a support having an application face on which the hydrophilic powder is disposed.

In the patch of the invention, the hydrophilic powder, in dry form, thus acquires adhesion in the presence of water, thus allowing the patch to be maintained during its application to a skin which has been advantageously previously moistened. The hydrophilic powder may be disposed on all or part of the application face of the patch, over a sufficient area to allow adhesion. According to one variant, the hydrophilic powder is disposed on the periphery of the application face of the support.

According to another variant, the hydrophilic powder forms pads distributed on the application side of the support.

According to another variant, the hydrophilic powder is disposed over the entire surface of the application face of the support. According to yet another variant, the patch further comprises a biologically active substance.

According to one variant, the substance is a powder mixed with the hydrophilic powder.

According to another variant, the substance is disposed on an area (s) of the application side of the distinct support (s) of the hydrophilic powder.

According to yet another variant, the hydrophilic powder comprises soluble polymer chains in water.

According to one variant, the hydrophilic powder comprises cellulose gum, ethylcellulose, hydroethylcellulose, a copolymer of N-vinyl-2-pyrrolidone and of vinyl acetate, or a 1-vinyl-2 polymer. pyrrolidone.

According to another variant, the patch further comprises a reservoir containing an aqueous solution placed in line with the hydrophilic powder.

According to another variant, the patch comprises a waterproof packaging in which water vapor and the support and the hydrophilic powder are included.

According to another variant, the support has a form of comma.

The invention further relates to a method of manufacturing a patch, comprising the application of a hydrophilic powder acquiring adhesion in the presence of water on the application side of a support. The support may be of various shapes and types, and in particular of flat shape or not, and of polymer, plastic, metal, textile and / or biological material, solid or semi-solid, etc.

According to one variant, the hydrophilic powder is applied to all or part of the application face. According to another variant, the hydrophilic powder is applied on the periphery of the application face or in the form of pads distributed on the application side of the support.

According to another variant, the method further comprises a step of applying a biologically active substance on the face of the support. According to another variant, the substance is applied in powder form as a mixture with the hydrophilic powder.

According to yet another variant, the substance and the hydrophilic powder are applied successively.

According to a variant, the powder and / or the substance are maintained on the support by electrostatic type forces.

Another subject of the invention relates to a method for the cutaneous application of a substance to the skin, comprising the application of a patch as defined above to the skin of a subject, the step of application being preceded or not by a step of pre-hydration of the skin.

Another subject of the invention relates to a method for hydrating the skin of a subject, comprising the application of a patch as defined above to a skin area to be moisturized.

Another subject of the invention relates to the use of a patch as defined above for the application of a substance to the skin, and / or for the delivery of a substance by epi- or trans- cutaneous to a subject, in particular a mammal, in particular a human being (for example a child or an adult). The patch may especially be used for the vaccination of subjects, for the desensitization of subjects, or for the delivery of any active substance, such as in particular biologically active and / or antigenic (poly) peptides, for example. The invention also relates to corresponding methods, comprising the application of a patch of the invention to the skin of a subject, the application step being preceded or not by a step of prehydrating the skin.

The patch can be used for the delivery of any active substance. Thus, a particular object of the invention lies in a method of delivering an active substance to a subject, comprising (i) applying a patch according to the invention to the skin of a subject, the patch comprising said active substance, and (ii) maintaining the patch for a period of time allowing the transfer of the substance into the skin. The substance is typically of a polypeptide nature, such as a hormone, a cytokine, a growth factor, a trophic factor, etc.

The substance contained in the patch may be formulated in any suitable vehicle or excipient, and may be in solid (powder), liquid, etc. form.

The patch can be used for example for the vaccination of subjects against any pathogen. Thus, a particular object of the invention resides in a method of vaccinating a subject against a pathogen, comprising (i) the application of a patch according to the invention to the skin of a subject, the patch comprising a specific antigen of said pathogen, and (ii) maintaining the patch for a period of time allowing the transfer of the antigen into the skin. The pathogen may be of a varied nature (virus, bacterium, parasite, etc.) and the antigen is typically of a polypeptide or lipid nature.

