Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
  • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
  • B05B5/08—Plant for applying liquids or other fluent materials to objects
  • B05B5/087—Arrangements of electrodes, e.g. of charging, shielding, collecting electrodes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
  • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
  • B01F33/30—Micromixers
  • B01F33/3031—Micromixers using electro-hydrodynamic [EHD] or electro-kinetic [EKI] phenomena to mix or move the fluids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
  • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
  • B05B5/08—Plant for applying liquids or other fluent materials to objects
  • B05B5/14—Plant for applying liquids or other fluent materials to objects specially adapted for coating continuously moving elongated bodies, e.g. wires, strips, pipes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D1/00—Processes for applying liquids or other fluent materials
  • B05D1/02—Processes for applying liquids or other fluent materials performed by spraying
  • B05D1/04—Processes for applying liquids or other fluent materials performed by spraying involving the use of an electrostatic field
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
  • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
  • B05B5/025—Discharge apparatus, e.g. electrostatic spray guns
  • B05B5/0255—Discharge apparatus, e.g. electrostatic spray guns spraying and depositing by electrostatic forces only
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
  • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
  • B05B5/08—Plant for applying liquids or other fluent materials to objects
  • B05B5/082—Plant for applying liquids or other fluent materials to objects characterised by means for supporting, holding or conveying the objects
  • B05B5/084—Plant for applying liquids or other fluent materials to objects characterised by means for supporting, holding or conveying the objects the objects lying on, or being supported above conveying means, e.g. conveyor belts
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D2252/00—Sheets
  • B05D2252/04—Sheets of definite length in a continuous process

Definitions

• the present invention relates generally to the manufacture of patches for the dermal application of substances.
• the invention relates more particularly to methods and devices for producing such patches by Electrohydraulic Spray (HDPE).
• the invention is applicable to the manufacture of any type of patch, used in particular in pharmaceutical, cosmetic, vaccine and / or diagnostic applications, in humans or animals.
• the dermal application of a substance by means of a patch has many applications in human or animal health. It can indeed allow the development of effective diagnostic tests or methods of transfer of active ingredients through the skin. Even if the human epidermis is a barrier against the entry into the body of external agents, the skin is not perfectly sealed. Several studies have shown at the experimental level the feasibility of such methods under various conditions. In addition, several patch systems are currently marketed in the field of allergy detection.
• the dermal application of substances has many advantages over other modes of administration such as injection, and in particular the absence of risk of contamination, the absence of pain, the ease of manipulation, or even the possibility for the patient to self-administer the substance.
• Different types of patch have been described in the literature. There may be mentioned patches intended for local action, such as for example plasters, patches, dressings or cups.
• patches have been described, intended for a general action, that is to say (trans) dermal patch systems.
• the substance can be delivered to the body either by passive diffusion, or by diffusion facilitated by a physico-chemical process (iontophoresis, electroporation, sonophoresis), or by a mechanical action (micro-needles).
• passive diffusion dermal patches a substance is typically deposited on a surface of the patch (called a support) and placed in contact with the skin.
• the patch may include an occlusive chamber or a condensation compartment. The application of the patch on the skin allows the contact between the substance and the skin and the diffusion of the substance in the layers of the epidermis or in the body.
• the electrostatic patch described above is typically prepared according to a manufacturing method using so-called “powder” systems, such as that presented in WO 07/122226.
• This method consists in applying, on a patch support, the bio logically active substance in the form of a dry powder, by means of a rotary roller (or propeller) which, in its rotational stroke, recovers from the powder and apply it against the support.
• this manufacturing system generates losses of powder and therefore of substance, also because of problems of deposition outside the patch support (on the periphery of the patch for example) and / or clogging of the powders on the walls of the deposition reactor, in particular when the powders have a very fine particle size or that the powder particles have a particular shape (for example powders obtained by freeze-drying).
• These losses force on the one hand to use large amounts of substance powder, which increases the manufacturing costs of the patch, but also generates difficulties to control the amounts of active substance deposited on the patch and the homogeneity of the deposit .
• the application WO 03/094811 relates to a method for manufacturing a dressing intended to treat wounds.
• This dressing which can be made directly on a wound or previously on a support, is obtained by depositing fibers that have no biochemical function.
• this document does not describe how to obtain a deposit of substance (active ingredient), homogeneous and controlled under industrial and pharmaceutical conditions, on the support of a patch.
• substance active ingredient
• a deposit that is as hydrophilic as possible is required so as to obtain rapid dissolution and complete as soon as the patch is placed on the skin.
• the present invention aims to provide an improved process for the industrial manufacture of patches, and in particular dry patches, using the ElectroSpray technique (or Electrohydraulic Spray or "HDPE").
