Method for depositing material onto a substrate

Abstract

To provide a technology that allows selective inversion of articles. This embodiment relates to a method for depositing a substance onto a substrate (6), comprising providing a substrate (6) at a distance from a conductive spray nozzle (1) having an outlet (2), supplying a liquid composition containing a substance to the spray nozzle (1), supplying compressed gas around the liquid composition flowing out of the outlet (2) of the spray nozzle (1), and applying an electric field downstream of the outlet (2) of the spray nozzle (1), thereby generating electrically charged droplets from the liquid composition between the outlet (2) of the spray nozzle (1) and the substrate (6), and collecting the generated droplets on the substrate (6). This embodiment also relates to equipment for carrying out this method.

Description

[Technical field]

[0001] The present invention relates to a method for depositing a material onto a substrate, and in particular to a method for depositing a biological material, such as a protein, onto a substrate, such as a patch. [Background technology]

[0002] The application of drugs to the skin by patches has many applications in human and animal health, indeed allowing the development of efficient diagnostic tests and therapeutics that transfer active ingredients to the skin.

[0003] The topical application of substances to the skin has many advantages over other administration methods such as injections, including no risk of contamination, no pain, ease of handling, and the ability for patients to self-administer drugs.

[0004] The following Patent Document 1 discloses a method for manufacturing a patch intended for application of a substance to the skin, in which the patch includes a conductive support and a liquid formulation of the substance is deposited on the support of the patch by electrohydrodynamic spraying (also known as "electrospray" technology).

[0005] While this approach has provided satisfactory results in many situations, the flow rates achievable with this method remain limited, particularly when the liquid agent has a relatively high conductivity.

[0006] Unfortunately, some of the therapeutic or diagnostic substances that are deposited on the patch must be provided in such relatively highly conductive liquids (eg, physiological serum-based formulations).

[0007] In other industrial fields, a "flow focusing" technique is used in which a second fluid flows around a first fluid coming out of a capillary line to generate droplets of the first fluid. Examples of literature relating to this flow focusing technique include the following Non-Patent Documents 1 to 4.

[0008] A technical comparison between flow focusing and electrospray is given in the following non-patent document 5.

[0009] A combination of the principles of electrospray and flow focusing techniques, often referred to as electro-flow focusing, has been proposed by the following Patent Document 2 and Non-Patent Documents 6 and 7.

[0010] The method of depositing a material onto a substrate must provide instant drying of the material on the substrate in order to be applicable to an industrial manufacturing environment. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2009 / 095591 [Patent Document 2] European Patent Application Publication No. 1,479,446 [Non-patent literature]

[0012] [Non-Patent Document 1] Generation of stationary liquid microthreads and microsized monodisperse sprays from gas flows, Ganan-Calvo, Physical Review Letters 80, 285-288, 1998 [Non-Patent Document 2] Perfectly monodispersed microbubbles by capillary flow focusing, Ganan-Calvo et al., Physical Review Letters 87, 274501, 2001 [Non-Patent Document 3] Enhancement of Liquid Atomization: From Flow Focusing to Flow Blurring, Ganan-Calvo, Applied Physics Letters 86, 214101, 2005 [Non-Patent Document 4] Aerodynamically assisted jet processing of viscous single-phase and multiphase media, Arumuganathar et al., Soft Matter, 3:605-612, 2007 [Non-Patent Document 5] Revisiting Capillary Cone Jet Physics: Electrospray and Flow Focusing, Ganan-Calvo et al., Physical Review E 79, 066305, 2009 [Non-Patent Document 6] Combining electrospray and flow focusing, Ganan-Calvo et al., J. Fluid Mech., 556, 421-445, 2006 [Non-Patent Document 7] Electro-flow focusing: high conductivity low viscosity limit, Ganan-Calvo, Physical Review Letters 98, 134503, 2007 Summary of the Invention [Problem to be solved by the invention]

[0013] Currently, there remains a need for methods of depositing materials on substrates (particularly on patches, or on substrates for making patches) that have improved yields without compromising the precision and quality of the deposition, particularly when the materials are provided in relatively highly conductive liquid formulations. [Means for solving the problem]

[0014] A first object of an embodiment of the present invention is to provide a method for depositing a substance on a substrate, comprising: providing a substrate at a distance from a conductive spray nozzle having an outlet; supplying a liquid composition containing a substance to the spray nozzle; supplying a compressed gas around the liquid composition flowing out of the outlet of the spray nozzle; and supplying an electric field downstream of the outlet of the spray nozzle to generate electrically charged droplets from the liquid composition between the outlet of the spray nozzle and the substrate; and collecting the generated droplets on the substrate.

[0015] In some embodiments, the substance is a peptide or protein, preferably an allergen, most preferably selected from peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens.

[0016] In some embodiments, the liquid composition has a conductivity of from 0.1 μS / m to 3 S / m, preferably from 1 mS / m to 20 mS / m.

[0017] In some embodiments, the liquid composition is delivered to the spray nozzle at a flow rate of at least 1 mL / h, preferably at least 1.5 mL / h.

[0018] In some embodiments, the compressed gas surrounding the liquid composition is at a pressure of 0.1 to 2 bar, preferably 0.3 to 1 bar, above atmospheric pressure.

