Method of depositing material onto a substrate

Abstract

To provide technique capable of selectively inverting an article.SOLUTION: A method for deposition of a substance onto a substrate (6) according to an embodiment of the present invention provides the substrate (6) with a distance from a conductive spray nozzle (1) having an outlet part (2), supplies a liquid composition containing the substance to the spray nozzle (1), supplies a compressed gas around the fluid composition flowing out from the outlet part (2) of the spray nozzle (1), and supplies an electric field to the downstream of the outlet part (2) of the spray nozzle (1), thereby generating charged droplets from the liquid composition between the outlet part (2) of the spray nozzle (1) and the substrate (6), charged and collecting the generated droplets onto the substrate (6). This embodiment also relates to a facility for performing the method.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for depositing a substance on a substrate, particularly a method for depositing a biological substance such as a protein on a substrate such as a patch.

Background Art

[0002] The application of drugs to the skin by patches has many uses in human and animal health. In fact, it enables the development of efficient diagnostic tests and treatment methods for transferring active ingredients to the skin.

[0003] The method of locally applying a substance to the skin has many advantages compared to other administration methods such as injection, including no risk of contamination, no pain, easy handling, and the patient can administer the drug himself.

[0004] In Patent Document 1 below, as a method for manufacturing a patch intended for applying a substance to the skin, the patch includes a conductive support, and a method for depositing a liquid agent of the substance on the support of the patch by electrohydrodynamic spraying (also known as "electrospray" technology) is disclosed.

[0005] This method has provided satisfactory results in many situations, but particularly when the liquid agent has relatively high conductivity, the flow rate achievable by this method remains limited.

[0006] Unfortunately, among the substances for treatment and diagnosis deposited on the patch, there are some that must be provided in such a liquid agent with relatively high conductivity (for example, a physiological serum-based preparation).

[0007] In other industrial fields, the "flow focusing" technology for generating droplets of a first fluid by flowing a second fluid around the first fluid emerging from a capillary line is utilized. Examples of documents related to this flow focusing technology include the following Non-Patent Documents 1 to 4.

[0008] A technical comparison of flow focusing and electrospray is conducted in Non-Patent Document 5 below.

[0009] A technique that combines the principles of electrospray and flow focusing, often referred to as electro-flow focusing, is proposed in the following Patent Document 2 and Non-Patent Documents 6 and 7.

[0010] For a method of depositing a substance onto a substrate to be applicable in an industrial manufacturing environment, the substance on the substrate must be dried instantly. [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 steady-state liquid microthreads and micro-sized monodisperse sprays of gaseous fluids, Ganan-Calvo, Physical Review Letters 80, 285-288, 1998. [Non-Patent Document 2] Perfectly monodisperse microbubbles produced 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 machining of viscous single-phase and multi-phase media, Arumuganathar et al., Soft Matter, 3:605-612, 2007. [Non-Patent Document 5] Revisions to Capillary Cone Jet Physics: Electrospray and Flow Focusing, Ganan-Calvo et al., Physical Review E 79, 066305, 2009. [Non-Patent Document 6] Combination of 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 [Overview of the project] [Problems that the invention aims to solve]

[0013] Currently, there is still a need for a method of depositing substances on substrates (especially on patches, or on substrates for making patches) that has improved yield without compromising the accuracy and quality of deposition, especially when the substance is supplied in a relatively conductive liquid. [Means for solving the problem]

[0014] A first object in 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 compressed gas around the liquid composition flowing out from the outlet of the spray nozzle, and supplying an electric field downstream of the outlet of the spray nozzle, thereby generating 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 selected from peptides or proteins, preferably allergens, most preferably allergens of peanuts, milk, eggs, walnuts, cashew nuts, pecans, pistachios, and hazelnuts.

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

[0017] In some embodiments, the liquid composition is supplied 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 0.1 to 2 bar, preferably 0.3 to 1 bar higher than atmospheric pressure.

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

[0020] In some embodiments, an electric field having a first magnitude is applied in a first region between the outlet portion of the spray nozzle and the outlet, and / or an electric field having a second magnitude is applied in a second region between the outlet and the substrate, the first magnitude is preferably 0.1 to 10 MV / m, more preferably 0.5 to 5 MV / m, and / or the second magnitude is preferably 0.02 to 1 MV / m, more preferably 0.1 to 0.5 MV / m, and / or preferably, the first magnitude is 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] Embodiments of the present invention also relate to equipment for depositing a substance 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; 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 containing the substance to be deposited to the spray nozzle; a gas inlet for supplying compressed gas to the chamber; and equipment for generating an electric field inside the chamber and / or between the chamber and the substrate.

