WO2023283203A1 - Dispositifs et utilisation de ces derniers pour diriger la dissipation d'une composition chargée après administration - Google Patents

Dispositifs et utilisation de ces derniers pour diriger la dissipation d'une composition chargée après administration Download PDF

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Publication number
WO2023283203A1
WO2023283203A1 PCT/US2022/036147 US2022036147W WO2023283203A1 WO 2023283203 A1 WO2023283203 A1 WO 2023283203A1 US 2022036147 W US2022036147 W US 2022036147W WO 2023283203 A1 WO2023283203 A1 WO 2023283203A1
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WIPO (PCT)
Prior art keywords
neurotoxin
minutes
less
electrodes
units
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PCT/US2022/036147
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English (en)
Inventor
Hal Gibson
Raymond WAGENKNECHT
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Regresar Medical Inc.
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Publication of WO2023283203A1 publication Critical patent/WO2023283203A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A61N1/303—Constructional details
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/328—Applying electric currents by contact electrodes alternating or intermittent currents for improving the appearance of the skin, e.g. facial toning or wrinkle treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes

Definitions

  • the Invention relates generally to the field of medical devices and more specifically to a device for directing the dissipation of a charged composition after injection by way of an applied electric field.
  • Eyebrow ptosis Is one of the more common complications in these cases; however, eyelid ptosis can also occur If the toxin dissipates into the levator paipebrae, This can cause not only the unwanted aesthetic of a “droopy eye” but also a decrease In the field of vision, which can lead to Injury. Also, unwanted dissipation can affect the tear glands. Neck weakness or difficulty swallowing (dysphagia) can occur as a result of injections to the jaw. Similarly, large doses of neurotoxin injected into the piatysma for the treatment of piatysma! bands and horizontal neck lines can produce weakness of the neck flexors and dysphagia and hoarseness. Further, immune response can be increased when Injected materials spread from desired treatment sites, in the case of dermal filler injections, the Injected material can spread beyond the treatment site, causing unwanted cosmetic effects, for example when treating the lip or cheeks.
  • [4] lontophoresis provides an alternative to injection, it delivers molecules across the skin barrier using a repulsive electric force.
  • traditional methods of iontophoresis do not offer the precision of injection and thus can also suffer from similar complications as injection.
  • An exemplary device Includes two electrodes spaced apart from one another on a flexible substrate so that a directional electric field can be generated between the two electrodes.
  • the flexible substrate is configured for placement against the skin of the subject and includes either a through gap positioned between the two electrodes that Is sized for permitting passage of an injection device; or a means for forming a through gap between the two electrodes that Is sized for permitting passage of an Injection device.
  • Exemplary Injection devices include syringe/needle end iontophoresis units.
  • the flexible substrate can be shaped for placement above the eyes of the subject and so that the through gap is position to permit intramuscular Injection of a charged composition at the subjects forehead,
  • the substrate may have a tearaway perforation that extends between the two electrodes.
  • the perforation can be torn to form the gap while the two electrodes remain In place or the perforation can be torn so that the two electrodes can be pulled away from one another so that the gap enlarges as the two electrodes are pulled away from each other.
  • the flexible substrate can include a tether that tethers the electrodes together.
  • a first of the two electrodes is encircled by a second of the two electrodes.
  • the two electrodes are substantially parallel to one another.
  • the two electrodes are positioned to follow different portions of the subject, such as one above the eyebrow and one below the hairline.
  • the device also Includes a power supply that supplies opposing charges to the two electrodes to power a directional electric field
  • the power supply Is provided in a separate system, where the system Includes the device(s) as set forth In this document,
  • the power supply plugs Into a power outlet or is a remote power supply.
  • the power supply Is battery powered and attached to a same flexible substrate as at least one of the two electrodes.
  • the power supply is configured for mounting to the subjects face or head, such as via a headband, mask or through use of an adhesive,
  • the device includes electrode connectors differ In shape between the two electrodes.
  • the device for the treatment of facial wrinkles.
  • the device is applied above the eyes of the subject, the subject receives an injection of a charged compound or solution through the through gap, and opposing charges are applied to the two electrodes to create the directional electric field so that the polarity encourages dissipation away from the eyes of the subject
  • the charged compound or solution includes a neurotoxin, optionally a botuiinum toxin (BoNT) selected from the group consisting of BoNT/A. BoNT/B, BoNT/C, BoNT/D, BoNT/E, BoNT/F. and BoNT/G.
  • the botuiinum toxin can include, for example, the 9G0kd BoNT/A complex, the 150kd neurotoxin component dissociated from the 900kd BoNT/A complex, or combinations thereof
  • the opposing charges are pulsed.
  • the device for the treatment of migraine Is provided.
  • the device can be positioned at a muscle selected from the group consisting of the procerus muscle, the corrugator muscle, the frontalis muscle, the occipitalis muscle, and the trapezius muscle; and the subject receives an injection of a charged compound or solution for the treatment of the migraine through the through gap.
  • exemplary compounds for use In migraine treatment include botuiinum toxin (BoNT), such as but not limited to BoNT/A, BoNT/E, and BoNT/B
  • FIGS. 1A-1 B are top and side views respectively of a non-limiting exemplary device 10 for directing dissipation of a charged composition after Injection including a substrate 12, an attractive electrode 20, a repellent electrode 30 and a through gap 40 embodied as a through bore 41 for accessing a treatment site after applying the device 10 to the skin.
  • FIGS. 1C-1 D are top and side views respectively of another non-limiting exemplary device 10 for directing dissipation of a charged composition after Injection Including a substrate 12, an attractive electrode 20, a repellent electrode 30 and a through gap 40 embodied as through slits 42 for accessing an injection site after applying the device 10 to the skin.
  • FIG. 1 E is a top view of another non-limiting exemplary device 10 for directing dissipation of a charged composition after injection including a substrate 12, an attractive electrode 20, a repellent electrode 30 and a through gap 40 for accessing a treatment site after applying the device 10 to the skin
  • a flexible tether 44 ensures the corresponding electrodes 20, 30 remain properly grouped.
  • FIGS. 3A-3B depict additional non-limiting exemplary devices 10 for directing dissipation of a charged composition after Injection for the treatment of glabellar lines, Including a substrate 12 with perforation 16, an attractive electrode 20, a repellent electrode 30.
  • FIG. 4 depicts a non-limiting system 100 for directing dissipation of a charged composition after Injection including an attractive electrode 20, a repellent electrode 30 and a power supply 72 configured as an EMS unit 70.
  • FIG. 5 depicts a non-limiting exemplary electrode configuration for use when directing dissipation of a charged composition after injection for the treatment of both frown or glabellar lines and crow’s feet.
  • FIG. 6 depicts a non-limiting exemplary electrode configuration for use when directing dissipation of a charged composition after Injection for the treatment both of forehead lines and crow’s feet.
  • FIG. 7A depicts attractive and repellent electrodes applied to a subject’s face prior to administration of botulinum treatment.
  • FIG. 8 depicts a starch test showing the results of a botulinum treatment administered between the two electrodes of FIG. 7 approximately two days after treatment.
  • the attracting electrode was placed above the repeilant electrode.
  • the white areas indicate the presence of botulinum toxin by the toxin’s ability to reduce perspiration, whereas the dark areas indicate the absence of toxin by the presence of perspiration. Lateral spreading between the injection sites is also observed.
  • FIG. 9 depicts a single substrate having an attractive electrode, a repellent electrode and a through gap between the two electrodes.
  • FIG. 10 depicts results of starch tests achieved using the electrode configuration of FIG. 9 approximately two days after injection of botuiinum toxin. The white areas show where the toxin has reduced perspiration, and the dark areas indicate normal perspiration after exercise.
  • Subject 1 left; low power electrodes were used on right side of the face (left side of image). The test injection shows better spreading in the treatment area as well as migrating “up” toward the attractive electrode as compared to the negative control (no electrodes) injected in the same horizontal plane.
  • Subject 2 (right); medium power electrodes used on left side of the face (right side of image). The test injection shows better spreading as well as migrating “down” toward the attractive electrode as compared to the negative control (no electrodes) Injected in the same horizontal plane (the electrodes were reversed on the two subjects).
  • FIG. 11 shows follow up starch test results from Subject 1 (left) and Subject 2 (right) approximately 20 weeks after the study conducted with the electrode configuration of FIG. 9 confirming the localized toxin remained in its targeted position.
  • FIG. 12 depicts an exemplary device embodied as a headband.
  • FIG. 13 is an underside of a portion of the headband shown in FIG. 12 depicting repeilant electrodes 30.
  • FIG. 14 is a table of botuiinum toxins that can be administered in the disclosed methods.
  • Described herein are devices and methods for directing dissipation of charged compositions after administration to a subject that not only improve the safety of procedures involving the administration of compositions such as neurotoxins but also improve spreading of the composition at the intended treatment area, thereby improving the quality, uniformity and longevity of the procedure.
  • the devices and methods are particularly useful to help prevent unwanted complications influenced by patient anatomy or when an understanding of the anatomy at the Injection site or treatment site is limited, such as the complex nature of the skin and facial muscles around the eyes across different subjects.