[0019] In some embodiments, the spray nozzle is disposed within a chamber, compressed gas is supplied to the chamber, and the liquid composition and compressed gas exit the chamber through an outlet of a conductive ejector.

[0020] In some embodiments, an electric field having a first magnitude is applied in a first region between the outlet of the spray nozzle and the discharge port, and / or an electric field having a second magnitude is applied in a second region between the discharge port and the substrate, the first magnitude being preferably 0.1 to 10 MV / m, more preferably 0.5 to 5 MV / m, and / or the second magnitude being preferably 0.02 to 1 MV / m, more preferably 0.1 to 0.5 MV / m, and / or preferably the first magnitude being greater than the second magnitude.

[0021] In some embodiments, the method does not include any drying step after collecting the droplets on the substrate.

[0022] In some embodiments, the method is for making a patch, preferably a therapeutic patch.

[0023] An embodiment of the present invention also relates to an apparatus for depositing a material on a substrate comprising a chamber including a conductive ejector having a discharge port, a conductive spray nozzle disposed within the chamber and having an outlet port, a support for positioning a substrate outside the chamber at a distance from the spray nozzle, a liquid supply line for supplying a liquid composition including a material to be deposited to the spray nozzle, a gas inlet for supplying compressed gas to the chamber, and an apparatus for generating an electric field within the chamber and / or between the chamber and the substrate.

[0024] In some embodiments, the device for generating an electric field is configured to generate an electric field both within the chamber and between the chamber and the substrate.

[0025] In some embodiments, the spray nozzle and the ejector are each connected to a high voltage power supply, and the fixture further includes a contact connecting the substrate to ground.

[0026] In some embodiments, the outlet of the spray nozzle has an inner diameter D of 50 to 500 μm, preferably 100 to 450 μm, more preferably 150 to 400 μm. i has.

[0027] In some embodiments, the discharge port of the ejector has an inner diameter D0 of 50 to 800 μm, preferably 100 to 600 μm, and more preferably 150 to 500 μm.

[0028] In some embodiments, the distance H between the outlet of the spray nozzle and the discharge port of the ejector may be 50 to 550 μm, preferably 60 to 400 μm, and more preferably 80 to 250 μm.

[0029] The present invention makes it possible to address the above identified needs, in particular by providing a method for depositing a substance onto a substrate (particularly onto a patch or for the manufacture of a patch) with improved yields, without compromising the accuracy and quality of the deposition, when the substance is provided in a liquid formulation with a relatively high conductivity.

[0030] This is accomplished by using electro-flow focusing techniques to generate droplets of the liquid composition and direct them onto the substrate. [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 is a diagram illustrating an example of equipment for carrying out the method according to the present embodiment. [Diagram 2] FIG. 2 is a schematic diagram showing details of the facility shown in FIG. 1.

[0032] In the following description the invention will now be explained in more detail, without being limited thereto.

[0033] liquid composition The substance deposited according to this embodiment may in particular be any pharmaceutical, cosmetic, vaccine and / or diagnostic substance.

[0034] By "substance" is meant a molecule or supramolecular assembly or a mixture of different molecules or supramolecular assemblies.

[0035] The substance may be of biological nature and may in particular be or contain an oligopeptide, polypeptide or protein, in particular an antigenic oligopeptide, polypeptide or protein, a hormone, a cytokine, an immunoglobulin, an allergen, a growth factor, a nutritional factor, a moisturizing compound or vitamin, or a chemically active ingredient. A preferred substance is one or more of an immunoreactive oligopeptide, polypeptide or protein selected from food allergens or human proteins involved in human autoimmune diseases. The most preferred substance is a food allergen selected from peanut, milk, egg, walnut, cashew, pecan, pistachio, hazelnut allergens.

[0036] It may also be or include one or more drugs or active ingredients, including, but not limited to, nicotine, caffeine, morphine, hydromorphone HCI, fentanyl, apomorphine HCI, scopolamine, chlorpheniramine, imiquimod, diphenhydramide, lidocaine, isotretinoin, ketoprofen, diclofenac, leuprolide, finasteride, and the like.

[0037] The substance to be deposited is provided in a liquid composition. The liquid composition consists of an aqueous and / or organic solvent. Mixtures of aqueous and organic solvents are also possible.

[0038] The substance is preferably dissolved in the liquid composition.

[0039] As the organic solvent, alcohols are preferred, and ethanol is particularly preferred.

[0040] The aqueous solvent is preferably deionized water or an aqueous buffer solution. The pH of the composition may be adjusted using, for example, citric acid, sodium hydroxide, Tris and / or histidine.

[0041] To facilitate evaporation of the liquid composition on the substrate, and if the material permits, it is advantageous to add an organic solvent to the aqueous solvent, in particular an alcohol (e.g., ethanol). In some embodiments, the liquid composition is thereby an aqueous solution containing 0.1-20% (total), preferably 0.5-10% (total), of an organic solvent, preferably an alcohol, more preferably ethanol. The use of such a solvent is optional, since some types of proteins may be incompatible with such organic solvents.

[0042] The liquid composition may contain the target substance in a total concentration of 0.01 to 20% by weight, preferably 0.05 to 10% by weight, more preferably 0.1 to 0.5% by weight.

