WO2020200407A1 - Micro-implants congelés et leur procédé de fabrication - Google Patents

Micro-implants congelés et leur procédé de fabrication Download PDF

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Publication number
WO2020200407A1
WO2020200407A1 PCT/EP2019/058096 EP2019058096W WO2020200407A1 WO 2020200407 A1 WO2020200407 A1 WO 2020200407A1 EP 2019058096 W EP2019058096 W EP 2019058096W WO 2020200407 A1 WO2020200407 A1 WO 2020200407A1
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WO
WIPO (PCT)
Prior art keywords
micro
implants
implant
frozen
unit
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2019/058096
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English (en)
Inventor
Véronique Burnier
Dominique Bordeaux
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LOreal SA
Original Assignee
LOreal SA
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Publication date
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Priority to PCT/EP2019/058096 priority Critical patent/WO2020200407A1/fr
Publication of WO2020200407A1 publication Critical patent/WO2020200407A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0216—Solid or semisolid forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays or needleless injectors
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/24—Thermal properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles

Definitions

  • the present invention relates to micro-implants for injecting into keratinous materials such as human skin, mucous membranes as lips for example, gums and scalp.
  • US 8167852 and US 8834423 disclose devices that comprise an array of micro implants (also called“microneedles”) carried by a support.
  • Such devices may be useful for delivery of cosmetic materials, drugs or vaccine into the skin.
  • An advantage is that they can penetrate the stratum comeum, epidermis or dermis without the pain caused by conventional needles and can be self-administered.
  • micro-implant devices have been described in various applications such as WO2008/139786, W02009/040548, W02015/147040 and WO2016/076442.
  • a liquid is poured in a mold and then dehydrated to form the solid micro-implants.
  • compositions that can form solid micro-implants after dehydration are not numerous which limits the range of actives and applications.
  • micro-implants when the micro-implants are injected into keratinous materials such as the skin, they dissolve or disintegrate under the action of moisture or water present therein, but the quantity of liquid available to moisture and/or solubilize the micro-implants is often too low, especially if the compounds present in the micro-implants require a high amount of moisture to dissolve or swell, such as hyaluronic acid or other polymers like alginates.
  • the present invention aims at satisfying this need and exemplary embodiments of the invention relate to a method for the preparation of at least one micro-implant to be injected into human keratinous materials, comprising freezing a material in a predefined shape suitable for injecting into said human keratinous materials.
  • the invention enables to generate numerous micro-implants made up from a wide variety of aqueous but also anhydrous compositions.
  • compositions having a freezing temperature to form hard objects under the conditions of injection may be used to form micro-implants according to the invention. This enlarges considerably the number of candidate compositions, which no longer need to be capable of forming solid materials through a dehydration or other process to make micro implants.
  • the composition of the at least one micro-implant is preferably frozen in a "needle-like” shape. Any microneedles array mold may be used to form micro-implants enabling their insertion into the skin. Once injected into the skin, the frozen micro-implants melt and return to a liquid state facilitating the diffusion of actives for example.
  • Any starting galenic form may be suitable to make the frozen micro-implants, provided the composition has a freezing temperature enabling the formation of solid micro implants as mentioned above.
  • the frozen micro-implants are capable to create openings in the stratum comeum, epidermis or dermis.
  • the micro-implants do not fracture when force is exerted on them to expel them into the skin.
  • composition once into the skin and when melted, may not have the same formulation or characteristics than before being frozen.
  • the above-mentioned predefined shape may be given by a mold cavity.
  • the frozen micro-implants that are formed may be removed from the mold before being injected but more preferably they are injected while they are hold by the mold, as will be detailed further below.
  • This enables to use micro-implants having shapes that could not be unmolded, such as shapes with cutbacks, hooks, etc.
  • This also enables shapes that would brake during a conventional de-molding process. This may enable to make a frozen micro-implant using a combination of different materials that would render the micro-implant difficult to unmold.
  • the composition used to form the frozen micro-implants may be introduced in a mold comprising multiple cavities in a liquid state and frozen when needed in such mold to reach a solid state.
  • the composition may be in liquid stage when stored and frozen in micro implants shape just before being introduced into the skin
  • the micro-implants may remain in the mold until they are injected into keratinous materials, in which case they may be injected through the mold.
  • the micro-implants are unmolded and separated from the mold before being injected. For this purpose, they may be attached to a backplate that serves to withdraw them from the mold and helps their holding and insertion into the skin.
  • micro-implants may be produced in advance in the solid form and kept in a cold environment at a temperature below their melting point until use to preserve their mechanical properties. They may be stored in a fridge or in a cooled storage compartment of an injecting device.
  • the micro-implants are solidified extemporaneously, by submitting the composition they are made of to a cold source.
  • the freezing may be performed in a same device as the one used for injecting the micro-implant into the keratinous materials.
  • a device may comprise a cooling unit with one of more Peltier cells for example.
  • the cavity in which the composition is frozen to make the at least one micro implant may form at least one cutback in the micro-implant, preventing the micro-implant from being unmolded. This may result in the micro-implant having an arrow shape for example.
  • the micro-implants may be made from a same composition.
  • at least one micro-implant is made from at least two different materials, both of which are solid and at least one of which is frozen.
  • the micro-implant may comprise a composite structure, having at least two different frozen materials. To form such a composite frozen micro implant, for example a first material is poured in a mold cavity in a liquid state, frozen, a second material is poured in the remaining space of the mold cavity in a liquid state and then is frozen.
  • the method of the invention may comprise sterilizing the micro-implants or any unit incorporating them.
  • the composition of the micro-implants may be sterilized while in a liquid state before being frozen.
  • the micro-implants may be sterilized while in the frozen state.
  • the micro-implants may be molded using a core of a unit in which the micro implants remain until they are injected into the skin.
  • the core serving to mold the material of the micro-implants may receive some mechanical treatment to facilitate the exit therefrom by the micro-implants when injection takes place. For example, holes or slits are made in the core to facilitate the deformation thereof when the micro-implants are expelled. These holes or slits made be made with a laser.
  • the core may also receive a surface treatment to lower or enhance its hydrophilicity or hydrophobicity for example.
  • the frozen micro-implants may also be molded in a column, which enables to inject micro-implants one after the other.
  • the formation of the micro-implants may comprise molding a column of micro-implants in a cavity of the core.
  • the column of frozen micro implants may comprise frangible areas facilitating separation of the micro-implants.
  • the micro-implants of the column may also be molded one after the other in the core. Two successive micro-implants of the column may be separated by a material facilitating separation of one micro-implant from the successive one in the column during the injection process.
  • the method of making the micro-implants may also comprise freezing the column in an elongated core that is cut to form the units.
  • the cut line may be perpendicular to the elongation axis of the core or in a variant may be oblique to form micro-implants with beveled ends.
  • Micro-implants may be formed extemporaneously by freezing some quantity of composition in liquid state, in a cavity of a device fed from a reservoir containing the composition in the liquid state. Once the micro-implant is frozen, it may be injected and then the cavity is filled again with some composition taken from the reservoir to prepare the next micro-implant.
  • the composition of the micro-implants may be cooled down at a temperature at least 5°C below the melting point of the composition.
