Method of depositing material on a substrate

Abstract

The present invention relates to a method for depositing a material on a substrate (6), comprising: providing a substrate (6) at a distance from a conductive spray nozzle (1) having an outlet (2); providing a liquid composition containing the material to the spray nozzle (1); providing a compressed gas around the liquid composition flowing out from the outlet (2) of the spray nozzle (1) and providing an electric field downstream of the outlet (2) of the spray nozzle (1) to generate an electrically charged liquid drop from the liquid composition between the outlet (2) of the spray nozzle (1) and the substrate (6); and collecting the liquid drop generated on the substrate (6). The present invention also relates to an apparatus for carrying out this method.

Description

Technology Field

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

[0002] There are many examples of the application of substances to the skin using patches for the health of humans or animals. In practice, this can enable the development of efficient diagnostic tests or treatment methods that deliver active ingredients to the skin.

[0003] Topical application of a substance to the skin has many advantages compared to other administration methods such as injection, particularly the absence of a risk of contamination, painlessness, ease of handling, and the ability for the patient to self-administer the substance.

[0004] Document WO 2009 / 095591 discloses a method for manufacturing a patch for skin application of a material, wherein the patch comprises a conductive support, and the method comprises depositing a liquid formulation of the material onto the support of the patch by electrohydrodynamic spraying (also known as "electrospray" technology).

[0005] While this method provides satisfactory results in various situations, the flow rate achievable with this method is limited, particularly when the liquid formulation has relatively high conductivity.

[0006] Unfortunately, some therapeutic or diagnostic materials of interest for deposition on patches must be provided in liquid formulations with such relatively high conductivity (e.g., physiological serum-based formulations).

[0007] In other industrial sectors, "flow focusing" technology has been used to generate droplets of a first fluid due to the flow of a second fluid surrounding the first fluid exiting a capillary. Exemplary literature regarding the aforementioned flow focusing technology is as follows:

[0008] ― Generation of steady liquid microthreads and micro-sized monodisperse sprays in gas streams , Ganan-Calvo, Physical Review Letters 80, 285-288, 1998;

[0009] ― Perfectly monodisperse microbubbling by capillary flow focusing , Ganan-Calvo et al., Physical Review Letters 87, 274501, 2001;

[0010] ― Enhanced liquid atomization: From flow-focusing to flow-blurring , Ganan-Calvo, Applied Physics Letters 86, 214101, 2005; and

[0011] ― Aerodynamically assisted jet processing of viscous single- and multi-phase media , Arumuganathar et al., Soft Matter, 3:605-612, 2007.

[0012] The following publication provides a comparison of flow focusing and electrostatic spraying technologies.

[0013] ― Revision of capillary cone-jet physics: electrospray and flow focusing , Ganan-Calvo et al., Physical Review E 79, 066305, 2009.

[0014] A combination of the principles of electrostatic spraying technology and flow focusing technology (sometimes referred to as electronic-flow focusing) is proposed in the following literature.

[0015] ― EP 1479446;

[0016] ― The combination of electrospray and flow focusing, Ganan-Calvo et al., J. Fluid Mech., 556, 421-445, 2006;

[0017] ― Electro -Flow Focusing: The High-Conductivity Low-Viscosity Limit , Ganan-Calvo, Physical Review Letters 98, 134503, 2007.

[0018] There is still a demand for methods to deposit materials onto substrates (particularly on patches or for manufacturing patches) without compromising the accuracy and quality of deposition, especially when materials are provided in liquid formulations with improved yields and relatively high conductivity. Furthermore, for methods to deposit materials onto substrates to be applicable in industrial manufacturing environments, the material must be able to be dried immediately on the substrate.

[0019] The first objective of the present invention is to provide a method for depositing a material on a substrate, the method being

[0020] ― Provide a substrate at a distance from a conductive spray nozzle having an outlet;

[0021] — Providing a liquid composition containing a substance to a spray nozzle;

[0022] — By providing a compressed gas around a liquid composition flowing out of an outlet of a spray nozzle and providing an electric field downstream of the outlet of the spray nozzle, an electrically charged liquid droplet is generated from the liquid composition between the outlet of the spray nozzle and the substrate; and

[0023] - Includes collecting liquid droplets generated on a substrate.

[0024] In some embodiments, the substance is selected from peptides or proteins, preferably allergens, most preferably peanuts, milk, eggs, walnuts, cashews, pecans, pistachios, and hazelnut allergens.

[0025] In some embodiments, the liquid composition has a conductivity of 0.1 μS / m to 3 mS / m, preferably 1 mS / m to 20 mS / m.

[0026] In some embodiments, the liquid composition is provided to a spray nozzle at a flow rate of at least 1 mL / h, preferably at least 1.5 mL / h.

[0027] 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.

[0028] In some embodiments, a spray nozzle is positioned within a chamber, compressed gas is supplied to the chamber, and the liquid composition and compressed gas are discharged from the chamber through an ejection opening within a conductive ejector.