[0024] In some embodiments, the device that generates the electric field is configured to generate an electric field both inside the chamber and between the chamber and the substrate.

[0025] In some embodiments, each of the spray nozzle and ejector is connected to a high-voltage power supply, and the equipment further has contacts that connect the base 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, and more preferably 150 to 400 μm. i It holds.

[0027] In some embodiments, the ejector port 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 needs identified above. In particular, the present invention provides a method for depositing a substance on a substrate (especially on a patch, or for the manufacture of a patch) with improved yield without impairing the accuracy and quality of deposition, when the substance is provided in a liquid formulation having relatively high conductivity.

[0030] This is achieved by generating droplets of the liquid composition using electro-flow focusing technology and guiding them onto a substrate. [Brief explanation of the drawing]

[0031] [Figure 1] This figure schematically shows an example of equipment for implementing the method according to this embodiment. [Figure 2] This diagram schematically shows the details of the equipment shown in Figure 1. [Modes for carrying out the invention]

[0032] Next, the present invention will be described in more detail without limiting it in the following description.

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

[0034] "Substance" means a single molecule or a supramolecular assembly, or a mixture of different molecules or supramolecular assemblies.

[0035] The substance may be of biological nature and may, in particular, be an oligopeptide, polypeptide or protein, especially an antigenic oligopeptide, polypeptide or protein, a hormone, cytokine, immunoglobulin, allergen, growth factor, nutritional factor, moisturizing compound or vitamin, or a chemically active component, or may contain such components. Preferred substances consist of one or more immunoreactive oligopeptides, polypeptides or proteins selected from food allergens or human proteins involved in human autoimmune diseases. Most preferred substances are food allergens selected from peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens.

[0036] Furthermore, it may also include, or contain, one or more drugs or active ingredients, including, nicotine, caffeine, morphine, hydromorphone HCl, fentanyl, apomorphine HCl, scopolamine, chlorpheniramine, imiquimod, diphenhydramide, lidocaine, isotretinoin, ketoprofen, diclofenac, leuprolide, finasteride, etc.

[0037] The substance to be deposited is provided in the form of a liquid composition. The liquid composition consists of an aqueous solvent and / or an organic solvent. A mixture of the aqueous solvent and the organic solvent is also possible.

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

[0039] Alcohols are preferred as the organic solvent, and ethanol is particularly preferred.

[0040] Deionized water or a buffered aqueous solution is preferred as the aqueous solvent. The pH of the composition may be adjusted, for example, using citric acid, sodium hydroxide, tris and / or histidine.

[0041] To promote the evaporation of the liquid composition on the substrate, and if the substance allows, it is advantageous to add an organic solvent, particularly an alcohol (e.g., ethanol), to the aqueous solvent. In some embodiments, the liquid composition is 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 solvents is optional, as some types of proteins may be incompatible with such organic solvents.

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

[0043] To stabilize the target substance 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 concentration will cause the solution to exhibit a certain ionic strength. Depending on the properties and concentration of these electrolytes, the solution will consequently have 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 for 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] Electrical conductivity may be measured using a conductivity probe.

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

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

[0048] Substrate and patch According to the present invention, the target substance is deposited on the substrate.

[0049] Once deposited on the substrate (and optionally after a drying step), the substance is preferably in a nearly dry form, and more preferably in the form of fine particles.

[0050] The substrate is preferably planar, flat, or film-like in principle, and preferably consists of two surfaces. In some embodiments, the substrate may include a recess that forms a chamber or reservoir.

[0051] The substrate may be rigid or semi-rigid. The substrate may be formed as individual patches before depositing material onto it. Therefore, the substrate may have shapes such as circular, square, rectangular, or elliptical.

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

[0053] The substrate preferably includes at least one conductive portion. In this embodiment, "conductivity" means "electrical conduction" or "electrical conductivity." The conductive portion may be on one surface of the substrate or in the bulk. Alternatively, the conductive portion may be a conductive layer provided on or within the substrate.

[0054] The substrate may include, or be composed of, different biocompatible materials, such as polymers (or multiple polymers), doped polymers (or multiple polymers), polymers (or multiple polymers) coated with conductive materials, textiles and / or biomaterials (or multiple biomaterials).

[0055] The substrate may, in particular, include at least one conductive surface positioned facing the spray nozzle. A preferred substrate thus includes, or is composed of, an insulating layer, such as an insulating polymer (film, fiber, etc.) layer, with at least one surface covered by a conductive layer.