• ElectroSpray technique or Electrohydraulic Spray or "HDPE"
• the method according to the invention makes it possible to control the size, the electric charge and the frequency of production of the droplets produced by HDPE from a liquid formulation and hence to control the size and the frequency of the particles of the substance projected. on the support of the patch, in order to obtain a homogeneous deposit, and to control the quantity of substance deposited on the patch.
• the charged particles follow the electric field lines between the nozzle and the support, which also makes it possible to precisely locate the location of the deposit on the support by controlling the field lines.
• the invention thus relates to a process for manufacturing a patch intended for the cutaneous application of a substance, the method comprising the electrohydrodynamic sputtering deposition of a liquid formulation of the substance on the support of the patch.
• Another subject of the invention relates to a method for manufacturing a patch intended for the cutaneous application of a substance, characterized in that the patch comprises a conductive support and in that the process comprises depositing the substance on electrohydrodynamic sputtering support of a liquid formulation of the substance.
• the substance is dissolved in a solvent to form the formulation before spraying, for example an aqueous solvent optionally comprising a surfactant.
• the substance or the liquid formulation is directly sprayed in the form of droplets having an average diameter less than or equal to about 20 microns, preferably 5 microns, more preferably to 1 micron.
• the formulation is sprayed at a rate of between 0.1 and 1.5 ml / hour.
• the spraying is carried out at a tension of between 1 and 10 kVolts.
• the method comprises a step of treating, preferably by heating, the support, during or after the spraying, to obtain a deposit in the form of dry residues or to reduce the moisture content of the product. deposit made.
• a particular object of the invention resides in a method of manufacturing a patch comprising a support coated with a substance, characterized in that it comprises the deposition by electrohydrodynamic spraying of the substance on the support, according to the following steps: a) placing a conductive support away from a spray nozzle; b) supplying the substance in liquid form to the spray nozzle; c) subjecting the substance to an electric field so as to form an aerosol between the nozzle and the support; and d) collecting on the support the aerosol formed.
• the substance is in liquid form (liquid formulation) and therefore it is the liquid formulation that is subjected to an electric field in step c).
• the method comprises an optional additional step of forming, machining and / or conditioning the support to form a patch.
• the invention also relates to a patch for the dermal application of a substance, obtainable by the manufacturing method described above.
• Another object of the invention resides in a patch comprising a conductive support.
• the invention also relates to an installation or a device for manufacturing a patch, characterized in that it comprises at least one electrohydrodynamic spraying device (preferably comprising at least one spray nozzle (11) and at least one counterelectrode and / or a ground contact arranged to generate an electric field and to form an aerosol from a formulation (21) between a nozzle and a support), and means for supplying the installation of conductive patch media (31).
• the device comprises a plurality of spray nozzles (11) operating simultaneously or not, each nozzle creating a deposit of substance on a patch support.
• the different nozzles are advantageously mounted on an insulating support.
• the process according to the invention is particularly advantageous for the manufacture of patches, in particular dry patches, because it ensures in particular: a homogeneity of the deposit over the entire surface of the patch to be coated with substance, which is particularly advantageous for a administration through the skin of the patient, - precise control of the dose deposited on each patch to meet in particular the regulatory pharmaceutical constraints, - a structure and quality of the deposit in each patch to obtain a deposit of substance the more bio-available possible (eg, solubilization of the deposit after laying the patch on the skin and thanks to perspiration).
• the invention furthermore describes means for reducing as much as possible the deposition time of the substance and for producing, in parallel and simultaneously, several deposits on the same machine, which is necessary for the implementation of a HDPE technology. for the application of substance on a patch at industrial production rates.
• the invention is adapted to any type of substance, in particular active substances such as antigens, allergens or medicaments, and to any type of patch, that is to say any device that can be applied to a skin area. a subject to bring it into contact with a substance or to create a zone of hydration.
• active substances such as antigens, allergens or medicaments
• patch that is to say any device that can be applied to a skin area.
• These may be passive, facilitated or mechanical diffusion patches, patches, dressings, plasters, cups or (trans) dermal patches.
• a passive diffusion-type dermal device of the occlusive or condensation chamber type is used.
• FIG. 1 illustrates a patch during manufacture according to an embodiment of the method according to the invention.
• Figure 2 is a sectional view of an exemplary patch structure.
• FIG. 3 illustrates a patch with conductive support.
• FIG. 4 illustrates a principle of a width for the manufacture of patches by
• Figure 5 illustrates a comparison of voltage and liquid flow operating domains obtained with peanut formulations with and without ethanol.
• FIG. 6 illustrates an example of deposition made on a PET / OR film with focusing of the aerosol by the polarized shielding ring and the polarization of the insulating washer of the patch.
• Figure 7 illustrates SEM images of a deposition of dry peanut particles made on a polymeric film covered with aluminum.