[0029] In an inlet embodiment, an electric field having a first size is applied to a first region between the outlet of the spray nozzle and the ejection opening; and / or an electric field having a second size is applied to a second region between the ejection opening and the substrate; and, preferably, the first size is 0.1 to 10 MV / m, more preferably 0.5 to 5 MV / m; and / or preferably, the second size is 0.02 to 1 MV / m, more preferably 0.1 to 0.5 MV / m; and / or preferably, the first size is larger than the second size.

[0030] In some embodiments, this method does not include any drying step after collecting liquid droplets on the substrate.

[0031] In some embodiments, this method is for manufacturing a patch, preferably a therapeutic patch.

[0032] The present invention also relates to equipment for depositing a material on a substrate, and the equipment is

[0033] ― A chamber including a conductive ejector having an ejection opening;

[0034] ― A conductive spray nozzle having an outlet disposed within a chamber;

[0035] ― A support for placing a substrate outside the chamber at a distance from the spray nozzle;

[0036] ― A liquid supply line for supplying a liquid composition containing a material deposited on a spray nozzle;

[0037] ― Gas inlet for supplying compressed gas to the chamber;

[0038] ― Includes equipment for generating an electric field inside the chamber and / or between the chamber and the substrate.

[0039] In some embodiments, the equipment for generating an electric field is configured to generate an electric field both inside the chamber and between the chamber and the substrate.

[0040] In some embodiments, the spray nozzle and the ejector are each connected to a high-voltage supply, and the apparatus further includes a contact for connecting the substrate to ground.

[0041] In some embodiments, the spray nozzle outlet has an inner diameter D i The depth is 50 to 500 μm, preferably 100 to 450 μm, more preferably 150 to 400 μm.

[0042] In some embodiments, the ejection opening has an inner diameter D o The range is 50 to 800 μm, preferably 100 to 600 μm, more preferably 150 to 500 μm.

[0043] In some embodiments, the distance H between the outlet and the ejection opening of the spray nozzle may be 50 to 550 μm, preferably 60 to 400 μm, more preferably 80 to 250 μm.

[0044] The present invention makes it possible to address the needs identified above. In particular, the present invention provides a method for depositing a material on a substrate (particularly on a patch, or for manufacturing a patch) having improved yield, particularly accuracy and quality of deposition when the material is provided in a liquid formulation having relatively high conductivity without damage.

[0045] This is achieved by generating a drop of a liquid composition and guiding the drop to a substrate using electron-flow focusing technology. Brief explanation of the drawing

[0046] FIG. 1 is a diagram showing an example of equipment for carrying out the method of the present invention in a schematic manner. Figure 2 is a drawing showing the details of the equipment of Figure 1 in a schematic manner. Specific details for implementing the invention

[0047] The present invention will now be described in more detail without limitation in the following description.

[0048] Liquid composition

[0049] The deposited material according to the present invention may be any pharmaceutical, cosmetic, vaccine and / or diagnostic material.

[0050] "Matter" means a single molecule or supramolecular assembly or a mixture of different molecules or supramolecular assemblies.

[0051] The substance may have biological properties and may be, in particular, an oligopeptide, polypeptide, or protein, particularly an antigenic oligopeptide, polypeptide, or protein, a hormone, cytokine, immunoglobulin, allergen, growth factor, nutritional factor, moisturizing compound, or vitamin, or may contain or be a chemically active ingredient. Preferred substances include one or more of immunoreactive oligopeptides, polypeptides, proteins selected from food allergens, or human proteins associated with human autoimmune diseases. Most preferred substances are food allergens selected from peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens.

[0052] In addition, it may contain one or more active ingredients or drugs in a non-limiting manner, including: nicotine, caffeine, morphine, hydromorphine HCl, fentanyl, apomorphine HCl, scopolamine, chlorpheniramine, imiquimod, diphenhydramide, lidocaine, isotretinoin, ketoprofen, diclofenac, leuprolide, finasteride, etc.

[0053] The material to be deposited is provided as a liquid composition. The liquid composition includes an aqueous and / or organic solvent. A mixture of an aqueous and organic solvent is also possible.

[0054] The material is preferably dissolved in a liquid composition.

[0055] As an organic solvent, alcohol, particularly ethanol, is preferred.

[0056] As a water-soluble solvent, deionized water or a buffered aqueous solution is preferred. The pH of the composition can be adjusted, for example, with citric acid, sodium hydroxide, Tris and / or histidine.

[0057] To accelerate the evaporation of the liquid composition on the substrate, and where the material permits, it may be advantageous to add an organic solvent, particularly an alcohol (e.g., ethanol), to the aqueous solvent. In some embodiments, the liquid composition is therefore an aqueous solution containing 0.1 to 20% (based on total volume), preferably 0.5 to 10% (based on total volume) of an organic solvent, preferably an alcohol, more preferably ethanol. Some types of proteins may not be compatible with such organic solvents, and therefore the use of such solvents is optional.

