Improved patch and method for using same to deliver active agents to the skin - Patents.com

Abstract

The present invention relates to a patch for administering an active agent to the skin of a subject, which simplifies manufacture, improves reproducibility of results, facilitates application of the patch to a subject, increases consistency of application, and demonstrates improved initial and long-term adhesion with reduced risk of premature delamination.

Description

[Technical field]

[0001] The present invention relates generally to patches for the delivery of active agents to a subject using the skin, a body part, and in particular to the use of patches to provide immunotherapy via a transdermal route. [Background technology]

[0002] DBV Technologies, the assignee of the present application, has pioneered the use of patches containing small amounts of allergens, such as biological substances, or food proteins, such as milk or peanut proteins, in water-soluble form, without adjuvants, electrostatically deposited on a substrate surface. Such patches may be used to determine a subject's immune response to exposure to an allergen, or to administer immunotherapy, where the subject wears the patch providing skin exposure to the allergen for weeks or months to promote tolerance to the allergen.

[0003] For example, U.S. Patent No. 7,635,488 describes a patch comprising a support that includes a central portion on which the allergen is coated as a solid dry deposit and a peripheral portion that can be adhesively bonded to the skin. When the peripheral portion is attached to the skin of a subject, the central portion of the support forms an occlusive or condensation chamber. The patch is worn for a specified period of time during which sweat exuded from the skin subject condenses in the chamber, solubilizing the solid deposit of allergen coated on the inner surface of the central portion of the support, allowing the allergen to contact the skin and penetrate the epidermis. U.S. Patent No. 8,968,743 describes the use of such a patch to deliver a vaccine via a transdermal route.

[0004] Such patches further include a circular foam ring disposed on the backing and acting as a waterproof joint between the backing of the patch and the subject's skin, whereby a sealed chamber defined as an occlusion or condensation chamber is obtained when the patch is applied to the skin.

[0005] It is important that the patch remain on the subject's skin for a predetermined period of time to provide the desired effect to the subject, however, to date, patch adhesion has been insufficient, resulting in inconsistent adhesion of the patch to the subject's skin and sometimes premature detachment.

[0006] It would therefore be desirable to provide a patch that improves consistency of delivery of active ingredients to the skin, handling of application, and ease of use.

[0007] It would also be desirable to provide a patch that facilitates application of the patch to a subject and increases consistency in application of the patch to a subject.

[0008] Additionally, it would be desirable to provide a patch with improved adhesion during the period of wear, reducing the risk of premature detachment from the subject's skin.

[0009] It would still further be desirable to provide a patch that is more resistant to abrasion caused by the subject's clothing rubbing against the patch, thereby further reducing the risk of the patch becoming dislodged. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] U.S. Patent No. 7,635,488 [Patent Document 2] U.S. Patent No. 8,968,743 [Patent Document 3] European Patent No. EP0051935A2 [Patent Document 4] British Patent No. GB2128479A Summary of the Invention [Means for solving the problem]

[0011] It is an object of the present invention to provide a patch for delivering a biologically active substance to the skin of a subject, the patch comprising a substrate, a biologically active substance disposed on the substrate, a foam ring having a periphery, a first skin-facing surface, and a first layer of adhesive disposed on the first skin-facing surface, the foam ring disposed under the substrate and which, when applied to the skin of a subject, forms an occluded or condensation chamber in which the biologically active substance is disposed, a breathable film disposed over the substrate and having an outer surface, a second skin-facing surface opposite the outer surface, and a second layer of adhesive disposed on the second skin-facing surface, and a paper applicator removably disposed on the outer surface of the breathable film. and a paper applicator having an opening with an inner edge, the paper applicator configured to apply the patch to the skin of a subject, a breathable film covering the substrate and a foam ring, the opening of the paper applicator surrounding and concentric with the foam ring, and the paper applicator having an opening, such as a V-shaped notch, to facilitate removal of the breathable film from an outer surface.

[0012] The present invention also relates to a patch for delivering a biologically active substance to the skin of a subject, the patch comprising: (i) a biocompatible substrate; (ii) a biologically active substance disposed on the substrate; (iii) a biocompatible foam ring having a periphery, or outer edge, skin-facing surface, and a layer of a biocompatible adhesive disposed on a first skin-facing surface, the foam ring disposed beneath the substrate, the foam ring forming a chamber in which the biologically active substance is disposed when the foam ring is applied to the skin of a subject; and (iv) an outer surface, a second skin-facing surface, The patch includes a biocompatible breathable film having a layer of a biocompatible adhesive disposed on a second skin-facing surface and a second skin-facing surface, and (v) a paper applicator removably disposed on the outer surface of the breathable film, the paper applicator having an opening with an inner edge, the paper applicator configured to apply the patch to the skin of a subject, the breathable film covering the substrate and the foam ring, the opening being around and concentric with the foam ring and forming a gap between the inner edge of the paper applicator and the periphery of the foam ring. Advantageously, the paper applicator has an open notch, such as a V-shaped notch, on the inner edge to facilitate removal of the breathable film from the outer surface.

[0013] The present invention also relates to a patch for delivering a biologically active substance to the skin of a subject, the patch comprising: a substrate; a biologically active substance disposed on the substrate; a foam ring having a periphery, a first skin-facing surface, and a first layer of a biocompatible adhesive disposed on the first skin-facing surface, the foam ring disposed beneath the substrate, the foam ring forming an occluded chamber when applied to the skin of the subject; a breathable film having an outer surface, a skin patient-facing surface, and a second layer of a biocompatible adhesive disposed on a second skin-facing surface; and a paper applicator removably disposed on the outer surface of the breathable film and configured to apply the patch to the skin of the subject, the paper applicator having an opening notch, such as a V-shaped notch, to facilitate removal of the breathable film from the outer surface.

[0014] According to the present invention, the opening notch extends partially on the paper applicator from an edge (inner edge or outer edge) of the paper applicator. The opening notch is open at the edge of the paper applicator and extends partially toward the opposite edge of said paper applicator. For example, the opening notch can be a U-shaped notch, a V-shaped notch, etc.

[0015] In accordance with the present invention, the patch comprises successive layers that cooperate with each other to improve adhesion of the patch to the subject's skin.

[0016] Considering the shortcomings observed with previously known patches, the patch made according to the present invention simplifies the manufacturing and improves the reproducibility of the patch for allergy testing or for providing delivery of active substances to the skin, such as the epidermis, as in transdermal immunotherapy. In particular, the patch of the present invention facilitates smooth and consistent application of the patch to the subject, improves long-term adhesion over the wearing time, and reduces the risk of premature detachment. "Long-term" means over the course of treatment, for example, over several hours, a day, or even longer than a day. Furthermore, the patch of the present invention shows improved resistance to detachment caused by the subject's clothing rubbing against the patch.

[0017] According to the principles of the present invention, the patch comprises multiple layers that are advantageously fabricated to have a round or rounded rectangular shape that reduces right angles that may otherwise cause premature loss of adhesion or result in the focal point lifting or rolling up due to friction caused by rubbing against clothing. The patch of the present invention generally comprises a substrate on which a predetermined amount of active agent of interest is deposited as a solid. A foam ring is bonded to the substrate around the active agent, thereby providing a preformed occlusion or condensation chamber that can be sealed against the skin to prevent water from entering. The foam ring and substrate may have substantially the same outer diameter.

[0018] The substrate may comprise any suitable material or combination of materials for supporting the active agent, and may be preferably bonded to the foam ring, for example, via an adhesive on the adjacent surface of the foam ring. For example, the substrate may comprise a polymer selected from cellulose plastics (such as cellulose acetate (CA) or cellulose propionate (CP)), polyvinyl chloride (PVC), polypropylene, polystyrene, polyurethane, polycarbonate, polyacrylates (such as polymethylmethacrylate (PMMA)), polyesters, polyethylene (PE), polyethylene terephthalate (PET), or fluoropolymers (such as polytetrafluoroethylene (PTFE)). The substrate may further comprise a conductive layer, for example, a coating comprising a metal layer or metal or metal oxide particles, such as titanium oxide, aluminum, or gold, to facilitate deposition of the active agent by electrospray. In one particular embodiment, the substrate comprises polyethylene terephthalate and a titanium layer coating on its skin-facing surface.

[0019] The foam ring may include any suitable combination of foam or biocompatible polymeric materials. In particular, the foam or polymeric materials may be or include polyethylene vinyl acetate (PEVA), low density polyethylene (LDPE), polypropylene (PP), polyethylene (PE), silicone, or mixtures thereof.

[0020] Advantageously, the ratio between the outer diameter and the inner diameter of the foam ring may be from about 1.20 to about 1.75, such as about 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, or 1.75. The thickness of the foam ring is sufficient to form a condensation or occlusion chamber between the subject's skin and the inner diameter of the foam ring when the patch is applied to the subject's skin.

[0021] The assembly is maintained on the skin by a breathable film covering the substrate. More specifically, the breathable film extends beyond the outer edge of the foam ring and adheres the patch to the subject's skin beyond the periphery of the foam ring. The dimensions of the breathable film are adapted to the dimensions of the foam ring such that the breathable film completely covers the foam ring and extends beyond the foam ring. For example, the diameter or a larger dimension of the breathable film is at least 10% larger than the diameter of the foam ring, such as 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% or more. In particular, the diameter or a larger dimension of the breathable film may be about 65%, ±5% higher than the diameter of the foam ring.