[0043] To stabilize the substance of interest in solution, the liquid composition may contain electrolytes in the form of acids, bases, salts, and / or mixtures thereof. These additives may buffer the solution at a certain pH and their concentrations such that the solution exhibits a certain ionic strength. Depending on the nature of these electrolytes and their concentrations, the solution will have a resulting electrical conductivity.

[0044] The electrical conductivity of the liquid composition may be 0.1 μS / m to 3 S / m, preferably 100 μS / m to 50 mS / m, and more preferably 1000 μS / m to 20 mS / m. Examples of possible ranges of electrical conductivity include 0.1 to 0.3 μS / m, 0.3 to 1 μS / m, 1 to 3 μS / m, 3 to 10 μS / m, 10 to 30 μS / m, 30 to 100 μS / m, 100 to 300 μS / m, 300 to 1000 μS / m, 1 to 3 mS / m, 3 to 10 mS / m, 10 to 30 mS / m, 30 to 100 mS / m, 100 to 300 mS / m, 300 to 1000 mS / m, and 1 to 3 S / m.

[0045] The electrical conductivity may be measured by a conductivity probe.

[0046] The liquid composition may include one or more additives, such as surfactants, which may be anionic, cationic, zwitterionic and / or non-ionic. Preferred surfactants are non-ionic surfactants, such as ethoxylated fatty alcohols.

[0047] The amount of surfactant in the liquid composition may in particular be in the range of 0.01 to 5% by weight, preferably 0.02 to 1% by weight, more preferably 0.05 to 0.5% by weight.

[0048] Substrate and Patch In accordance with the present invention, a substance of interest is deposited on a substrate.

[0049] The material, once deposited on the substrate (and optionally after a drying step), is preferably in substantially dry form, and more preferably in particulate form.

[0050] The substrate is preferably essentially planar or flat or film-like, and preferably has two sides, hi some embodiments the substrate may include depressions forming chambers or reservoirs.

[0051] The substrate may be rigid or semi-rigid. The substrate may be formed as individual patches prior to depositing the material thereon. Thus, the substrate may have, for example, a circular, square, rectangular or oval shape.

[0052] In other embodiments, the substrate is provided in the form of a plate or strip, for example as a roll, and the substance is deposited on the substrate, which is then cut into shaped pieces to provide the patches.

[0053] The substrate preferably includes at least one conductive portion. In this embodiment, "conductive" or "conductive" means "electrically conductive" or "electrically conductive". The conductive portion may be on one side of the substrate or in the bulk. The conductive portion may also be a conductive layer provided on or in the substrate.

[0054] The substrate may comprise or consist of different biocompatible materials, such as, inter alia, polymer(s), doped polymer(s), polymer(s) coated with conductive material, textiles and / or biomaterial(s).

[0055] The substrate may in particular comprise at least one conductive surface arranged facing the spray nozzle. A preferred substrate thus comprises or consists of an insulating layer, such as an insulating polymer (film, fibre, etc.) layer, covered on at least one surface with a conductive layer.

[0056] The conductive material used in the substrate (in particular for providing a conductive layer) may be inorganic (for example metal) or organic (for example consisting of carbon, graphite or oxide(s)). The metals are preferably gold, silver, platinum, titanium or aluminium. The conductive layer(s) advantageously have a thickness of 2 to 40 nm, preferably 5 to 20 nm and most preferably about 10 nm.

[0057] In the case of a conductive layer made of graphite, the graphite may be deposited on the substrate in advance or in-line immediately prior to depositing the material on the substrate, by projection of a neutral or charged aerosol, or by impregnation of the film by passing it through a bath of graphite solution.

[0058] Forming a conductive layer on the substrate prior to material deposition can also be accomplished by metallization or oxide deposition, the oxide preferably being tin-doped indium oxide (ITO).

[0059] Plasma treatment may also be used to improve adhesion at the deposit-substrate interface or to deposit the conductive moiety itself.

[0060] Thus, in some embodiments, the method according to the present invention includes one or more preliminary steps of modifying the substrate, for example by plasma treatment at low or atmospheric pressure and / or metallization and / or oxide deposition and / or graphite deposition.

[0061] In some embodiments, the substrate may be a polyethylene terephthalate (PET) film covered with a conductive gold or titanium layer, which may further include an insulating double-adhesive crown, such as polyethylene (PE) / ethylene vinyl acetate (EVA) foam.

[0062] The substrate may in particular be a strip in the form of a roll that is gradually wound up. The strip is advantageously a support film consisting of a conductive layer or in the form of a conductive film (e.g. gold-coated PET), a foamed film containing regularly spaced holes attached to a conductive film, each of which not covered by the conductive layer or the foamed film forms an area for deposition of the substance of interest; Equipped with.

[0063] Preferably, the support film is wider than the foam film. Preferably, each foam-enclosed deposition area is in electrical contact with the entire conductive surface of the support film.

[0064] After depositing the substance on the substrate, the substrate or a patch formed therefrom is advantageously packaged such that the substance deposit is protected from the external environment.The patch may thus be provided with a peelable film on its surface, covering the substance deposit and, optionally, also covering the portion of the substrate that does not contain the deposited substance.