  • the devices and methods are also useful In Instances where there Is a risk of Improper Injection technique, such as by newly trained personnel or In Instances where injections are difficult to properly administer.
  • the devices and methods can also Improve the quality of treatment and patient experience by creating more uniformity In therapeutic delivery over the treatment area.
  • the devices and methods can direct dissipation of the neurotoxin to more thoroughly “fill the gap” between and around injection sites, thereby reducing the number of injections needed for each treatment area,
  • the device operates using an adjustable but low power charge that does not cause patient discomfort and in fact, during testing was found to present less discomfort than the preceding administration of the composition itself.
  • the adjustability of the power permits the device to be used across different subjects that may have different skin thicknesses, tensile strength, and sensitivities at the same or different areas of the body.
  • administer means the step of giving (l.e. administering) a material such as a pharmaceutical composition or active Ingredient or dermal filler to a subject.
  • a material such as a pharmaceutical composition or active Ingredient or dermal filler to a subject.
  • the materials disclosed herein can be administered via a number of appropriate routes, however as described
  • the compositions are locally administered by e.g. Intramuscular, intradermal, or subcutaneous routes of administration, such as by Injection, topically, or use of an implant.
  • Nonlimiting examples include syringe/needle Injection and iontophoresis.
  • Attractive electrode means an electrode to which an attractive charge is applied in relation to the administered composition or component thereof (e g. after dissociation at physiological pH). That is, an electrode with a positive charge or polarity would be an “attractive electrode” when used to direct dissipation of a composition or a component thereof having a net negative charge after administration,
  • Attractive charge means a charge that attracts the Injected composition, a component of the Injected composition (e g. after dissociation from a complex at physiological pH), or a component of the injected material (e.g. charged Ingredient)
  • An example Is the 150kd neurotoxin component of the BoNT/A molecule, for example by use of an electric charge.
  • An “attractive charge” has an opposite charge or polarity compared to the composition or component that Is to be attracted.
  • Botulinum toxin or "botu!inum neurotoxin” means a wild type neurotoxin derived from Clostridium botuiinum, as well as modified, recombinant, hybrid and chimeric botuiinum toxins.
  • a recombinant botuiinum toxin can have the light chain and/or the heavy chain thereof made recombinant!y by a non-Clostridia! species,
  • Botulinum toxin encompasses the botuiinum toxin serotypes A, B, C, D, E, F, G and H.
  • Botuiinum toxin also encompasses both a botuiinum toxin complex (i.e, the 300, 600 and 900 kDa BoNT/A complexes) as well as pure botuiinum toxin (I.e. the 150 kDa BoNT/A neurotoxic molecule), all of which are useful in the practice of the embodiments of the present disclosure.
  • a botuiinum toxin complex i.e, the 300, 600 and 900 kDa BoNT/A complexes
  • pure botuiinum toxin I.e. the 150 kDa BoNT/A neurotoxic molecule
  • Clostridial neurotoxin means a neurotoxin produced from, or native to, a Clostridia! bacterium, such as Clostridium botuiinum, Clostridium butyricum or Clostridium beratti, as well as a Clostridial neurotoxin made recombinant!y by a non- Clostridia! species
  • “Dermal filler” means compositions used for aesthetic treatments that are injected into or below the skin Typically, they are designed to effectively reduce the appearance of unwanted wrinkles, contour and create volume, and to revitalize the skin. Suitable fillers can Include hyaluronic acid, polyalkyiimide, polylactic acid, Polymethyl-methacrylate microspheres (PMMA), and the like.
  • Electrode means an electrically conductive material that applies a charge to the subject to effect treatment.
  • An “electrode” can be provided In any suitable pattern.
  • Injection site means the site where the Injection or Iontophoresis occurs.
  • “Flexible substrate” means the substrate can bend to follow the contour of the body or tissue where applied.
  • “Limiting” the dissipation of an administered material means that the composition, a component of the composition (e.g, after dissociation of a complex), or a different component of the Injected material Is limited In Its dissipation away from the Intended treatment site so that the total area affected by the administered material Is less than the total area would be In the absence of the limiting action,
  • “Localizing” as used herein means directing, increasing, or minimizing the dissipation of an administered material
  • Intermediate-acting refers to a botulinum toxin that produces effects more slowly that a fast-acting toxin such as BoNT/E.
  • Neuron means a biologically active molecule with a specific affinity for a neuronal ceil surface receptor. “Neurotoxin” Includes Clostridial toxins both as pure toxin and as complexed with one or more non-toxin, toxin-associated proteins, for example HN-33.
  • Patient or “subject” means a human or non-human mammal receiving medical or veterinary care.
  • “Pharmaceutical composition” means a formulation that includes an active Ingredient (e.g, neurotoxin)
  • a “pharmaceutical composition” can be a dermal filler.
  • the word “formulation” means that there is at least one additional Ingredient, such as a pharmaceutically acceptable carrier or stabilizer to assist with delivery, (such as, for example and not limited to, an albumin (such as a human serum albumin or a recombinant human albumin) and/or sodium chloride)
  • a pharmaceutically acceptable carrier or stabilizer to assist with delivery such as, for example and not limited to, an albumin (such as a human serum albumin or a recombinant human albumin) and/or sodium chloride)
  • a pharmaceutical composition Is therefore a formulation which is suitable for diagnostic, therapeutic or cosmetic administration to a subject, such as a human patient.
  • the pharmaceutical composition can be in a lyophilized or vacuum dried condition, a solution formed after reconstitution of the iyophifized or vacuum dried pharmaceutical composition with saline or water, for example, or as a solution that does not require reconstitution.
  • a pharmaceutical composition can be liquid, semi-solid, or solid.
  • a pharmaceutical composition can be animal-protein free,
  • “Pharmaceutically acceptable carrier” refers to a substance that serves as a vehicle for improving the efficiency of delivery that is compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof,
  • “Purified botuiinum toxin” means a pure botuiinum toxin or a botuiinum toxin complex that is Isolated, or substantially Isolated, from other proteins and impurities which can accompany the botuiinum toxin as it is obtained from a culture or fermentation process.
  • a purified botuiinum toxin can have at least 95%, and more preferably at least 99% of the non-botu!inum toxin proteins and impurities removed,
  • repellent electrode means an electrode to which a repellent charge is applied In relation to the composition, component of the composition, or component of the administered material for dissipation. That is, an electrode with a positive charge or polarity would be a repeliant electrode when used to direct dissipation of a composition having a net positive charge at physiological pH.
  • repelent charge means a charge that repels the administered composition, component of the composition or component of the administered material, for example by way of a magnetic or electric charge.
  • a “repeliant charge” has a same charge or polarity as the composition, component of the composition or component of the material that Is to be repelled
  • Subcutaneous administration as used herein comprises administration below the skin, which Is intended to also Include Intramuscular administration.
  • Substantiai!y free means present at a ievei of iess than one percent by weight of a pharmaceutical composition or other material in which the weight percent of a substance is assessed.
  • Therapeutic formulation means a formulation that can be used to treat and thereby a!ieviate a disorder or a disease and/or symptom associated thereof, such as a disorder or a disease characterized by an activity of a peripheral muscle or nerve,
  • Therapeutically effective amount means the level, amount or concentration of an agent (e g. such as a botuiinum toxin or pharmaceutical composition comprising botu!inum toxin) needed to elicit a biological or medical response that Is being sought.
  • an agent e g. such as a botuiinum toxin or pharmaceutical composition comprising botu!inum toxin
  • a “therapeutically effective amount” of charge or voltage Is that which is sufficient to Influence the position of the administered composition, component of the composition, or component of the administered material.
  • a “therapeutically effective amount” will treat a disease, disorder or condition without causing significant negative or adverse side effects
  • Toxin-na ' ive means a patient to whom a neurotoxin has not been administered, for example a Clostridial toxin, for example BoNT/A.
  • Treatment means an alleviation or a reduction (which Includes some reduction, a significant reduction a near total reduction, and a total reduction), resolution or prevention (temporarily or permanently) of a disease, disorder or condition, so as to achieve a desired therapeutic or cosmetic result, such as by healing of injured or damaged tissue, or by altering, changing, enhancing, improving, ameliorating and/or beautifying an existing or perceived disease, disorder or condition.
  • Treatment site or “Treatment area” means the region of the body that Is to be treated by the composition.
  • the device directs dissipation to or within the “treatment area.”
  • Unit or “U” means an amount of active agent (e.g. BoNT) standardized to have equivalent neuromuscular blocking effect as a Unit of commercially available agent (e.g, BoNT/A).
  • active agent e.g. BoNT
  • BoNT/A a unit of commercially available agent
  • the systems, devices and methods are used to direct dissipation an administered neurotoxin away from an area where the dissipation of the neurotoxin is not desired, such as an area that can cause a complication (e.g. eyebrow ptosis/eyelid ptosis), in other embodiments, the systems, devices and methods are used to direct dissipation of an administered neurotoxin towards an intended treatment area (e.g. skin wrinkles). In still other embodiments, the systems, devices and methods are used to direct dissipation of an administered neurotoxin both away from a region where the presence of the neurotoxin is not desired and towards an intended treatment area.