[0022] Advantageously, the breathable film has rounded or rounded corners.

[0023] The adhesive layer on the foam ring and / or the breathable film may comprise an acrylic adhesive, a hydrocolloid adhesive, a polyurethane adhesive, or a silicone adhesive.

[0024] The patch may be provided in a ready-to-use form with a release liner in a protective role that is removed to expose the sticky surface of the foam ring and the adhesive layer of the breathable film. The patch further comprises a paper applicator associated with the non-sticky surface of the breathable film. This paper applicator improves the stiffness of the patch, facilitating handling, and may then be removed by a caregiver while leaving the patch attached to the subject's skin. By "configured to apply the patch to the subject's skin" it is meant that the paper applicator of the patch comprises a means for at least partially recovering the breathable film to temporarily provide a slight stiffness to the patch to facilitate handling, and allowing peeling from the breathable film.

[0025] The paper applicator has a substantially ring shape (e.g., circular or oval) to match the shape of the breathable film. The paper applicator has a central opening that is circular or oval in shape. The paper applicator is configured such that the opening of the paper applicator matches with the foam ring.

[0026] The width of the paper applicator, corresponding to the dimension extending radially from the outer edge to the inner edge of the paper applicator (i.e., the edge bounding the aperture), may be about 5% to about 20%, such as about 8%, 9%, 9.5%, 10%, 12%, 15%, 15.5%, 16%, 17%, 18%, 19%, of the larger dimension of said paper applicator. That is, the larger dimension, i.e., diameter, of the aperture of the paper applicator may be about 80% to 95%, such as about 81%, 82%, 83%, 84%, 84.5%, 85%, 88%, 90%, 90.5%, 91%, 92%, of the larger dimension of said paper applicator. For example, the width of the paper applicator is from about 8% to about 16%, such as from about 9% to about 9.5%, or from about 15% to about 15.5%, of the larger dimension of the paper applicator.

[0027] The larger dimension of the opening is strictly larger than the diameter of the foam ring (e.g., at least 105%, at least 110%, at least 125%, or at least 150% of the outer diameter of the foam), so that the portion of the breathable film that forms a crown around the foam ring (herein "gap") extends around and between the inner edge of the paper applicator and the periphery of the foam ring. In particular, the width of the gap (i.e., the distance between the inner edge of the paper applicator and the periphery of the foam ring) may be about 1 / 4 to 2 / 3 of the distance between the outer edge of the breathable film and the periphery of the foam ring, e.g., between 1 / 3 to 1 / 2, or between 1 / 2 to 2 / 3 of the distance between the outer edge of the breathable film and the periphery of the foam ring. The width of the gap may be constant around the entire circumference of the foam ring, or the width of the gap may vary around the foam ring, being larger in some areas and smaller in others. In certain embodiments, the gap has a round shape. In another embodiment, the gap has a rectangular shape.

[0028] The width of the paper applicator can be about 10% to about 200% of the width of the gap between the foam ring and the paper applicator, for example, about 20% to about 180% of the width of the gap, or about 50% to about 150% of the width of the gap, or about 80% to about 120% of the width of the gap, or about 90% to about 110% of the width of the gap, or about 100% of the width of the gap. For example, the width of the paper applicator is about 10% to about 95%, such as about 20% to about 95%, or about 50% to about 95%, of the width of the gap.

[0029] In certain embodiments, the width of the paper applicator covers approximately half the distance that the breathable film extends beyond the outer edge of the foam ring.

[0030] The paper applicator may comprise any suitable material, such as a combination of materials, such as siliconized paper (e.g., paper coated on one or both sides with silicone and optionally including a hydrophobic coating such as PTFE).

[0031] According to the present invention, the paper applicator may have an opening notch, such as a V-shaped notch, to facilitate removal of the breathable film from the outer surface. The notch may be managed on the inner edge or the outer edge of the paper applicator. In particular, the opening notch may be oriented radially to the inner edge of the paper applicator and extend partially from the inner diameter of the paper applicator toward its outer diameter. Alternatively, the opening notch may be oriented radially to the outer edge of the paper applicator and extend partially from the outer diameter of the paper applicator toward its inner diameter.

[0032] In particular, the opening notch is a V-shaped notch, which may lead to either the inner or outer edge of the paper applicator and may be radially oriented to extend from the inner diameter of the paper applicator partially toward its outer diameter, or vice versa. The V-shaped notch may be formed at an angle α of about 45°±10° to facilitate gripping of the edge of the notch. Additionally, the apex of the V-shaped notch may be curved (e.g., a rounded apex) to avoid sharp edges that may hinder manufacturing.

[0033] The apex of the notch may be aligned with one or several continuous slits extending radially from the apex of the notch to the outer edge (or inner edge) of the paper applicator. Advantageously, the slits do not extend completely across the width of the paper applicator, thereby ensuring that the paper applicator cannot come free during manufacturing. These slits may facilitate further peeling of the paper applicator after the patch is attached to the subject's skin. The notches and optional slits allow for the paper applicator to be removed with reduced shear applied to the breathable film and / or foam ring.

[0034] In particular, the paper applicator comprises a plurality of aligned, discontinuous slits extending radially in succession from an edge of the paper applicator towards an open notch, advantageously one of said plurality of slits being open at an end or apex of the notch.

[0035] For example, a paper applicator may include a V-shaped notch and a number of aligned slits, one of which opens on the apex of the V-shaped notch.

[0036] In particular, the paper applicator comprises an open notch, such as a V-shaped notch, and two consecutive slits. The open notch is oriented radially on the paper applicator, with the open end of the notch leading to a first edge of the paper applicator. The first slit extends radially from the closed end, or apex, of the notch, partially toward the opposite edge (i.e., the second edge) of the paper applicator. The second slit extends radially between the first slit and the second edge. The first slit may open on the apex of the notch. Alternatively or in addition, the second slit may open on the second edge.

[0037] The distance between two consecutive slits depends on the number of slits, the size of each slit, and / or the distance between the apex of the notch and the opposite edge of the paper applicator. For example, the open notch extends radially from the edge of the paper applicator over a portion of 40% to 60% of the width of the paper applicator. The paper applicator further comprises two consecutive slits. The first slit extends from the apex of the notch and has a length of about 10% to about 15% of the width of the paper applicator, and the second slit has a length of about 10% to about 15% of the width of the paper applicator. The uncut portion of the paper applicator extending between the two consecutive slits has a length of about 10% to about 25% of the width of the paper applicator.

[0038] Advantageously, the outer edge of the paper applicator overlaps the outer edge of the breathable film.

[0039] Further in accordance with the principles of the present invention, the release liner includes a slit that facilitates peeling the liner from the patch to expose the foam ring and the adhesive side of the breathable film without substantially distorting the film. In particular, the slit may be asymmetrically positioned to be offset from the portion of the substrate that defines the condensation chamber. This may inhibit moisture from entering the condensation chamber through the slit. The slit may overlap the foam ring to facilitate peeling the release liner from the remainder of the assembly.

[0040] In addition, in a non-limiting example, the paper applicator is configured in the shape of a ring having a width of about one-half the width of the film that extends beyond the outer edge of the foam ring. The paper applicator may also include radially oriented notches, e.g., having a V-shape, such that the paper is not completely split, but only cut on both sides, and is easily torn by hand, facilitating peeling of the paper applicator from the outer surface of the breathable film after the patch is applied to the subject's skin. Advantageously, the paper applicator is configured such that the patch does not lift off the subject's skin when the applicator is removed.

[0041] The slit on the release liner is advantageously located on the first half of the patch, while the opening notch and optional slit on the paper applicator are preferably located on the second opposite half of the patch. Alternatively or in addition, the longitudinal axis of the slit on the release liner extends perpendicular to the longitudinal axis of the opening notch of the paper applicator. Thereby, the removal of the release liner does not distort the part of the paper applicator that has the opening notch. This limits the risk of the paper applicator peeling off in an uncontrolled and / or undesirable manner.

[0042] In one particular embodiment, the patch is round or rectangular in shape; - the diameter or larger side of the breathable film is between 40mm±5mm and 55mm±5mm, preferably between 45mm±1mm and 50mm±1mm; - the outer diameter of the foam ring is between 20mm±5mm and 35mm±5mm, preferably between 25mm±1mm and 30mm±1mm; the inner diameter of the foam ring (corresponding to the diameter of the obstruction chamber) is between 15 mm ± 5 mm and 25 mm ± 5 mm, preferably between 18 mm ± 1 mm and 20 mm ± 1 mm; - the diameter of the substrate is substantially equal to the outer diameter of the foam ring; - The outer edge of the paper applicator overlaps the outer edge of the breathable film, - the diameter or larger dimension of the opening of a paper applicator is between 30 mm ± 5 mm and 52 mm ± 5 mm, such as between 32 mm ± 1 mm and 44 mm ± 1 mm, or between 38 mm ± 1 mm and 52 mm ± 1 mm. The paper applicator may have an open notch, such as a V-shaped notch, directed radially from the inner edge of the paper applicator partially toward its inner diameter, and one or two slits may extend radially from the apex of the V-shaped notch toward the outer edge of the paper applicator.

[0043] The active substance may be disposed on the substrate in any suitable manner. In one non-limiting example, the biologically active substance may be attached to the substrate by electrostatic forces. However, it will be understood that the biologically active substance may be applied in any suitable manner, such as, for example, spraying and drying, or using an adhesive. In some examples, the biologically active substance is selected from an allergen, an antigen, or a biologically active polypeptide (or peptide). The substance may include particles.