[0056] The conductive material used in the substrate (especially for supplying the conductive layer) may be inorganic (e.g., a metal) or organic (e.g., consisting of carbon, graphite, or oxide(s)). The metal is preferably gold, silver, platinum, titanium, or aluminum. The conductive layer(s) may 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 deposition of graphite onto the substrate may be performed in advance or on the line immediately before depositing the material onto the substrate. The deposition of graphite may be carried out by projecting a neutral or charged aerosol, or by impregnating the film by passing it through a graphite solution bath.

[0058] Forming a conductive layer on the substrate before material deposition can also be achieved by metallization or oxide deposition. The oxide is preferably tin-doped indium oxide (ITO).

[0059] Furthermore, plasma treatment may be used to improve the adhesion between the deposition-substrate interface or to deposit the conductive portion itself.

[0060] Therefore, in some embodiments, the method according to this embodiment includes one or more preliminary steps of modifying the substrate, for example, by plasma treatment at low pressure 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. It may further include an insulating double-bonded crown, such as polyethylene (PE) / ethylene vinyl acetate (EVA) foam.

[0062] The substrate may be, in particular, a roll-shaped strip that is gradually wound up. The strip may, 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 having pores at regular intervals attached to a conductive film, wherein each portion of the foamed film not covered by the conductive layer or the foamed film forms a deposition region of the target substance. It is equipped with.

[0063] Preferably, the support film is wider than the foam film. Preferably, each deposition region surrounded by the foam is in electrical contact with the entire conductive surface of the support film.

[0064] After depositing a substance onto a substrate, the substrate or a patch formed from the substrate is advantageously packaged so that the substance deposit is protected from the external environment. Therefore, the patch may have a peelable film on its surface that covers the substance deposit and optionally also covers a portion of the substrate that does not contain the deposited substance.

[0065] The method according to this embodiment makes it possible to fabricate any type of patch, i.e., any device that can be applied to a skin area of ​​a subject to bring it into contact with a target substance. This includes patches with passive, facilitative, or mechanical diffusion, adhesive patches, bandages, adhesive plasters, cupours, and transdermal patches.

[0066] Adhesives include, or consist of, an adhesive or coating on a suitable support, comprising one or more target substances and optionally one or more diluents, emollients, and adhesives. 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 so that they can be optionally cut. They may be applied on top of adhesive bandages and covered with perforated material.

[0067] Medicated bandages are applied to small lesions of the skin to provide local action, and consist of or comprise an adhesive bandage to which a substance has been applied.

[0068] The adhesive patch may include, or consist of, an adhesive bandage comprising a plastic disc on which an adhesive containing a substance is placed. The adhesive may further contain components such as gum arabic or gelatin and water.

[0069] Patches involving passive, facilitated, or mechanical diffusion typically include a support on which the substance is deposited and, optionally, a device to facilitate the cell permeation process (such as by the application of electrical pulses, ultrasound, or microneedles).

[0070] Preferably, the patch is a dry patch, more preferably an occluded type, and even more preferably an electrostatic patch as described in the document International Publication No. 02 / 071950.

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

[0072] The patch manufactured according to this embodiment may be fitted to an animal or a human subject, preferably a human subject.

[0073] To ensure the preservation of the patches within the packaging, and to avoid deterioration of the active ingredients in the deposited material in particular, and to maintain microbiological quality, the patches may undergo additional treatments such as pasteurization or ionization.

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

[0075] General principles of material deposition by electroflow focusing The method according to this embodiment includes depositing a substance onto a substrate by spraying a liquid composition onto the substrate using electro-flow focusing technology.

[0076] Figures 1 and 2 show equipment capable of performing electro-flow focusing deposition. This equipment consists of a conductive spray nozzle 1 within a chamber 3. Compressed gas is supplied to the chamber 3 via a gas inlet 10. The spray nozzle 1 is connected to or directly formed from a liquid supply line 9.

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

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

[0079] The liquid composition flows out from the outlet 2 of the spray nozzle, preferably forming a liquid cone 7, which is then subdivided into droplets. Droplet formation is achieved by the flow of compressed gas from the chamber 3 through the discharge port 4 and / or by the action of electrostatic repulsion forces that cause droplet formation in the electrospray process. Due to the pressure gradient between the chamber 3 and the external environment of the chamber 3, the compressed gas is pushed out of the chamber 3 through the discharge port 4 as a gas flowstream. The gas fluid surrounds the liquid cone 7, forming an aerodynamic sheath around it (as indicated by the arrows in Figure 1). The liquid cone 7 forms droplets in a complex process that may occur within the chamber 3 between the outlet 2 of the spray nozzle and the top of the ejector, and within the (preferably cylindrical) volume of the discharge port 4.