[0065] The method according to the present invention allows the creation of any type of patch, i.e. any device that can be applied to an area of ​​the skin of a subject to contact the substance of interest, including patches with passive, facilitated or mechanical diffusion, adhesive patches, dressings, bandages, cupules and transdermal patches.

[0066] The bandages comprise or consist of an adhesive or coating, including one or more of the subject substances and optionally one or more diluents, emollients and adhesives, on a suitable support. The adhesive may be such that it softens at skin temperature and adheres to the skin. They may be formed as sheets of variable size, to be cut as desired. These may be applied over the adhesive bandage and covered with a perforated material.

[0067] Medicated bandages are applied locally to small lesions of the skin and consist of or consist of an adhesive bandage to which is applied a bandage containing a substance.

[0068] The adhesive patch may comprise or consist of an adhesive bandage comprising a plastic disc onto which is placed an adhesive containing the substance, the adhesive may further comprise ingredients such as gum arabic or gelatin and water.

[0069] Patches involving passive, facilitated or mechanical diffusion typically include a support onto which the substance is deposited and, optionally, a device for promoting cell permeabilization (by application of electrical pulses, ultrasound, microneedles, etc.).

[0070] Preferably, the patch is a dry patch, more preferably of the occlusive type, even more preferably an electrostatic patch as described in document WO 02 / 071950.

[0071] The patch manufactured according to this embodiment may be used in particular for pharmaceutical, cosmetic, vaccine and / or diagnostic applications, and is preferably intended to be applied to the skin, for example to detect the body's susceptibility to a deposited substance or to deliver a therapeutic amount of a deposited substance to the body.

[0072] A patch manufactured according to this embodiment may be adapted for application to an animal or human subject, preferably a human subject.

[0073] To ensure the preservation of the patch within the packaging and in particular to avoid alteration of the active principle of the deposited material and to preserve its microbiological quality, the patch may be subjected to further treatments, such as, for example, pasteurisation or ionisation.

[0074] In some embodiments, the periphery of the patch is configured to contact the skin and form a sealed condensation chamber that contains the substance.

[0075] General principles of material deposition by electro-flow focusing The method according to the present invention comprises depositing a material onto a substrate by spraying a liquid composition onto the substrate using electro-flow focusing techniques.

[0076] 1 and 2 show an installation capable of performing electro-flow focusing deposition. The installation consists of a conductive spray nozzle 1 in a chamber 3. The chamber 3 is supplied with compressed gas via a gas inlet 10. The spray nozzle 1 is connected to or formed directly in a liquid supply line 9.

[0077] The spray nozzle 1 has an outlet section 2 through which the liquid composition exits the spray nozzle. The chamber 3 has a plate-like conductive ejector 5 that forms the bottom of the chamber 3. The ejector 5 has a discharge port 4 facing the outlet section 2 of the spray nozzle 1.

[0078] The substrate 6 is disposed outside the chamber 3, facing the discharge port 4 (and the spray nozzle 1).

[0079] The liquid composition flows out of the outlet 2 of the spray nozzle and preferably forms a liquid cone 7, which breaks up into droplets. The formation of droplets is achieved by the flow of compressed gas from the chamber 3 through the outlet 4 and / or by the action of electrostatic repulsion, which is responsible for the droplet formation in the electrospray process. Due to a pressure gradient between the chamber 3 and the environment outside the chamber 3, the compressed gas is forced out of the chamber 3 through the outlet 4 as a flow stream of gas. The gas fluid surrounds the liquid cone 7 and forms an aerodynamic sheath around it (as indicated by the arrows in FIG. 1). The liquid cone 7 forms droplets in a complex process that may occur inside the (preferably cylindrical) volume of the outlet 4, in the chamber 3 between the outlet 2 of the spray nozzle and the top of the ejector.

[0080] Furthermore, the droplets are charged by an electric field, as described below, resulting in electrostatic repulsion.

[0081] In this way, an aerosol 8 of droplets is formed between the outlet 4 and the substrate 6 .

[0082] In some embodiments, the installation may comprise a plurality of chambers 3 as described above for simultaneously spraying the liquid composition onto a plurality of deposition areas on the same substrate 6 or on respective different substrates 6. These chambers 3 may be arranged, for example, in a row or in a plurality of rows. The number of chambers 3 may be, for example, between 2 and 10. More preferably, the chambers 3 and in particular the spray nozzles 1 thereof are mounted on an insulating support.

[0083] Chamber The outlet section 2 of the spray nozzle may preferably have a circular internal shape. The internal shape of the cavity within the nozzle leading to the outlet section 2 may be, for example, cylindrical with the same internal diameter along its length, or conical with an increasing internal diameter along the length of the cavity.

[0084] The outlet 2 of the spray nozzle may have an inner diameter D of, for example, 50 to 500 μm, preferably 100 to 450 μm, more preferably 150 to 400 μm, and most preferably 200 to 300 μm. i It should be noted that, in the case where the outlet part 2 of the spray nozzle has a non-circular shape, the diameter means the maximum dimension of the internal passage in a plane perpendicular to the main direction of the liquid flow.