[0058] The liquid composition may contain the substance of interest at a total concentration of 0.01 to 20 wt.%, preferably 0.05 to 10 wt.%, more preferably 0.1 to 0.5 wt.%.

[0059] To stabilize the substance of interest in the solution, the liquid composition may contain electrolytes in the form of acids, bases, salts, and / or mixtures thereof. These additives can buffer the solution at a given pH, and their concentrations allow the solution to exhibit a given ionic strength. Depending on the properties of these electrolytes and their concentrations, the solution acquires resulting electrical conductivity.

[0060] The 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 conductivity ranges are as follows: 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; 1 to 3 S / m.

[0061] Conductivity can be measured with a conductivity probe.

[0062] The liquid composition may include one or more additives, such as surfactants, which may be, for example, cations, anions, zwitterionics, and / or non-ionics. A preferred surfactant is a non-ionic surfactant, such as an ethoxylated fatty alcohol.

[0063] The amount of surfactant in the liquid composition may be in the range of particularly 0.01 to 5 wt.%, preferably 0.02 to 1 wt.%, and more preferably 0.05 to 0.5 wt.%.

[0064] PCB and patch

[0065] According to the present invention, a material of interest is deposited on a substrate.

[0066] When deposited on a substrate (and after an optional drying step), the material is preferably in a substantially dry form, more preferably in the form of fine particles.

[0067] The substrate is preferably basically planar or flat or is in the shape of a film and preferably includes two faces. In some embodiments, the substrate may include a recess forming a chamber or a reservoir.

[0068] The substrate can be rigid or semi-rigid. The substrate can be formed into individual patches before material is deposited thereon. Thus, it can have, for example, circular, square, rectangular, or elliptical shapes.

[0069] In another embodiment, the substrate is provided in the form of a plate or a strip, such as a roll. A material is deposited on the substrate, and then the substrate is cut into shaped pieces to provide a patch.

[0070] The substrate preferably comprises at least one conductive portion. "Conductive" or "conducting" means "electrically conductive" or "electrically conducting" in this application. The conductive portion may be on one side or most of the substrate. The conductive portion may be a conductive layer on or within the substrate.

[0071] The substrate may include or be composed of different biocompatible materials, particularly, for example, polymer(s), doped polymer(s), polymer(s) coated with conductive material(s), textiles and / or biological material(s).

[0072] The substrate may include at least one conductive surface positioned particularly toward the spray nozzle. Accordingly, a preferred substrate may include or be composed of an insulating layer (e.g., an insulating polymer (film, fiber, etc.)) having at least one surface covered with a conductive layer.

[0073] The conductive material used on the substrate (particularly to provide a conductive layer) may be of inorganic nature (e.g., metal) or organic nature (e.g., carbon, graphite, or oxide(s). The metal is preferably gold, silver, platinum, titanium, or aluminum. The conductive layer(s) advantageously have a thickness of 2 to 40 nm, preferably 5 to 20 nm, and most preferably about 10 nm.

[0074] In the case of a conductive layer made of graphite, graphite deposition on the substrate may be performed either in advance or during the process immediately before depositing the material on the substrate. Graphite deposition may be performed by projecting a neutral or charged aerosol or by impregnating a film by passing it through a graphite solution bath.

[0075] Forming a conductive layer on a substrate prior to the deposition of the material can also be achieved by metallization or oxide deposition. The oxide is preferably indium oxide (ITO) doped with tin.

[0076] A plasma process can also be performed to promote adhesion to the deposition-substrate interface or to deposit the conductive portion itself.

[0077] Accordingly, in some embodiments, the method of the present invention comprises one or more preliminary steps of modifying a substrate, for example, by a plasma process at low pressure or atmospheric pressure and / or metallization and / or deposition of oxide and / or deposition of graphite.

[0078] In some embodiments, the substrate may be a polyethylene terephthalate (PET) film covered with a conductive gold or titanium layer. The substrate may further include an insulating double-bonded crown, for example, made of polyethylene (PE) / ethylene-vinyl acetate (EVA) foam.

[0079] The substrate may be a roll-shaped strip that is gradually unwound, in particular. The strip advantageously comprises the following:

[0080] ― A support film comprising a conductive layer or in the form of a conductive film (e.g., gold-coated PET);

[0081] — A foamed film having evenly spaced holes adhered to a conductive film, wherein each part of the conductive layer or film is not covered by the foamed film forming a deposition area for the material of interest.

[0082] Preferably, the support film is wider than the foam film. Preferably, each deposition area surrounded by the foam is electrically in contact with the entire conductive surface of the support film.

[0083] After depositing a material on a substrate, the substrate or a patch formed from the substrate is advantageously packaged so that the deposited material is protected from the external environment. Accordingly, the patch may include a peelable film that covers the deposited material on its surface and optionally also covers a portion of the substrate that does not contain the deposited material.