[0080] Furthermore, as will be described later, the droplets become charged by the electric field, generating electrostatic repulsion.

[0081] In this way, a droplet aerosol 8 is formed between the discharge port 4 and the substrate 6.

[0082] In some embodiments, the apparatus may comprise multiple chambers 3 as described above for simultaneously spraying a liquid composition onto multiple deposition areas on the same substrate 6 or on each of different substrates 6. These chambers 3 may be aligned, for example, in one or more rows. The number of chambers 3 may be, for example, 2 to 10. More preferably, the chambers 3 and in particular their spray nozzles 1 are mounted on an insulating support.

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

[0084] The outlet portion 2 of the spray nozzle has an inner diameter D which may be, 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 has the following characteristics. Furthermore, if the outlet portion 2 of the spray nozzle has a non-circular shape, the diameter refers to 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 supply the liquid composition from the tank to the spray nozzle 1 at a controlled liquid flow rate. 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 droplet size and to allow evaporation of the solvent after or during deposition.

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

[0089] One pump device can be connected to multiple spray nozzles 1, or different individual pump devices can be connected to different spray nozzles 1.

[0090] The discharge port 4 of the ejector 5 may preferably have a circular shape. The discharge port 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. If the discharge port 4 has a non-circular shape, the diameter refers to 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 as the distance 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 port 4 and the base 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 base 6.

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

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

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

[0097] Therefore, the pressure inside chamber 3 may be, for example, 0.05 to 5 bar, preferably 0.1 to 2 bar, and more preferably 0.3 to 1 bar higher than atmospheric pressure.

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

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

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

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

[0102] Preferably, the magnitude of the electric field experienced by the liquid composition in the first region inside 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 the second region outside the chamber 3 (i.e., between the ejector 3 and the substrate 6).

[0103] In the first region, it is preferable that the magnitude of the electric field acting on the liquid composition is substantially uniform.

[0104] It is preferable that the magnitude of the electric field experienced by the liquid composition in the second region is approximately uniform.

[0105] The magnitude of the electric field experienced by the liquid composition 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 experiences 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 droplet formation and ensures that any droplets formed in this region are reliably charged.

[0108] The electric field in the second region is useful for directing and concentrating the droplet onto the substrate or into 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 polarized by connecting it to a first high-voltage power supply, and the ejector 5 may also be polarized by connecting it to a second high-voltage power supply.

[0111] The first and second high-voltage supplies may be different, or they may be the same high-voltage supply with a voltage divider setting. Furthermore, the high-voltage power supply may be a DC generator.

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

[0113] An electric field is generated in the first region due to the 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 includes a conductive portion as described above. This conductive portion may be grounded by connecting it to one or more grounded metal conductors.

[0115] Alternatively, the substrate 6 can be polarized by connecting it to another high-voltage power source (connected via one or more metal conductors).

[0116] Alternatively, a counter electrode adjacent to the substrate 6, for example, in contact with it, may be used, and this counter electrode may be grounded or polarized by being connected to a high-voltage power supply. For example, the substrate 6 may be placed on a support that is grounded or polarized by being connected to a high-voltage power supply.

[0117] An electric field is generated in the second region due to the voltage difference between the ejector 5 and the substrate 6 or the counter electrode adjacent to the substrate 6.

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

[0119] In some embodiments, the shield electrode may be positioned on the upper surface of the substrate 6 or between the ejector 5 and the substrate 6. This shield electrode may be, for example, ring-shaped, 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 to a high-voltage power supply or connected to ground.

[0120] The shield electrode may comprise a conductive portion and an insulating portion. The shield electrode may also be positioned perpendicular to the spraying direction of the composition, preferably at a distance of 1 to 50 mm from the ejector 5. The shield electrode generates a controlled electrostatic repulsion force between the shield electrode and the charged droplet, thereby allowing for better control of the diameter of material deposition on the substrate. Therefore, the diameter of the deposition will depend on the potential applied to the shield electrode.

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

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

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

[0124] Furthermore, an insulating collar (such as an adhesive insulating collar) may be provided on the substrate 6 to concentrate the electric field lines in the deposition region of the substrate 6 and to demarcate the deposition region.

[0125] Preferably, the solvent present in the droplets of the liquid composition evaporates substantially when the method according to this embodiment is carried out. This evaporation may occur mostly or completely during the deposition step itself, in which case a drying step is unnecessary.