• Figure 8 illustrates SEM images of porous peanut layer deposits made on a PET polymer film covered with gold.
• FIG. 9 illustrates a profile (made between the center and the edge of the deposit) of the elementary composition of porous peanut layer deposits made on a PET polymer film covered with gold.
• the invention relates to an improved industrial patch production method, an installation or a device for its implementation, as well as new patches having advantageous properties that can be used in any mammal in pharmaceutical, cosmetic or diagnostic applications, for example.
• the invention is based in particular on a step of electrohydrodynamic spraying of a liquid formulation constituting or containing a substance of interest, for depositing said substance of interest on a conductive support adapted to the manufacture of patch.
• the invention makes it possible, for the first time, to deposit a substance on the support of a patch by electrohydrodynamic spraying.
• this method makes it possible to control the size, the charge and the frequency of the particles projected on the support of the patch, and to obtain a homogeneous deposit and to control the quantity of substance deposited. on the patch.
• ElectroSpray, or electrohydrodynamic spraying is a process used to produce substances, often in dry form and in very small quantities, for example for the analysis of substances in spectroscopy, the manufacture of micro-deposits of substance for the diagnosis, the coating of surfaces with active substances, the production of micro and nano particles, or the production of micro fibers (see in particular WO 99/49981, WO2006 / 010845, US 7,259,109, US 5,349,186, FR 1 288 034, FR 1 087 802).
• HDPE has certain limitations and technical constraints that may seem incompatible with a pharmaceutical and industrial use, which requires speed, robustness and biocompatibility. Among these constraints, we can mention in particular: - the low flow of substances produced, synonymous with a low yield,
• the present invention now shows that HDPE can be adapted to the industrial and controlled manufacture of patches.
• the present invention also results from the development of optimal conditions in which the spraying process can be implemented for the manufacture of patches.
• a particular object of the invention lies in a method of manufacturing a patch comprising a support coated with a substance, characterized in that it comprises the deposition of the substance (21) on the support (31), by electrohydraulic spraying, according to the following steps: a) placing a conductive support (31) away from a spray nozzle (11); b) supplying the liquid formulation substance (21) to the spray nozzle (11); c) subjecting the formulation (21) to an electric field so as to form an aerosol (22) between the nozzle (11) and the support (31); and d) collecting particles from the aerosol (22) formed on the support (31).
• the present application now shows that it is possible to obtain, by HDPE, homogeneous and reproducible deposits, under conditions compatible with an industrial and pharmaceutical use.
• the present application also describes the optimum conditions under which this process may be implemented, and in particular the liquid formulation of the substance sprayed, the voltage used, the flow rate used, the geometry of the electrodes, in order to obtain regular and homogeneous deposits. .
• the polarization of the nozzle (11) induces the separation of the electric charges carried by the ions present in the liquid.
• the positive and negative charges within the liquid separate and those of the same polarity as the nozzle (11) migrate to the surface of the liquid: the liquid is polarized .
• the electric charges of opposite polarity to the applied potential are at the nozzle-liquid interface while a part of the charges of the same polarity are on the surface of the liquid. If the electric field on the surface of the liquid increases sufficiently, the pressure normal electric to the surface of the liquid, directed towards the interior of the drop, increases.
• the electric and hydrodynamic pressures are in equilibrium on the surface of the liquid: there is Electro-HydroDynamic balance.
• the nozzle exit drop takes the form of a stable liquid cone (Taylor cone) at the end of which a jet of liquid emerges.
• Hydrodynamic instability propagates along the jet which fragments into highly charged micron droplets.
• the electrostatic repulsions between the charged drops create a radial extension effect inducing the formation of an aerosol (22) and thus promote the homogeneity of the projection by preventing any inter-particle agglomeration or coagulation.
• the invention shows in particular that it is possible to obtain industrially, from the control of the frequency and the diameter of the droplets constituting the aerosol (22), a particle size deposition controlled or a controlled deposition of layered substance.
• the electric field is formed by the voltage applied between the liquid at the outlet of the nozzle and one or more electrodes, with any combination of the following counter-electrodes: a counter-electrode (16) polarized or connected to the ground, the support being arranged between the nozzle and the counter-electrode (16), a counter-electrode (12) in the form of a ring or plate which is perforated, polarized or connected to ground, arranged between the spray nozzle and the support, and one or more contact (s) (41, 44) connected to the ground and in contact with the support (31).
• the electric field is formed by applying a potential difference between the spray nozzle (11) and the support (31), the latter being connected to ground.
• the electric field is formed by applying a potential difference between the spray nozzle (11) and a counter-electrode (12) in the form of a ring, plate or plate which is perforated, polarized or connected to ground, arranged between the spray nozzle and support.