[0044] Preferably, the patches are prepared and / or stored in a single-use tear-away pouch, typically under vacuum or an inert atmosphere such as dry nitrogen.

[0045] The above, and other advantages of the present invention will become apparent after consideration of the following detailed description when read in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout. [Brief description of the drawings]

[0046] [Figure 1A] FIG. 1 is a plan view of one embodiment of a reference patch employed in clinical trials of transdermal immunotherapy. [Figure 1B] FIG. 1 is a cross-sectional view of one embodiment of a reference patch employed in clinical trials of transdermal immunotherapy. [Figure 2A] FIG. 1B is a perspective view of the patch of FIG. 1A. [Figure 2B] FIG. 1C is an exploded perspective view of the patch of FIG. [Figure 3A] FIG. 2 is a plan view of a patch according to an embodiment of the present invention. [Figure 3B] FIG. 3B is a plan view of notch detail A shown in FIG. 3A. [Figure 4] FIG. 3C is an exploded perspective view of the patch of FIGS. 3A and 3B. [Figure 5A] FIG. 2 is a plan view of a patch according to another embodiment of the present invention. [Figure 5B] FIG. 5B is a plan view of notch detail B shown in FIG. 5A. [Figure 6] FIG. 5C is an exploded perspective view of the patch of FIGS. 5A and 5B. [Figure 7] FIG. 5 is a perspective view of the patch of FIGS. 3A-3B and 4. [Figure 8] FIG. 8 is a side view of the patch of FIG. [Figure 9] FIG. 8 is a side view of the patch of FIG. [Figure 10] FIG. 8 is a side view of the patch of FIG. [Figure 11] FIG. 8 is a side view of the patch of FIG. [Figure 12] FIG. 8 is a top view of the patch of FIG. 7. [Figure 13] FIG. 8 is a rear view of the patch of FIG. [Figure 14] FIG. 8 is an exploded perspective view of the patch of FIG. 7. [Figure 15] FIG. 7 is a perspective view of the patch of FIGS. 5A-5B and 6. [Figure 16] FIG. 16 is a side view of the patch of FIG. 15. [Figure 17] FIG. 16 is a side view of the patch of FIG. 15. [Figure 18] FIG. 16 is a side view of the patch of FIG. 15. [Figure 19] FIG. 16 is a side view of the patch of FIG. 15. [Figure 20] FIG. 16 is a top view of the patch of FIG. 15. [Figure 21] FIG. 16 is a rear view of the patch of FIG. 15. [Figure 22] FIG. 16 is an exploded perspective view of the patch of FIG. 15. [Figure 23] FIG. 2 is a schematic illustrating an intermediate operation in the application of a reference patch (previously contemplated by the applicant) showing the removal of a release liner from the edge of the breathable film. [Figure 24] FIG. 2 is a schematic illustrating an intermediate operation in the application of a reference patch (previously contemplated by the applicant) showing the removal of a release liner from the edge of the breathable film. [Diagram 25] FIG. 2 is a schematic illustrating an intermediate operation in applying a reference patch (previously contemplated by the applicant), illustrating the peel fronts and their concentration near the condensation chamber. [Figure 26] 1A-1D are schematic illustrations of intermediate operations in applying a patch of the invention; FIG. 1C illustrates an embodiment of the patch of the invention; [Figure 27] 1A-1D are schematic illustrations of intermediate operations in the application of a patch of the present invention, illustrating the removal of a release liner. [Figure 28] 1A-1D are schematic illustrations of intermediate operations in the application of a patch of the present invention, illustrating the removal of a release liner. [Figure 29] 1 illustrates an exemplary patch design in accordance with the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] A patch constructed according to the principles of the present invention provides an improvement over the patches described in commonly assigned U.S. Patent Nos. 7,635,488 and 8,968,743. As described herein, the improvement is to reduce the risk of premature detachment by methods including simplifying manufacturability, improving reproducibility of results for allergy testing or providing transdermal immunotherapy ("EPIT"), promoting and enhancing consistency of application of the patch to a subject, and / or exhibiting improved long-term adhesion during treatment, and / or providing improved resistance to detachment caused by the subject's clothing rubbing against the patch while reducing uncomfortable levels of pain upon removal.

[0048] As used herein, the term "transdermal" is intended to mean applied to the skin. Transdermal administration typically involves application to the skin under conditions sufficient to allow the compound to penetrate or diffuse into at least the superficial layers of the skin, such as the stratum corneum and optionally one or more other epidermal layers.

[0049] As used herein, the term "biocompatible" is intended to mean not harmful to living tissue.

[0050] As used herein, the term "breathable" is intended to mean permeable to water vapor, e.g., having a non-zero water vapor transmission rate.

[0051] As used herein, the term "ring" is intended to mean a structure that encloses an area. The ring may have any suitable shape, such as a substantially circular, substantially oval, substantially rounded square, substantially rounded rectangular, or the like. The ring may have an outer or exterior edge and an inner or interior edge. The shapes of the outer and interior edges may be similar to each other or different from each other. "Rounded" means having a radius of curvature that is compatible with circular and rectangular patch shapes, as opposed to sharp right-angled corners. For example, the rounded shape may have a radius of curvature of at least about 10% of the patch dimension, or at least about 20% of the patch dimension, or at least about 50% of the patch dimension, illustratively at least about 5 mm, at least about 9 mm (e.g., for a rounded rectangular patch having a size of about 36 mm by about 44 mm), or at least about 22 mm (for a circular patch having a diameter of about 44 mm).

[0052] As used herein, the terms "substantially," "approximately," "approximately," and "about" used throughout this specification are used to describe and take into account small changes or variations, such as those due to dimensional variations. For example, these may refer to ±10% or less, such as ±5% or less, such as ±2% or less, such as ±1% or less, such as ±0.5% or less, such as ±0.2% or less, such as ±0.1% or less, such as ±0.05% or less.

[0053] As used herein, the terms "biologically active substance", "active substance", "active ingredient" and similar terms are intended to mean a substance for diagnostic, therapeutic or prophylactic purposes. The biologically active substance or component may be an allergen, an antigen, a small molecule drug, or any therapeutic substance of interest such as a hormone, an aptamer, an antibody, or the like. The biologically active substance may be a peptide, a polypeptide including a recombinant protein, an oligo- or polysaccharide, a nucleic acid, or the like. The biologically active substance or component may be an isolated molecule or even an extract such as a protein extract. The biologically active substance or component may be combined with any suitable excipient. In a preferred embodiment, the biologically active substance is selected from an allergen, an antigen, or a biologically active polypeptide (or peptide). For example, the biologically active substance may be a food allergen such as an allergen from egg, milk, or peanut, a protein extract obtained from such food, or an aeroallergen such as an allergen from dust mites or pollen. The patch of the present invention may be used to provide desensitization, i.e., to increase tolerance to a given allergen, in a subject who has an allergy to said allergen. In other embodiments, the biologically active substance may be derived from a pathogen, such as a pathogenic bacterium or virus, and the patch is used in a method to provide vaccination against such pathogens.

[0054] As used herein, the term "open notch" refers to a notch that is not completely cut, including an end opening on an edge (inside or outside) of a paper applicator. The open notch extends from an end of the paper applicator partially toward the opposite edge of said paper applicator. In other words, the open notch does not extend across the entire width of the paper applicator. The open notch may have any shape that indicates an open end, such as U-shaped, V-shaped, etc.

[0055] As described below, in some examples, the biologically active substance is "dry layer coated". For example, the substance can be either available as a dry layer or transformed or processed (e.g., through freeze drying, heating and spraying, micronization, etc.) to become a dry layer. For example, the substance can be in a solid state, typically in the form of aggregates or aggregated particles. In other examples, the active substance can be in the form of a liquid or semi-solid (e.g., a gel, jelly, foam, or paste). The active substance can be applied to the relevant non-tacky portion of the substrate in any suitable manner, where it can be dried to form a solid or maintained in liquid or semi-solid form. In some examples, the active substance is not mixed with an adhesive, excipient, or other ingredient. In some other embodiments, the active substance is present in combination with one or several pharma- ceutically acceptable excipients.

[0056] This material may be naturally or commercially available in the form of a dry layer, i.e. in the form of individualized particles, which does not require any particular treatment or modification other than perhaps reducing the size of the particles, if necessary.

[0057] The material may alternatively be available in the form of a large solid, in which case it may be preferable to first reduce the material to individualized particles, optionally after transformation aimed at ensuring its preservation without denaturation.

[0058] In a further alternative form, the natural substance may be in liquid form. In such a situation, the substance may be freeze-dried to obtain a dry layer coating form. The dry layer coating form may be obtained by known techniques such as freeze-drying (freezing and sublimation under vacuum) or heating and spraying, the choice of these techniques, especially the degree of micronization, being left to the evaluation of the skilled person as a function of the physicochemical properties of the substance under consideration.

[0059] In order to package and store the patch, and in particular to avoid alterations of the substance due to the surrounding air, the particles are typically subjected to a specific treatment, such as freeze-drying, more particularly any treatment known to the person skilled in the art.