[0085] A pumping device may be used to deliver a controlled liquid flow rate of the liquid composition from the tank to the spray nozzle 1. In some embodiments, a syringe pump may be used as the pumping device.

[0086] The liquid composition may be stored in a refrigerated place, for example at −20° C. The liquid composition may be delivered to the spray nozzle 1 at a temperature between 4 and 60° C., preferably at room temperature (i.e., typically 20° C. to 25° C.).

[0087] The liquid flow rate may be adjusted to control the size of the droplets and to allow evaporation of the solvent after or during deposition.

[0088] The flow rate to the spray nozzle 1 (or each spray nozzle 1) may be, for example, 0.01-100 mL / h, preferably 0.1-50 mL / h, more preferably 0.5-20 mL / h, even more preferably 1-10 mL / h, and most preferably 1.5-8 mL / h. Possible flow rate ranges include 0.5-1 mL / h, 1-1.5 mL / h, 1.5-2 mL / h, 2-3 mL / h, 3-5 mL / h, 5-10 mL / h, 10-20 mL / h, and 20-50 mL / h.

[0089] One pumping device may be connected to several spray nozzles 1, or alternatively, different individual pumping devices may be connected to different respective spray nozzles 1.

[0090] The outlet 4 of the ejector 5 may preferably have a circular shape. The outlet 4 has an inner diameter D0 which may be 50 to 800 μm, preferably 100 to 600 μm, more preferably 150 to 500 μm, and most preferably 200 to 500 μm. When the outlet 4 has a non-circular shape, the diameter means the maximum dimension of the internal passage in a plane perpendicular to the main direction of the liquid flow.

[0091] The distance H between the outlet 2 of the spray nozzle and the discharge port 4 of the ejector may be 50 to 550 μm, preferably 60 to 400 μm, more preferably 70 to 250 μm, and most preferably 80 to 180 μm. This distance is measured from the bottom of the spray nozzle 1 to the top surface of the ejector 5.

[0092] The ratio H / D0 may be, for example, 0.2 to 1.5, preferably 0.3 to 1.2, and more preferably 0.75 to 1.

[0093] The distance h between the ejector outlet 4 and the substrate may be 10 to 120 mm, preferably 20 to 100 mm, and more preferably 30 to 80 mm. This distance is measured as the distance from the bottom surface of the ejector 5 to the top surface of the substrate 6.

[0094] Compressed Gas The compressed gas used in the method according to the present invention may be, for example, air, nitrogen, nitrous oxide, carbon dioxide, an inert gas such as argon, or a mixture thereof. For safety reasons, the preferred gas is either air or nitrogen.

[0095] The source of gas may be, for example, a pressurized gas bottle connected to the gas inlet 10. Alternatively, a gas compressor may be used to provide compressed gas to the gas inlet 10.

[0096] The flow of compressed gas into the chamber 3 and through the ejector 5 can be controlled by pressure or flow rate.

[0097] Thus, the pressure in the chamber 3 may for example be in the range 0.05 to 5 bar, preferably 0.1 to 2 bar, more preferably 0.3 to 1 bar above atmospheric pressure.

[0098] The gas flow rate into the chamber 3 (or from the outlet 4) may be in the range of, for example, 0.02 to 10 Ln / min, preferably 0.05 to 5 Ln / min, and more preferably 0.1 to 1 Ln / min.

[0099] Control of the injection of compressed gas may be achieved, for example, by using a regulator connected to a mass flow control system that can be controlled using either pressure or flow rate set points.

[0100] electric field The liquid composition is exposed to an electric field generated in chamber 3 and / or between chamber 3 and substrate 6. Preferably, an electric field is generated both in chamber 3 and between chamber 3 and substrate 6.

[0101] The electric field is preferably constant in time.

[0102] It is preferable that the magnitude of the electric field experienced by the liquid composition in a first region within the chamber 3 (i.e., between the spray nozzle 1 and the ejector 3) is greater than the magnitude of the electric field experienced by the liquid composition in a second region outside the chamber 3 (i.e., between the ejector 3 and the substrate 6).

[0103] The magnitude of the electric field experienced by the liquid composition in the first region is preferably approximately uniform.

[0104] The magnitude of the electric field experienced by the liquid composition in the second region is preferably approximately uniform.

[0105] The magnitude of the electric field that the liquid composition is subjected to in the first region may be, for example, 0.1 to 10 MV / m, preferably 0.5 to 5 MV / m, and more preferably 1 to 2.5 MV / m.

[0106] The magnitude of the electric field that the liquid composition receives in the second region may be, for example, 0.02 to 1 MV / m, preferably 0.1 to 0.5 MV / m, and more preferably 0.1 to 0.2 MV / m.

[0107] The electric field in the first region contributes to the generation of droplets and also contributes to ensuring that any droplets formed in this region are charged.

[0108] The electric field in the second region is useful for directing and concentrating the droplets onto the substrate or onto a desired deposition zone on the substrate.

[0109] To generate an electric field in the first region, the spray nozzle 1 is made of a conductive material, preferably a metal such as stainless steel (or any biocompatible conductive material), and the ejector 5 is made of a conductive material, preferably a metal (while the other walls of the chamber 3 are preferably insulated).

[0110] The spray nozzle 1 may be polarised by being connected to a first high voltage power supply, and the ejector 5 may be polarised by being connected to a second high voltage power supply.