• the electric field is formed by applying a potential difference between the liquid formulation at the end of the spray nozzle (21), via this spray nozzle (11), and the counter-electrode (12). ) ring (also referred to as shielding ring), polarized or grounded.
• the electric field is formed by applying a potential difference between the spray nozzle (11) and one or more contacts (41, 44) connected to the ground and in contact with the support (31).
• the spraying device comprises a counter-electrode (12) (also referred to as a shielding ring) ( Figure 6).
• This shielding ring (12) is made of conductive material, typically made of metallic material. It may have a conductive portion and an insulating portion.
• the shielding ring (12) is preferably in the form of a metal ring or a perforated plate arranged perpendicular to the spray direction of the formulation, preferably at a distance of between 0 and 30 millimeters from the nozzle (11).
• the shielding ring (12) thus traversed by the aerosol (22) projected on the support of the patch (31) ensures the stability of the process. It can be connected to ground or a high voltage generator.
• the shield ring has the following advantages: i) Possibility of controlling the diameter of the deposits.
• the potential applied to the ring makes it possible to control the intensity of the electrostatic repulsions between the polarized ring and the charged drops of the same polarity as the ring. In which case, the higher the potential applied to the ring, the more the electrostatic repulsions between the ring and the drops increase.
• the area of the support covered by the droplet flow, and therefore the diameter of the deposit decreases as the potential applied to the ring increases; ii) Increase the robustness of the process by shielding the production area, ie by stabilizing the production of the aerosol, no longer between the nozzle and the support but between the nozzle and the shielding ring. In such a case, and for optimal dimensions, shapes and ring position, aerosol production is almost independent of what happens outside the area between the nozzle and the ring. .
• This stability requirement is a real necessity in the case of the industrial manufacturing of patches to make the process sufficiently robust, avoid destabilization and thus obtain a sufficient effective production time.
• the spray nozzle may be totally conductive, or totally insulating, or have a conductive portion and an insulating portion. It forms, when it is conducting and connected to a high-voltage power supply (13), an electrode for polarizing the formulation (21). When it is insulating, it is the support of the nozzle, in direct contact with the liquid to be polarized, which is then conductive and connected to the high voltage.
• the nozzle (11) typically has a circular orifice for the passage of the liquid formulation (21), the outer diameter is advantageously between 0.05 and 8 millimeters and whose inner diameter is advantageously between 0.05 and 1 millimeter.
• the device may comprise a plurality of spray nozzles (11) and the formulation (21) is sprayed by a plurality of nozzles (11).
• one of the disadvantages of the electrospray process is the low liquid flow delivered by a nozzle (OG: 0.1-100 ml / h), inducing a low production yield.
• a system comprising several nozzles has been developed, which makes it possible to increase by the same number of patches produced per unit of time.
• Such a system has been realized by the inventors, in spite of the technical difficulties related to the foreseeable problems of interference between electric fields and electrostatic effects of edge. Indeed, the electric fields required for HDPE must be similar from one nozzle to another and in particular do not undergo edge effects conducive to spatial changes in the electric field.
• the electric charge field of space consisting of the charged particles induces coulombic repulsions between them advantageously preventing inter-particle coagulation but can, on the one hand, disturb the stabilization of the process interacting with neighboring sprays, on the other hand influencing the direction of aerosols. But these must be, on the one hand perpendicular to the surface of the support and, on the other hand, for an industrial production, to be parallel to each other.
• the method of the invention comprises simultaneous spraying, from several nozzles, preferably from 2 to 10 nozzles.
• the nozzles used are mounted on an insulating support. High voltage power supply
• the electric field required for the formation of the aerosol (22) is generated by the use of a high-voltage DC supply.
• the electrospray device thus advantageously comprises a positive or negative high-voltage supply (13), applying a potential difference between the nozzle (11) and the support, and / or the counter-electrode, and / or the shielding ring during the entire production of the patches (21).
• the power supply (13) typically provides a current of -5 to +5 microamperes and applies a DC voltage of -30 to +30 kilo volts.
• the method is implemented at a voltage of between 1 and 10 kVolts.
• the substance is used in the liquid form process.
• the nature of this liquid formulation can be adapted to improve the performance of the process.
• the inventors have shown that the electrical conductivity and the viscosity of this formulation can be controlled and, in certain cases, adapted to obtain the best industrial performance of the process.
• the substance is preferably dissolved in a solvent. The amount of dissolved substance depends on its solubility.
• the solvent may be any solvent compatible with a pharmaceutical use, preferably organic, capable of solubilizing the substance of interest.
• the solvent used in the process for dissolving the substance and thereby constituting the liquid formulation can be selected according to the properties of the substance and the rate or quality of drying that is desired.