The patch can also be used for desensitizing subjects to allergens. Thus, a particular object of the invention lies in a method for desensitizing a subject to an allergen, comprising (i) applying a patch according to the invention to the skin of a subject, the patch comprising a specific antigen of said allergen, and (ii) maintaining the patch for a period of time allowing the transfer of the antigen into the skin.

In the above methods, the application of the patch is preferably preceded by hydration (or moistening) of the skin. Other characteristics and advantages of the invention will emerge clearly from the description which is given hereinafter, by way of indication and in no way limitative, with reference to the appended drawings, in which:

FIG 1 is a top view of the adhesive side of a patch according to the invention;

FIG 2 is a side sectional view of the patch of Figure 1 placed in a package;

FIG. 3 is a view from above of the adhesive face of a patch variant; FIG. 4 is a view from above of the adhesive face of another variant of patch;

FIG 5 is a side view of the face of a user on which the patch is applied.

The invention proposes forming the adhesive for maintaining a patch by means of a hydrophilic powder that acquires adhesion in the presence of water. The invention is suitable for any type of patch, that is to say any device that can be applied to a skin area of a subject to bring it into contact with a substance or create a hydration zone. The device typically comprises a support which can be of various shapes and types, and in particular of flat shape or not, and of polymer material, plastic, metal, textile and / or biological material, solid or semi-solid, etc.

Different types of devices can be used for the implementation of the present invention. In particular, the patches described in documents EP 1 367 944 or FR2, 866,553 may be mentioned. Such patches typically include a polymeric material (eg, a plastic film) on the surface of which a powder can be attached via electrostatic forces.

Another type of patch that can be used for the implementation of the invention is, for example, a patch described in application EP1356821, which mentions the successive use of an adhesive film, intended to remove part of the stratum corneum, and a patch for epicutaneous penetration of the vaccine.

Other patch systems, such as stamps, cups, etc. can be used in the context of the present invention.

Figures 1 and 2 illustrate a first embodiment of a patch 1 according to the invention, intended in this case for the dissemination of an active substance in the body of the user. The patch 1 comprises a support 4. The support 4 has an application face on which a hydrophilic powder 2 is disposed. A substance 3 is also advantageously arranged on the application face. The substance 3 is intended to penetrate the epidermis in a manner known per se. The hydrophilic powder 2 is present in dry form and acquires adhesion in the presence of water. The hydrophilic powder 2 then turns into a sticky gel on the skin, thus allowing the adhesion of the patch 1.

Thus, the adhesion power of the patch 1 during its application is not reduced by a long storage period. In addition, the adhesion power in the presence of water is relatively reduced, which facilitates the removal of patch 1 without pain. It is possible to use any hydrophilic powder 2 that turns into an adhesive in contact with a moist medium and that makes it possible to adhere and maintain the patch 1 on the skin. The hydrophilic powder 2 is preferably a biocompatible and inert powder, it does not interact with the active ingredients of the substance 3 and does not create side reactions either. The hydrophilic powder 2 is advantageously a hydrocolloid or a hydrogel, that is to say that it comprises water-soluble polymer chains. The hydrophilic powder may especially comprise the following compounds: cellulose gum (in particular diffused under the commercial reference blanose), ethylcellulose (in particular diffused under the commercial reference ethocel), hydroethylcellulose (in particular diffused under the commercial reference (natrosol), a copolymer of N-vinyl-2-pyrrolidone and of vinyl acetate (especially diffused under the reference commercial Plasdone S-630), and / or a polymer of 1-vinyl-2-pyrrolidone (especially diffused under the commercial reference Plasdone K-29/32).