[0111] The first and second high voltage supplies may be different or may be the same high voltage supply with a voltage division configuration, and the high voltage power source may be a DC generator.

[0112] The spray nozzle 1 and the ejector 5 are electrically insulated from each other, so that they form respective electrodes.

[0113] An electric field is generated in the first region due to a voltage difference between the spray nozzle 1 and the ejector 5. Depending on the distance h, this voltage difference may be, for example, 50V to 1000V, preferably 100V to 800V, and more preferably 100V to 600V.

[0114] The substrate 6 preferably comprises a conductive portion as described above, and may be grounded by connecting the conductive portion to one or more metallic conductors that are grounded.

[0115] Alternatively, the substrate 6 can be polarized by connection (through one or more metallic conductors) to a separate high voltage power supply.

[0116] Alternatively, a counter electrode may be used that is adjacent to, e.g., in contact with, the substrate 6, and this counter electrode may be grounded or polarized by connection to a high voltage power supply. For example, the substrate 6 may be disposed on a support that is itself grounded or polarized by connection to a high voltage power supply.

[0117] A voltage difference between the ejector 5 and the substrate 6 or a counter electrode adjacent to the substrate 6 creates an electric field in the second region.

[0118] This voltage difference may be from 1 to 20 kV, preferably from 2 to 15 kV, more preferably from 3 to 10 kV, and further preferably from 4 to 7 kV.

[0119] In some embodiments, a shield electrode may be placed on the top surface of the substrate 6 or between the ejector 5 and the substrate 6. This shield electrode may be, for example, a ring or a plate with one or more openings to allow the aerosol 8 to reach the substrate 6. This shield electrode may be polarized by connecting it to a high voltage power supply or may be connected to ground.

[0120] The shield electrode may comprise a conductive portion and an insulating portion. The shield electrode may also be disposed perpendicular to the spray direction of the composition, preferably at a distance of between 1 and 50 mm from the ejector 5. The shield electrode allows for better control of the diameter of the material deposit on the substrate by generating a controlled electrostatic repulsion between the shield electrode and the charged droplets. The diameter of the deposit will therefore depend on the potential applied to the shield electrode.

[0121] The high voltage power supply used in this embodiment may be adapted to supply, for example, a DC current of −5 to +5 mA and apply a DC voltage of −30 to +30 kV.

[0122] Deposition of material The aerosol produced according to the present embodiment preferably consists of droplets having a median distribution diameter (Dn50) of 1-50 μm, preferably 2-20 μm, more preferably 5-15 μm, and most preferably 8-12 μm (as measured by a phase Doppler anemometer PDA).

[0123] The target substance is deposited in at least one deposition area on the substrate 6. This deposition area is preferably disc-shaped. It may have a diameter of 1-100 mm, preferably 2-50 mm, more preferably 5-45 mm, most preferably 10-40 mm. If the deposition area has a shape other than disc-shaped, the diameter refers to the maximum dimension of the deposition area.

[0124] Additionally, the substrate 6 may be provided with an insulating collar (such as an adhesive insulating collar) to concentrate the electric field lines at the deposition area of ​​the substrate 6 and to separate the deposition area.

[0125] Preferably, the solvent present in the droplets of the liquid composition is substantially evaporated when the method according to the present embodiment is carried out, which evaporation may take place mostly or completely during the deposition step itself, in which case no drying step is necessary.

[0126] To facilitate evaporation during the deposition step, the substrate 6 may be heated. For example, the substrate 6 may be brought to a temperature of 20-80° C., preferably 25-70° C., more preferably 30-60° C., and most preferably 35-55° C. Heating may be achieved by placing the substrate 6 on a heated support, such as, for example, a piece of metal (e.g., stainless steel or aluminum) electrically heated by a resistor. The temperature may be regulated, for example, by a heat-resistant temperature detector.

[0127] Alternatively, the deposition step may be followed by a drying step, which may include one or more of convection heating, radiation heating (e.g., by ultraviolet or infrared radiation), freeze-drying, or circulation of a dry gas.

[0128] Working Example The following examples illustrate the invention without limiting it.

[0129] Example 1: Deposition of 300 μg of milk protein into a patch The patch was manufactured using the apparatus shown in FIGS.

[0130] Inner diameter D of nozzle 1 i The diameter D0 of the discharge port 4 in the ejector 5 is 300 μm, and the diameter D0 of the discharge port 4 in the ejector 5 is 400 μm. The distance H between the outlet 2 of the nozzle and the discharge port 4 of the ejector is 80 μm.

[0131] The patch consists of a support 6 of polyethylene terephthalate (PET) film covered with a thin conductive titanium layer (10 nm) and a double-adhesive insulating crown of PET / EVA foam.

[0132] Liquid exits the nozzle 1 while the gas and liquid mixture passes through the ejector outlet 4. Both the nozzle outlet 2 and the outlet 4 have a circular internal shape.

[0133] The chamber 3, consisting of the volume between the nozzle and the ejector, is pressurized to 0.7 bar above atmospheric pressure with N2O or N2 or a 50 / 50 mixture of N2O / N2, which flows through the outlet at a rate of 0.7 Ln / min.