[0084] The method of the present invention enables the manufacture of any type of patch, that is, any device that can be applied to a skin area of ​​a target to come into contact with a substance of interest. This includes patches with passive, facilitated, or mechanical diffusion, adhesive patches, bandages, plasters, cupules, and (trans)skin patches.

[0085] The plaster comprises, or consists of, an adhesive mass or coating agent containing one or more substances of interest and optionally one or more diluents, softeners, and adhesives on a suitable support. The adhesive mass may soften at skin temperature to adhere to the skin. It may be formed into sheets of various sizes that can be optionally cut. It may be attached to an adhesive bandage and covered with a perforating material.

[0086] Medicinal bandages are applied to small skin lesions for local action and may include or consist of adhesive bandages with attached bandage material covered with a substance.

[0087] The adhesive patch may comprise or be composed of an adhesive bandage having a plastic disc on which a mass of adhesive containing a substance is placed. The mass of adhesive may further contain components such as gum arabic or gelatin and water.

[0088] A patch having passive, facilitated, or mechanical diffusion generally comprises a support on which a material is deposited and a device for optionally facilitating cell penetration (by the application of electric pulses, ultrasound, microneedles, etc.). Preferably, the patch is a dry patch, more preferably an occlusive type, and much more preferably an electrostatic patch, as described in WO 02 / 071950.

[0089] A patch produced according to the present invention may be used particularly in pharmaceutical, cosmetic, vaccine, and / or diagnostic applications. The patch is preferably intended to be applied to the skin, for example, to detect the body's sensitivity to a deposited substance or to deliver a therapeutic amount of a deposited substance to the body.

[0090] The patch produced according to the present invention may be suitable for animals or human subjects, preferably human subjects.

[0091] To ensure the preservation of the packaged patch and, in particular, to prevent changes in the active ingredients of the deposited material and to preserve microbiological quality, additional processes such as pasteurization or ionization may be performed on the patch.

[0092] In some embodiments, the periphery of the patch is configured to come into contact with the skin to create a sealed concentration chamber containing a substance.

[0093] former- Flow In focusing General principles of material deposition

[0094] The method of the present invention includes depositing a material on a substrate by spraying a liquid composition onto the substrate using electron-flow focusing technology.

[0095] A possible setup for performing electron-flow focusing deposition is illustrated in FIGS. 1 and 2. This setup includes a conductive spray nozzle (1) within a chamber (3). Compressed gas is supplied to the chamber (3) through a gas inlet (10). The spray nozzle (1) is connected to a liquid supply line (9) or formed directly on the liquid supply line.

[0096] The spray nozzle (1) includes an outlet (2) through which a liquid composition exits the spray nozzle. The chamber (3) includes a conductive ejector (5), which is a plate forming the bottom of the chamber (3). The ejector (5) has an ejection opening (4) facing the outlet (2) of the spray nozzle (1).

[0097] The substrate (6) is placed outside the chamber (3) opposite the ejection opening (4) (and spray nozzle (1)).

[0098] The liquid composition flows out from the spray nozzle outlet (2) to form a liquid cone (7) that splits into liquid droplets. The formation of the droplets is achieved by the flow of compressed gas from the chamber (3) through the ejection opening (4) and / or by the action of electrostatic repulsion responsible for droplet formation in the electrostatic spraying process. Due to the pressure gradient between the chamber (3) and the environment outside the chamber (3), the compressed gas is discharged out of the chamber (3) through the ejection opening (4) as a flowing stream of gas. The gas stream surrounds the liquid cone (7) and forms an aerodynamic sheath around it (as shown by the arrow in FIG. 1). The liquid cone (7) forms droplets through a complex process that may occur in the chamber (3) between the nozzle outlet (2) and the top of the ejector, which is an internal (preferably cylindrical) volume of the ejection opening (4).

[0099] In addition, liquid droplets become charged due to the electric field, as explained further below, generating electrostatic repulsion.

[0100] Therefore, an aerosol (8) of liquid droplets is formed between the ejection opening (4) and the substrate (6).

[0101] In some embodiments, the apparatus may include multiple chambers (3) as described above to simultaneously spray a liquid composition onto multiple deposition areas on the same substrate (6) or different respective substrates (6). These chambers (3) may be arranged, 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 insulating supports.

[0102] chamber

[0103] The spray nozzle outlet (2) may preferably have a circular internal shape. The internal shape of the cavity within the nozzle leading to the nozzle outlet (2) may have, for example, a cylindrical shape having the same inner diameter along its length, or a conical shape having an inner diameter that increases along the length of the cavity.

[0104] The spray nozzle outlet (2) may have an inner diameter D, 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. If the spray nozzle outlet (2) is non-circular, the diameter represents the maximum dimension of the internal passage in a plane perpendicular to the main direction of liquid flow.

[0105] A pumping device may be used to provide a liquid composition from a tank to a spray nozzle (1) at a controlled liquid flow rate. In some embodiments, a syringe pump may be used as the pumping device.