Water intake can be achieved by various means: natural (perspiration, perspiration of the user during application) or artificial (external water supply, for example by means of a spray, glove, cotton, gel or moisturizer advantageously comprising more than 80% water). An artificial water supply can also be achieved by providing the patch 1 with a reservoir (not shown) and placed in line with the hydrophilic powder 2. The reservoir then includes an aqueous solution. The reservoir may be formed of a tear-off envelope so as to imbibe the hydrophilic powder 2.

In the example of FIG. 1, the hydrophilic powder 2 is integral with the periphery of the support 4. The hydrophilic powder 2 is disposed on the periphery of the application face of the support 4 and surrounds a surface covered with the substance 3. The periphery of the application face of the support 4 thus serves as a fastener on the user's skin, while the central part of the application face makes it possible to press the substance 3 against the skin of the user.

As illustrated in Figure 2, the patch 1 advantageously comprises a sealed package 5 in which the support 4 is disposed. This conditioning 5 makes it possible to keep the hydrophilic powder 2 dry before the use of the patch 1. The packaging also protects the substance 3. The packaging 5 may have a zone of weakness intended to facilitate its tearing.

FIG. 3 illustrates another embodiment of a patch 1 according to the invention. According to this embodiment, the patch 1 comprises pads 6 of hydrophilic powder distributed on the application side of the support 4. The pads 6 are distributed in a surface covered by the substance 3. Thus, the substance 3 is always close of a stud 6, which thus guarantees its good veneer against the skin of a user.

FIG. 4 illustrates another embodiment of a patch 1 according to the invention. In this example, the application face of the support 4 is covered with a powder 7, comprising a mixture of the hydrophilic powder and the substance. Thus, a uniform adhesion of the powder 7 to the skin is ensured, which ensures a homogeneous application of the substance on the skin. In addition, the adhesion surface is thus optimized, which ensures a good maintenance of the patch 1 while avoiding a local concentration of efforts during the tearing of the patch 1. In these various embodiments, it can be provided that the Application side of the support 4 has electrostatic properties. It can then be provided that the hydrophilic powder 2 (and optionally the substance 3 in the form of powder) is kept in contact with the application face by electrostatic forces, as described in patent EP 1 367 944. Other modes of application of the hydrophilic powder 2 can also be envisaged.

Although the support 4 illustrated in FIGS. 1 to 4 is flat, other geometries may also be envisaged, in particular supports comprising a depression forming a chamber, tank patches, rigid or semi-rigid supports, planar or otherwise, and in different types of materials.

In the embodiments of Figures 1 to 4, the patches are approximately comma-shaped. As illustrated in FIG. 5, such a form of patch 1 is particularly suitable for an application on the face 8 of a user, between the cheekbone of the cheek and the nasal septum.

According to a variant not illustrated, the patch may comprise a peelable adhesive film overhanging the application side of the support, and thus the powder (2) and / or the substance 3. This peelable film allows the skin to be exfoliated to remove a part of the stratum corneum. Once the film is peeled, penetration into the body of the applied substance is improved.

The patch 1 may especially be used for the vaccination of subjects, for the desensitization of subjects, or for the delivery of an active substance, such as in particular biologically active and / or antigenic (poly) peptides, for example. The patch can thus be used for the vaccination of subjects against any pathogen. Thus, a particular object of the invention lies in a method of vaccinating a subject against a pathogen, comprising (i) the application of a patch according to the invention to the skin of a subject, the patch comprising an antigen specific for said pathogen, (ii) maintaining the patch for a period of time allowing the transfer of the antigen into the skin. If necessary, an exfoliation step will precede the step of maintaining the patch. The pathogen may be of a varied nature (virus, bacterium, parasite, etc.) and the antigen is typically of a polypeptide or lipid nature. The patch can also be used for desensitizing subjects to allergens. The patch can also be used for the delivery of any active substance. The substance is typically of a polypeptide nature, such as a hormone, a cytokine, a growth factor, a trophic factor, etc. Although the illustrated embodiments detail a patch for the application of an active substance, the invention also applies to a patch free of such substance. Thus, a patch according to the invention may also be covered only with the hydrophilic powder, in particular for moisturizing the skin of the user for cosmetic applications. The format of such a patch is then advantageously occlusive. An occlusive patch is for example obtained by arranging the hydrophilic powder on the periphery of the application face of the support. As in the embodiment of FIG. 3, the hydrophilic powder may also form studs distributed on the application face of the support. As in the embodiment of Figure 4, the hydrophilic powder may also be disposed over the entire surface of the support. Such a patch may also include a sealed package in which the carrier and the hydrophilic powder are included.