  • an intended treatment area e.g. skin wrinkles
  • neurotoxins that carry a charge at physiological pH and which are used in treatments such as cosmetic procedures and in the treatment of migraine.
  • the 9G0kd complex of BoNT/A has a published isoelectric point of roughly 9.2.
  • BoNT/A carries a net positive charge.
  • Our studies demonstrate that by applying a negative source charge to the skin, BoNT/A can be selectively dissipated toward a desired treatment site.
  • a positive source charge to the skin at a second location, for example around part or all of the perimeter of a treatment site, we were able to repel BoNT/A away from that second location.
  • applying a directional field that has both positive and negative sources we successfully migrated the charged composition to the desired treatment area and prevented migration in areas where the presence of BoNT/A was not desired.
  • Type E (BoNT/E) has a published isoelectric point of about 6; therefore, at physiological pH values the toxin carries a net negative charge, and the “opposite” approach to that used with BoNT/A is appropriate, though conformational aspects of an administered material can affect its predicted isoelectric point, and thus idea! placement and strength of the forces applied can vary.
  • the isoelectric point of the 150kd neurotoxin component of BoNT/E has a published isoelectric point of roughly 6. Thus, at physiological pH values, the 150kd neurotoxin component of BoNT/E carries a net negative charge.
  • the 150kd toxin by applying a positive source charge to or around or near a location, for example a desired treatment or injection site, the 150kd toxin can be “fixed” in or dissipation can be attracted to that location.
  • a negative source charge to a second location, for example around part or all of the perimeter of a treatment site, the 15Qkd toxin can be repelled or dissipated away from that second location.
  • One implication of the demonstrated ability to direct the dissipation of neurotoxins is that the systems, devices and methods can reduce the risk of unwanted effects or complications that can occur as a result of administration of the composition. For example, by directing the dissipation of botulinum toxins away from the eyes during cosmetic procedures, the incidence of brow ptosis, eyelid ptosis and other complications can be reduced, in addition, directing the dissipation of compounds to smaller treatment sites can reduce an adverse “immunogenic footprint”.
  • botulinum toxins are typically injected intramuscularly and bind rapidly. Without being bound by theory it is believed that not all of the material is bound immediately, and this materia! can dissipate from a treatment site to surrounding tissue, thereby increasing the odds of triggering an immunogenic reaction in the patient. It is believed the this component is highly affected by the devices and methods disclosed herein.
  • Directing the dissipation of administered materials can also increase the effect duration of administered materials themselves, for example the effect duration of a neurotoxin injection, or the effect duration of a dermal filler injection, thereby increasing the time duration before treatment is repeated.
  • Directing the dissipation of materials can also increase the effect intensity of injected materials, for example the effect intensity of a neurotoxin injection, or the effect intensity of a derma! filler injection.
  • Directing the dissipation of materials can also accelerate the uptake of injected materials, for example the uptake of a neurotoxin injection, by increasing the effective concentration of the material, increased uptake can also be achieved by repeated contraction of a muscle in a treatment area to increase uptake while localization goals are achieved.
  • “77] Directing the dissipation of the injected materials can equilibrate the spread of the materials over a desired treatment area, thus decreasing the amount of toxin required to achieve a desired effect.
  • “baby BOTOX” refers to an administration technique that utilizes minimal toxin amounts injected into a number of sites and is often used as a preventative measure among younger patients.
  • disclosed embodiments can be used to direct dissipation throughout a treatment area such as the forehead to achieve a more equal distribution of the toxin while minimizing the number of injections required.
  • the systems, devices and methods can direct the dissipation of any charged composition, component of a composition, or component of an injected material that is positioned and able to move underneath the skin, such as at least up to a depth of few millimeters or so beneath the dermal layer.
  • the suitability of a composition or component for dissipation can be assessed by its charge at physiological pH or measuring it’s isoelectric point using techniques known in the art to which the invention belongs.
  • Disclosed embodiments include systems and devices for directing, localizing, increasing, or minimizing the dissipation of charged compositions after administration, for example injected or iontophoresed pharmaceutical compositions.
  • the systems and devices increase the spread or dissipation of administered materials, for example injected pharmaceutical compositions.
  • the systems and devices decrease the spread or dissipation of administered materials.
  • the systems and devices operate by applying an energy field, for example an electromagnetic field (EMF) such as an electric field, an electric charge, an electric current, a magnetic field, or combinations thereof, to the outer skin, which directs dissipation of charged compositions.
  • EMF electromagnetic field
  • dissipation can be directed for charged compositions including, for example, biologies, analgesics, anesthetics, neurotoxins, proteins, DNA, viruses, dermal fillers, and the like,
  • an exemplary device 10 Includes a flexible substrate 12, to which Is applied two electrodes 20, 30 spaced apart from one another.
  • One electrode 20, 30 Is designated an attractive electrode 20 and the other a repel!ant electrode 30,
  • the flexible substrate 12 Is configured for placement against the skin of the subject where the electric charge or field Is to be applied and preferably does not pierce the skin. This electric charge acts on charged compositions to direct their dissipation towards the attractive electrode 20 and away from the repei!ant electrode 30.
  • the electric charge is applied to the administered composition by a flexible substrate 12 having at least two electrode 20, 30 of opposite charge or polarity secured to but preferably not penetrating the skin.
  • the substrate 12 can be formed from any suitable material having sufficiently flexibility for maintaining contact against the skin of the subject during operation and Is preferably not electrically conductive so that the applied charge can be delivered solely through the electrodes 20, 30.
  • the substrate 12 can be formed from, a textile, fabric, polymer, or foam material to which the electrodes 20, 30 can be applied, such as by gluing electrically conductive wire or fiber. Electrodes 20, 30 can be sandwiched between substrate 12 layers, where a lower layer Is preferably perforated to form a plurality of ports through which electric charge can traverse,
  • the device 10 is configured as a patch having an attractive electrode 20, a repellent electrode 30 extending at least partially around the perimeter of the attractive electrode 20, and a gap 40 In the form of a through bore 41 , or port Inside the attractive electrode 20 to allow for administration of a composition via iontophoresis or injection.
  • this configuration can be applied before or after administration of a compound and would tend to direct dissipation so that the charged composition or components are “fenced In” or kept within the perimeter established by the repeilant electrode 30,
  • FIGS, 1C and I D also depict a device 10 configured as a patch but having the attractive electrode 20 extending at least partially around the perimeter of the repeilant electrode 30, and a gap 40 in the form of a through slits 42 positioned between the attractive electrode 20 and the repeilant electrode 30 to allow for administration of a composition via Iontophoresis or Injection, As such, this configuration can be applied before or after administration of a compound and would tend to direct dissipation so that the charged composition or components are dissipated outward towards the the attractive electrode 20 and away from the repeilant electrode 30.
  • FIGS. 1 E-2F provide different configurations where the device 10 has attractive electrodes 20 and repeilant electrodes 30 substantially parallel to one another, and a gap 40 positioned between the attractive electrode 20 and the repeilant electrode 30 to allow for administration of a composition via iontophoresis or Injection before or after applying the device 10,
  • FIGS, 2A-2F provide a variation where attractive electrodes 20 and repellent electrodes 30 are tethered 44 to one another, thereby allowing electrodes 20, 30 to be spaced apart at variable distances for optimum effect and injection therebetween.
  • the flexible substrate 12 is perforated 16 between the two electrodes 20, 30, thereby permitting the two electrodes 20, 30 to be pulled away from one another at the one end by tearing along the perforation 16.
  • the substrate 12 Is depicted In an arced embodiment Intended to follow a path from a bridge of the nose and along the eyebrow.
  • the flexibility of the substrate 12 permits the repeilant electrode 30 to be placed close to the eyebrow to repel a charged composition away from the eyebrow and after torn along the perforation, the attractive electrode 20 can be placed higher on the subjects forehead (see also FIG. 5 and FIG. 6).
  • This configuration Is useful for the prevention of ptosis and Is adjustable across a variety of patients.
  • the substrate 12 is at least 0.5, 1.0, or 1.5 inches in length but is usually shorter than 4 inches so.
  • the electrodes can be applied using an adhesive to maintain their position substantially as shown in FIG. 7 and 9.
  • the substrate 12 is secured to the skin using a hydrogel as known the the art to which the invention belongs.
  • the substrate 12 can be integrated into a headband.
  • An example of a headband configuration is shown in FIG. 12.
  • the substrate 12 forms part of a mask or a wrap that at least partially presses against the subject during treatment.
  • the electrodes 20, 30 are exposed on the underside of the substrate 12.
  • the electrodes 20, 30 can be attached, for example reversibly, to a strap, mask, or headband to help maintain their position on the body.
  • a disclosed strap or headband comprises elastic or another stretchable material to secure the eiectrode(s) to the treatment area, for example around the head.
  • Embodiments can comprise multiple straps, masks, or headbands, for example one strap, mask, or headband securing the attractive electrode 20 and another strap, mask, or headband securing the repellent electrode 30,
  • Disclosed electrodes 20, 30 can include “snaps" or other connectors to reversibly attach the electrodes 20, 30 to a battery 50 or to a wire connected to the power supply 72.