[0126] To promote evaporation during the deposition step, the substrate 6 may be heated. For example, the substrate 6 may be heated 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 performed, for example, by placing the substrate 6 on a heated support such as a metal piece (e.g., stainless steel or aluminum) electrically heated by a resistor. The temperature may be controlled, for example, by a heat-resistant temperature detector.

[0127] Alternatively, a drying step may be provided after the deposition step. The drying step may include one or more of the following: heating by convection, heating by irradiation (e.g., by ultraviolet or infrared light), freeze-drying, or circulation of a drying gas.

[0128] Examples The following examples illustrate the present invention without limiting it.

[0129] Example 1: Deposition of 300 μg of milk protein onto a patch The patches were manufactured using the apparatus shown in Figures 1 and 2.

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

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

[0132] The liquid exits from nozzle 1, while the mixture of gas and liquid passes through the ejector's outlet 4. Both the nozzle's outlet 2 and the outlet 4 have a circular inner surface shape.

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

[0134] The substrate for deposit formation also serves as the counter electrode, is positioned at a distance h of 45 mm from the discharge port, and is connected to the ground.

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

[0136] A highly electrically conductive liquid was supplied to the nozzle at a flow rate of 3 mL / h. The liquid was an aqueous formulation containing 2.5 g / L of milk protein and 0.5 g / L of Brij O2 as a nonionic surfactant, with a pH of 7.2, an electrical conductivity of 27000 μS / m, and a surface tension of 38 mN / m. When sprayed for 150 seconds under these conditions using a substrate heater set to 50°C, a circular dried deposit containing milk protein was formed on a substrate with a diameter of 24 mm.

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

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

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

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

[0141] Under these conditions, a circular, dried deposit containing 300 μg of milk protein, with a diameter of 24 mm, was formed on a substrate heated to 50°C.

[0142] When using the same composition in the electrospray deposition technology based on Patent Document 1, the maximum flow rate at which stable spray operation is possible is 1 mL / h. This means that the spraying process is time-consuming to create patches with the same amount of active ingredient, thus demonstrating the limitations of electrospray deposition technology when used with highly electrically conductive liquids.

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

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

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

[0146] The nozzle is supplied with a liquid at a flow rate of 3 mL / h. The liquid contains peanut protein at a concentration of 4 g / L, Brij O2 as a nonionic surfactant at a concentration of 1 g / L, and 10 wt% ethanol. This liquid 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 using a substrate heater set to 50°C, circular dried deposits containing peanut protein were formed on a substrate with a diameter of 24 mm.

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

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

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

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

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

[0152] When the same composition is used in the electrospray deposition technology based on the above-mentioned Patent Document 1, the presence of electrical discharge hinders the stable operation of the process, making it impossible to generate patches.

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

[0154] [Table 1]

Claims

1. A method for depositing one or more allergens on a substrate (6), The steps include: providing the base body (6) at a distance from the conductive spray nozzle (1) having an outlet portion (2); The steps include supplying a liquid composition containing one or more of the above-mentioned allergens and having a conductivity of 1 mS / m to 20 mS / m to the spray nozzle (1), The steps include generating charged droplets from the liquid composition between the outlet portion (2) of the spray nozzle (1) and the substrate (6) by providing an electric field downstream of the outlet portion (2) of the spray nozzle (1), The steps include supplying gas to the area surrounding the liquid composition flowing out from the outlet (2) of the spray nozzle (1), The steps include collecting the generated droplets onto the substrate (6) and Equipped with, A method for selecting one or more allergens from the group consisting of peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens.

2. The liquid composition has a conductivity of 1 mS / m to 3 mS / m. The method according to claim 1.

3. The liquid composition has a conductivity of 3 mS / m to 10 mS / m. The method according to claim 1.

4. After collecting droplets on the substrate (6), the process does not include a drying step. The method according to claim 1.

5. The one or more allergens are selected from the group consisting of peanut and egg allergens. The method according to claim 1.

6. The one or more allergens include peanut allergens. The method according to claim 1.

7. The one or more allergens include egg allergens. The method according to claim 1.

8. The one or more allergens include milk allergens. The method according to claim 1.

9. The one or more allergens include at least one selected from the group consisting of oligopeptides, polypeptides, and proteins. The method according to any one of claims 1 to 8.

10. The one or more allergens are present in the liquid composition at a total concentration of 0.01 to 20% by weight. The method according to any one of claims 1 to 8.

11. For manufacturing a selection from the group consisting of patches and therapeutic patches. The method according to any one of claims 1 to 8.

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