  • the composition may be frozen by placing it in a cold environment such as a freezing compartment of a fridge, or by exposing it a cold gas, liquid nitrogen or dry ice or other kind of ice, or by contact to a cold surface.
  • the injection of the micro-implants may be performed using a same or similar device as the ones already known for injecting known non frozen solid micro-implants, provided the injection takes place before the temperature of the micro-implants increases to a limit where they lose their desired mechanical properties.
  • the injection is preferably performed with devices that are configured to avoid or slow down the melting process prior the micro-implants are injected.
  • the injection may be performed using a device that comprises a cold source used to keep the micro-implants at a low temperature, such as for example a Peltier cell or cold mass brought before use of the device to a low temperature below the melting point of the frozen micro-implants.
  • the injection device may be cooled with the unit containing the micro-implants.
  • the injection may also be performed with a device that comprises a reservoir containing the composition in a liquid state and a cold source to freeze some quantity of the composition taken from the reservoir to form the at least one frozen micro-implant.
  • a further object of the present invention thus relates to an injection system for injecting at least one material into human keratinous materials, comprising:
  • an injection device configured for applying a pressure to the at least one frozen micro-implant to expel the latter into the human keratinous materials.
  • the injection system may comprise at least one treatment unit defining at least one cavity containing at least partially the at least one micro-implant. This cavity is advantageously the one in which the composition has been frozen.
  • the unit may comprise at least one puncturable region through which the at least one micro-implant is expelled.
  • the unit can be squeezable, hard, soluble, refillable and/or made of material that is able to recover original shape after being compressed.
  • the unit may comprise at least one puncturable membrane fixed onto a core defining at least partially the at least one cavity and through which the at least one micro implant is expelled.
  • the system may comprise, as mentioned above, a cold source for lowering temperature of the composition of the micro-implant prior to injection into the keratinous materials.
  • the temperature to which the composition is cooled down may be below 0°C.
  • the injection device preferably comprises a cold source to keep the micro implants at a temperature below the melting point of the composition before being injected.
  • the system may comprise a heat source for applying heat to a region of the keratinous materials where injection takes place. This heat may be applied prior to the injection to facilitate the melting of the micro-implants once they have been injected into the keratinous materials. The heat may also be applied after the injection or before and after the injection.
  • the heat source may comprise a surface that is heated at a temperature ranging between 2°C and 100°C, preferably from 2°C to 60°C and more preferably from 30° to 60° C.
  • the injection device may comprise an impacting member configured for contacting a proximal end of the at least one frozen micro-implant to expel it into the skin. The micro-implant is preferably hold during this contact by a core of a unit, as mentioned above.
  • the impacting member may be driven by any appropriate means such as for example an electromechanical actuator, a spring, a pneumatic or hydraulic device, a pyrotechnic device, or a pressure exerted manually on a surface and transferred to the frozen micro implants.
  • Manual pressure may also be exerted directly on the unit or impacting member to push the frozen micro-implants into the skin.
  • the impacting member may have a contact surface configured for contacting simultaneously the proximal end of a plurality of frozen micro-implants.
  • This surface may be flat or have any other appropriate shape, for example if the face of the unit that contacts the skin is not planar but convex.
  • the unit may comprise a squeezable core to allow the impacting member to push the frozen micro-implants along a distance long enough for them to leave the core.
  • the impacting member may have a plurality of individual projections each for contacting a respective proximal end of a frozen micro-implant.
  • projections also called “counter-needles”
  • the presence of projections may enable to use a rigid core as the core does not need to collapse for the micro-implants to be pushed out of the core.
  • the projections may enter the cavities to push the frozen micro-implant out thereof.
  • the impacting member may impact a plurality of frozen micro-implants simultaneously or in a sequence. In the latter case, the impacting member may oscillate between an impacting position and a raised position and move, between two consecutive impacts, to be in line with the next micro-implant to impact.
  • the injection device may comprise at least one chamber for receiving the unit.
  • the system may be configured for selective expelling of the micro-implants.
  • the injection device and the unit may be movable relative to each other for selection of the at least one micro-implant to expel.
  • the injection device and the unit are rotatable one relative to the other for selection of the at least one micro-implant to expel.
  • the system may inject totally or partially micro-implants being explants into the skin providing an internal but also external skin treatment.
  • the system may comprise an energy generator, e.g. a motor or a spring, for displacing the impacting member relative to the unit or vice versa.
  • the system may be able to perform skin diagnosis and to transfer data to another data center, or device, etc.
  • the system may comprise an image sensor and a processor for automated detection of a target zone of the keratinous material and for signaling a user when the system is properly positioned relative to the target zone prior to expelling the at least one micro implant and/or for automated triggering of the injection of the at least one micro-implant when the system is properly positioned relative to the target zone.
  • the image sensor may be an optical sensor such as a camera or a non-optical sensor such as a capacitive sensor.
  • the system may be connected by a wireless connection or by a cable to a terminal such as a smartphone or a diagnosis device.
  • the wireless connection may be Wi-Fi or Bluetooth.
  • the system may comprise a pedestal or base unit to receive the device to enable data transfer and charging the device.
  • the target zone may comprise a wrinkle and/or any skin depression or other skin default, such as for example achromia, or over-pigmented spots, etc.
  • the system is configured for detecting the displacement of the injection system along the skin to compensate this off-centering before triggering the injection.
  • This displacement may be detected optically.
  • the system may comprise an electromechanical actuator for vibrating the unit and/or the injection device. This may help to create a massaging action against pain and/or improving the diffusion of the material within the stratum comeum, epidermis or dermis.
  • the system may comprise a cold source for lowering the temperature of the unit and/or of the keratinous materials prior to, during or after the injection. This may help maintain the micro-implants in the frozen state and may also reduce inflammatory side effects, pain and/or make the dermis or epidermis firmer.
  • the system may comprise a heat source for increasing the temperature of the unit and/or the keratinous materials prior to, during or after the injection. This may help the micro-implants to melt and diffuse into the skin.
  • the system may comprise a light source for projecting light onto a target zone where the at least one micro-implant is to be injected. This may help the user to position the system in the area to be treated and/or facilitate detection of wrinkles or other element to treat with the system.
  • the system may comprise at least one electrode for subjecting a target zone where the at least one micro-implant is to be injected to a microcurrent.
  • the microcurrent may help the material of the micro-implant to penetrate deeper in the tissue, for example by pushing some actives into the skin by iontophoresis.
  • the microcurrent may also generate actives or enhance some inner reactions or enhance active diffusion by repulsion, or convective streams.
  • the injection device may be removed right after the injection or left in place for a predetermined amount of time.
  • the system may comprise a storage compartment for storing a plurality of the treatment units.
  • a storage compartment may be a cartridge in which a set of units are present. The user may insert the cartridge into the injection device and replace it by a new one after all units of the cartridge have been used.
  • This compartment may be heat insulated and/or cooled, to prevent the frozen micro-implants to melt too quickly.
  • the injection device may be configured for holding more than one cartridge, which may contain units with micro-implants of different volumes, materials and/or lengths or shapes.
  • the system may comprise a feeding mechanism configured for automatic replacement of a used unit present by a fresh unit coming from the storage compartment.