The process for manufacturing a patch according to the invention typically comprises a step of applying a hydrophilic powder to all or part of the application face of a support. In a particular embodiment, the method also comprises the application of a biologically active substance to the application side of the patch support. Any powdering method known per se can be used. The hydrophilic powder may be secured to the periphery of the support, for example so as to surround a surface covered with an active substance. Furthermore, the hydrophilic powder can be applied to the support to form pads distributed on the application side of the support. These pads can be formed in a surface covered by the substance active. The areas of active substance and hydrophilic powder can be defined by powdering devices forming different patterns or using patterns.

It is also possible to apply a mixture of hydrophilic powder and a powder including an active substance on the application side of the support. The application of a powder mixture is particularly suitable for a patch having a flat support.

The hydrophilic powder and the active substance may also be applied to the application side of the support during successive distinct steps.

Claims

1. Patch (1) for cutaneous application, characterized in that it comprises:

a hydrophilic powder (2) acquiring an adhesion power in the presence of water;

a support (4) having an application face on which the hydrophilic powder (2) is arranged.

2. Patch according to claim 1, wherein the hydrophilic powder (2) is disposed on the periphery of the application face of the support (4).

3. Patch according to claim 1 or 2, wherein the hydrophilic powder forms pads (6) distributed on the application side of the support (4).

4. The patch of claim 1, wherein the hydrophilic powder (2) is disposed over the entire surface of the application face of the support (4).

5. Patch according to one of claims 1 to 4, characterized in that it further comprises a biologically active substance (3).

6. The patch of claim 5, wherein the substance (3) is a powder (7) mixed with the hydrophilic powder (2).

7. The patch of claim 5, wherein the substance (3) is disposed on a (s) zone (s) of the application side of the distinct support (s) of the hydrophilic powder (2).

8. Patch according to any one of the preceding claims, wherein the support (4) has a comma shape.

The patch of any preceding claim, wherein the hydrophilic powder (2) comprises water soluble polymer chains.

The patch of claim 9 wherein the hydrophilic powder (2) comprises cellulose gum, ethylcellulose, hydroethylcellulose, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and / or a 1-vinyl-2-pyrrolidone polymer.

11. The patch according to claim 1, further comprising a reservoir containing an aqueous solution placed directly above the hydrophilic powder.

A patch according to any one of the preceding claims, comprising a water-vapor-tight package (5) in which the support (4) and the hydrophilic powder (2) are included.

13. A method of manufacturing a patch (1), comprising the application of a hydrophilic powder acquiring adhesion in the presence of water on all or part of the application side of the patch support.

14. The method of claim 13, wherein the hydrophilic powder is applied on the periphery of the application face or in the form of pads distributed on the application side of the support.

15. Method according to one of claims 13 to 14, further comprising a step of applying a biologically active substance on the face of the support.

16. The method of claim 15, characterized in that the substance is applied in powder form in admixture with the hydrophilic powder.

17. The method of claim 15, characterized in that the substance and the hydrophilic powder are applied successively.

18. Method according to one of claims 13 to 17, characterized in that the powder and / or the substance are maintained on the support by electrostatic type forces.

19. Use of a patch according to one of claims 1 to 12 for the preparation of a product for vaccination, for desensitization or for the delivery of any active substance to a subject, or for the hydration of the skin.