[0060] Within the context of the present invention, the term "electrostatic forces" generally refers to any non-covalent force involving an electric charge. More specifically, the term refers to two types of forces that can act separately or together: the Coulombic forces between the space charge of the surface and the charged particles, and / or the Van der Waals forces between the space charge of the surface and the particles. The strength of the forces between the surface and the particles can be enhanced or lowered by the presence of a thin water film due to the presence of moisture. Generally, the patch is made and stored in a dry place. The moisture is preferably low enough to allow the active ingredient to be preserved until the patch is applied to the skin. The moisture content can be adjusted to achieve a suitable adhesion until the patch is applied to the skin.

[0061] As used herein, the term "substrate" refers to any support made of a biocompatible material suitable for supporting an active substance. In a non-limiting example, the substrate is conductive to facilitate deposition of the active substance using an electrospray process in which a voltage is applied between the substrate and an electrospray nozzle from which a liquid containing the active substance emerges that is dispensed and guided to the substrate via an electric field. After the deposition process, electrostatic forces between the substrate and the active substance may hold the active substance to the substrate until the patch is applied to the skin in a manner as described elsewhere herein to form a closure or condensation chamber. Illustratively, the substrate may include metal particles.

[0062] The patch of the present invention can be used to deliver or expose a substance through or to the skin of a mammalian subject.As described above, the substance is directly or indirectly bound to the surface of the patch through electrostatic force.In particular, the patch of the present invention comprises a support or substrate to which a biologically active substance (coated with a dry layer) is directly or indirectly bound through electrostatic force.The substrate is associated with a foam ring spacer that, together with the substrate, forms a chamber when the patch is applied to the skin of a subject, thereby allowing the release of the biologically active substance through wetting.

[0063] With reference to Figures 1A, 1B, 2A, and 2B, details of the construction of a reference patch previously contemplated by the applicant are provided as a context for clarifying the improvements described and claimed herein.

[0064] In Figure 1A, a plan view of the reference patch 10 is illustrated as looking at the surface facing away from the subject's skin when removed from its storage pouch. Figure 1B is a cross-sectional view of the patch 10, with the layers separated from one another for clarity. The patch 10 includes a breathable film 11 having a biocompatible adhesive layer 12 disposed on a skin-facing surface thereof, a label 13, a substrate 14, a foam ring 15 having an adhesive-bearing lower surface 16, and a release liner 17. The release liner 17 engages the adhesive layer 12 of the breathable film 11 and the adhesive-bearing lower surface 16 of the foam ring 15, and is peeled off prior to application of the patch 10 to the subject's skin. The biologically active substance is bound to the skin-facing surface of the substrate 14 by electrostatic forces. The foam ring 15 supports the biologically active agent on the substrate 14 so that it is not in contact with the subject's skin, so that when applied to the subject's skin, the foam ring 15 and substrate 14 form a chamber C that collects moisture emanating from the skin. The collected moisture hydrates the skin while allowing the solid active agent particles to solubilize and penetrate the patient's epidermis (the underlying stratum corneum).

[0065] 2A-2B, the patch 10 includes a paper applicator 18 lightly attached to the outwardly facing surface of the breathable film 11. The paper applicator 18 serves as a protective layer for the breathable film 11 and facilitates the caregiver in firmly attaching the patch 10 to the subject's skin. The paper applicator 18 includes an opening 19 that surrounds the periphery of the substrate 14 and the foam ring 15. In this manner, it is intended that the caregiver presses the foam ring 15 to adhere it to the skin, but does not inadvertently press down on the center of the substrate 14, crushing the biologically active material and placing it in direct contact with the subject's skin. The opening 19 is very close to the periphery of the substrate 14 and the foam ring 15. As will be explained below, during testing, it was discovered that a high degree of coverage of the paper applicator 18 over the outer surface of the breathable film 11 unintentionally places a greater tension on the breathable film 11 when the paper applicator 18 is subsequently removed. Additionally, the inventors have found that instead of providing a paper surface covering about 50% to 90% of the breathable film (surface paper to breathable film ratio), the inclusion of a conforming V-shaped notch instead of the slit in the design of Figures 2A-2B improves the conformity of the breathable film during patch application to the skin compared to the designs of Figures 1A-1B and 2A-2B.

[0066] 1A-1B and 2A-2B, patch 10 includes removable tabs 20a and 20b for gripping patch 10 when release liner 17 is removed. As further determined during subsequent testing conducted at the direction of the inventors, tabs 20a and 20b increase the effort of manipulating patch 10 in preparation for placement on a subject's skin, while at the same time making the device more complex and less manufacturable. Additionally, it was demonstrated that the shear forces applied in peeling the tabs promote peeling of edges and corners of the patch. As described below, the improved patch of the present invention eliminates removable tabs 20a and 20b, thereby reducing manufacturing effort and improving handling and repeatability of patch application.

[0067] The failure kinetics in peeling an adhesive from a surface is a well-known mechanism. Essentially, in homogeneous media, the peel front is orthogonal to the pulling direction and the peel force is proportional to the length of the peel front. In patches as described herein, peeling can occur against weakly attached layers, such as the release liner (peelable layer) protecting the wound dressing. For example, Figures 23-25 ​​illustrate in schematic form the intermediate operations in applying a patch of the invention (i.e., the reference patch). One of the problems in peeling the patch system of the invention is that it contains two regions of different adhesion and stiffness (see Figure 23). The foam ring forming the patch chamber is hard with a high adhesive load, whereas the PU adhesive (part of the dressing) is soft with a low adhesive load. Thus, when peeling of the patch from the release liner is initiated at one of its border edges (Figure 24), the peel front propagates in a straight line until it reaches the ring edge (Figure 25). Thus, the peel force can suddenly induce large concentrated tensions, causing severe distortion (wrinkling) and mechanical damage to the soft PU layer of the adhesive. This problem occurred with the reference patch when the peel tab was used to peel the patch from the release liner.

[0068] Peel tabs are commonly used in wound dressings and may be made from a peelable paper sheet that covers the adhesive of the dressing (see, for example, European Patent No. EP0051935A2). The peel tab may include a handle for applying the dressing to the skin. In such designs, the release liner is made from a single release portion that covers the entire adhesive of the dressing, including or excluding the peel tab area.

[0069] In other designs, the release liner is made in two parts, a first part disposed on one side of the dressing and a second part disposed on the remaining part of the dressing, the first part being adapted to provide a handle by which the second part can be grasped and peeled from the adhesive (see, for example, UK Patent No. GB2128479A).

[0070] In the patch of the present invention, the parting line of the release liner may not penetrate or cross the chamber, and the chamber may maintain its integrity and airtightness. For example, in the patch of the present invention (FIGS. 26-28), the parting line separating the release liner may be located on the foam ring that forms the patch chamber (FIG. 26). As such, when the patch is bent, a large portion is gripped and easily peeled off (FIGS. 27 and 28). Thus, the peel force is applied directly to the adhesive of the ring and does not lead to tension in the PU adhesive layer.

[0071] The remainder of the release liner remains attached to the foam ring, forming a stiff handle and allowing placement on the skin without significant wrinkling of the dressing. After placement on the skin, the remainder of the release liner can be peeled off while the main adhesive area is in contact with the skin.

[0072] Still referring to Figures 2A and 2B, the paper applicator 18 includes slits 21 designed to aid in removal of the paper applicator 18 after the patch 10 has been firmly attached to the subject's skin. In particular, the slits 21 were designed to facilitate peeling of the paper applicator 18 from the breathable film 11. However, as observed during early clinical trials, the slits 21 proved difficult to employ and contributed to excessive tension on the breathable film 11 during removal of the paper applicator 18. As further observed in Figures 1A, 2A, and 2B, the patch 10 includes corners 22 that are rounded but form substantially right angles. As determined during early clinical trials and subsequent laboratory testing, such as those described in the Examples below, these substantially right angle corners 22 contributed to premature loss of adhesion between the breathable film 11 and the subject's skin, as well as providing a focal point for friction between the patch 10 and clothing worn over the subject. Additionally, the V-shaped notches of the patch of the present invention are radially oriented and as such, the force applied to remove the paper applicator of the present invention is in the opposite direction to the adhesive force and has a lower magnitude, does not substantially deform the breathable film of the present invention and limits the peel force applied to the breathable film of the present invention.

[0073] 3A, 3B, and 4, an embodiment of a patch constructed in accordance with the principles of the present invention is described. Construction of patch 30 has similar components to patch 10 of FIGS. 1A-1B and 2A-2B, but is constructed based on extensive in vitro testing to improve adhesion to a subject's skin, improve handling, manufacturability, and reproducibility of results, and reduce the risk of premature delamination.

[0074] In the example illustrated in Figures 3A, 3B, and 4, patch 30 comprises a release liner 31 having a slit 32, a foam ring 33 having a biocompatible adhesive layer on a first, skin-facing surface disposed in contact with release liner 31, a substrate 34 carrying a biologically active substance on a lower, skin-facing surface 35, a breathable film 36 having an outer surface 37 and a layer of biocompatible adhesive 38 disposed on the skin-facing surface, and a paper applicator 39 disposed on the outer surface 37 of breathable film 36. It will be understood that all components of a patch of the present invention are biocompatible even if not specifically described as such.