  • the electrodes comprise Integral batteries
  • the device 10 comprises electrode connectors that differ In shape between the two electrodes 20, 30
  • disclosed systems comprise lead connection points or electrode power connection points (collectively, “connectors”) that are non-generic.
  • a lead that connects the power supply 50 or controller to the electrode 20 comprising the attractive charge comprises a connector that enables connection of the lead to the attractive charge source or electrode 20, and not the repellent charge source or electrode 30, and vice versa.
  • leads can comprise mechanical shapes that differ in shape and render connection possible with only one of the attractive or repellent charge sources or electrodes 20, 30. In embodiments, such different shapes can comprise square shapes, round shapes, triangular shapes, and combinations thereof.
  • the electrodes 20, 30 can be reversibly attached to the strap, mask, or headband.
  • the strap, mask, or headband can comprise holes or void regions, so as to provide a “pass-through” for connecting a power supply 20 to the electrodes 20, 30.
  • Further embodiments comprise devices 10 that require a power supply 72, for example a power supply 72 (or battery 50) connected to electrodes 20, 30 such that one or more electrodes 20, 30 produces a negative electric charge, and one or more electrodes 20, 30 produces a positive electric charge.
  • Substrates 12 suitable for use with disclosed embodiments can comprise resorbable materials.
  • Substrates 12 suitable for use with disclosed embodiments can comprise clear or opaque materials.
  • the power supply 72 comprises an energy source suitable for use with the body.
  • a direct current (DC) energy source can comprise pulsed DC.
  • the power supply comprises a controller, for example to adjust power supply parameters such as Intensity, duration, and the like.
  • a display for example an LCD dlspiay or the like, to reflect power supply parameters such as Intensity, duration, and the like.
  • the power supply 72 and controller can be Bluetooth enabled to transmit data, such as power supply 72 parameters such as intensity, duration, and the like, to an additional device such as a smartphone.
  • the power supply 72 or battery 50 is connected to the electrodes 20, 30via a wired connection.
  • Embodiments can also comprise integrated electrode systems wherein at least two electrodes 20, 30 are embedded into a substrate 12 that covers the entire treatment area.
  • a disclosed embodiment Includes a flexible substrate that fits against a patient’s head or a portion thereof, with the attractive and repellent electrodes 20, 30 placed to effectively apply a directional electric field across a treatment area, such as the forehead (see FIG. 9), the side of the head, the jaw, etc
  • the substrate 12 can comprise an injection “template”, with gaps 40, slits 42, or through bores 41 in the substrate where injections are to be made.
  • substrates 12 for positioning template electrodes 20, 30 can comprise voids, slots, or holes In locations typically used for neurotoxin injections, such as between the eyebrows for glabellar line treatments, or along the hairline for a forehead treatment
  • Such template embodiments can further comprise color coding and Instructions for use.
  • the flexible substrate 12 is clear or transparent, such that the electrodes 20, 30 are visible through the substrate 12, thus providing visual confirmation of exact electrode 20, 30 placement or compound Injection when applied to a patient.
  • an electric field can comprise voltages suitable for application to the mammal.
  • a suitable electric field can comprise voltages appropriate for non-lethal application to the body of a mammal, for example a human.
  • the voltage can comprise sub-muscle contraction levels.
  • the voltage can comprise levels that cause muscle contraction. For example, in embodiments that both localize administered materials as well as Increase their uptake, muscle contraction can be beneficial.
  • Disclosed embodiments comprise “active” devices that utilize a power source such as AC or DC power, or pulsed RF or pulsed current, such as high voltage pulsed current or pulsed DC, or “passive” devices that do not require external power.
  • a power source such as AC or DC power, or pulsed RF or pulsed current, such as high voltage pulsed current or pulsed DC, or “passive” devices that do not require external power.
  • the electrical energy can be derived from dissimilar metals creating a battery, for example wherein the dissimilar metals are located on a separate dressing or bandage, whereas those embodiments with an external power source can require conductive electrodes in a spaced-apart configuration to predetermine the electric field shape and strength, in active devices, DC current can be used.
  • electrodes 20, 30 can be powered by battery 50.
  • FIG. 2A and 2D depict configurations where a battery 50 is electrically connected to electrodes 20, 30 via lead 52. in such embodiments, battery 50 may be adhesively applied remote from the treatment site.
  • battery 50 is attached to the substrate 12 and powers electrodes 20, 30.
  • FIG. 2C and 2F battery 50 is electrically connected to regulator 60 for regulating output to electrodes 20, 30. Configurations including regulator 60 may be desired when a same device 10 is configured for two or more different treatments or treatment locations utilizing different charge or voltage.
  • FIG. 4 Another embodiment is depicted in FIG. 4, where the electrodes 20, 30 are configured for connection to a EMS device 70, or a similar power supply 72 that can provide an appropriate charge or voltage to the skin.
  • Embodiments disclosed herein comprise bioelectric devices that comprise electrodes 20, 30.
  • Such devices can include an electrode 20, 30 formed from a first conductive material, the material including a metal species; and a second electrode 20, 30 formed from a second conductive material, the material including a metal species capable of defining at least one voltaic cell for spontaneously generating at least one electrical current with the metal species of the first electrode 20, 30 when the first, and second electrodes 20, 30 are connected via a conductive solution such as that within the body, and the first and second electrodes 20, 30 are not in physical contact with each other.
  • Certain embodiments utilize an external power source such as AC or DC power or pulsed RF or pulsed current, such as high voltage pulsed current or pulsed AC or DC
  • the attractive/repellent electric charge, field, or current are applied around, to, or about the treatment site.
  • electrodes 20, 30 are powered by, for example between 1 and 60V and applied about 1-3 cm apart, with the attractive electrode 20 applied upon or near the treatment site and the repellent electrode 30 applied to form a partial or complete perimeter around the treatment site so as to deter dissipation from the treatment site.
  • the distance between the attractive and repellent electrodes 20, 30 can be determined based on the voltage applied to affect the most beneficial treatment.
  • the attractive and repellent electrodes 20, 30 can be applied 1mm apart, 2mm apart, 3mm apart, 4mm apart, 5mm apart, 6mm apart, 7mm apart, 8mm apart, 9mm apart, 10mm apart, 11 mm apart, 12mm apart, 13mm apart, 14mm apart, 15mm apart, 16mm apart, 17mm apart, 18mm apart, 19mm apart, 2cm apart, 2.5cm apart, 3cm apart, 3.5cm apart, 4cm apart, 4.5cm apart, 5cm apart, 5.5cm apart, 6cm apart, 6.5cm apart, 7cm apart, 7.5cm apart, 8cm apart, 8.5cm apart, 9cm apart, 10cm apart, 10.5cm apart, 11cm apart, 11.5cm apart, 12cm apart, 12.5cm apart, 13cm apart, 13.5cm apart, 14cm apart, 14.5cm apart, 15cm apart, 15.5cm apart, 16cm apart, 16.5cm apart, 17cm apart, 19mm
  • 20, 30 can be, for example, at least 1mm apart, at least 2mm apart, at least 3mm apart, at least 4mm apart, at least 5mm apart, at least 6mm apart, at least 7mm apart, at least 8mm apart, at least 9mm apart, at least 10mm apart, at least 11 mm apart, at least 12mm apart, at least 13mm apart, at least 14mm apart, at least 15mm apart, at least 16mm apart, at least 17mm apart, at least 18mm apart, at least 19mm apart, at least 2cm apart, at least 2,5cm apart, at least 3cm apart, at least 3.5cm apart, at least 4cm apart, at least 4.5cm apart, at least 5cm apart, at least 5.5cm apart, at least 6cm apart, at least 6.5cm apart, at least 7cm apart, at least 7.5cm apart, at least 8cm apart, at least 8.5cm apart, at least 9cm apart, at least 10cm apart, at least 10.5cm apart, at least 11c
  • the distance between the attractive and repellent electrodes 20, 30 can be, for example, not more than 1mm apart, not more than 2mm apart, not more than 3mm apart, not more than 4mm apart, not more than 5mm apart, not more than 6mm apart, not more than 7mm apart, not more than 8mm apart, not more than 9mm apart, not more than 10mm apart, not more than 11 mm apart, not more than 12mm apart, not more than 13mm apart, not more than 14mm apart, not more than 15mm apart, not more than 16mm apart, not more than 17mm apart, not more than 18mm apart, not more than 19mm apart, not more than 2cm apart, not more than 2.5cm apart, not more than 3cm apart, not more than 3.5cm apart, not more than 4cm apart, not more than 4,5cm apart, not more than 5cm apart, not more than 5.5cm apart, not more than 6cm apart, not more than 6,5cm apart, not more than 7cm apart, at not more than
  • the distance between the attractive and repellent electrodes 20, 30 can be, for example, between 1 and 20mm, between 2 and 18mm, between 4 and 16mm, between 6 and 14mm, between 8 and 12mm, or the like, in embodiments, the distance between the attractive and repellent electrodes 20, 30 can be, for example, between 1 and 10mm, between 1 and 9mm, between 1 and 8mm, between 1 and 7mm, between 1 and 6mm, between 1 and 5mm, between 1 and 4mm, between 1 and 3mm, between 1 and 2mm, or the like, in embodiments, the distance between the attractive and repellent electrodes 20, 30 can be, for example, between 2 and 10mm, between 2 and 9mm, between 2 and 8mm, between 2 and 7mm, between 2 and 6mm 2 and 5mm, between 2 and 4mm, between 2 and 3mm, or the like,
  • the distance between the attractive and repellent electrodes 20, 30 can be, for example, between at least 1 and 20mm, at least 2 and 18mm, at least 4 and 16mm, at least 6 and 14mm, at least 8 and 12mm, or the like, in embodiments, the distance between the attractive and repellent electrodes can be, for example, between at least 1 and 10mm, at least 1 and 9mm, at least 1 and 8mm, at least 1 and 7mm, at least 1 and 6mm, at least 1 and 5mm, at least 1 and 4mm, at least 1 and 3mm, at least 1 and 2mm, or the like.