• the solvent may be water, which makes it possible to avoid the deterioration of certain substances during the production of the patches.
• an alcohol to the aqueous formulation, for example ethanol.
• the liquid formulation is therefore an aqueous solvent comprising from 0 to 15% (by total volume of the solution), preferably from 1 to 10% (by total volume of the solution) of alcohol. preferably ethanol.
• the results obtained show that such a formulation is particularly suitable for mixtures of proteins, such as allergens.
• the results obtained also show that the use of ethanol makes it possible to improve the stability of the process, as illustrated in FIG.
• the liquid formulation comprises the substance dissolved in an aqueous solvent comprising 1 to 10% ethanol.
• This type of formulation is particularly suitable for polypeptides (e.g., proteins) and peptides.
• the solvent is an alcohol, such as, for example, ethanol.
• the inventors have shown that it is particularly advantageous to add to the liquid formulation a surfactant, preferably in an amount of between 0.05 and 2% by weight. .
• the formulation comprises: - a solvent
• a pharmaceutical grade surfactant preferably in an amount of between 0.05 and 2% (by total weight of the solution).
• An example of a formulation is: an aqueous solvent, comprising 0-15% alcohol (in total volume of the solution); and
• a surfactant in an amount of between 0.05 and 2% (by total weight of the solution).
• the surfactant may be any surfactant compatible with a pharmaceutical use, such as for example the VOLPO N20. In addition, it may be preferred to dialyze the substance prior to its formulation.
• the substance contained or constituted by the liquid formulation (21) deposited on the patch may be any substance (and / or its synthetic analogs) pharmaceutical, cosmetic, vaccine and / or diagnostic.
• the substance (21) may be of a biological nature and contain, in particular, oligopeptides, (poly) peptides or biologically active and / or antigenic proteins, hormones, cytokines, immunoglobulins, allergens, growth factors, trophic substances, moisturizing compounds, vitamins or chemical molecules.
• drugs or active principles of various kinds may also contain drugs or active principles of various kinds, analogous or non-organic, and non-exhaustively: nicotine, caffeine, morphine, hydromorphone HCl, fentanyl, apomorphine HCl, Scopolamine, chlorpheniramine, imiquimod, diphenhydramide, Lidocaine, Isotretinoin, Ketoprofen, Diclofenac, Leuprolide, Finasteride, etc.
• the substance may also be a combination of biological and non-biological compounds.
• a pumping device (14) is used to bring the formulation (21) present in a reservoir (15), at the spray nozzle (11) with a controlled liquid flow.
• a syringe pump is used as a pumping device.
• it is generally taken from the reservoir (15) at a temperature of between 4 and 60 ° C., preferably 20 ° C.
• the flow of liquid is adjusted to control the size of the droplets formed and allow an acceptable evaporation of the solvent, after or during the deposition.
• the nominal flow rate of the formulation (21), for 1 nozzle (11), may for example be between 0.01 and 100 milliliters / hour.
• the nominal flow rate for 1 nozzle of the formulation (21) is between 0.01 and 10 milliliters / hour, preferably between 0.01 and 1.5 ml / hour, most preferably between 0. , 1 and 1.5 ml / hour.
• the inventors have indeed shown that this flow makes it possible to obtain droplets of lower average size. at 20 ⁇ m, preferably at 5 ⁇ m, typically at about 1 ⁇ m, ensuring the formation of homogeneous deposits.
• the flow rate is particularly regulated between 0.7 and 1.3 ml / hour.
• each nozzle is connected to a particular pump, the pumps being operated simultaneously to produce an identical flow rate for the same duration.
• the pump is equipped with a motor to change the direction of pumping.
• the syringe is either filled without disassembly of the latter by pumping the formulation via a container, or emptied by feeding the nozzles of the formulation.
• the device comprises a conduit (17) surrounding the free end of the nozzle (11), and intended to convey a gas.
• the gas is carbon dioxide.
• the conduit (17) is then connected to a gas supply (18) and opens at the free end of the nozzle (11). It is also possible to confine the enclosure of the projection device and replace the air with a more insulating gas.
• carrier refers to the material or surface area of the patch on which the substance contained in the formulation (21) is deposited by spraying.
• the support can be of shape and of varied nature.
• the support (31) must be conductive, superficially or in the mass, that is to say based on material (s) conductor (s) or treated surface or mass to be made conductive by any known technique of the skilled person.
• the support may thus comprise or consist of different biocompatible materials, such as for example polymer material, doped polymer, polymer coated with a conductive layer on one or both sides, metal, textile and / or biological material, etc.
• the support is made of conductive material (s).
• the support comprises at least one conductive face, which is arranged facing the nozzle.
• a preferred support is thus composed of an insulating layer, for example an insulating polymer (film, fiber, etc.) coated on at least one face with a conductive layer.