[0075] The foam ring 33 may include any suitable combination of foam or biocompatible polymeric material suitable for spacing the substrate from the skin to define the chamber, and any suitable medical grade pressure sensitive adhesive on its upper and lower surfaces. Preferably, the foam ring 33 and the adhesive thereon have sufficient strength and flexibility so that when applied to the skin, they maintain the occlusion or condensation chamber seal even when the skin is bent or stretched. In non-limiting examples, the foam or polymeric material may be or include polyethylene vinyl acetate (PEVA), low density polyethylene (LDPE), polypropylene (PP), polyethylene (PE), or silicone. In non-limiting examples, the adhesive on the upper and / or lower surfaces of the foam ring 33 (and within other components of the patch 30) may include an acrylic adhesive, a hydrocolloid adhesive, a polyurethane adhesive, or a soft silicone adhesive. The foam ring 33 may have any suitable shape and dimensions to support the substrate 34 above the skin of the subject and form the chamber when applied to the subject. For example, the foam ring 33 may have an outer diameter between about 10 mm and about 100 mm, such as between about 20 mm and about 50 mm, or between about 20 mm and about 30 mm. Additionally or alternatively, the foam ring 33 may have an inner diameter that is at least about 1 mm smaller than any of the above outer diameters (i.e., the width of the foam ring 33 may be at least about 1 mm). In particular, the inner diameter of the foam ring 33 may be about 2 mm to 50 mm smaller than the outer diameter, or about 2 mm to 20 mm smaller than the outer diameter, or about 5 mm to 15 mm smaller than the outer diameter. In some examples, the ratio of the outer diameter to the inner diameter of the foam ring may be about 1.25 to about 1.5 (e.g., an outer diameter of about 26 mm to an inner diameter of about 18 mm, resulting in a foam ring width of about 3 mm to about 4 mm). The foam ring 33 can have any suitable thickness, for example, from about 0.1 mm to about 1 mm, for example, from about 0.5 mm to about 0.9 mm. In one non-limiting example, the foam ring 33 preferably has an outer diameter of 26 mm±5 mm, an inner diameter of about 18 mm±5 mm, and a thickness of about 0.5 mm±0.2 mm.The foam ring 33 and the substrate 34 may have substantially the same outer diameter as one another. For example, the components may be assembled together and then stamped together.

[0076] The paper applicator 39 may comprise any suitable material, combination of materials, such as siliconized paper (e.g., paper coated with silicone on one or both sides, and optionally including a hydrophobic coating such as PTFE). According to one aspect of the present invention, the paper applicator 39 has a ring shape with a V-shaped notch 40 that may be radially oriented to extend from an inner diameter 41 partially toward an outer diameter 42. As shown in FIG. 3B, corresponding to detail A of FIG. 3A, the V-shaped notch 40 preferably has a rounded apex 43 aligned with at least one slit, e.g., slits 44a and 44b, to facilitate tearing of the paper applicator 39 after the patch 30 is firmly pressed onto the subject's skin. In addition, the paper applicator 39 preferably comprises a central opening 45 having an inner diameter at least about 1 mm larger than the outer diameter of the foam ring 33 to provide a gap of at least about 1 mm between the foam ring and the paper applicator. The inner diameter of the paper applicator 39 may be, for example, about 1 mm to about 20 mm larger than the outer diameter of the foam ring 33, or about 2 mm to about 10 mm larger than the outer diameter of the foam ring 33, or about 3 mm to about 5 mm larger than the outer diameter of the foam ring 33. The paper applicator 39 may have any suitable outer diameter that is at least 1 mm larger than the inner diameter of the paper applicator 39 (i.e., the paper applicator 39 may have a width of at least 1 mm). For example, the paper applicator 39 may have a width of about 1 mm to about 20 mm, or about 2 mm to about 10 mm, or about 3 mm to about 5 mm. In some examples, the width of the paper applicator 39 is about 10% to about 95% of the gap 46, for example, about 20% to about 95% of the gap 46, or about 50% to about 95% of the gap 46. In one non-limiting example, the width of the paper applicator 39 is selected to cover approximately half the distance that the breathable film 36 extends beyond the outer edge of the foam ring 33 (i.e., to have approximately the same width as the gap 46), and to have a minimum width of 3 mm to provide sufficient stiffness for easy handling.In one non-limiting example, the paper applicator 39 may have an inner diameter, corresponding to the diameter of the aperture, of about 30 mm to 40 mm (e.g., about 35 mm) and a width of about 2 mm to 4 mm (e.g., about 3 mm), thereby providing a gap 46 (see FIG. 3A) of about 4 mm to 5 mm (e.g., about 4.5 mm) to the periphery of the foam ring 33. As described below, the width of the paper applicator 39 and / or the size of the gap 46 may contribute to better control of the placement of the patch 30 during initial placement and to better adhesion over time, improving manufacturability and uniformity of results compared to patch 10 as described in the Examples below.

[0077] In particular, during initial clinical trials of patch 10 of Figures 1A-1B and 2A-2B, it was observed that after a relatively short period of time, e.g., significantly less than a 24 hour treatment period, the patch began to lose adhesion to the skin of subjects as described in the Examples below. This loss of adhesion was believed to result solely from the removal of paper applicator 18, which was peeled away from the outer surface of film 11 immediately after patch 10 was applied. In addition, removal of the peel tab was believed to have induced shear forces at the edges and corners of the patch. The loss of adhesion was believed to result from a different cause, which patch 30 of the present invention addresses. First, in patch 10, the inner diameter of opening 19 of paper applicator 18 is very close to the periphery of foam ring 15. Second, it was observed that slit 21 of paper applicator 18 was difficult to manipulate. These two features of patch 10 were observed during testing to require more force to lift paper applicator 18 off the outer surface of film 11 and more manipulation to grasp and open slit 21. Together, these features of patch 10 contributed to greater pulling forces being applied to film 11 after patch 10 was initially placed, reducing both initial and long-term adhesion.

[0078] In accordance with the principles of the present invention, as determined by in vitro testing as described in the Examples below, Applicant has determined that it is preferable to reduce the width of the paper applicator 39 in the patch 30, thereby providing a gap 46 (visible breathable film space) that reduces the coverage of the paper applicator and reduces the tension applied to the breathable film 36 and the adhesive layer 38 on the foam ring 33 upon removal of the paper applicator 39, while still providing sufficient surface and rigidity of the paper applicator to facilitate handling of the assembly during application. Thus, in some examples, the skin patch 30 preferably includes a gap 46 having a width of at least about 3.0 mm from the periphery of the foam ring 33, more preferably about 3.0 mm to 5.5 mm, e.g., about 4.5 mm, and the paper applicator 39 has a width of at least 3.0 mm, more preferably about 3.0 mm to 5.5 mm, e.g., about 4.5 mm. The V-shaped notch may extend at least 50% of the width of the paper applicator, preferably between 40% and 60%. The distance between two consecutive slits may be at least 0.1 mm, such as 0.25 mm or more, preferably between about 0.20 mm and about 1.00 mm, more preferably between about 0.5 mm and about 1.00 mm. As can be expected, the gap 46 reduces the coverage of the paper applicator 39 on the patch 30. The smaller coverage of the paper applicator 39 results in a greater initial and long-term adhesion of the patch 30 to the skin of the subject, since the force required to remove the paper applicator 39 is significantly smaller compared to that of the paper applicator 18 of the patch 10. For example, the stiffness of the paper impairs the conformability of the breathable film 36 on the skin, and therefore the larger the gap 46 in the breathable film, the easier it is to maintain the adhesive on the skin during removal of the paper applicator.

[0079] The V-notch 40 and slits 44a and 44b illustrated in FIG. 3B also contribute to long-term adhesion, manufacturability, and repeatability of initial and long-term adhesion by reducing the amount of caregiver manipulation required to peel the paper applicator 39 from the outer surface 37 of the breathable film 36. The V-notch 40 is preferably formed at an angle α of about 45° to allow the caregiver to easily grasp the edge of the notch. Additionally, the V-notch 40 preferably includes a rounded apex 43 to avoid sharp edges that may interfere with packaging. The notch 40 is also preferably adjacent to the slit 44a. The slits 44a and 44b do not extend completely across the width of the paper applicator, thereby ensuring that the paper applicator 39 cannot come free during manufacturing. The force tearing the slits 44a and 44b is applied from the center to the periphery of the patch, and therefore does not exert substantially any force on the edges or corners, as is the case with peel tab designs. The orientation of the force applied by the paper applicator to the breathable film of the present invention is appropriately oriented so as to not substantially exert a shear force on the adhesive edge. In comparison, the peel tab is an extension of the breathable film 11, and the applied force induces a shear stress and deforms the breathable film in order to remove the peel tab. The paper applicator is larger and covers almost the entire surface of the breathable film 11. The patch of the present invention does not include a peel tab, and the risk of deforming the breathable film 36 during application is substantially lower. For example, the inventors have observed during in vitro testing that the configuration of the notch 40 and slits 44a and 44b significantly increases the ease with which the paper applicator 39 can be torn by a caregiver after the patch 30 is applied to a subject. In this manner, manipulation of the patch is reduced after application to the subject, and the amount of tension applied to the patch upon removal of the paper applicator 39 is further reduced compared to the patch 10.