[0106] The liquid composition can be stored, for example, in a refrigerated location of -20°C. The liquid composition can be transferred to a spray nozzle (1) at a temperature between 4 and 60°C, preferably at ambient temperature (i.e., generally 20°C to 25°C).

[0107] The liquid flow rate can be adjusted to control the droplet size and enable permissible evaporation of the solvent after or during deposition.

[0108] The flow rate for the spray nozzle (1) (or each) 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, much more preferably 1 to 10 mL / h, 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.

[0109] A single pumping device can be connected to multiple spray nozzles (1), or different individual pumping devices can be connected to different spray nozzles (1).

[0110] The ejection opening (4) inside the ejector (5) may preferably have a circular shape. This may have an inner diameter D which can be 50 to 800 μm, preferably 100 to 600 μm, more preferably 150 to 500 μm, and most preferably 200 to 500 μm. o It can have. If the ejection opening (4) is non-circular in shape, the diameter represents the maximum dimension of the internal passage in a plane perpendicular to the main direction of the liquid flow.

[0111] The distance H between the spray nozzle outlet (2) and the ejection opening (4) 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 of the ejector (5).

[0112] Ratio H / D o It can be, for example, 0.2 to 1.5, preferably 0.3 to 1.2, and more preferably 0.75 to 1.

[0113] The distance h between the ejection opening (4) and the substrate may be 10 to 120 mm, preferably 20 to 100 mm, more preferably 30 to 80 mm. This distance is measured from the bottom of the ejector (5) to the top of the substrate (6).

[0114] compressed gas

[0115] The compressed gas used in the method of the present invention 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 air or nitrogen.

[0116] The gas source may be, for example, a compressed gas bottle connected to the gas inlet (10). Alternatively, a gas compressor may be used to supply compressed gas to the gas inlet (10).

[0117] The flow of compressed gas into the chamber (3) and through the ejector (5) can be controlled by pressure or flow rate.

[0118] Accordingly, the pressure inside the chamber (3) may be, for example, in a range of 0.05 to 5 bar higher than atmospheric pressure, preferably 0.1 to 2 bar higher than atmospheric pressure, and more preferably 0.3 to 1 bar higher than atmospheric pressure.

[0119] The gas flow rate into the chamber (3) (or through the ejection opening (4)) may be in the range of, for example, 0.02 to 10 Ln / min, preferably 0.05 to 5 Ln / min, more preferably 0.1 to 1 Ln / min.

[0120] Control of the injection of compressed gas can be achieved by using a regulator connected to a mass flow control system that can be controlled, for example, using a pressure or flow rate setpoint.

[0121] Electric field

[0122] The liquid composition receives an electric field generated inside the chamber (3) and / or between the chamber (3) and the substrate (6). Preferably, the electric field is generated inside the chamber (3) and between the chamber (3) and the substrate (6).

[0123] The electric field is preferably constant over time.

[0124] The magnitude of the electric field received by the liquid composition in the first region within the chamber (3) (i.e., between the spray nozzle (1) and the ejector (3)) is preferably greater than the magnitude of the electric field received by the liquid composition in the second region within the chamber (3) (i.e., between the ejector (3) and the substrate (6)).

[0125] The magnitude of the electric field received by the liquid composition in the first region is preferably substantially uniform.

[0126] In the second region, the magnitude of the electric field received by the liquid composition is preferably substantially uniform.

[0127] The magnitude of the electric field received 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, more preferably 1 to 2.5 MV / m.

[0128] The magnitude of the electric field received by the liquid composition in the second region may be, for example, 0.02 to 1 MV / m, preferably 0.1 to 0.5 MV / m, more preferably 0.1 to 0.2 MV / m.

[0129] The electric field within the first region can contribute to the formation of liquid droplets and also ensures that all droplets formed in this region become electrically charged.

[0130] The electric field within the second region is useful for directing and focusing droplets onto the substrate or a desired deposition area on the substrate.

[0131] To generate an electric field within 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 (with the other wall of the chamber (3) preferably insulated).

[0132] The spray nozzle (1) can be polarized by connecting it to a first high-voltage supply, and the ejector (5) can also be polarized by connecting it to a second high-voltage supply.

[0133] The first high-voltage supply and the second high-voltage supply may be different or may be the same high-voltage supply provided with a voltage divider setting. The high-voltage supply may be a DC generator.

[0134] The spray nozzle (1) and the ejector (5) are electrically insulated from each other. Therefore, they form respective electrodes.

[0135] The voltage difference between the injection nozzle (1) and the ejector (5) generates an electric field in the first region. Depending on the distance h, this voltage difference may be, for example, 50 V to 1000 V, preferably 100 V to 800 V, more preferably 100 V to 600 V.

[0136] The substrate (6) preferably includes a conductive portion as described above. The conductive portion can be grounded by connecting it to one or more metal conductors connected to ground.