• the conductive layer or layers covering one or both sides of the support may be of inorganic nature (of metal for example) or organic (comprising for example carbon, graphite, or oxide (s)).
• the metal is preferably gold, silver, platinum or aluminum.
• the conductive layer or layers advantageously have a thickness of between 5-40 nm, preferably between 5-20 nm.
• the deposition of graphite on the support (31) can be carried out beforehand, or in line, just before the electrohydrodynamic spraying step of the formulation (21).
• the deposition of graphite can be done by spraying a neutral or charged aerosol, or by dipping by passing the film in a bath of graphite solution.
• the formation of the conductive layer of the support before the spraying step may, in addition, be carried out by metallization or oxide deposition.
• the oxide is preferably indium oxide doped with tin (ITO).
• a plasma treatment may also be performed to promote, among other things, adhesion to the deposition-support interface.
• the invention resides in a method further comprising a step of treating the support before the spraying step consisting of a plasma treatment at low pressure or at atmospheric pressure, and / or metallization. and / or an oxide deposit and / or a graphite deposit.
• the support is a support of polyethylene terephthalate (PET) film coated with a thin layer of conductive gold (15 nm).
• PET polyethylene terephthalate
• the resulting patch may further comprise an insulating double-adhesive crown, for example made of PE-PP foam.
• the support therefore comprises at least one electrically conductive face formed, for example, according to the methods described above, and the aerosol (22) is projected onto this electrically conductive face.
• the support of the patch on which the substance is projected is essentially plane.
• the support consists of an insulating polymer coated with a conductive layer and the electric field is formed by applying a potential difference between the spray nozzle (11) and the support
• the electric field is formed by applying a potential difference between the spray nozzle (11) and the support disposed between the nozzle and the counter-electrode. (16).
• the shape and nature of the patch media may vary.
• the support (31) illustrated in Figures 1, 2 and 3 is flat, other geometries can be envisaged.
• supports comprising a depression forming a chamber, tank patches, rigid or semi-rigid supports, planar or not, of circular, square, rectangular, oval, etc., as required.
• the support used in the process can be previously machined in the form of a patch.
• the patch is directly used in the method of the invention.
• the support is previously coated with substance according to the method of the invention, and subsequently used to form a patch.
• the support (31) may for example be in the form of a film or roll on which the substance is projected. The patch intended for the end user will then be cut later from this film.
• the conductive surface of the support must preferably be perfectly connected to the mass during the entire duration of the deposition and during the transfer from one patch to another, to allow the flow of the charges of the particles which are deposited and which accumulate on the support, in a particularly advantageous mode, the patch support is presented in the form of a roll width that is rolled out as and when.
• the width advantageously comprises:
• the conductive support for example in the form of a film (for example, PET coated with gold), and
• the support film is wider than the foam film, so that each foam-covered support zone is in electrical contact with the entire conductive surface (upper face) of the support film.
• This support film region will be connected, in manufacture to ground, via a conductive roller, itself connected to ground.
• the patch is cut (external cut) after filing. Filing process
• the liquid formulation is supplied to the nozzle, preferably under the formulation and flow conditions mentioned.
• the electric field is formed, resulting in the formation of an aerosol, whose droplets preferably have an average size less than about 5 microns.
• the particles which form on the support from the aerosol are collected on the support of the patch, which is then, or simultaneously treated to evaporate any solvent residue and form and dry deposit.
• any solvent residues in which said substance is dissolved can be evaporated.
• the evaporation can be obtained passively, or by accelerated evaporation, for example by convection heating, irradiation (for example, with ultraviolet or infrared), by lyophilization or circulation of dry gas.
• the drying of the support (31) is carried out by placing it in a flow of hot air.
• the method of the invention further comprises a step of evaporation of the solvent during and / or after the deposition of the aerosol (22) so as to obtain a substance in the form of dry residues.
• the evaporation step can be carried out by heating, by convection, by irradiation, by lyophilization and / or by circulation of dry gas.
• most deposit methods, such as dry deposits generally result in active substance losses outside the area of interest.
• another major advantage of the invention lies in the focusing of the flow of active substance towards this area of interest (FIG. 6). As shown diagrammatically in FIG.
• the area covered by the stream of charged drops is controlled at two levels: by the potential applied to the ring, and / or by a material delimitation of the deposit zone, this delimitation being able to be carried out by the adhesive flange constituting the peripheral part of the patch (in particular for the condensation chamber patches); this collar being electrically insulating.
• the insulating flange, constituting the finished patch precisely delimits an area in which the electric field lines terminate and focus. This phenomenon thus makes it possible to focus the flow of active substances, which follow the field lines, exclusively in the center of the patch, avoiding any loss of active substance outside the area of interest and forming a perfectly localized deposit.