[0080] The substrate 34 may comprise any suitable material or combination of materials for supporting the active agent, and may be preferably bonded to the foam ring 33, for example, via an adhesive on the adjacent surface of the foam ring. In some examples, the substrate 34 may comprise a polymer. Non-limiting examples of suitable polymers include cellulose plastics (such as cellulose acetate (CA) or cellulose propionate (CP)), polyvinyl chloride (PVC), polypropylene, polystyrene, polyurethane, polycarbonate, polyacrylates (such as polymethylmethacrylate (PMMA)), polyester, polyethylene (PE), polyethylene terephthalate (PET), or fluoropolymers (such as polytetrafluoroethylene (PTFE)). In non-limiting examples where electrospraying is used to deposit the active agent, the substrate 34 may comprise a conductive layer, for example, a coating comprising metal particles or metal oxide particles such as titanium oxide, aluminum, or gold, to allow positive or negative charges to be distributed on the backing during the electrospraying process and deposition of the compound of interest. In one non-limiting example, the substrate 34 of the patch 30 comprises polyethylene terephthalate and a titanium layer coating on the skin-facing surface that is used to dissipate electrical current in the electrospray process. The biologically active substance may be bound to the substrate without the use of an adjuvant, so that the substance retains its reactogenicity. In some examples, the substrate 34 is at least partially transparent, and the skin surface within the chamber may be visually inspected to monitor for potential adverse effects without removing the patch 30. In other examples, the substrate 34 is opaque. The breathable film 36 of the patch 30 preferably comprises a translucent polyurethane (or silicone) material partially coated with a biocompatible medical grade pressure sensitive adhesive and has water permeability (water vapor transmission rate). Non-limiting examples of suitable adhesives are described elsewhere herein.

[0081] Advantageously, the circular shape of the breathable film 36 avoids right angle corners, such as corner 22 of patch 10, which were observed to be initiation points for film delamination during in vitro peel testing. In particular, several test rigs were developed to create mechanical and physical constraints to simulate the rubbing of a patient's clothing against the patch when applied to a simulated subject's skin. The first test rig included a piece of fabric rubbed in a reciprocating motion over the patch and simulated skin with a reproducible force for a specified number of cycles, thereby allowing multiple patch configurations to be tested. The second test rig was developed to mimic a repetitive skin stretch constraint for a patch applied to simulated skin with different % of stretch. Patch delamination was assessed according to the number of cycles required to achieve score adhesion by visual observation. The third test rig, with a robotic arm and scratching finger, was developed to mimic a human scratching finger on a patch applied to simulated skin. Based on such simulations, some of which are further described in the Examples below, the inventors have found that the substantial elimination of right angle corners significantly increases the adhesive strength of the patch of the present invention, and that increasing the breathable adhesive surface of the patch significantly increases adhesive strength with both circular and rounded rectangular shapes. This conclusion is confirmed by in vivo test results on healthy adult human skin as described in the Examples.

[0082] In a non-limiting example, the patch 10 of FIGS. 1A-1B and 2A-2B may be approximately 1100 mm 2 whereas the patch 30 in Figs. 3 and 4 has a diameter of about 45 mm and a total patch area of ​​about 1500 mm 2 From 1520mm 2 where the increase in area is about 30% and the increase in breathable film area is about 60%. It will be understood that these values ​​are by way of example only and that other absolute and relative sizes of breathable film 36 may be used as appropriate.

[0083] Patch 30 further differs from patch 10 in that patch 30 completely eliminates peel tabs 20a and 20b, and their removal has also been observed to reduce initial adhesion during placement of patch 10. In patch 30, breathable film 36 does not include any kind of tabs. Instead, release liner 31 includes slits 32 along the ridges of the patch. The slits are asymmetrically positioned to be offset from the portion of the substrate that defines the condensation chamber, which may inhibit moisture from passing through the slits into the condensation chamber. The slits may overlap the foam ring to facilitate peeling the release liner from the remainder of the assembly. For example, a larger portion of the release liner may be removed, leaving a smaller portion of the release liner attached to the foam ring to be used as a handle for properly positioning and attaching the assembly to the skin in the manner described with reference to Figures 26-28. In one non-limiting example, the slit 32 defines a width 47 that is located diagonally to one side and in the middle of the foam ring width (about 11 mm), as depicted in Figure 3A. In this manner, the release liner 31 can be easily removed from the skin-facing surfaces of the breathable film 36 and foam ring 33 by having the caregiver slightly bend the patch and grasp the edge of the release liner exposed by the slit 32. The patch, free of most of the release liner, is then applied to the subject's skin, whereupon a small portion of the release liner can be easily removed, and the patch is then fully adhered to the skin by firmly pressing the paper applicator 39 in addition to other adhesive surfaces within the patch 30, after which the paper applicator 39 can be torn at the V-shaped notch 40 and removed from the outer side 37 of the breathable film 36.

[0084] In some examples, patch 30 optionally further comprises a label 48, illustratively "DBV" or any other suitable letter and number combination, as shown in Figure 3A, which may be printed using an inkjet printer, preferably using food grade inks, on the outer surface 37 of breathable film 36, or on the inner surface of the breathable film and / or on the adhesive on the skin-facing side of the breathable film. In one embodiment, the label information may be applied to the adhesive film 37 while still in roll form by running the breathable film through an inkjet printer before it is cut to shape.

[0085] The aforementioned features, both alone and in combination, have been determined, using in vivo and in vitro testing conducted at the direction of the assignee of the present application, to significantly enhance and improve the manufacturability, ease of handling and application, and initial and long-term adhesion of patch 30 compared to patch 10, for example, as further described in the Examples below.

[0086] 5A, 5B, and 6, a second embodiment of a patch constructed in accordance with the principles of the present invention is described. Patch 50 is constructed similarly to patch 30 of FIGS. 3A-3B and 4, and includes all of the various inventive features described above with respect to patch 30. More specifically, patch 50 includes release liner 51 having slits 52, foam ring 53 having a biocompatible adhesive layer disposed in contact with release liner 51, substrate 54 carrying a biologically active substance bonded to its lower skin-facing surface 55, breathable film 56 having outer surface 57 and layer 58 of biocompatible, medical grade, pressure sensitive adhesive disposed on its skin-facing surface, and paper applicator 65 disposed on outer surface 57 of film 56.

[0087] The foam ring 53 may be made of similar materials and have similar dimensions as described for the foam ring 33. For example, the foam ring 53 may have any suitable shape and dimensions to support the substrate 54 above the subject's skin and form a chamber when applied to the subject. For example, the foam ring 53 may have an outer diameter of between about 10 mm and about 100 mm, such as between about 20 mm and about 50 mm, or between about 20 mm and about 40 mm. Additionally or alternatively, the foam ring 53 may have an inner diameter that is at least about 4 mm smaller than any of the above outer diameters (i.e., the width of the foam ring 33 may be at least about 2 mm). Additionally, the inner diameter of the foam ring 53 may be about 2 mm to 50 mm smaller than the outer diameter, or about 2 mm to 20 mm smaller than the outer diameter, or about 5 mm to 15 mm smaller than the outer diameter. The foam ring 53 may have any suitable thickness, for example, about 0.1 mm to about 1 mm, for example, about 0.5 mm to about 0.9 mm. In one non-limiting example, the foam ring 53 may have an outer diameter of 20 mm to 30 mm (e.g., about 26 mm), an inner diameter of about 10-20 mm (e.g., about 18 mm), and a thickness of about 0.7 mm to 0.9 mm (e.g., about 0.8 mm). The foam ring 53 and the substrate 54 may have substantially the same outer diameter as one another. For example, these components may be assembled together and then stamped together.

[0088] In this example, the paper applicator 65 has a substantially ring-shaped shape with an oval opening 60 along its inside and a rounded rectangular perimeter 61 coextensive with the breathable film 56. The paper applicator 65 may have a V-shaped notch 62 extending from the oval opening 60 partially toward the perimeter 61. As shown in detail B of FIG. 5B, the V-shaped notch 62 may have a rounded apex 63 that is preferably radially oriented and aligned with the slits 64a and 64b to facilitate tearing of the paper applicator 65 after the patch 50 has been firmly pressed onto the subject's skin. The minor axis of the opening 60 may be at least about 1 mm larger than the outer diameter of the foam ring 53 to provide a gap of at least about 1 mm between the foam ring and the paper applicator. The minor axis of the aperture 60 may be, for example, about 1 mm to about 20 mm larger than the outer diameter of the foam ring 53, or about 2 mm to about 10 mm larger than the outer diameter of the foam ring 53, or about 3 mm to about 5 mm larger than the outer diameter of the foam ring 53. The rounded rectangular periphery 61 of the paper applicator may have any suitable dimension that is at least 1 mm larger than the minor axis of the aperture 60 (i.e., the paper applicator 65 may have a width of at least 1 mm). For example, the paper applicator 61 may have a width of about 1 mm to about 20 mm, or about 2 mm to about 10 mm, or about 3 mm to about 5 mm. In some examples, the width of the paper applicator 59 may be about 10% to about 200% of the width of the gap between the foam ring 53 and the paper applicator 61, such as about 20% to about 180% of the width of the gap, or about 50% to about 150% of the width of the gap, or about 80% to about 120% of the width of the gap, or about 90% to about 110% of the width of the gap, or about 100% of the width of the gap. In one non-limiting example, the width of the paper applicator 65 is selected to cover about half the distance that the breathable film 56 extends beyond the outer edge of the foam ring 53 (i.e., to have approximately the same width as the gap) and to have a minimum width of 3 mm to provide sufficient stiffness for easy handling.In one non-limiting example, the minor axis of the oval opening 60 has an inner diameter of about 30 mm and a major axis of about 38 mm, thereby providing a minimum gap 66 (see FIG. 5A) of about 3.0 mm to the periphery of the foam ring 53. As with patch 30 described above, the width of the paper applicator 39 and the size of the gap 46 contribute to better control of the placement of patch 30 upon initial placement, as well as better long term adhesion, better manufacturability, and uniformity of results, as compared to patch 10.