  • the system may be configured for automatic identification of a unit.
  • the injection device may operate under different conditions depending the unit that has been identified.
  • the system may allow its operation in any direction such as for example head up or down.
  • a further object of the present invention is a non-therapeutic method for treating keratinous materials, comprising injecting at least one micro-implant in a frozen state into the keratinous materials using the system as defined above.
  • the at least one frozen micro-implant is integrally expelled from the unit during the injection.
  • the method may be performed for treating wrinkles and/or any skin depression or other skin default, such as for example achromia.
  • the core holding the frozen micro-implants may be re-used in the manufacture of another unit. Otherwise, it may be discarded.
  • the core does not penetrate in the skin when the micro-implants are expelled. However, in a variant, some portion of the core may penetrate in the skin together with the micro-implant.
  • the material of the core is, in the latter case, preferably bio compatible and/or bioresorbable, and may be selected to dissolve or disintegrate in the skin.
  • the core may be water soluble.
  • the one or more micro-implants are preferably integrated into a unit, which can serve to mold the micro-implants, as explained above.
  • the unit may be pressed against the body before injection.
  • the unit may have for this purpose an application surface for contacting the keratinous materials when the at least one micro-implant is expelled out of the unit.
  • the unit holding the one or more frozen or frozen able micro-implants may define a plurality of cavities, a plurality of micro-implants being received each in a corresponding cavity of the unit and having each at least one portion of a same shape as the corresponding cavity.
  • the unit may comprise an array of cavities. This array may comprise cavities regularly or randomly spaced along two directions that are perpendicular to each other.
  • the shape of a cavity may correspond exactly to the shape of an entire micro-implant.
  • the height of the cavity may thus correspond exactly to the height of the micro-implant. All the longitudinal axes of the cavities may be parallel to each other. In a variant, the longitudinal axes of the cavities may not be parallel. Cavities with non-parallel axes may allow the core of the unit to better conform to some portion in relief of the body.
  • the core is preferably polymeric, e.g. elastomeric, the core comprising for example a silicone elastomer.
  • the core may deform in reversible manner during injection of the micro-implants.
  • the core may be squeezed during the injection.
  • the core may also be teared or pierced to some extent by the micro-implants during injection.
  • the core may be deformed during injection so that the longitudinal axes of at least two cavities take an orientation one relative to the other.
  • the core is non-elastomeric.
  • the core may comprise at least one material selected among PMMA, PDMS or other polymers. In such case, the core may be perforated and/or broken by the micro-implants during injection.
  • the core may be soluble in a liquid, for example water or another solvent or composition.
  • the core while dissolving may be partially injected with the micro-implants.
  • the solubility of the core may be useful to ease extraction of the micro-implants from the core, as it may fragilize the core for example.
  • the core is preferably biocompatible.
  • the core is preferably bioresorbable.
  • the core may be permeable to liquids or gas.
  • the injection system may be configured in such a manner that some gas penetrates in the skin. Having the core permeable to gas may aid the gas to penetrate the skin. The gas that has penetrated the skin may contribute to expand locally the skin, which may be beneficial in some applications where one seeks to bring volume to the skin such as wrinkle reduction.
  • the core may be squeezable thanks to the use of an elastomeric material or thanks to the presence of voids and/or micro spaces or channels that can collapse under the pressure exerted to expel the micro-implants.
  • the core may have a solid structure or may be made by shaping a sheet to form the cavities.
  • the core may have a composite structure with a solid body defining hollows and an internal liner present at least in said hollows to define the boundaries of cavities in which the micro-implants are located. This may enable the use of a body of low mechanical strength and high porosity, while the presence of the liner allows to mold the micro-implants with a precise shape and surface state.
  • the unit may comprise at least one puncturable region through which the at least one micro-implant is expelled.
  • the presence of a puncturable region provides a protective barrier at the distal end of the micro-implants and may help preserve sterile conditions of the micro-implants.
  • the unit may comprise at least one puncturable sealing membrane through which the at least one micro-implant is expelled.
  • the sealing membrane may comprise a metal, preferably aluminum and/or a polymer, for example polypropylene.
  • the sealing membrane may be removed or not before injection. When the sealing membrane is not removed, it is preferably biocompatible and/or bioresorbable.
  • the unit may comprise a protective cover fixed onto the core on the proximal side of at least one micro-implant. The protective cover may be detachable from the core prior to the use of the system.
  • the unit may comprise between 1 and 5000 micro-implants per cm 2 .
  • the area with micro-implants may be of outline circumscribed to a circle of diameter ranging from 3 mm to 80 mm, better from 5 mm to 50 mm.
  • the spacing within the array of two adjacent micro-implants may range from 50LUTI to 50 mm in both x and y directions of the plane.
  • the thickness of the unit may range for example from 25 microns to 30 mm, preferably from 25 microns to 10 mm, for example about 3mm.
  • a micro-implant may have a largest transverse dimension at its base no greater than 1500 microns, for example a largest transverse dimension ranging from 1 to 1500 microns.
  • the section of a micro-implant is preferably circular, in which case the largest diameter of a micro-implant may range from 1 to 1000 microns, preferably between 200 and 400 microns.
  • a length of the micro-implant may range from 100 to 1500 microns, better from 200 to 800 microns, even better from 400 to 600 microns.
  • the micro-implant may comprise a proximal cylindrical portion of constant section and a distal portion having a section that narrows toward the tip of the micro-implant, for example a conical distal portion.
  • the proximal and distal portions of a micro-implant may be of substantially same length, for example 1 P * 0,8 ⁇ Id ⁇ 1 P * 1 .2, where 1 P is the length of the proximal portion and Id is the length of the distal portion.
  • the length of the proximal portion may range from 200 to 400 micron and the length of the distal portion may range from 200 to 400 microns also. Other ranges are possible, of course.
  • the micro-implant may also have a truncated distal portion, or a chamfered distal portion, or a beveled distal portion.
  • the micro-implant may be at least partially porous to gas or liquid.
  • the core may comprise cavities each containing a column made of a plurality of frozen micro-implants superimposed axially.
  • the number of micro-implants in a column may be reduced by one micro-implant each time an injection takes place.
  • the force for pushing the micro-implant situated at the distal end of the column into the skin may be exerted on the micro-implant situated at the opposite end of the column.
  • all the micro-implants of the column may be identical or different.
  • the concentration of one compound may vary gradually along the frozen micro-implants of the column, or two consecutive micro-implants may comprise different compounds.
  • the unit may be discarded after first use or after all micro-implants have been expelled therefrom.
  • the unit can be re-usable to generate new micro implants.
  • the core when empty, may be used for molding new micro-implants.
  • the material of the core may be re-shaped to form new mold cavities.
  • All the frozen micro-implants of the unit may be made of a same material.
  • some of the frozen micro-implants are made of a first material and some others are made of at least one second material different from the first one.
  • the at least one frozen micro-implant may be made of different materials; for example, a proximal portion of the frozen micro-implant is made in a first material and a distal portion of the micro-implant is made of a second material different from the first one.
  • the micro-implant may comprise at least two portions of different hardness.