• the patch according to the invention consists of a support (31) on which was deposited by electrospray a substance (21), present in the form of dry deposit (33).
• the patch is advantageously conditioned so that the dry deposit (33) is isolated from the external environment.
• the patch (3) may comprise, in a particular embodiment, a peelable film (32) covering the powder (33) and the portion of the support (31) that is not covered. by the powder (33).
• the peelable film (32) is intended to be removed before applying the patch (3) to the skin.
• the invention is suitable for any type of patch, that is to say any device that can be applied to a skin area of a subject to bring it into contact with a substance or create a hydration zone.
• patch any device that can be applied to a skin area of a subject to bring it into contact with a substance or create a hydration zone.
• These may be passive, facilitated or mechanical diffusion patches, patches, dressings, plasters, cups or patches
• the plasters consist of an adhesive mass, or coated, containing one or more substances, one or more diluents, emollients and adhesive agents spread in a uniform layer on a suitable support.
• the adhesive mass is such that it softens and then adheres to the skin at skin temperature.
• the plasters retain the shape given to them during manufacture and adhere to the parts to which they have been applied. They are presented in the form of sheets of variable size, possibly to be cut. They can be fixed on a plaster and covered with a perforated material at its center to limit contact.
• the medical dressings are intended to be applied to small skin lesions for local action and consist of a plaster on which is attached at its center a dressing material covered with a substance.
• the patches are intended to be applied to the skin to highlight the sensitivity of an organ to a substance.
• These stamps consist of a plaster with a plastic disk in the center on which is placed an adhesive mass containing the substance.
• the adhesive mass further contains such elements as gum arabic or gelatin and water.
• the passive diffusion, facilitated or mechanical patches typically comprise a support on which is deposited the substance in dry form and, where appropriate, a device to facilitate cell permeation (application of electrical pulsations, ultrasound, microneedles, etc.. ).
• a dry patch is preferably used, in particular of the occlusive type, in particular an electrostatic patch as described in WO 02/071950.
• the patch according to the invention can be used in particular in pharmaceutical, cosmetic, vaccine and / or diagnostic applications.
• the patch may be subjected to additional treatment, such as, for example, pasteurization, ionization and more generally any treatment known to those skilled in the art.
• Another subject of the invention relates to a patch for the cutaneous application of a substance, said patch comprising said substance disposed on a support zone of the patch, said support zone being electrically conductive.
• the conductive support may be of conductive material (s) or surface-treated or mass-treated to be conductive.
• a more particular object of the invention relates to a patch for the cutaneous application of a substance, the patch comprising a support comprising a layer electrically conductive layer and an insulating layer, the electrically conductive layer being on the face of the support intended to be exposed to the skin, the substance being in dry form and immobilized on the conductive surface of the support.
• the substance is advantageously in the form of microparticles. It may be any biological substance as described above, in particular protein or peptide, for example antigens or allergens.
• the periphery of the support is adapted to create, in contact with the skin, a sealed chamber containing said substance.
• FIG. 1 illustrates an ElectrohydroDynamic Spray device (1) during the manufacture of a patch (FIGS. 2 and 3) according to an embodiment of the method of the present invention.
• the spraying device (1) comprises a nozzle (11) having a liquid passage orifice, fed by a pumping device (14) which takes a liquid formulation (21) into a reservoir (15). ).
• the liquid formulation (21) contains BSA (bovine serum albumin) dissolved in water. This formulation (21) is preferably supplied to the spray nozzle (11) at a constant rate during spraying.
• the counterelectrode (16) is disposed axially and away from the nozzle (11).
• the counterelectrode (16) is connected to ground.
• the support (31) of a patch (3) is placed between the spray nozzle and the counter-electrode (16).
• This support (31) consists of a polyethylene polymer doped with carbon.
• the spraying device (1) further comprises a conduit (17) connected to a gas supply (18) and surrounding the free end of the nozzle (11).
• BSA has been solubilized in water of low electrical conductivity (preferably between 10 and 100 ⁇ S / m).
• the BSA deposition was carried out under stable conditions for a BSA concentration of between 0.1 and 5 mg / mL, liquid flow rates between 0.1 and 2.5 mL / h, and tensions between 4 and 7 kV, a nozzle distance (11) / against electrode (16) of 0.5 to 1.5 cm, at atmospheric pressure, for a CO2 flow rate of between 3 and 6 L / min and nozzles of outside diameters and inside respectively between [0,11 - 0,60] mm and [0,006 - 0,1] mm.