[0137] Alternatively, the substrate (6) can be polarized by connecting it to another high-voltage supply (through one or more metal conductors).

[0138] Alternatively, a counter-electrode adjacent to the substrate (6), for example, in contact with the substrate (6), may be used, which can be polarized by being connected to ground or by being connected to a high-voltage supply. For example, the substrate (6) may be positioned on a support that is itself grounded or also polarized by being connected to a high-voltage supply.

[0139] The voltage difference between the ejector (5) and the substrate (6) or between the counter-electrode adjacent to the substrate (6) generates an electric field in the second region.

[0140] The above 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.

[0141] In some embodiments, the shielding electrode may be positioned on top of the substrate (6) or between the ejector (5) and the substrate (6). The shielding electrode may be, for example, ring-shaped or a plate having one or more openings to allow the aerosol (8) to reach the substrate (6). The shielding electrode may be polarized by connecting to a high-voltage supply or connected to ground.

[0142] The shielding electrode may include a conductive portion and an insulating portion. It may be positioned perpendicular to the spraying direction of the composition, preferably at a distance between 1 and 50 mm from the ejector (5). The shielding electrode enables better control of the diameter of the material deposition on the substrate by generating a controlled electrostatic repulsion between the shielding electrode and the charged droplet. Thus, the diameter of the deposition depends on the potential applied to the shielding electrode.

[0143] The high-voltage supply used in the present invention can be modified to provide, for example, a DC current of -5 to +5 mA and to apply a DC voltage of -30 to +30 kV.

[0144] Material deposition

[0145] The aerosol produced according to the present invention comprises droplets with 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 flowmeter PDA).

[0146] The material of interest is deposited on at least one deposition area on the substrate (6). The deposition area is preferably disc-shaped. Its diameter may be 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 area is non-disk-shaped, the diameter represents the maximum dimension of the deposition area.

[0147] An insulating collar (such as an adhesive insulating collar) can be provided on the substrate (6) to define the boundaries of the deposition area by focusing the electric field line on the deposition area of ​​the substrate (6).

[0148] Preferably, the solvent present in the drop of the liquid composition evaporates substantially when the method of the present invention is performed. Such evaporation may occur substantially or entirely during the deposition step itself, where a drying step is not required.

[0149] To aid in evaporation during the deposition step, the substrate (6) may be heated. For example, the substrate (6) may be placed at a temperature of 20 to 80°C, preferably 25 to 70°C, more preferably 30 to 60°C, and most preferably 35 to 55°C. Heating may be performed by placing the substrate (6) on a heated support, such as a piece of metal (e.g., stainless steel or aluminum) that is electrically heated by a resistor, for example. The temperature may be controlled, for example, by a resistance temperature detector.

[0150] Alternatively, a drying step may be provided after the deposition step. The drying step may include one or more of heating by convection, heating by radiation (e.g., ultraviolet or infrared radiation), freeze-drying, or circulation of drying gas.

[0151] Examples

[0152] The following examples are illustrative and do not limit the invention.

[0153] Example 1: Milk protein on a patch 300μg deposition

[0154] The patch is manufactured using the device shown in FIGS. 1 and FIGS. 2.

[0155] The nozzle (1) has an inner diameter D i The diameter is 300 μm, and the ejector (5) has a diameter D of the ejection opening (4). o The distance H between the nozzle opening (2) and the ejection opening (4) is 80 μm.

[0156] The patch consists of a support (6) made of a polyethylene-terephthalate (PET) film covered with a thin conductive titanium layer (10 nm) and a double-adhesive insulating crown made of PET / EVA foam.

[0157] While the mixture of gas and liquid passes through the discharge opening (4), the liquid exits through the nozzle (1). Both the nozzle outlet (2) and the discharge opening (4) have a circular internal shape.

[0158] The chamber (3) containing the volume between the nozzle and the ejector is pressurized by a 50 / 50 mixture of N2O or N2 or N2O / N2 gas at a pressure 0.7 bar higher than atmospheric pressure, and this gas flows through the ejection opening at a flow rate of 0.7 Ln / min.

[0159] The substrate for deposition formation also serves as a counter-electrode and is placed at a distance h of 45 mm from the ejection opening and connected to ground.

[0160] The nozzle (1) and the ejector (5) are connected to a voltage supply, 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); thus, the nozzle-ejector voltage difference is 200 V.

[0161] A liquid formulation having high electrical conductivity is supplied to the nozzle at a flow rate of 3 mL / h. It is a water-soluble formulation containing milk protein at a concentration of 2.5 g / L and Brij O2, a nonionic surfactant, at a concentration of 0.5 g / L, which has a pH of 7.2, an electrical conductivity of 27,000 μS / m, and a surface tension of 38 mN / m. Using a substrate heater set to 50°C, a circular dry deposit containing milk protein is formed on a substrate having a diameter of 24 mm for 150 seconds under these spray conditions.