  • the micro implant may comprise a distal portion of a greater hardness than that of a proximal portion. Having a distal portion of greater hardness may help perforate the skin.
  • the at least one micro-implant may comprise at least one anchoring relief for anchoring the micro-implant into the keratinous materials.
  • the at least one micro-implant may comprise at least one of a serrated or harpooning head. The freezing of the composition allows formation of cutbacks in the micro-implants.
  • the unit may have a disk shape.
  • the unit may have other shape, such as a pellet shape with no circular outline, for example a polygonal outline, or a band or ribbon shape.
  • the unit may comprise at least two frozen micro-implants of different materials, volumes, lengths and/or shapes.
  • Micro-implants of different materials, volumes, lengths and/or shapes may be situated in respective distinct areas of the unit or may be distributed uniformly within the array.
  • a rear face of the or each of the frozen micro-implant may be free and deprived of attachment to a backing layer.
  • a frozen micro-implant may comprise at least one cutback preventing it from being unmolded. This may help the micro-implant to resist backpressure exerted by the tissue in which it is injected. This may help reduce loss a material.
  • the tips of the frozen micro-implants may be situated in a same plane.
  • a face of the unit intended to contact the skin may be planar.
  • the tips of the micro-implants are not situated in a same plane, and the face of the unit intended to contact the skin may not be planar.
  • this face is having a shape that matches the shape of the skin in the area to be treated.
  • the face is having a shape convex toward the outside, and the tips are situated along a surface that is parallel to this face. Since the micro-implants need not be unmolded prior to injection, the non-planar shape does not raise unmolding issues.
  • a further object of the invention is a treatment unit suitable for use in a system as defined above, comprising:
  • Such unit may be provided to the user in a packaging that is to be opened or not before use.
  • Such a packaging may be a bag and do not need to be rigid, as the core provides some protection to the micro-implants.
  • Such packaging can be a tube with one or two caps at each end.
  • the micro-implants may be packaged in a core of a unit as defined above where the composition is frozen. This avoids the need to detach the micro-implants from the core prior injection, as the mold may be configured to allow the micro-implants to be injected while being hold by the mold.
  • the core defines at least partially at least one cavity used to mold the micro implants and the core may be used as a package for protecting and holding the micro implants until use. This may render the packaging of the micro-implants less expensive and/or cumbersome, as there may be no further need of a hard packaging.
  • the frozen micro implants may be better protected from pressure, humidity or other environment factors by the unit until use.
  • the cost of the packaging may be reduced.
  • the micro implants remain in the core until use, this makes it easier to inject the entire micro-implants in the body, with no loss of material. Wastes are reduced and delivery is increased.
  • the absence of a conventional backplate helps penetration of the micro-implants into the stratum comeum, dermis or epidermis and induce a better delivery of the material to be injected, even in skin regions of high suppleness.
  • micro-implants may be packaged in frozen state, as mentioned above.
  • micro-implants may be packaged in a thermally insulated package, comprising for example polystyrene or polyurethane foam
  • the micro-implants may also be packaged in a package capable of being stored at ambient temperature, the composition of the micro-implants being in a liquid state during storage. Then, this package is put in a cold environment prior to the use of the micro implants, to freeze the composition and form the solid micro-implants ready for injection.
  • the micro-implants may also be produced from a reservoir in which the composition is in a fluid state and that is supplied to a shaping cavity configured to freeze a predefined quantity of the composition to produce at least one solid micro-implant.
  • the composition may be packaged in a cartridge defining said reservoir.
  • the invention also helps to associate micro-implants of different materials in a same treatment unit.
  • the micro-implants may be made of any material capable of freezing and become hard enough in the frozen state to be injected into the keratinous materials.
  • the composition in frozen state during injection will transform into liquid thanks to body temperature and or an external heat source and diffuse homogeneously into the skin.
  • Any galenic having a freezing point enabling formation of a micro-implant hard enough to be inserted into the skin is appropriate.
  • the invention it is possible to envisage numerous of new compositions which are not able to form dry or hard implantable micro-implants after being dehydrated. Furthermore, thanks to the invention it is possible to set-up multiple compositions containing very unstable active compounds, such as for example Vitamin C, retinol or peptides.
  • the invention also allows to insert a wide variety of aqueous and anhydrous compositions into the keratinous materials such as oils or waxes, inter alia.
  • the invention makes it possible to set up numerous preservative free formulations to avoid intolerance side effects.
  • the at least one material of the micro-implant preferably has a melting point below 37°C, so that the heat of the body will cause the micro-implant to melt.
  • the at least one micro-implant may carry actives that may be cosmetic actives, or drugs or vaccines.
  • the micro-implant may be made of a material that is resorbable, preferably water-dissolvable or soluble in any body fluid.
  • the at least one micro-implant may comprise at least two materials that are selected to react when melted.
  • the reaction may cause a gas to be generated. This gas may cause a local expansion of the skin, which may be useful for wrinkle reduction.
  • the gas may also improve blood circulation.
  • the material of the micro-implants may be of high swell ability and high viscoelasticity once melted.
  • Preferred embodiments of the invention include frozen micro-implants made of or comprising at least one of the following compounds, and mixture of these materials:
  • -actives preferably cosmetic actives, such as vitamin C and its derivatives, retinol and its derivatives, ceramides, Minoxidil, caffeine,
  • - fibers that are bio compatible, from natural origin or synthetic, such as ones made from hyaluronic acid, alginates, polylactic acid, viscose, acrylates, polyamides, polyolefins, in particular polypropylene, ...
  • mineral fillers such as silica, organic fillers such as starches, polymeric fillers such as Expancel,
  • PDGF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • KGF keratinocyte growth factor
  • TGF-b Fibroblast growth factor 1 or 2 (FGF-1, -2), ...
  • any cosmetic products that are regulated in the European Union since 11 July 2013 by Regulation (EC) No 1223/2009 of 30 November 2009 on cosmetic products may be used according to the invention to form hard micro-implants when frozen.
  • the frozen micro-implants may also contain any product from the list of substances that cannot be included in the composition of cosmetic products as given by Annex II of this Regulation.
  • the frozen micro-implants may also contain any product from the list of substances which cannot be used in cosmetic products except for the restrictions and conditions laid down in the list given in Annex III of this Regulation.
  • the frozen micro-implants may contain any dye or pigment that cosmetic products may contain, as given by Annex IV of this Regulation, as well as any preservatives that cosmetic products may contain as given by Annex V, as well as any ultraviolet filters that cosmetic products may contain, as given by Annex VI.
  • the frozen micro-implants are made from compositions that are preferably biocompatible.
  • biocompatible it is meant that the compositions are capable to fulfill specific functions with appropriate responses from the skin.
  • composition of the frozen micro-implants is preferably sterile, and of single use.
  • the frozen micro-implant preferably comprises at least one bio-polymer. Thanks to bio-polymer mechanism and the injection at high quantity and at the right depth into sites which cannot be reached using topical applications, long lasting and visible effects are obtained.
  • the cosmetic frozen micro-implant may be resorbable, i.e. may completely transform from solid (frozen) stage to liquid into the skin within a few seconds after being implanted.