• characterizations were made on the deposits: i) The mass of protein was, first of all, quantified by performing assays with the bicinchonic acid (BCA). These assays confirmed the deposition of protein on the conductive supports in amounts between 1 and 50 micrograms for BSA concentrations between 0.1 and 5 mg / mL and a deposition time of one minute. ii) The observations made by Scanning Electron Microscopy (SEM) then made it possible to verify the homogeneous distribution of dry residues on the patch and the non-degradation of the proteins by the method according to the invention was verified with the help of a electrophoresis gel which revealed no structural modification of the protein. iii) In addition, the maintenance of one of the main functions provided by the BSA protein (antigen-antibody recognition) has been validated by a radial immunodiffusion method.
• BCA bicinchonic acid
• the patch consists of: a polyethylene terephthalate (PET) film support covered with a thin layer of conductive gold (15 nm), and an insulating double-adhesive crown in PET foam (Figure 3).
• PET polyethylene terephthalate
• Figure 3 an insulating double-adhesive crown in PET foam
• the patch on which a deposit is made by ElectroSpray is provided with a conductive support whose conductive surface of the support must be perfectly connected to the ground or to a voltage generator and this during the whole duration of the deposit and during the transfer of one patch to another to allow the flow of charges that are deposited at the same time as the particles of substance that accumulate on the support. Knowing that the conductive surface is disposed facing the nozzle, it is, most of the time not possible to directly perform this grounding simply by contacting the support on a table itself grounded . The solution found is to present the material constituting the patches in the form of a roll width that is unfolded as and when.
• the web comprises: - the conductive support in the form of a film (for example, PET coated with gold, and - a foam film with circular holes at regular intervals and stuck on the conductive film, the zone visible support through each hole constituting a deposition area of a patch ( Figure 4).
• a film for example, PET coated with gold
• a foam film with circular holes at regular intervals and stuck on the conductive film, the zone visible support through each hole constituting a deposition area of a patch ( Figure 4).
• the support film is wider than the foam film so that each foam-covered support zone is in electrical contact with the entire conductive surface (upper face) of the support film.
• This support film zone will be connected, in manufacture to ground, via a conductive roller, to ground.
• the patch is cut (external cut) after filing.
• the evaporation of the solvent (s) during the transit time of the drops suspended in the gas is sufficient for the substance to occur on the patch, in the form of dry particles, distinct and well individualized (Figure 7).
• the size of these particles facilitates their adhesion to the support under the action, in particular, Van der Waals forces.
• the particle flow rate and the nature of the solvent are such that the peanut proteins are deposited on the support in wet form and can then aggregate to each other.
• these deposits are in the form of a homogeneous layer.
• the dissolution of this layer is extremely easy, which makes the substance extremely available, as evidenced by the tests carried out with deposits made by the inventors with BSA or peanut proteins.
• Test patches made by this technique, and deposited on patients allergic to peanut, showed the speed of action of the patch, due to the high availability of the substance.
• Scanning electron microscopy (SEM) images identify the morphology of these deposits and their two characteristics:
• the nozzle (11) is fed with liquid peanut formulation (21) to be deposited, at a liquid flow rate advantageously equal to 0.7 ml / h.
• the nozzle (11) is placed 18 mm from a width of preformed patches (FIG. 4) consisting mainly of a PET / OR support (surface conductor) and a double-adhesive foam washer (insulating).
• the nozzle (11) and the liquid (21) containing the peanut protein extract are polarized at high voltage by a high voltage supply (14), preferably around 9-9.5 kV.
• the conductive surface of the support is connected to the ground, thus disposing all the supports of the preformed patches to ground.
• a shielding ring (12) is disposed at 5 mm from the nozzle ( 11). In a preferred embodiment, it is polarized at 2.2 kV.
• the support used is a PET polymer film (23 ⁇ m thick) covered with a thin layer of gold (15 nm).
• the sprayable peanut formulation by the ElectroSpray process is obtained by dissolving the peanut protein extract in a mixture of milliQ water, ethanol (99.9%) and a nonionic surfactant (Volpo N20). .
• Zone B The multi-cone jet mode no longer exists in nozzle-ring-plane configuration. Beyond the maximum voltage of the stable mode, the cone of liquid remains centered with respect to the axis of the nozzle but pulsed discharges disturb the production mode.
• Zone C The process stability in nozzle-ring-plane configuration is no longer possible due to pulse discharges.
• zones B and C can be attributed to a modification of the electric field lines between the nozzle and the counter electrode considered (ring or plane connected to the mass).
• a third type of protein has been tested to confirm the feasibility of the deposition of active ingredient by HDPE, for the manufacture of patches in particular.
• the appearance of the deposits is similar to that of the peanut deposits.
• the diameter of between 3 and 3.3 cm can be explained by the inter-electrode distance which is about 30% greater than that usually used for groundnuts.

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• 2008
  • 2008-01-23 FR FR0850406A patent/FR2926466B1/fr active Active
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