  • the distance between the attractive and repellent electrodes can be, for example, between at least 2 and 10mm, at least 2 and 9mm, at least 2 and 8mm, at least 2 and 7mm, at least 2 and 6mm, at least 2 and 5mm, at least 2 and 4mm, at least 2 and 3mm, or the like,
  • the distance between the attractive and repellent electrodes 20, 30 can be, for example, between not more than 1 and 20mm, not more than 2 and 18mm, not more than 4 and 16mm, not more than 6 and 14mm, not more than 8 and 12mm, or the like, in embodiments, the distance between the attractive and repellent electrodes 20, 30 can be, for example, between not more than 1 and 10mm, not more than 1 and 9mm, not more than 1 and 8mm, not more than 1 and 7mm, not more than 1 and 6mm, not more than 1 and 5mm, not more than 1 and 4mm, not more than 1 and 3mm, not more than 1 and 2mm, or the like, in embodiments, the distance between the attractive and repellent electrodes 20, 30 can be, for example, between not more than 2 and 10mm, not more than 2 and 9mm, not more than 2 and 8mm, not more than 2 and 7mm, not more than 2 and 6mm, not more than 2 and 5mm, not more than 2 and 4mm, not more than 2 and 3mm
  • disclosed devices 10 can comprise a circular or “donuf shaped device 10 (including a gap 40 or through bore 41 in the center) comprising an outer electrode 30 producing a repellent field, for example an electric field.
  • disclosed devices 10 can comprise an electrode 30 producing a repellent electric field that can be applied with the void or through bore 40 directly over the treatment site and the primary substrate 12 of the device 10 surrounding the treatment site. This type of embodiment can be particularly suitable for use with treatments where no spread of the injected material is desired.
  • disclosed devices 10 can be applied prior to the injections, then the injection is made through the void, through bore 40 or through slit 42 region.
  • disclosed devices 10 can comprise a circular or “donut” shaped device 10 comprising an electrode 30 producing a repellent field, for example an electric field, around the perimeter, while an electrode 20 producing an attractive field is in the center (See. FIG. 1A).
  • This type of embodiment can be particularly suitable for use with treatments where no spread of the injected material is desired.
  • the devices 10 can also be configured as elongated strips. Such configurations may be more preferred when a generally linear, repellent border is desired such as above the eyes during glabellar line treatment or during treatment of forehead lines.
  • a disclosed embodiment comprises linear electrodes 20, 30 placed above the eyebrows and below the hairline, for example to repel dissipation toward the eyes while increasing spread of the injected material throughout the forehead (see FIGS. 5-6).
  • the difference of the standard potentials of the electrodes 20, 30 providing attractive and repellent fields can be in a range from about 0.05 V to approximately about 10.0 V.
  • the standard potential can be about 0.05 V, about 0.06 V, about 0.07 V, about 0.08 V, about 0.09 V, about 0.1 V, about 0,2 V, about 0.3 V, about 0,4 V, about 0.5 V, about 0.6 V, about 0,7 V, about
  • the electric field between the constitutionale and repei!ent electrodes 20, 30 can be, for example, 20 volt/cm, 19 volt/cm, 18 volt/cm, 17 volt/cm, 16 volt/cm, 15 volt/cm, 14 volt/cm, 13 volt/cm, 12 volt/cm, 11 volt/cm, 10 volt/cm, 9 volt/cm, 8 volt/cm, 7 volt/cm, 6 volt/cm, 5 volt/cm, 4 volt/cm, 3 volt/cm, 2 volt/cm, 1 volt/cm, or the like.
  • the eiectric field between the attractive and repellent eiectrodes 20, 30 can be, for example, between 20 volt/cm and 1 v/cm, between 19 volt/cm and 2 v/cm, between 18 volt/cm and 3 v/cm, between 17 volt/cm and 4 v/cm, between 16 volt/cm and 5 v/cm, between 15 volt/cm and 6 v/cm, between 14 volt/cm and 7 v/cm, between 13 volt/cm and 8 v/cm, between 12 volt/cm and 9 v/cm, between 11 volt/cm and 10 v/cm, or the iike.
  • the eiectric fieid between the attractive and repeiient eiectrodes 20, 30 can be, for exam pie, no more than 20 volt/cm, no more than 19 volt/cm, no more than 18 volt/cm, no more than 17 volt/cm, no more than 16 volt/cm, no more than 15 volt/cm, no more than 14 volt/cm, no more than 13 volt/cm, no more than 12 volt/cm, no more than 11 volt/cm, no more than 10 volt/cm, no more than 9 volt/cm, no more than 8 volt/cm, no more than 7 volt/cm, no more than 6 volt/cm, no more than 5 volt/cm, no more than 4 volt/cm, no more than 3 volt/crn, no more than 2 volt/cm, no more than 1 volt/cm, or the like,
  • the electric field between the attractive and repellent electrodes 20, 30 can be, for example, no less than 20 volt/em, no less than 19 volt/cm, no less than 18 volt/cm, no less than 17 volt/cm, no less than 16 volt/cm, no less than 15 volt/cm, no less than 14 volt/cm, no less than 13 volt/cm, no less than 12 volt/cm, no less than 11 volt/cm, no less than 10 volt/cm, no less than 9 volt/cm, no less than 8 volt/cm, no less than 7 volt/cm, no less than 6 volt/cm, no less than 5 volt/cm, no less than 4 volt/cm, no less than 3 volt/cm, no less than 2 volt/cm, no less than 1 volt/cm, or the like,
  • Embodiments can comprise an electric current between the attractive and repellent electrodes 20, 30.
  • systems and devices disclosed herein can produce a low level electric current between the attractive and repellent electrodes 20, 30 of between for example about 1 and about 200 micro-amperes, between about 10 and about 190 micro-amperes, between about 20 and about 180 micro-amperes, between about 30 and about 170 micro-amperes, between about 40 and about 160 micro amperes, between about 50 and about 150 micro-amperes, between about 60 and about 140 micro-amperes, between about 70 and about 130 micro-amperes, between about 80 and about 120 micro-amperes, between about 90 and about 100 micro-amperes, between about 100 and about 150 micro-amperes, between about 150 and about 200 micro-amperes, between about 200 and about 250 micro-amperes, between about 250 and about 300 micro-amperes, between about 300 and about 350 micro-amperes, between about 350 and about
  • systems and devices disclosed herein can produce a iow ievei eiectric current of between for example about 1 micro-ampere and about 1 milli- ampere, between about 50 and about 800 micro-amperes, between about 200 and about 600 microamperes, between about 400 and about 500 micro-amperes, or the iike.
  • systems and devices disclosed herein can produce a iow ievei electric current of about 10 micro-amperes, about 20 micro-amperes, about 30 microamperes, about 40 micro-amperes, about 50 micro-amperes, about 60 micro- amperes, about 70 micro-amperes, about 80 micro-amperes, about 90 micro- amperes, about 100 micro-amperes, about 1 10 micro-amperes, about 120 micro- amperes, about 130 microamperes, about 140 micro-amperes, about 150 micro- amperes, about 160 micro-amperes, about 170 micro-amperes, about 180 micro- amperes, about 190 micro-amperes, about 200 micro-amperes, about 210 micro- amperes, about 220 micro-amperes, about 240 microamperes, about 260 micro- amperes, about 280 micro-amper
  • the disclosed systems and devices can produce a low level electric current of not more than 10 micro-amperes, or not more than about 20 micro- amperes, not more than about 30 micro-amperes, not more than about 40 micro- amperes, not more than about 50 micro-amperes, not more than about 60 micro- amperes, not more than about 70 micro-amperes, not more than about 80 micro- amperes, not more than about 90 micro-amperes, not more than about 100 micro- amperes, not more than about 1 10 micro-amperes, not more than about 120 micro- amperes, not more than about 130 micro-amperes, not more than about 140 micro- amperes, not more than about 150 micro-amperes, not more than about 160 micro- amperes, not more than about 170 micro-amperes, not more than about 180 micro- amperes, not more than about 190 micro-amperes, not more than
  • systems and devices disclosed herein can produce a iow level eiectric current of not iess than about 11.8mA, not iess than about 11.9mA, not less than about 12.0mA, not iess than about 12.1 mA, not iess than about 12.2mA, not less than about 12 3mA, not less than about 12.4mA, not iess than about 12.5mA, not less than about 12.6mA, not less than about 12.7mA, not less than about 12.8mA, not less than about 12.9mA, not less than about 13.0mA, not less than about 13.1 mA, not iess than about 13.2mA, not less than about 13.3mA, not less than about 13.4mA, not less than about 13.5mA, not less than about 13.6mA, not less then about 13.7mA, not iess than about 13.8mA, not iess than about 13.9mA, not less than about 14.0mA, not
  • disclosed devices can provide an electric field of greater than physiological strength to a depth (as measured from the surface of the device) of, at least 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 23 mm, 29 mm, 30 mm, 31 mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, or more.