[0162] Example 2: Using a different set of geometric parameters on the patch 300μg of Milk protein deposition

[0163] In this example, the nozzle (1) has an inner diameter D i α is 200 μm and the diameter D of the ejection opening (4) o is 200 μm. The distance H between the nozzle and the ejector is 200 μm.

[0164] The chamber (3) is pressurized with N2O or N2 or a mixture of N2O / N2 at a pressure higher than atmospheric pressure of 0.7 bar, and this gas flows through the ejector orifice at a flow rate of 0.3 Ln / min.

[0165] The counter-electrode (substrate) is placed at a distance h of 70 mm from the discharge opening (4) and connected to ground.

[0166] The nozzle and ejector are connected to a voltage supply, the nozzle is polarized to 6.4 kV (electric field E1 = 2 MV / m) and the ejector is polarized to 6 kV (E2 = 0.13 MV / m); thus, 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 duration is 150 seconds.

[0167] These conditions result in a circular dry deposit containing 300 μg of milk protein with a diameter of 24 mm formed on a substrate heated to 50°C.

[0168] In electrostatic spray deposition technology according to WO 2009 / 095591, using the same composition, the maximum flow rate at which stable operation of the spray is possible is 1 mL / h, which means that the spraying process takes longer to produce a patch with the same amount of active ingredient, thus demonstrating the limitations of electrostatic spray deposition technology for use with electrically conductive liquids.

[0169] Example 3: On the patch 250μg of Peanut protein deposition

[0170] In this example, the nozzle (1) has an inner diameter D i α is 200 μm and the diameter D of the ejection opening (4) o is 200 μm. The distance H between the nozzle and the ejector is 200 μm.

[0171] The chamber (3) is pressurized by N2O or N2 or a mixture of N2O / N2 at a pressure 0.7 bar higher than atmospheric pressure, and this gas passes through an ejector orifice at a flow rate of 0.35 LN / min.

[0172] The counter-electrode (substrate) is placed at a distance h of 70 mm from the discharge opening (4) and connected to ground.

[0173] The nozzle and the ejector are connected to a voltage supply, the nozzle is polarized at 6.4 kV (electric field E1 = 2 MV / m) and the ejector is polarized at 6 kV (E2 = 0.13 MV / m); thus, the nozzle-ejector voltage difference is 400 V.

[0174] The liquid formulation is supplied to the nozzle at a flow rate of 3 mL / h. The liquid formulation contains peanut protein at a concentration of 4 g / L, Brij O2, a nonionic surfactant, at a concentration of 1 g / L, and 10 wt.% ethanol. The liquid formulation has a pH of 7.6, an electrical conductivity of 7000 μS / m, and a surface tension of 38 mN / m. Under conditions of using a substrate heater set to 50°C and spraying for 90 seconds, a circular dry deposit containing peanut protein is formed on a substrate having a diameter of 24 mm.

[0175] For comparison, when using electrostatic spray deposition technology according to WO 2009 / 095591, the maximum possible liquid flow rate is 1.6 mL / h.

[0176] Example 4: On the patch Physiological saline solution deposition

[0177] A water-soluble formulation containing D-mannitol (1,2,3,4,5,6-hexanehexol) at a concentration of 1 g / L and physiological saline (0.9% NaCl) is used to simulate white deposition; the electrical conductivity is 1.2 S / m. The nozzle (1) has an inner diameter D i α is 200 μm, and the diameter D of the ejection opening (4) o is 200 μm. The distance H between the nozzle and the ejector is 200 μm.

[0178] The chamber (3) is pressurized by N2O or N2 or a mixture of N2O / N2 at a pressure 0.7 bar higher than atmospheric pressure, and this gas passes through an ejector orifice at a flow rate of 0.35 LN / min.

[0179] The counter-electrode (substrate) is placed at a distance h of 70 mm from the discharge opening (4) and connected to ground.

[0180] The nozzle and ejector are connected to a voltage supply, the nozzle is polarized to 6.4 kV (electric field E1 = 2 MV / m), and the ejector is polarized to 6 kV (E2 = 0.13 MV / m); thus, the nozzle-ejector voltage difference is 400 V. In this case, the conductivity of this liquid is more than about 100 times that of the milk formulation; the same result was a dry deposition of 24 mm diameter on a substrate heated to 50°C.

[0181] In electrostatic spray deposition technology according to WO 2009 / 095591, if the same composition is used, it is impossible to create a patch because there is an electrical discharge that interferes with the stable operation of the process.