[0134] The deposition substrate also serves as a counter electrode, is placed at a distance h of 45 mm from the outlet and is connected to ground.

[0135] The nozzle 1 and the ejector 5 are connected to a voltage source, the nozzle 1 is polarized to 6.2 kV (electric field E1 = 2.5 MV / m), and the ejector 5 is polarized to 6 kV (electric field E2 = 0.13 MV / m), and the nozzle-ejector voltage difference is 200 V.

[0136] A highly conductive liquid was fed to the nozzle at a flow rate of 3 mL / h. The liquid was an aqueous formulation containing milk protein at a concentration of 2.5 g / L and Brij O2 as a non-ionic surfactant at a concentration of 0.5 g / L, with a pH of 7.2, a conductivity of 27000 μS / m, and a surface tension of 38 mN / m. Spraying for 150 seconds under these conditions, with the substrate heater set at 50° C., resulted in the formation of a circular dry deposit containing the milk protein on a substrate with a diameter of 24 mm.

[0137] Example 2: Deposition of 300 μg of milk protein into patches using different sets of geometric parameters In this example, the inner diameter of nozzle 1 is D i The diameter D0 of the discharge port 4 is 200 μm. The distance H between the nozzle and the ejector is 200 μm.

[0138] The chamber 3 is pressurized to a pressure 0.7 bar higher than atmospheric pressure with N2O or N2, or a N2O / N2 mixed gas, and this gas flows through the ejector orifice at a flow rate of 0.3 Ln / min.

[0139] The counter electrode (substrate) was placed at a distance h of 70 mm from the discharge port 4 and was connected to ground.

[0140] The nozzle and ejector are connected to a voltage source, the nozzle is polarized at 6.4 kV (electric field E1 = 2 MV / m) and the ejector at 6 kV (E2 = 0.13 MV / m), and the nozzle-ejector voltage difference is 400 V. The liquid formulation is the same as that used in Example 1. The liquid flow rate is 3 mL / h and the spray time is 150 s.

[0141] These conditions resulted in the formation of a circular dry deposit on the substrate heated to 50° C., 24 mm in diameter and containing 300 μg of milk protein.

[0142] When the same composition was used with the electrospray deposition technique based on the above-mentioned patent document 1, the maximum flow rate at which the spray could be stably operated was 1 mL / h, meaning that the spraying process would be laborious to create a patch with the same amount of active ingredient, thus demonstrating the limitations of the electrospray deposition technique for use with liquids of high electrical conductivity.

[0143] Example 3: Deposition of 250 μg of peanut protein into patches In this example, the inner diameter of nozzle 1 is D i The diameter D0 of the discharge port 4 is 200 μm. The distance H between the nozzle and the discharge port is 200 μm.

[0144] The chamber 3 is pressurized to 0.7 bar above atmospheric pressure with N2O or N2 or a N2O / N2 mixed gas, which flows through the ejector orifice at a flow rate of 0.35 Ln / min. The counter electrode (substrate) is disposed at a distance h of 70 mm from the discharge port 4 and is connected to ground.

[0145] The nozzle and ejector are connected to a voltage source, the nozzle is polarized to 6.4 kV (electric field E1 = 2 MV / m) and the ejector is polarized to 6 kV (electric field E2 = 0.13 MV / m), and the voltage difference between the nozzle and ejector is 400 V.

[0146] The nozzle is supplied with the liquor at a flow rate of 3 mL / h. The liquor contains peanut protein at a concentration of 4 g / L, Brij O2 as a non-ionic surfactant at a concentration of 1 g / L, and 10 wt% ethanol. The liquor has a pH of 7.6, an electrical conductivity of 7000 μS / m, and a surface tension of 38 mN / m. When sprayed for 90 seconds under these conditions with the substrate heater set at 50° C., a circular dry deposit containing peanut protein was formed on a substrate with a diameter of 24 mm.

[0147] For comparison, when using the electrospray deposition technique based on the above-mentioned Patent Document 1, the maximum possible liquid flow rate is 1.6 mL / h.

[0148] Example 4: Deposition of saline onto the patch An aqueous preparation of saline (0.9% sodium chloride) containing D-Mannitol (1,2,3,4,5,6-Hexanehexol) at a concentration of 1 g / L was used to mimic the white precipitate. The electrical conductivity is 1.2 S / m. The inner diameter D of nozzle 1 i The diameter D0 of the discharge port 4 is 200 μm. The distance H between the nozzle and the ejector is 200 μm.

[0149] The chamber 3 is pressurized with N2O or N2 or N2O / N2 mixed gas at a pressure 0.7 bar higher than atmospheric pressure, and this gas flows through the ejector orifice at a flow rate of 0.35 Ln / min.

[0150] The counter electrode (substrate) was placed at a distance h of 70 mm from the discharge port 4 and was connected to ground.

[0151] The nozzle and ejector were connected to a voltage source, the nozzle was polarized at 6.4 kV (electric field E1 = 2 MV / m) and the ejector was polarized at 6 kV (E2 = 0.13 MV / m), and the voltage difference between the nozzle and the ejector was 400 V. In this case, the liquid had a conductivity about 100 times higher than the emulsion, which was the same as the result of obtaining a dry deposit with a diameter of 24 mm when the substrate was heated to 50 °C.