[0089] As explained above, in initial clinical trials of patch 10, it was observed that the patch began to lose adhesion shortly after it was first applied to a subject's skin. It is believed that this loss of adhesion occurs solely as a result of removing paper applicator 18 after patch 10 has been applied and the peel tab has been removed. As with the embodiment of FIGS. 3A-3B and 4, this loss of adhesion is addressed for patch 50 by reducing the width of paper applicator 65, which reduces the tension applied to breathable film 56 and adhesive layer 58 on foam ring 53 upon removal of paper applicator 65. For example, D may be the dimension of the patch between the outer perimeter of foam ring 53 and the outer perimeter of patch 50, and the width of paper applicator 65 may be between about 40%-60% of D. In some examples, gap 66 has a minimum width of at least about 3.0 mm between the inside of elliptical opening 60 and the perimeter of foam ring 53. Gaps 66 reduce the extent to which paper applicator 65 covers patch 50, but less coverage reduces the force required to remove paper applicator 65. In this manner, paper applicator 65 of patch 50 provides greater initial and long-term adhesion of patch 50 to the subject's skin compared to that of patch 10.

[0090] The V-notch 62 and slits 63a and 63b also contribute to long-term adhesion, manufacturability, and repeatability of initial and long-term adhesion by reducing the amount of caregiver manipulation required to peel the paper applicator 65 from the outer surface 57 of the breathable film 56. In particular, the V-notch 62 is preferably formed at an angle α of about 45° to allow the caregiver to easily grasp the edge of the notch. Furthermore, the V-notch 62 preferably includes a rounded apex 63 to avoid sharp edges that may interfere with packaging or manufacturing, for example, where sharp corners may cause problems for tools for rotary cutting. The notch 62 is also preferably adjacent to a slit 64a. The slits 64a and 64b do not extend completely across the width of the paper applicator 65, thereby ensuring that the paper applicator cannot come free during manufacturing. As observed in in vivo testing, the configuration of notch 62 and slits 64a and 64b significantly enhances the ease of removal of paper applicator 65 after patch 50 has been applied to a subject. As with the prior embodiment, manipulation of patch 50 is reduced after application to a subject, and less tension is applied to the patch upon removal of paper applicator 65 compared to patch 10.

[0091] Substrate 54 may include any suitable material or combination of materials for supporting an active agent, and may suitably be attached to the foam ring, for example, via an adhesive on an adjacent surface of foam ring 53. Non-limiting examples of materials for use in substrate 54, and for attaching active agents thereto, are described elsewhere herein.

[0092] The breathable film 56 of patch 50 preferably comprises a translucent, biocompatible polyurethane material coated with a biocompatible, medical grade, pressure sensitive adhesive. Non-limiting examples of suitable adhesives are described elsewhere herein. Advantageously, the rounded rectangular shape of breathable film 56 avoids right angle corners, such as corner 22 of patch 10. Similarly, as observed in the test rig described above with respect to patch 30, in the example, rounded corners 68 do not become a focal point for premature delamination of the film. Additionally, the total adhesive area of ​​patch 50 is increased as compared to patch 10 of FIGS. 1A-1B and 2A-2B. For example, patch 10 has a thickness of approximately 1156 mm. 2 patch 50 has a total patch area of ​​approximately 1550 mm 2 30.degree. C., an area increase of about 34%. It will be appreciated that these values ​​are by way of example only and that other sizes of breathable film 56 may be suitably used.

[0093] Patch 50 also differs from patch 10 in that it completely eliminates peel tabs 20a and 20b, the removal of which has been observed to reduce initial adhesion upon placement of patch 10. For example, patch 50 does not include removable tabs on breathable film 56, but instead includes a diagonal slit 52 in release liner 51, placed on one side and in the middle of foam ring width 66 between the slit and the center of substrate 54, as depicted in FIG. 5A. This configuration facilitates removal of release liner 51 from the skin-facing surfaces of adhesive film 56 and foam ring 53 by having the caregiver slightly bend the patch and grasp the edge of the release liner exposed by slit 52, in the manner described with reference to FIGS. 26-28. Patch 50 may then be positioned on the subject's skin and adhered to the skin by pressing firmly over the entire patch surface, including paper applicator 65. The paper applicator 65 may be torn at the V-notch 62 and removed from the outer side 57 of the breathable film 56 .

[0094] In some examples, patch 50 further includes a label 67, as shown in Figure 5A, illustratively "VIASKIN DBV 712" or any other suitable combination of letters and numbers, which may be printed on the inside or outside surface of breathable film 56 using an inkjet printer and food grade inks. Preferably, the label information may be applied to breathable film 57 while still in roll form by running the film through an inkjet printer before it is cut to shape.

[0095] As with patch 30, the above-mentioned features of patch 50, taken individually and in combination, have been determined in in vitro and in vivo testing conducted at the direction of the assignee of the present application to significantly enhance and improve the manufacturability, ease of handling and application, and initial and long-term adhesion of patch 50. As described below in the Examples, several in vivo tests have been performed on healthy adult human skin with the same conclusions reached in the in vitro testing, i.e., superior adhesion of the claimed patch compared to the reference patch described with reference to Figures 1A-1B and 2A-2B.

[0096] It will be understood that the patch of the present invention may be manufactured using any suitable combination of operations. In one non-limiting example, manufacturing the patch 30 or patch 50 may include providing (i) a substrate, (ii) a biologically active substance, (iii) a foam ring having a periphery, a first skin-facing surface, and a layer of a biocompatible adhesive disposed on the first skin-facing surface, (iv) a biocompatible breathable film having an outer surface, a second skin-facing surface, and a second layer of a biocompatible adhesive disposed on the second skin-facing surface, and (v) a paper applicator having an opening with an inner edge. Manufacturing the patch may include attaching a biocompatible foam ring under the substrate, which forms an occluded chamber when applied to the skin of the subject. Manufacturing the patch may also include disposing a biologically active substance on the substrate for delivery to the skin of the subject through the chamber. Manufacturing the patch may also include concentrically applying a biocompatible breathable film over the substrate and the foam ring. Manufacturing the patch may also include attaching a biocompatible paper applicator onto the outer surface of the breathable film such that the aperture is concentric with the foam ring and provides a gap between an inner edge of the paper applicator and a periphery of the foam ring. The paper applicator may be configured to be removed from the outer surface after the patch is pressed onto the subject's skin. In one particular embodiment, a method for producing a patch comprises: - providing a paper applicator having (i) a substrate, (ii) a biologically active substance, (iii) a foam ring having a periphery, a first skin-facing surface, and a layer of a biocompatible adhesive disposed on the first skin-facing surface, (iv) a biocompatible breathable film having an outer surface, a second skin-facing surface, and a second layer of a biocompatible adhesive disposed on the second skin-facing surface, and (v) an aperture with an inner edge; - applying a biocompatible foam ring under the substrate to form an occlusion chamber when applied to the subject's skin; - disposing a biologically active substance on a substrate for delivery to the skin of a subject through a chamber; - applying a biocompatible breathable film over the substrate and the foam ring; - attaching a biocompatible paper applicator onto an outer surface of the breathable film such that the opening is concentric with the foam ring and provides a gap between an inner edge of the paper applicator and a periphery of the foam ring, the paper applicator being configured to be removed from the outer surface after the patch has been pressed onto the subject's skin. Preferably, the release notch is already present on the paper applicator before it is applied onto the breathable film.

[0097] In some instances, the biologically active material is bound to the substrate by electrostatic forces, hi some instances, the biologically active material comprises particles.

[0098] In some examples, manufacturing the patch may further include forming an open notch, such as a V-shaped notch, in the paper applicator to facilitate removal of the breathable film from the outer surface. In some examples, the V-shaped notch is radially oriented. In some examples, the V-shaped notch has a rounded apex. In some examples, manufacturing the patch further includes forming at least one slit in the paper applicator aligned with the open notch to further facilitate removal of the film from the outer surface.

[0099] In some examples, fabricating the patch includes attaching a biocompatible release liner to the first and second adhesive layers. In some examples, fabricating the patch includes forming a slit in the release liner to facilitate removal from the first and second adhesive layers. In some examples, the slit is asymmetrically positioned in the release liner and offset from the chamber.

[0100] In some examples, providing a breathable film includes providing a breathable film having a circular shape. In some examples, providing a breathable film includes providing a breathable film having a rectangular shape with rounded corners. In some examples, providing a breathable film includes providing a translucent breathable film. In some examples, providing a breathable film includes providing a breathable film having a pre-printed label on a surface facing the second skin.

[0101] In some instances, the biologically active substance is selected from an allergen, an antigen, and a biologically active polypeptide. EXAMPLES

[0102] The following examples are intended to be purely illustrative and not limiting of the invention.

[0103] In vitro testing: stretch, scratch and peel tests In vitro tests were developed to mimic and study various constraints and stressors imposed on the system to predict in vivo adhesion performance under extreme conditions capable of simulating patient use and to identify areas of improvement. In vitro tests were used to study factors that contribute to adhesion in the patch of the present invention (which may be referred to as the mVP system or mVP patch) compared to the patch described with reference to Figures 1A-1B and 2A-2B (which may be referred to herein as the cVP system or cVP patch).