  • injectable bio-polymer acceptable for skin injection purposes may be used, as for example the ones allowed by the American Food and Drug Administration (FDA) or the French“Annips de securite du medicament et des wall de sante” (ANSM).
  • FDA American Food and Drug Administration
  • ANSM French“Annipso de securite du medicament et des wall de sante”
  • the frozen composition may include at least one active compound or molecule or polymer to get added benefits.
  • composition before being frozen may be a fluid or a paste or a mix of powders, particles.
  • the composition may contain at least one material in the dispersed and or solubilized state.
  • compositions that become solid via any kind of cooling process may be used to form frozen micro-implants according to the invention.
  • the micro-implants may be made from any coloring compositions capable to be frozen for correcting skin color disorders or performing a permanent or long-lasting make up or improving skin tone or skin homogeneity.
  • Freezable compositions according to the invention may comprise pigments and or dyes or a mix of the two kinds to correct or erase skin color disorders, such as achromia, alopecia, vitiligo, scars, for example from acne, depigmented spot-areas, over-pigmented areas and spots, or also to attenuate the dark circles under the eyes.
  • Pigments can be mineral or organic.
  • Dyes can be natural (plants, roots, leaves extracts) or can be synthetic.
  • composition of the at least one frozen micro-implant according to the invention may comprise at least one coloring material listed below, and any mixture containing these materials.
  • the composition may contain at least one pigment such as the ones given below.
  • the composition is delivered deeper inside skin, by-passing the stratum comeum layer, which is not possible with topical applications.
  • the composition of the micro-implants diffuse into the skin layers and deliver coloring compounds.
  • the composition may comprise an aqueous phase and at least one pigment, which may be chosen from organic or mineral pigments.
  • This pigment is a pigment approved for use in cosmetics by CTFA and the FDA used in cosmetic formulations.
  • said pigment is water-dispersible.
  • the pigment is oil-dispersible or with limited solubility in water.
  • the pigment may be oil-soluble and/or water-soluble.
  • this pigment is a non-lamellar mineral pigment, more preferably a metal oxide, such as iron oxides, titanium dioxide, aluminum oxide, zirconium oxides, zinc oxide, or composite oxides, particularly an iron oxide selected from red iron oxide, yellow iron oxide or black iron oxide, or a mixture thereof, or Prussian blue, manganese violet, or ultramarine blue.
  • a metal oxide such as iron oxides, titanium dioxide, aluminum oxide, zirconium oxides, zinc oxide, or composite oxides, particularly an iron oxide selected from red iron oxide, yellow iron oxide or black iron oxide, or a mixture thereof, or Prussian blue, manganese violet, or ultramarine blue.
  • compositions considered according to the invention to form frozen micro- implants may comprise in particular at least one compound selected from (and their mixtures):
  • composition may also comprise at least one organic pigment, as for example a diketopyrrolopyrroles (DPP), as the ones described in EP-A-542669, EP-A-787730, EP- A-787731 and WO-A- 96/08537.
  • DPP diketopyrrolopyrroles
  • composition is for example one of the solutions of bio-pigments
  • the coloring material may be melanin.
  • the largest dimension of the pigments may range between 0.1 micrometers and 300 micrometers, preferably between 0.2 micrometers and 100 micrometers.
  • the dimension of the pigments may be adjusted to fit the size of the frozen micro-implants.
  • the frozen composition containing the one or more coloring materials may have an aqueous phase.
  • This aqueous phase may account for at least 5 % by weight relative to the weight of the composition of the frozen micro-implants.
  • the aqueous phase may comprise or consist in glycols, water, propane 1, 3, diol, or ethanol, and their mixtures.
  • the composition of the at least one micro-implant contains a lipo- soluble or hydro-soluble coloring agent.
  • concentration of such coloring agent in water or oil may be very low to generate skin color modification, preferably from 0.01% to 5% by weight.
  • the composition of the micro-implant is a liquid composition comprising high refraction index particles, interference particles, reflection particles, light absorbent particles, in particular non-transparent particles or particles modifying the path of light, in order to prevent or enhance reflection, or to reduce or hide light.
  • the composition may comprise coloring, blurring or mattifying particles.
  • the particles may be particles of nacre, silica, starch, bentonite, or clay.
  • Such a composition allows coloring or dermal- pigmenting the skin thanks to the optical properties of the particles they contain.
  • the composition may be able to protect skin from ultra-violet damages or to bring skin glow.
  • the composition may comprise hydroxyapatite particles or insoluble calcium alginate particles or aluminum oxide or noble metals, such as gold.
  • the depth of injection of the coloring material may be chosen according to the desired effect and may also depend on the desired duration of the effect, the length being greater for example when a long-lasting effect is required.
  • the at least one frozen micro-implant may contain any composition with at least one active compound for anti-ageing, whitening, moisturizing, ...
  • composition of the at least one micro-implant may comprise at least one bio polymer, preferably an alginate or hyaluronic acid, and an ion solution, in particular a divalent ion solution.
  • the composition may comprise at least one bio-polymer being able to be modified while in contact with another bio-polymer and/or an alcalin solution or acid solution.
  • the composition may comprise at least one compound able to crosslink in-situ, swell or become hard or semi-hard when being neutralized by a change of pH, or when adding a source of energy, such light.
  • the composition may comprise at least one compound which is activable by any source of energy, being especially electroactivable and/or photoactivable.
  • a bio-polymer considered according to the invention may be the alginate Novabel® from Merz, resorbable in 3 to 6 months.
  • the composition of the frozen micro-implant comprises a sodium alginate and a calcium solution, preferably a CaCCb calcium carbonate solution.
  • a sodium alginate and a calcium solution preferably a CaCCb calcium carbonate solution.
  • Such a sodium alginate is derived from brown sea weeds, and may be a FMC® injectable polymer powder solubilized in water.
  • a compound is a hydrophilic colloid, or hydrocolloid, defined as a colloid system in which the colloid particles are hydrophilic polymers dispersed in water.
  • the bio-polymer and the ion solution may be mixed before their freezing and injection as a frozen micro-implant into the skin.
  • the bio-polymer and the ion solution are separately injected as respective frozen micro-implants into the skin, for example with a ratio of 50% each.
  • the reaction of the compositions of the micro-implants is advantageously triggered by heat once injected into the skin.
  • At least part of the material in which are made the frozen micro-implants may be used, once injected into the skin (including scalp or lips) to generate an in-situ reaction by reacting with a composition delivered by other frozen micro-implants or delivered in any other way, for example with conventional microneedles.
  • the frozen micro-implants may comprise two bio-polymers able to be modified while in contact with another, and to react together for generating the in-situ reaction when the frozen micro-implants are injected into the skin.
  • the reaction may be modulated at will, especially enhanced or delayed, by using at least one buffer and/or sequestrant.
  • injectable bio-polymer acceptable for skin injection purposes may be used, as for example the ones allowed by the American Food and Drug Administration (FDA) or the French“Annips de securite du medicament et des wall de sante” (ANSM).
  • FDA American Food and Drug Administration
  • ANSM French“Annipso de securite du medicament et des wall de sante”
  • the viscosity of the composition of the micro-implants before freezing may range from 1.10 3 Pa s 1 to 10000 Pa s 1 , preferably from 1.10 3 Pa s 1 to 3000 Pa s 1 .