[0152] If the same compositions are used in the electrospray deposition technique according to US Pat. No. 5,399,233, it is not possible to produce patches, as the presence of electrical discharges prevents the stable operation of the process.

[0153] The following table summarizes the parameters of the apparatus and liquid compositions used in the various examples.

[0154] [Table 1]

Claims

1. A method for depositing one or more allergens on a substrate (6), comprising the steps of: providing said substrate (6) at a distance from a conductive spray nozzle (1) having an outlet port (2); supplying the liquid composition comprising one or more allergens to the spray nozzle (1) at a flow rate of 3 to 50 mL / h; supplying a compressed gas selected from the group consisting of nitrogen, nitrous oxide, carbon dioxide, inert gas, argon, and mixtures thereof, around the liquid composition flowing out of the outlet (2) of the spray nozzle (1) and providing an electric field downstream of the outlet (2) of the spray nozzle (1), thereby generating electrically charged droplets from the liquid composition between the outlet (2) of the spray nozzle (1) and the substrate (6); collecting the generated droplets on a substrate (6); Equipped with The compressed gas is supplied into a chamber (3) in which the spray nozzle (1) is disposed, and the liquid composition and the compressed gas flow out of the chamber (3) through an outlet (4) of a conductive ejector (5); The one or more allergens are selected from the group consisting of peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens. method.

2. The liquid composition has a conductivity of 0.1 μS / m to 3 S / m. The method of claim 1.

3. The compressed gas surrounding the liquid composition is at a pressure of 0.1 to 2 bar higher than atmospheric pressure. The method according to claim 1 or claim 2.

4. The compressed gas surrounding the liquid composition has a pressure of 0.3 to 1 bar above atmospheric pressure. The method according to any one of claims 1 to 3.

5. applying an electric field having a first magnitude to a first region between the outlet (2) of the spray nozzle (1) and the discharge port (4) and / or applying an electric field having a second magnitude to a second region between the discharge port (4) and the substrate (6); The first magnitude is between 0.1 and 10 MV / m, and / or the second magnitude is between 0.02 and 1 MV / m, and / or the first magnitude is greater than the second magnitude. The method according to any one of claims 1 to 4.

6. The first magnitude is 0.5 to 5 MV / m, and / or the second magnitude is 0.1 to 0.5 MV / m. The method of claim 5.

7. After collecting the droplets on the substrate (6), no drying step is involved. The method according to any one of claims 1 to 6.

8. For producing one selected from the group consisting of a patch and a therapeutic patch. The method according to any one of claims 1 to 7.

9. The liquid composition is supplied to the spray nozzle (1) at a flow rate selected from the group consisting of 3 to 5 mL / h, 3 to 10 mL / h, 3 to 20 mL / h, 5 to 10 mL / h, 5 to 20 mL / h, 5 to 50 mL / h, 10 to 20 mL / h, 10 to 50 mL / h, and 20 to 50 mL / h. The method according to any one of claims 1 to 8.

10. The compressed gas is selected from the group consisting of nitrogen, nitrous oxide, and mixtures thereof. The method according to any one of claims 1 to 9.

11. An apparatus for depositing one or more allergens on a substrate (6), comprising: a chamber (3) including a conductive ejector (5) having a discharge port (4); a conductive spray nozzle (1) disposed within the chamber (3) and having an outlet (2); a support for positioning said substrate (6) outside said chamber (3), away from said spray nozzle (1); a liquid supply line (9) for supplying the liquid composition comprising the one or more allergens to be deposited to the spray nozzle (1) at a flow rate of 3 to 50 mL / h; a gas inlet (10) for supplying to said chamber (3) a compressed gas selected from the group consisting of nitrogen, nitrous oxide, carbon dioxide, inert gases, argon, and mixtures thereof; a device for generating an electric field in the chamber (3) and / or between the chamber (3) and the substrate (6); Equipped with The one or more allergens are selected from the group consisting of peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens. Equipment.

12. The electric field generating device is configured to generate an electric field both within the chamber (3) and between the chamber (3) and the substrate (6). The facility according to claim 11.

13. Further comprising a contact for connecting the base (6) to ground, Each of the spray nozzle (1) and the ejector (5) is connected to a high voltage power source.

13. The installation according to claim 11 or 12.

14. The outlet (2) of the spray nozzle has an inner diameter Di of 50 to 500 μm. The facility according to any one of claims 11 to 13.

15. The distance H between the outlet (2) of the spray nozzle (1) and the discharge port (4) is 50 to 550 μm. The facility according to any one of claims 11 to 14.

16. The liquid composition is supplied to the spray nozzle (1) at a flow rate selected from the group consisting of 3 to 5 mL / h, 3 to 10 mL / h, 3 to 20 mL / h, 5 to 10 mL / h, 5 to 20 mL / h, 5 to 50 mL / h, 10 to 20 mL / h, 10 to 50 mL / h, and 20 to 50 mL / h. The facility according to any one of claims 11 to 15.

17. The compressed gas is selected from the group consisting of nitrogen, nitrous oxide, and mixtures thereof. The facility according to any one of claims 11 to 16.

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