[0182] The following table summarizes the parameters used in various examples for the device and liquid composition:

[0183]

Claims

Claim 1 A method for depositing one or more allergens on a substrate (6), comprising: providing a substrate (6) at a distance from a conductive spray nozzle (1) having an outlet (2); providing a liquid composition containing the one or more allergens to the spray nozzle (1) at a flow rate of 3 to 50 mL / h; and providing a compressed gas around the liquid composition flowing out from the outlet (2) of the spray nozzle (1) and providing an electric field downstream of the outlet (2) of the spray nozzle (1) to generate an electrically charged liquid droplet from the liquid composition between the outlet (2) of the spray nozzle (1) and the substrate (6); A method comprising collecting the generated liquid droplet on the substrate (6); wherein the spray nozzle (1) is disposed within the chamber (3), the compressed gas is supplied to the chamber (3), so that the pressure within the chamber (3) is 0.05 to 5 bar higher than atmospheric pressure, and the liquid composition and the compressed gas are discharged from the chamber (3) through the ejection opening (4) in the conductive ejector (5). Claim 2 A method according to claim 1, wherein one or more allergens are selected from peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens. Claim 3 A method according to claim 1, wherein one or more allergens are selected from peanut, milk, and egg allergens. Claim 4 The method of claim 1, wherein the liquid composition has a conductivity of 0.1 μS / m to 3 S / m. Claim 5 The method of claim 1, wherein the liquid composition has a conductivity of 1 mS / m to 20 mS / m. Claim 6 The method of claim 1, wherein the liquid composition is supplied to the spray nozzle (1) at a flow rate of 3 to 10 mL / h. Claim 7 A method according to claim 1, wherein the compressed gas surrounding the liquid composition is at a pressure 0.1 to 2 bar higher than atmospheric pressure. Claim 8 The method of claim 1, wherein the compressed gas surrounding the liquid composition is at a pressure 0.3 to 1 bar higher than atmospheric pressure. Claim 9 A method according to claim 1, wherein an electric field having a first size is applied to a first region between the outlet (2) of the spray nozzle (1) and the ejection opening (4); and / or an electric field having a second size is applied to a second region between the ejection opening (4) and the substrate (6). Claim 10 A method according to claim 9, satisfying at least one of: a) the first size is 0.1 to 10 MV / m, or 0.5 to 5 MV / m; b) the second size is 0.02 to 1 MV / m, or 0.1 to 0.5 MV / m; or c) the first size is larger than the second size. Claim 11 A method according to claim 1, which does not include any drying step after collecting the liquid droplets on the substrate (6). Claim 12 A method according to claim 1, wherein the compressed gas is selected from the group consisting of nitrogen, nitrous oxide, carbon dioxide, argon, and mixtures thereof. Claim 13 A method according to claim 12, wherein the compressed gas is selected from the group consisting of nitrogen, nitrous oxide, and mixtures thereof. Claim 14 A method according to any one of claims 1 to 13, for manufacturing a patch or a therapeutic patch. Claim 15 Equipment for depositing one or more allergens on a substrate (6), said equipment comprising: — a chamber (3) including a conductive ejector (5) having an ejection opening (4); — a liquid supply line (9) for supplying a liquid composition containing said one or more allergens to be deposited on a spray nozzle (1); — a conductive spray nozzle (1) having an outlet (2) disposed within the chamber (3) — said equipment is configured to supply said liquid composition containing said one or more allergens to said spray nozzle (1) at a flow rate of 3 to 50 mL / h — — a support for placing said substrate (6) outside the chamber (3) at a distance from said spray nozzle (1); — a gas inlet (10) for supplying compressed gas to said chamber (3) — said equipment is configured such that the pressure inside said chamber (3) is 0.05 to 5 bar higher than atmospheric pressure — — an electric field inside said chamber (3) and / or between said chamber (3) and said substrate (6) Equipment including equipment for producing. Claim 16 In claim 15, the equipment for generating the electric field is configured to generate an electric field both inside the chamber (3) and between the chamber (3) and the substrate (6). Claim 17 The apparatus of claim 15, wherein each of the spray nozzle (1) and the ejector (5) is connected to a high-voltage supply and further comprises a contact for connecting the substrate (6) to ground. Claim 18 The apparatus according to claim 15, wherein the inner diameter Di of the spray nozzle outlet (2) is 50 to 500 μm, or 100 to 450 μm, or 150 to 400 μm. Claim 19 In claim 15, the inner diameter D of the ejection opening (4) o Equipment having a diameter of 50 to 800 μm, or 100 to 600 μm, or 150 to 500 μm. Claim 20 The apparatus of claim 15, wherein the distance H between the outlet (2) and the ejection opening (4) of the spray nozzle (1) is 50 to 550 μm, or 70 to 250 μm, or 80 to 180 μm. Claim 21 In claim 15, the compressed gas is selected from the group consisting of nitrogen, nitrous oxide, carbon dioxide, argon, and mixtures thereof. Claim 22 In claim 15, the facility wherein one or more allergens are selected from peanut, milk, egg, walnut, cashew, pecan, pistachio, and hazelnut allergens. Claim 23 In claim 15, the facility, wherein one or more allergens are selected from peanut, milk, and egg allergens. Claim 24 An apparatus according to any one of claims 15 to 21, wherein the substrate is a patch or a therapeutic patch.

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