  • disclosed devices can provide an electric field of greater than physiological strength to a depth (as measured from the surface of the device) of, not more than 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, S mm, 10 mm, 1 1 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, 30 mm, 31 mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, or more.
  • TENS can be applied at high frequency ⁇ >50 Hz) with an Intensity below motor contraction (sensory intensity) or low frequency ( ⁇ 10 Hz) with an Intensity that produces motor contraction.
  • the attractive electrode 20 is placed atop the treatment area.
  • EMS 70 can be applied with an Intensity below motor contraction or with minimal motor contraction.
  • the attractive electrode 20 is placed atop the treatment area, or across the treatment area opposite or thereabouts from the repellent electrode.
  • an electric charge, field, current, or combinations thereof Is applied using a system 100 comprising devices 10 comprising electrodes 20, 30.
  • a disclosed device 10 can comprise conductive wet or dry electrodes 20, 30.
  • the device comprises attractive and repellent electrodes 20, 30, said attractive and repellent electrodes 20, 30 comprising opposing charges.
  • electrodes 20, 30 can comprise platinum or stainless steel, with one of the effete/repeilent electrodes 20, 30 comprising a positive charge, and the other comprising a negative charge.
  • Disclosed embodiments further comprise electrodes 20, 30 that can be used without skin preparation or the use of electrolytic gels.
  • Disclosed electrodes 20, 30 can comprise at least one penetrator, which limits the depth of application, and/or anchors the electrode 20 30 or other device during normal application; and the use of stops which are integral with or separate from the penetrator that adjust the depth of application of the penetrator, and/or allows for uniform application of the electrode or other device over unprepared skin.
  • Electrodes 20, 30 comprising a substrate, and at least one penetrator formed from a conductive material and protruding from the substrate wherein the penetrator is capable of piercing the stratum corneum or outer layer of the skin.
  • the size and shape of the penetrator is such that the penetrator(s) will not break or bend during normal use, will limit the depth the penetrator enters the skin under typical application conditions, and/or will anchor the electrode to prevent motion substantial movement. Therefore, preferably, the appropriate aspect ratio of the height to the average width of the penetrator, slope of the edge(s) or side(s) of the penetrator, and/or height of the penetrator are selected to make an electrode wherein the penetrator(s) will not break or bend, and will better anchor the electrode during application. The height of the penetrator(s) is measured from the tip of the penetrator perpendicular to the substrate.
  • the penetrator(s), preferably, has a height from about 20 to about 150 pm, and more preferably from about 40 to about 100 pm.
  • the aspect ratio of the penetrator is ratio of the height divided by the average width of the penetrator.
  • the average width of the penetrator is measured by faking the widest average cross-section dimension of the cross-sections of the penetrator perpendicular to the height.
  • the penetrator(s), preferably, has an aspect ratio of less than about 5, more preferably of less than about 2, even more preferably of less than about 1.5 and most preferably of less than about 0.75.
  • the slope of the edge(s) or side(s) of the penetrator is measured by drawing a line tangent to the edge or the side of the penetrator(s) at any given point to the substrate 12 and measuring the angle between the line and where it intersects the upper surface 14 of the substrate. While it is understood that the slope may or may not vary substantially along the edge or side of the penetrator(s), preferably the slope is less than about 80 degrees over substantially ail of the edge or side of the penetrator 18, more preferably is less than about 70 degrees, and most preferably is less than about 80 degrees.
  • the penetratorfs) are used to push through the high impedance upper layer or stratum corneum of the epidermis to reduce the contact impedance of the electrode. Preferably, the penetrafor(s) also "lock" the electrode into the chosen skin region.
  • Disclosed embodiments further comprise a EMS device 70 calibrated for use with disclosed methods.
  • disclosed EMS devices 70 comprise specific settings and electrodes suitable for use with specific muscles and neurotoxin formulations or brands.
  • a disclosed EMS device 70 as described herein comprises specific electrodes, voltages, and power settings designed to accommodate neurotoxin formulations.
  • disclosed devices comprise electrodes 20, 30 suitable for narrow application of an electric field, for example for use as a repellent force in a glabellar line neurotoxin treatment, or larger electrodes, for example for use in treating larger muscles, or larger treatment areas.
  • Further embodiments comprise specific settings and electrodes 20, 30 suitable for use with specific treatment areas and dermal filler brands or formulations.
  • Disclosed power/controller device 70 embodiments comprise means for use, such as dials, buttons, a touchscreen, Bluetooth capability, a readable media slot, or the like to program the device to, for example, apply appropriate internal parameters for a BOTOX ® treatment of the glabellar area, or a BOTOX ® treatment of headache, or a DYSPORT ® treatment of cervical dystonia, or a MYOBLOC ® treatment of headache, a XEOMiN* treatment of hyperhidrosis, a dermal filler treatment of the cheeks, or a dermal filler treatment of the lips.
  • a BOTOX ® treatment of the glabellar area or a BOTOX ® treatment of headache
  • a DYSPORT ® treatment of cervical dystonia or a MYOBLOC ® treatment of headache
  • a XEOMiN* treatment of hyperhidrosis a dermal filler treatment of the cheeks, or a dermal filler treatment of the lips.
  • the disclosed power/controller device 70 allows the user to input the type, brand, or formulation of administered material and the treatment area, and the device will configure Itself to apply preferred voltages or currents, as well as Indicate to the user, for example visually, the appropriate electrodes to use with a specific treatment, and where to place the electrodes.
  • a mechanical force can be applied to limit an injected material from dissipating.
  • a mechanical force such as that applied by an adhesive strip can be used to limit dissipation.
  • the mechanical force can be applied In combination with an EMF force.
  • the mechanical force can be applied with a clear adhesive tape or substrate.
  • Disclosed embodiments can comprise use of a system comprising a controller to provide and apply the voltage or current parameters for an optimal treatment.
  • the system 100 Includes programming so that user Is prompted to: a. Input a medical procedure such as a neurotoxin, dermal filler, or drug administration; b. input the type or brand (or both) of neurotoxin or dermal filler or drug; and c. Input the area of treatment,
  • the system processes the Input information, configures itself to supply the correct treatment voltages / currents or ranges thereof, and then directs the practitioner as to any or all of: a the appropriate treatment location or location range; b the appropriate Injection location or location range; c. the number of Injections or range; d the appropriate material concentration and dosage or range; e the appropriate electrodes to employ; and f. placement of the electrodes or range of placement.
  • photographs of the treatment area are taken, for example, both before, during, and after the procedure.
  • the device “maps” the Injection and electrode locations on to the photograph to assist the practitioner.
  • a record of the administration can then be transmitted to the practitioner’s record-keeping system, ora patient’s phone, or the like.
  • a “running” total of the patient’s neurotoxin exposure can be maintained, in terms of units administered, total protein or dermal filler administered, treatment locations, and the like.
  • Further embodiments can comprise prompting the patient to submit an evaluation of the procedure to the practitioner, or a review of the service to a database, such as a consumer review database.
  • Further embodiments comprise user Input to confirm that the procedure directed by the device (In terms of dosage, electrodes, voltages, etc.) was followed correctly. In embodiments this confirmation can then be supplied to a third party, for example the device or system manufacturer, a regulatory body, or an Insurance organization.
  • Further embodiments comprise collection of data by a third party such as the device manufacturer in order to track device performance and patient satisfaction,
  • Embodiments can include neurotoxin administrations to treat, for example, pain, muscle-related conditions including dystonia, spasticity and bladder conditions, depression, cosmetic concerns, and combinations thereof.
  • an attractive force for example the attractive electrode (determined based upon the physical properties of an Injected material, whether published or determined by experimentation) of, for example, a power/controlier device can be placed on top of or in the vicinity of the injection site of a neurotoxin, with the repellent electrode of the device placed, for example, an inch or less from the attractive electrode.
  • the attractive electrode 20 can be placed over the injected material treatment site, or beyond the treatment site “opposite” the repellent electrode 30.
  • the electrodes 20, 30 can be “wet” or “dry” electrodes. Wet electrodes 20, 30 typically use an electrolytic material as a conductor between the skin and the electrode. Dry electrodes typically consist of a single metal that acts as a conductor between the skin and the electrode.