  • the viscosity is measured at 25 °C and under 1 atm, with a Rheomat 180 viscometer equipped with MK-R-1, 2 or 3 mobile according to the viscosity range and the corresponding measurement cup MB-R-1, 2 or 3 at a rotation speed of 200 min 1 , the measurement being carried out after 10 minutes of rotation (time at which the stabilization of the viscosity and the speed of rotation of the mobile is observed).
  • the cosmetic composition may be resorbable, i.e. may completely dissolve or be bio degraded or assimilated into the skin, in 3 to 6 months, or in 6 to 24 months, which corresponds to slowly resorbable.
  • the composition is definitive, non-resorbable.
  • the at least one frozen micro-implant may comprise at least one cosmetic filler.
  • the cosmetic filler preferably comprises at least one bio-polymer. Thanks to bio polymers mechanism and the injection at high quantity and at the right depth into sites which cannot be reached using topical applications, long lasting and visible effects are obtained.
  • the cosmetic filler may be resorbable, i.e. may completely dissolve or be biodegraded into the skin, in 3 to 6 months, or in 6 to 24 months, which corresponds to slowly resorbable.
  • the composition is definitive, non-resorbable.
  • the own collagen production of the user may be stimulated thanks to the delivered filler, and long-lasting effects of filling can be observed
  • injectable bio-polymer acceptable for skin injection purposes may be used, as for example the ones allowed by the American Food and Drug Administration (FDA) or the French“Annips de securite du medicament et des wall de sante” (ANSM).
  • FDA American Food and Drug Administration
  • ANSM French“Annipso de securite du medicament et des wall de sante”
  • the viscosity of the composition prior to being frozen may range from 1.10 3 Pa s 1 to 10000 Pa s 1 , preferably from 1.10 3 Pa s 1 to 3000 Pa s 1 .
  • the viscosity is measured at 25 °C and under 1 atm, with a Rheomat 180 viscometer equipped with MK-R-1, 2 or 3 mobile according to the viscosity range and the corresponding measurement cup MB-R-1, 2 or 3 at a rotation speed of 200 min 1 , the measurement being carried out after 10 minutes of rotation (time at which the stabilization of the viscosity and the speed of rotation of the mobile is observed).
  • the cosmetic filler may comprise at least one of hyaluronic acid from low to high molecular weight, and/or crosslinked, hydroxyapatite particles, polylactic acid, alginate, cellulose, monomethyltrisilanol orthohydroxy benzoate de sodium, polyacrylamide, a mix of hyaluronic acid and lidocaine, or a mix of hyaluronic acid and dextran microbubbles, and any mixture of the above compounds and mixes.
  • the cosmetic filler may be associated with at least one active compound or molecule or polymer to get added benefits.
  • Fig. 1 illustrates various steps of an example of a method according to the invention
  • Fig 2 is a diagrammatic view of an example of an injection system according to the invention.
  • Fig. 3 is a partial and schematic view in longitudinal section of an injection system according to an exemplary embodiment of the invention.
  • Fig. 4 is a perspective view of the device of Fig.3,
  • Fig. 5 shows in isolation a micro-implant
  • Fig. 6 shows a treatment unit comprising micro-implants according to a variant embodiment
  • Fig. 7A illustrates the ejection of the micro-implants out of the unit of Fig.6
  • Fig. 7B illustrates the injection of the micro-implants of the unit of Fig.6 in the dermis or epidermis
  • Fig. 7C shows the unit of Fig.6 after ejection of the micro-implants
  • Figs. 8 and 9 show variant embodiments of treatment units
  • Fig. 10 is a schematic and partial view of a variant embodiment of a device in accordance with the invention.
  • Figs. 11 and 12 are similar views to Fig.10 of variant embodiments,
  • Fig. 13 shows a set of treatment units
  • Fig. 14 shows a variant embodiment of a unit
  • Fig. 15 is a schematic block diagram of a variant of an injection device
  • Fig. 16 illustrates a composite micro-implant
  • Fig. 17 shows in elevation a variant embodiment of a micro-implant
  • Fig. 18 shows a variant of unit
  • Fig. 19 shows another variant of unit
  • Fig. 20 is a schematic representation of a variant of an injection device
  • Fig. 21 shows a unit comprising a column of micro-implants
  • Fig. 22 is a schematic view of a mold used for the manufacture of micro-implants according to a variant embodiment of the invention.
  • Fig. 23 illustrates the unmolding and the use of the micro-implants according to this variant embodiment.
  • FIG. 1 shows various steps of a method according to the invention.
  • the method comprises a step 200 of providing a fluid composition to make the frozen micro-implants.
  • This composition is poured or injected into at least one cavity at step 201.
  • This cavity will give its shape to the frozen micro-implant and may be needle-like, as will be detailed below.
  • composition is cooled down at step 202 to freeze and become hard.
  • composition once frozen and shaped as at least one micro-implant may be injected at step 203 into the skin, while still present in said cavity, or may be unmolded and injected separately.
  • heat may be applied to the treated area at step 204.
  • Heat may be applied after injection has taken place, but in variants heat is applied prior to injection.
  • the injection of the micro-implants may be performed with a system 10 comprising, as shown in Figure 2, at least one treatment unit 20 and an injection device 30 for acting on the unit 20.
  • the unit 20 comprises the at least one frozen micro-implant.
  • the injection device 30 comprises any appropriate mechanism 230 for exerting pressure on the micro-implants to force them into the skin. Examples of such mechanisms will be given below.
  • the injection device 30 may also comprise a cold source 231, if desired, to maintain the micro-implants at a temperature below their melting point or to slow the melting process, or in some variants, to freeze the composition of the micro-implants.
  • a cold source may be active, comprising for example one or more Peltier cells, of be passive, comprising for example a cooled mass of a material with high thermal inertia or a material with a change of state cooled at a low temperature, such a carbon dioxide ice.
  • the injection device 30 may comprise a heat source 232 to supply heat to the treated area, to help the composition of the micro-implants to melt once injected into the skin.
  • the injection device 30 may also comprise a Human Machine Interface 233 and a control unit 234 to control the various components of the injection device.
  • This control unit 234 may be based on a microcontroller or any other appropriate processing equipment.
  • the unit 20 may be introduced in the injection device 30 as will be exemplified below.
  • the injection device 30 is configured to make the frozen micro implants at the time of use so there is no longer a need to introduce a unit 20 containing the micro-implants in the injection device.
  • the injection device may comprise a reservoir of the composition used to make the micro-implants and an appropriate freezing chamber where some quantity of the composition supplied by the reservoir is injected to form at least one micro-implant by freezing the composition in this chamber, as will be detailed later.
  • the injecting system 10 shown in Figs.3 and 4 comprises a treatment unit 20 and an injection device 30 for acting on the unit 20.
  • the unit 20 comprises a core 21 and frozen micro-implants 40 housed therein.
  • One frozen micro-implant 40 is shown in Fig.5. It may comprise as shown a cylindrical portion 41 of length l P and diameter c and a conical head 42.
  • the overall length e of the micro-implant may range from 25 pm to 2000 pm.