[0104] A stretching bench was used to evaluate the peel resistance through mimicking real-life skin stretching conditions. This involved attaching the patch to a substrate with properties (e.g., surface tension) similar to human skin and mechanically stretching the patch to various degrees consistent with normal human activity. This also allowed the effect of the position of the back during application (i.e., curved or straight posture) on the adhesive performance to be evaluated. In vitro testing was used to evaluate the effect of scratching using a robotic arm with rubber "fingers." The robotic arm was programmed in various ways to mimic scratching associated with topical irritation / itching, with the patch attached to a rubber material with a surface tension similar to human atopic skin.

[0105] In addition, various mVP patch designs were compared with cVP patch designs in terms of their ability to resist friction. A test platform was designed and used to simulate the behavior of the patch under pressure and friction by performing back and forth movements with varying applied force, direction, and frequency. These in vitro evaluations and collaborative efforts allowed us to evaluate the effects of mechanical forces and identify geometries and specific prototypes to proceed to in vivo analysis.

[0106] In vivo testing The in vivo adhesive performance of multiple mVP patch designs and cVP patches was evaluated in 48 healthy adult volunteers in a study with a 24-hour application time for each system. In this study, examiners applied four systems per participant per day over two days (at least 48 hours between days 1 and 2). Each participant wore two of the same four systems (eight systems in total) each day, with one group of systems applied with the participant in a hunched position and the other systems applied with the participant in a straight-back position, thereby evaluating mVP patch adhesive performance including the effects of posture during system application. Participants were encouraged to participate in any physical activity they wished, but these activities were expected to be similar on both days, and factors such as type of activity and immersion were documented by the participant. Adhesion, ease of removal, and pain during removal were evaluated.

[0107] Participants in this study were generally active throughout the day of application, with 96% reporting some physical activity and 92% reporting water immersion. Adhesion scores both at application and 24 hours later were generally very good, with little evidence of delamination or disruption of the occlusion chamber. Notably, all mVP patch designs demonstrated better adhesion than the cVP patch, regardless of the two positions in which the system was applied. The mVP patch designs caused less pain on removal, but pain scores were generally low and the patches were considered to be painless on removal.

[0108] Patch Design Five mVP systems (circular and rounded rectangular) have been studied in vivo with the ultimate goal of developing them for use in future clinical studies. Figure 29 illustrates the exemplary patch designs of the study. These in vivo evaluations to date have been conducted in non-peanut allergic participants aged at least 18 years, using prototypes that do not contain peanut proteins.

[0109] CHAMP: A study comparing the adhesive strength of cVP patches with mVP patch designs in healthy volunteer subjects The purpose of this study was to compare the adhesive performance of five mVP patch designs against cVP. The adhesive study was conducted on healthy adult participants (60 randomly selected), of whom 23% reported a history of atopic dermatitis / eczema, over a planned application duration of 24 hours. Each participant wore all six systems, with the location of application randomly selected by the participant. Figure 29 shows images of the five mVP patches studied, namely, three round-shaped patches B, C, D, and two rounded rectangular patches F, and H (also referred to herein as mVP-B, mVP-C, mVP-D, mVP-F, and mVP-H, respectively), along with the dimensions of the PU dressing in contact with the skin (breathable film 36 or 56). Participants were required to shower and participate in three separate 10-minute exercise sessions during the study.

[0110] The results of this study confirm that the cVP patch did not perform as well as the mVP patch. In particular, some cVP patches, with respect to the mVP, experienced lift-off or delamination of the dressing edge upon application (with the previous IFU). In addition, some cVP systems experienced partial delamination of the foam ring relatively after 20 hours, whereas few mVP systems experienced adhesion failure. Overall, 15.0% (9 / 60) of participants experienced adhesion failure of the cVP patch by 20 hours, whereas few participants experienced adhesion failure of the mVP patch by 20 hours. Similar results were obtained at 24 hours. All systems were judged to be well tolerated and easy to remove at 24 hours.

[0111] Although preferred illustrative embodiments of the present invention have been described above, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the invention. [Explanation of symbols]

[0112] 10 Patch 11 Breathable film 12 Adhesive layer 13. Label 14 Base material 15 Foam Ring 16 Adhesive-backed bottom surface 17 Release Liner 18 Paper applicator 19 Aperture 20a, 20b Removable tabs 21 Slit 22 Corner 30 Patches 31 Release Liner 32 Slit 33 Foam Ring 34 Substrates for holding biologically active substances 35 Skin-facing lower surface 36 Breathable Film 37 Outer surface 38 layers 39 Paper applicator 40 V-notch 41 Inner diameter 42 Outer diameter 43 Rounded Vertices 44a, 44b Slit 45 Central opening 46 Gap 47 Width 50 Patches 51 Release Liner 52 Slit 53 Foam Ring 54 Base material 55 Skin-facing lower surface 56 Breathable Film 57 Outer surface 58 layers 60 Oval opening 61 Rounded rectangular perimeter 62 V-notch 63a, 63b Slit 64a, 64b Slit 65 Paper Applicator 68 Rounded Corners

Claims

1. A patch for delivering a biologically active substance to the skin of a subject, comprising: A substrate; a biologically active material disposed on the substrate; a foam ring having a periphery, a first skin-facing surface, and a first layer of adhesive disposed on the first skin-facing surface, the foam ring disposed beneath the substrate and, when applied to the skin of a subject, forming an occlusion or condensation chamber in which the biologically active substance is disposed; a breathable film disposed on the substrate, the breathable film having an outer surface, a second skin-facing surface opposite the outer surface, and a second layer of adhesive disposed on the second skin-facing surface; a paper applicator removably disposed on the outer surface of the breathable film, the paper applicator having an opening with an inner edge, the paper applicator configured to attach the patch to the skin of a subject; and Equipped with the breathable film covers the substrate and the foam ring, the opening in the paper applicator is continuous and circumferential to and concentric with the foam ring, and the paper applicator has an opening notch to facilitate removal of the breathable film from the outer surface. patch.

2. The patch of claim 1 , wherein the release notch is open on the inner edge of the paper applicator.

3. The patch of claim 1 or 2, wherein the opening notches are radially oriented.

4. The patch of claim 1 , wherein the release notch is a V-shaped notch.

5. The patch of claim 4 , wherein the V-shaped notch has a rounded apex.

6. 6. The patch of claim 4 or 5, wherein the V-shaped notch is formed at an angle α of about 45°±10°.

7. 10. The patch of claim 1, wherein the paper applicator includes at least one slit aligned with the opening notch, the at least one slit extending from an edge of the paper applicator toward the opening notch to further facilitate removal of the breathable film from the outer surface.

8. 8. The patch of claim 7, wherein the paper applicator comprises a plurality of aligned slits, one slit extending from an apex of the open notch.

9. The patch of claim 8 , wherein one slit opens on the apex of the open notch.

10. 2. The patch of claim 1, wherein the release notch is a V-shaped notch, and the paper applicator includes at least one slit aligned with the V-shaped notch, the at least one slit extending from an outer edge of the paper applicator toward the V-shaped notch to further facilitate removal of the breathable film from the outer surface.

11. 11. The patch of claim 10, wherein the paper applicator includes a plurality of slits, one slit extending from the rounded apex of the V-shaped notch.

12. The patch of claim 11 , wherein one slit opens on the rounded apex of the V-shaped notch.

13. 10. The patch of claim 1, wherein the inner diameter of the opening in the paper applicator is about 80% to 95% of the larger dimension of the paper applicator.

14. 10. The patch of claim 1, further comprising a release liner removably disposed on the first layer of adhesive and the second layer of adhesive.

15. 15. The patch of claim 14, wherein the release liner comprises slits to facilitate removal from the first layer of adhesive and the second layer of adhesive.

16. 16. The patch of claim 15, wherein the release liner slit is two-part, asymmetrically positioned, and centered across the width of the foam ring and offset from the occlusion or condensation chamber.

17. 10. The patch of claim 1, wherein the foam ring is circular and the breathable film has a rectangular shape with circular or rounded corners.

18. The patch of claim 1 , wherein the substrate is moisture-impermeable.

19. The patch of claim 1 , wherein the biologically active substance is selected from an allergen, an antigen, and a biologically active polypeptide.

20. providing a paper applicator having (i) a substrate, (ii) a biologically active substance, (iii) a foam ring having a periphery, a first skin-facing surface, and a layer of biocompatible adhesive disposed on the first skin-facing surface, (iv) a biocompatible breathable film having an outer surface, a second skin-facing surface, and a second layer of biocompatible adhesive disposed on the second skin-facing surface, and (v) an opening with an inner edge and an open notch; applying the biocompatible foam ring under the substrate to form an enclosed chamber when applied to the subject's skin; disposing the biologically active substance on the substrate for delivery to the skin of a subject through the closed chamber; concentrically applying the biocompatible breathable film over the substrate and the foam ring; attaching the biocompatible paper applicator onto the outer surface of the breathable film such that the opening is concentric with the foam ring and a gap is provided between the inner edge of the paper applicator and the periphery of the foam ring, the paper applicator being configured to be removed from the outer surface after the patch has been pressed onto the subject's skin; A method for producing the patch of claim 1, comprising:

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