  • Disclosed embodiments comprise methods of controlling release from “depot” drug administration.
  • an electric barrier can be established around a subcutaneous drug deposit, such as, for example, insulin or an analgesic.
  • chemo-denervating agent for example a neurotoxin.
  • the chemo-denervating agent can be a Clostridial neurotoxin or a component thereof, for example a botuiinum toxin such as botuiinum toxin A (BoNT/A), botuiinum toxin B (BoNT/B), botuiinum toxin E (BoNT/E), botuiinum toxin F (BoNT/F) or the neurotoxin components thereof, combinations thereof, and devices as disclosed herein.
  • BoNT/A botuiinum toxin A
  • BoNT/B botuiinum toxin B
  • BoNT/E botuiinum toxin E
  • BoNT/F botuiinum toxin F
  • kits for example comprising a neurotoxin or combinations thereof, disclosed devices, and instructions for use.
  • Disclosed embodiments comprise articles of manufacture that include packaging materia! and an amount of a cosmetic agent, for example a derma! filler such as hyaluronic acid (HA), and devices as disclosed herein
  • a cosmetic agent for example a derma! filler such as hyaluronic acid (HA)
  • kits for example comprising a dermal filler or fillers, disclosed systems and devices, and instructions for use
  • compositions can comprise a topical agent, for example a cream or gel comprising an attractive EMF, to apply to a treatment area following a treatment
  • a topical agent for example a cream or gel comprising an attractive EMF
  • a cream that produces an attractive force can be applied over an injected material treatment site, such as the lips or the glabellar line area.
  • compositions can comprise a topical agent, for example a cream or gel comprising a repellent EMF, to apply near a treatment area following a treatment.
  • a topical agent for example a cream or gel comprising a repellent EMF
  • a cream that produces a repellent force can be applied to limit dissipation of an Injected material from a treatment site, such as the lips or the glabellar line area.
  • Further embodiments can comprise the use of a conductive material, for example a liquid, for example a hydrogel, between the electrodes and the skin surface, to lower the resistance of the skin
  • a conductive material for example a liquid, for example a hydrogel
  • a conductive material for example a liquid, for example a hydrogel
  • Embodiments comprise modified neurotoxins, said modification comprising increasing the inherent “charge” of the molecule, to increase the effect of disclosed embodiments.
  • Embodiments can also comprise adjusting the pH or conductivity of an injected material formulation.
  • Embodiments can also comprise adjusting the isoelectric point (pi) of an injected material or component thereof, for example using recombinant technologies, so as to make the material or component thereof more susceptible to manipulation via disclosed systems, devices, and methods.
  • Embodiments comprise methods for directing dissipation of materials, for example topically applied, injected, or iontophoresed pharmaceutical compositions.
  • Embodiments comprise the use of, for example, an energy field, for example an electromagnetic field (EMF) such as an electric field, an electric charge, an electric current, a magnetic field, or combinations thereof, to localize administered compositions.
  • EMF electromagnetic field
  • Administered compositions can comprise, for example, biologies, analgesics, anesthetics, biologies neurotoxins (both as complexes such as BoNT/A 9G0kd, or the neurotoxin component alone, such as the 150kd neurotoxin component of BGNT/A), proteins, DNA, viruses, dermal fillers, and the like.
  • Localizing the injected materials can eliminate or reduce the spread or dissipation of the materials, thereby eliminating or reducing the risk of unwanted effects, as well as minimizing the “immunogeniefootprinf that can result from an administration.
  • Localizing the materials can increase the effect duration of administered materials, for example the effect duration of a neurotoxin injection, or the effect duration of a dermal filler injection, thereby increasing the time duration before treatment is repeated.
  • Localizing the materials can increase the effect intensity of injected materials, for example the effect intensity of a neurotoxin injection, or the effect Intensity of a dermal filler injection.
  • Embodiments comprise methods for increasing the spread or dissipation of injected materials, for example injected pharmaceutical compositions.
  • Embodiments comprise the use of, for example, an energy field, for example an electromagnetic field (EMF) such as an electric field, an electric charge, an electric current, a magnetic field, or combinations thereof, to dissipate injected compositions
  • EMF electromagnetic field
  • injected compositions can comprise, for example, biologies, neurotoxins, proteins, DNA, viruses, dermal fillers, and the like.
  • Embodiments comprise methods for directing the spread or dissipation of injected materials, for example injected pharmaceutical compositions.
  • Embodiments comprise the use of, for example, an energy field, for example an electromagnetic field (EMF) such as an electric field, an electric charge, an electric current, a magnetic field, or combinations thereof, to localize injected compositions
  • EMF electromagnetic field
  • injected compositions can comprise, for example, biologies, neurotoxins, proteins, DNA, viruses, dermal fillers, and the like.
  • the attractive and repeiient forces are applied to form an uninterrupted perimeter around a treatment area.
  • the attractive and repeiient forces are applied to form a discontinuous perimeter around a treatment area.
  • the attractive and repeiient forces are applied parallel to each other around a treatment area.
  • the attractive force is placed on top of a treatment area, while the repeiient force is applied away from the treatment area to reduce or prevent dissipation away from the treatment area.
  • the repeiient force is placed on top of a treatment area, while the attractive force is applied away from the treatment area to increase directional dissipation away from a sensitive treatment area.
  • the attractive or repeiient force is placed beyond a treatment area opposite the corresponding opposite force, such that the force is exerted across the treatment area.
  • a material Is injected subcutaneously to, for example, between 1 and 15mm tissue depth, then an attractive force comprising an electric charge is applied to, around, or partially around the treatment site.
  • an electrode 20 placed on but not penetrating the skin applies the attractive force.
  • the order of this operation can be reversed, such that the force Is applied before, during, or after the administration; however, most preferably the electrode 20 is at least applied to the skin before injection to avoid pressing against the treatment site after injection.
  • a material is Injected subcutaneously to, for example, between 1 and 15mm tissue depth, then a repellent force comprising an electric charge Is applied around or partially around the treatment site, to “shield” an area where dissipation is to be avoided or limited.
  • a repellent force comprising an electric charge Is applied around or partially around the treatment site, to “shield” an area where dissipation is to be avoided or limited.
  • an electrode 30 placed on but not penetrating the skin applies the repellent force.
  • the order of this operation can be reversed, such that the force Is applied before, during, or after the administration; however, most preferably the electrode 30 is at least applied to the skin before injection to avoid pressing nearby the treatment site after injection.
  • a material Is injected subcutaneously to, for example, between 1 and 15mm tissue depth, then an attractive force comprising an electric charge Is applied to, around, or partially around the treatment site, and a repellent force comprising an electric charge is applied around or partially around the treatment site, wherein the attractive and repellent forces comprise opposite electric charges.
  • electrodes 20, 30 are placed on but not penetrating the skin to apply the attractive and repellent forces. The order of this operation can be reversed, such that the force is applied before or after the administration; however, most preferably the electrodes 20, 30 are at least applied to the skin before injection to avoid pressing nearby the treatment site after Injection.
  • the attractive and repellent forces establish an electric field. In embodiments wherein there Is electrical conductivity between the attractive and repellent forces, an electric current can be established.
  • localizing the injected materials can comprise applying an energy field, for example an electric charge, field or current, or combinations thereof, to at least one injection site, or applying an energy field, for example an energy field, for example an electric charge, field or current, or combinations thereof, surrounding at least one Injection site, and combinations thereof.
  • an energy field for example an attractive electric charge, field or current, or combinations thereof
  • an energy field for example a repellent electric charge, field or current, or combinations thereof, can be applied around the perimeter of one or multiple injection sites.
  • methods of minimizing an Immune response caused by Injected materials can comprise applying an energy field, for example an electric charge, field or current, or combinations thereof, to at least one Injection site, or surrounding at least one injection site.
  • an attractive energy field for example an electric charge, field or current, or combinations thereof
  • a repellent energy field for example an electric charge, field or current, or combinations thereof, can be applied around the perimeter or a part thereof of one or multiple injection sites.
  • the energy field can comprise, for example, an electric field, electric charge, electric current, a magnetic field, a combination thereof, or the like.
  • an electric field can be applied to an injection site through the use of an electrode supplying a suitable voltage to produce an attractive field to “attract” the materials
  • an electric field can be applied to surround (either partially or completely) an Injection site through the use of an electrode supplying a suitable voltage to produce a repellent field to “repel” the materials.
  • both attractive and repellent field are applied. In this manner, the spread or dissipation of the injected materials can be reduced or eliminated.
  • treatment of migraine in disclosed embodiments can comprise neurotoxin injections into at least one of the following muscles comprising the corrugator, the procerus, the frontalis, the temporalis, the occipitalis, the cervical paraspina! muscles, and the trapezius.
  • at least one of the corrugator, the procerus, the frontalis, the temporalis, the occipitalis, the cervical paraspina! muscles, and the trapezius are specifically excluded from injection, in disclosed embodiments, the treatment involves 31 injections of 5 units per injection, for a total of 155 units.
  • 5 units can be injected into each corrugator muscle.