  • the diameter c may range from 100 microns to 3mm.
  • the length of the proximal portion l P may range from 50pm to 50mm.
  • the diameter c is for example equal to 350 microns.
  • the length e is for example equal to 500 microns.
  • the length l P is for example equal to 250 microns.
  • the frozen micro-implant 40 is to be injected in its entirety in the stratum comeum, epidermis or dermis and is made of one or more materials listed above selected depending the desired action.
  • the micro-implants 40 are made of hyaluronic acid or derivatives thereof.
  • the core 21 serves as a mold for the freezing and shaping of the micro-implants 40 and serves to protect them until use.
  • Various materials may be used for the core 21 depending the way the frozen micro-implants 40 are forced out of it.
  • the material of the core 21 is selected to allow the frozen micro-implants 40 to be extracted when the impacting member of the injecting device 30 applies on their upper end 43 a force directed toward their tip 44.
  • This force is exerted in this embodiment by a corresponding rod 31 held by a plate 32 that moves in a cylindrical guide 33.
  • the plate 32 may be attached by its face opposite the rods 31 to a stem 34 that is connected to a driving mechanism (not shown) configured for moving the stem forward when the micro-implants 40 are to be forced into the skin.
  • the driving mechanism may comprise an electromechanical device such as an electrical motor or a spring.
  • the invention is not limited to a specific device for driving the rods 31 and the latter may be driven in various manners based for example on a pyrotechnic device, a pneumatic or a hydraulic device, inter alia, or manual force.
  • the core 21 may deform elastically to allow the micro-implants to leave their corresponding cavity within the core 21.
  • the core 21 may comprise portions that are perforated by the micro-implants 40 or tom or otherwise damaged.
  • the rods 31 are preferably of a cylindrical shape of same diameter as the micro implants 40 and are centered with respect to the micro-implants 40. This way the rods 31 can penetrate into the cavities to push the micro-implants.
  • Their length is preferably greater than e so that there is no need to compress the core 21 with the plate 32 to expel the micro-implants 40 out of it.
  • the end face of the rods 31 is preferably of a shape that is complementary to that of the end of the micro-implants that will be impacted by the rod.
  • the end face of the rods 31 may be flat and perpendicular to the longitudinal axis of the guide 33, as shown.
  • the proximal end 43 of the micro-implants 40 preferably has a corresponding flat surface, so that the area of contact between the rod and the micro implant is maximal. This help reduce the risk of fracturing the micro-implant when pushing it out of the mold.
  • the user places the unit 20 in a corresponding chamber of the injection device 30, and then positions the system 10 so that the unit 20 is positioned against the zone where the frozen micro-implants should be injected.
  • the user triggers the driving mechanism that causes the rods 31 to hit the frozen micro-implants and expel them out of the core 21.
  • the user may withdraw the injection system 10 and proceed to the replacement of the treatment unit with a new one.
  • the micro-implants are expelled in their entirety in the stratum comeum, epidermis or dermis, and there should not remain any non-injected portions of the micro-implants 40 trapped within the core 21.
  • the unit 20 comprises in this embodiment a core 21 defining cavities 26 having the same shape as the frozen micro-implants 40 contained therein, and protective films 28 and 29 covering respectively the proximal and distal faces of the core 21.
  • the bottom of the cavities 26 lie at a non-zero distance from the distal face of the core 21 so that the cavities are closed at their bottom end by the material of the core 21.
  • the cavities 26 are closed at their opposite end by the film 28, which contacts one end of the micro-implants 40.
  • the films 28 and 29 constitute a barrier that helps preserve sterile conditions of the frozen micro-implants 40.
  • Films 28 and 29 may remain on the core 21 when the unit is used. In a variant, the films 28 and/or 29 are removed prior the placement of the unit in the injection device.
  • the films 28 and/or 29 are present in the injection device during use thereof, the films may be perforated during the injection process.
  • the core 21 may be made of a material than can be compressed during the injection phase, that may be performed thanks to an injection device comprising as the impacting member a pressure plate 38 as shown in Fig. 7A.
  • the pressure plate 38 may have a planar surface intended to contact the film 28. The pressure is transmitted to the proximal end of the frozen micro-implants 40.
  • the film 29 may lie on the zone where the frozen micro-implants 40 are to be injected.
  • the core 21 may collapse under the pressure that is exerted by the plate 38, thus allowing the micro-implants to be pushed forward through the film 29 into the dermis or epidermis D, as shown in Fig.7B.
  • the core 21 may not restore its initial shape and thickness, as illustrated in Fig.7C.
  • the core 21 is used as a mold for the material of the micro-implant in a fluid state.
  • the films 28 and 29 may be attached to the core 21 after or before the micro-implants 40 are frozen.
  • the film 29 may be attached to the core 21 before the material serving to make the micro-implants is poured in the cavities of the core 21.
  • the film 28 may be attached to the core 21 before or after the material to make the micro-implants is frozen. If the film 28 is brought before the material has frozen, it may help the film 28 to adhere to the remainder of the unit 20.
  • a treatment unit 20 may comprise identical micro-implants 40 or micro-implants of different size and/or materials.
  • the injection device 30 may be configured for selective injection of one or more of these micro-implants, depending on various criteria such as for example the size and/or nature of the zone to treat and/or the nature of the treatment to perform.
  • the unit 20 forms a sealed package in which the micro-implants are isolated from ambient air by the material of the core and/or by a sealing membrane on the proximal side of the micro-implants.
  • the micro-implants may be in frozen state.
  • the micro-implants are in a fluid state within the unit, and are frozen before use.
  • Fig.9 shows a variant of the unit 20 comprising various sets of frozen micro implants 40a, 40b, 40c and 40d made of different materials and/or shapes. Each set may be present in a specific region of the unit, for example a specific angular sector as shown.
  • the unit may comprise frozen micro-implants of various heights and/or sizes.
  • the injection device may comprise a memory in which characteristics and locations of each micro-implant 40 of the unit 20 is stored. This information may be accessed based on an identifier of the unit. For example, the unit and or a packaging of the unit bears a barcode which is read by the injection system. Based on the read information, and/or on possible extra information inputted by the user on an HMI such as a keyboard or tactile screen for example, the injection system determines automatically which micro-implants should be expelled and injected in the skin.
  • the injection system may select automatically the micro-implants needed for injection based for example on the dose of each material to inject.
  • the injection device may comprise individual rods that may be controlled independently of the others. Rods can be of different length, diameter and shape. They can move up and down. There may be as many of these rods as there are frozen micro-implants.
  • the injection device may be configured to memorize the position of the micro-implants that have already been expelled out of the unit. In this way, the injection device can determine which rods should be actuated to expel the remaining micro-implants after each use.
  • the injection device may also contain less rods than there are frozen micro implants and the injection system is configured for allowing a displacement of the unit relative to the injection device once all the micro-implants of a given area of the unit have been expelled. This displacement may be a rotation of the unit 20 and/or of the rods 31 and plate 32, as shown in Fig.10.
  • the system may also comprise one or more actuating rods that are carried by a carriage that is mobile relative to the unit in the x and y directions.
  • the injection system 10 may comprise at least one pressure sensor and be configured to allow injection only when a threshold pressure is exceeded on the skin. This helps reduce the suppleness of the skin and improve the penetration of the micro-implants in the skin.
  • the injection system may comprise a suction part to harden the skin and to help penetration of the micro-implants. This help also to level the surface of the skin to make equal distance between skin and micro-implants
  • Fig.11 shows an injection system in which the injection device 30 is equipped with a sensor 52 represented schematically, which may be a pressure sensor.
  • This sensor provides an indication of the pressure of the injection system 10 against the skin.
  • the injection device 30 may comprise a processor controlling the driving mechanism used for moving the rods 31 or other pressure means serving to expel the frozen micro-implants 40.
  • This processor receives the signal from the pressure sensor and can trigger the injection only once a given pressure is reached.
  • the presence of a pressure sensor in the injection device may help generate the right pressure for frozen micro-implant insertion according to the skin mechanical properties.
  • the injection system 10 may also comprise an identification sensor 55 (shown schematically) to identify the unit 20 that is used. Based on this identification, the injection device may operate according to a specific program, for example.
  • Identification may be performed thanks to the presence on the unit of a specific mark, such as a barcode as mentioned above.
  • the core 21 may be made of a material that is soluble in a specific solvent, such as water for example.
  • the unit 20 may be put into contact with this solvent prior to the micro- implants being expelled.
  • the solvent may modify the rigidity of the core 21 and facilitate the deformation of the core that is necessary to allow the micro-implants to leave the core.
  • the injection may also take place in presence of a liquid selected to increase the solubility of the material of the micro-implants into the dermis or epidermis or other medium into which the micro-implants are injected.
  • This liquid L may be present above the unit 20 as shown in Fig.12.
  • the injection device 30 may first drive the micro-implants out of the core 21 and then force some liquid to follow the micro-implants into the dermis or epidermis.
  • the liquid may be cooled at a temperature close to that of the frozen micro-implant to prevent them from melting before injection takes place.
  • a plurality of units 20 having frozen micro-implants or not, may be packaged in a same cartridge 50, as shown in Fig.13.
  • a cartridge may be tube-like.
  • the injection device 30 may then be configured to extract from the cartridge one unit 20 at a time. If the micro-implants of the unit are not already in a frozen state, then the micro-implants are cooled below the freezing temperature. When a unit has been used, it is ejected from the system and a new unit is withdrawn from the cartridge.
  • the micro-implants 40 may be given various shapes, including shapes with undercuts that would prevent the micro-implants from being unmolded from the core 21.
  • Fig.14 shows a treatment unit 20 comprising frozen micro implants 40 having an arrow shape.
  • the frozen micro-implants comprise at least one cutback 60 preventing them from unmolding.
  • the injection device may be provided with a target sensor that serves to recognize a given area in order to treat it automatically.
  • the target sensor detects a wrinkle and the injection device is configured to inject the micro-implants only in the wrinkle area.
  • the injection device may recognize zones which will not be treated such like moles, birthmarks, etc...
  • the injection device may comprise as illustrated in Fig. 15 an image sensor 110 and a processor 111 (which may be the control unit 234 of Fig. 2) for automated detection of a target zone of the keratinous material and for signaling a user when the system is properly positioned relative to the target zone prior to expelling the at least one micro- implant and/or for automated triggering of the injection of the at least one micro-implant when the system is properly positioned relative to the target zone.
  • a processor 111 which may be the control unit 234 of Fig. 2
  • the injection device may comprise an interface 112 and an actuator 113 for actuating an impacting member to expel the micro-implants.
  • the interface 112 may comprise a tactile screen and/or some buttons to select operating parameters.
  • Fig. 16 illustrates the possibility for the frozen micro-implants 40 to be of composite nature, with for example a distal portion 40b made of a material with different properties, for example higher hardness than the proximal portion 40a.
  • a distal portion 40b made of a material with different properties, for example higher hardness than the proximal portion 40a.
  • the distal end of the frozen micro-implant may have various shapes. It is not necessarily conical. It may be flat, round or beveled, as shown in Fig. 17.
  • the core 21 may have an elongated shape and the units may be formed by cutting the elongated core in successive portions, as illustrated in Fig.18. By varying the spacing between the cutting lines, one may vary the length of the frozen micro-implants 40.
  • the cutting line may be oblique relative to the longitudinal axis of the core 21 so as to form beveled distal ends for the micro-implants.
  • the core 21 may be flexible and deformed to take the shape of the body portion S against which the unit is applied prior to injection of the frozen micro-implants, as shown in Fig. 19.
  • the injection device comprises an enclosure 110 that has an opening that is configured for being placed on the skin.
  • a vacuum pump creates a vacuum in the space 100 inside the enclosure which causes the skin S to deform towards the unit.
  • the intensity of the vacuum one may cause the skin to deform more or less towards the unit.
  • the vacuum may also help to homogenize skin properties prior to the injection.
  • frozen micro-implants are superimposed axially in a column and are delivered to the skin one after the other, in a succession.
  • the frozen micro-implant situated at the bottom of the column is forced into the skin thanks to pressure applied on the frozen micro-implant situated at the top.
  • the frozen micro-implants may be identical or made of different materials or have a varying concentration of an active ingredient. For example, the concentration varies from bottom to top, to take into account the need to vary the power of a treatment in time.
  • the first injection delivers micro-implants with smaller concentration, and the concentration increases progressively with the following injections. In a variant; the first injection has the strongest concentration, and then the concentration decreases with the following injections. All the micro-implants may be frozen in a single stage in the core 21. In a variant, the micro-implant are frozen one after the other, to make a pile of frozen micro-implants.
  • the composition serving to make the micro-implants is stored in a reservoir 235 of the injection device, as shown in Fig.2.
  • This reservoir may be a cartridge that is inserted into the injection device and is removed therefrom once empty.
  • the injection device comprises a shaping chamber 236 that is fed with some quantity of the composition in a liquid state.
  • the composition present in this chamber is frozen to form at least one frozen micro-implant in solid state.
  • the composition P serving to make the frozen micro-implants is poured of injected into a mold 1 provided with cavities 2 having the shape to be given to the micro-implants, as shown in Fig. 22.
  • the composition P is poured in the mold 1 and a backplate 4 is pressed against the product present at the opening of the cavities. Then the composition is frozen.
  • the frozen micro-implants 5 are unmolded, as shown in Figure 23, they remain attached to the backplate 4. They then may be used in any suitable injection device.
  • the invention applies to any target zone of keratinous materials including not only skin but also mucous membranes as lips for example, gums and scalp.

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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
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  • Biomedical Technology (AREA)
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  • Hematology (AREA)
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Abstract

L'invention concerne un procédé de préparation d'au moins un micro-implant à injecter dans des matières kératiniques humaines comprenant la congélation d'un matériau dans une forme prédéfinie adaptée à l'injection dans lesdites matières kératiniques humaines
PCT/EP2019/058096 2019-03-29 2019-03-29 Micro-implants congelés et leur procédé de fabrication Ceased WO2020200407A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023194712A1 (fr) * 2022-04-03 2023-10-12 Smith Michael Brett Patch médical

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