  • 5 units can be injected into the muscle
  • 5 units can be injected into each of 4 sites in the muscle
  • 5 units can be injected into each of 8 sites in the muscle.
  • 5 units can be injected into each of 8 sites in the muscle.
  • 5 units can be injected into each of 4 sites in the muscle.
  • 5 units can be injected into each of 6 sites in the muscle.
  • Disclosed methods of treatment can comprise treating the indications of Table 1:
  • Disclosed methods comprise treatment of the bladder comprising placing a cystoscope into the bladder and injecting a neurotoxin into numerous sites in via a needle that fits through the cystoscope.
  • Disclosed hyperhidrosis treatments can comprise administration of, for example, 100 U of BoNT/A reconstituted with 2.5 mL of 0.9% sterile saline subdivided into 25 subdermai injections.
  • Disclosed depression treatment methods can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting neurotoxin into the corrugators, orbicularis oculi, and the frontalis muscle.
  • Disclosed frown line treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin into the corrugator and procerus.
  • Disclosed horizontal forehead lines treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin into the frontalis, (see FIG. 7 and FIG. 9)
  • Disclosed crow ' s feet treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin into the orbicularis (see FIG. 5 and FIG. 8).
  • Disclosed bunny line treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin or dermal filler into the nasalis.
  • Disclosed radial lip line treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin or dermal filler into the orbicularis.
  • Disclosed Marionette line treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin or dermal filler into the depressor anguli.
  • Disclosed “gummy smile” treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin or dermal filler into the levator labii superioris.
  • Disclosed chin line treatments can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and injecting a neurotoxin or dermal filler into the menta!is.
  • disclosed methods can comprise neurotoxin administration.
  • disclosed methods can comprise applying attractive and repellent forces to the surface of the skin without physically penetrating the skin with electrodes; and administration of neurotoxins such as BOTOX ® , DYSPORT ® , MYOBLOC ® , XEOM!N ® , JEUVEAU ® , combinations thereof, and the like.
  • Disclosed treatment methods comprising BOTOX ® administration can comprise treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication, prophylaxis of headaches in adult patients with chronic migraine (>15 days per month with headache lasting 4 hours a day or longer), temporary Improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adults ⁇ 65 years of age, treatment of upper limb spasticity in adult patients, treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain, treatment of severe axiilary hyperhidrosis that is inadequately managed by topical agents in adult patients, treatment of blepharospasm associated with dystonia in patients >12 years of age, treatment of strabismus in patients >12 years of age, treatment of facial wrinkles, and the like.
  • a neurologic condition
  • Disclosed treatment methods comprising DYSPORT ® can comprise treatment of cervical dystonia in adults, temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adults ⁇ 65 years of age, treatment of upper and lower limb spasticity in adults, treatment of upper limb spasticity in pediatric patients 2 years of age and older, excluding spasticity caused by cerebral palsy, treatment of lower limb spasticity in pediatric patients 2 years of age and older, and the like.
  • Disclosed treatment methods comprising XEOMIN ® can comprise treatment of chronic sialorrhea, upper limb spasticity, cervical dystonia, blepharospasm, temporary improvement in the appearance of moderate to severe glabellar lines with corrugator and/or procerus muscle activity, and the like.
  • Disclosed treatment methods comprising MYOBLOC ® can comprise treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia in adults, treatment of chronic sialorrhea in adults, and the like.
  • Disclosed treatment methods can comprise avoidance of adverse effects, for example avoidance of neck pain, headache, worsening migraine, muscular weakness, dysphagia, and eyelid ptosis.
  • Disclosed treatment methods can comprise extended duration of effect as compared to methods known in the art.
  • disclosed embodiments can comprise an extended duration of effect of at least 5% greater, at least 10% greater, at least 15% greater, at least 20% greater, at least 25% greater, at least 30% greater, at least 35% greater, at least 40% greater, at least 45% greater, at least 50% greater, at least 55% greater, at least 60% greater, at least 65% greater, at least 70% greater, at least 75% greater, at least 80% greater, at least 85% greater, at least 90% greater, at least 95% greater, at least 100% greater, or more, or the like.
  • Disclosed treatment methods can comprise accelerated onset of effect as compared to methods known in the art.
  • disclosed embodiments can comprise an accelerated onset of effect of at least 5% greater, at least 10% greater, at least 15% greater, at least 20% greater, at least 25% greater, at least 30% greater, at least 35% greater, at least 40% greater, at least 45% greater, at least 50% greater, at least 55% greater, at least 60% greater, at least 65% greater, at least 70% greater, at least 75% greater, at least 80% greater, at least 85% greater, at least 90% greater, at least 95% greater, at least 100% greater, or more, or the like.
  • Disclosed treatment methods can comprise increased intensify of effect as compared to methods known in the art.
  • disclosed embodiments can comprise an increased intensity of effect of at least 5% greater, at least 10% greater, at least 15% greater, at least 20% greater, at least 25% greater, at least 30% greater, at least 35% greater, at least 40% greater, at least 45% greater, at least 50% greater, at least 55% greater, at least 60% greater, at least 65% greater, at least 70% greater, at least 75% greater, at least 80% greater, at least 85% greater, at least 90% greater, at least 95% greater, at least 100% greater, or more, or the like.
  • Disclosed treatment methods can comprise lessening the immunogenic effect as compared to methods know in the art.
  • disclosed embodiments can comprise an immunogenic effect of at least 5% less, at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, at least 75% less, at least 80% less, at least 85% less, at least 90% less, at least 95% less, at least 100% less, or more, or the like.
  • Disclosed treatment methods can comprise lessening the required dosage to achieve the desired effect as compared to methods know in the art.
  • disclosed embodiments can comprise a dosage of at least 5% less, a dosage of at least 10% less, a dosage of at least 15% less, a dosage of at least 20% less, a dosage of at least 25% less, a dosage of at least 30% less, a dosage of at least 35% less, a dosage of at least 40% less, a dosage of at least 45% less, a dosage of at least 50% less, a dosage of at least 55% less, a dosage of at least 60% less, a dosage of at least 65% less, a dosage of at least 70% less, a dosage of at least 75% less, a dosage of at least 80% less, a dosage of at least 85% less, a dosage of at least 90% less, a dosage of at least 95% less, or the like.
  • the administered material is formulated In unit dosage form; for example, a neurotoxin can be provided as a sterile solution In a vial or as a vial or sachet containing a iyophilized powder for reconstituting in a suitable vehicle such as saline for injection.
  • a suitable vehicle such as saline for injection.
  • routes of administration and dosages are provided, the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill In the art.
  • the route and dosage for administration of a Clostridial neurotoxin according to the present disclosure can be selected based upon criteria such as the solubility characteristics of the neurotoxin chosen as well as the Intensity and scope of the condition being treated.
  • the neurotoxin can be administered in an amount of between about 10 U/kg and about 35 Li/kg. In an embodiment, the neurotoxin Is administered in an amount of between about 10 U/kg and about 25 U/kg, In another embodiment, the neurotoxin is administered In an amount of between about 10 U/kg and about 15 U/kg. in another embodiment, the neurotoxin is administered In an amount of between about 1 U/kg and about 10 U/kg.
  • an administration of from about 1 unit to about 500 units of a neurotoxin, such as a botulinum type E, provides effective therapeutic relief, in an embodiment, from about 5 units to about 200 units of a neurotoxin, such as a botuiinum type E, can be used and In another embodiment, from about 10 units to about 100 units of a neurotoxin, such as a botuiinum type E, can be locally administered into a target tissue such as a muscle.
  • administration can comprise a dose of about 10 units of a neurotoxin, or about 20 units of a neurotoxin, or about 30 units of a neurotoxin, or about 40 units of a neurotoxin, or about 50 units of a neurotoxin, or about 60 units of a neurotoxin, or about 70 units of a neurotoxin, or about 80 units of a neurotoxin, or about 90 units of a neurotoxin, or about 100 units of a neurotoxin, or about 1 10 units of a neurotoxin, or about 120 units of a neurotoxin, or about 130 units of a neurotoxin, or about 140 units of a neurotoxin, or about 150 units of a neurotoxin, or about 160 units of a neurotoxin, or about 170 units of a neurotoxin, or about 180 units of a neurotoxin, or about ISO units of a neurotoxin, or about 200 units of a neurotoxin
  • administration can comprise a dose of not less than 10 units of a neurotoxin, not less than 20 units of a neurotoxin, not less than 30 units of a neurotoxin, not less than 40 units of a neurotoxin, not less than 50 units of a neurotoxin, not less than 60 units of a neurotoxin, not less than 70 units of a neurotoxin, not less than 80 units of a neurotoxin, not less than SO units of a neurotoxin, not less than 100 units of a neurotoxin, not less than 110 units of a neurotoxin, not less than 120 units of a neurotoxin, not less than 130 units of a neurotoxin, not less than 140 units of a neurotoxin, not less than 150 units of a neurotoxin, not less than 160 units of a neurotoxin, or about 170 units of a neurotoxin, or about 180 units of a neurotoxin, not less than 190 units of
  • administration can comprise a dose of not more than 10 units of a neurotoxin, not more than 20 units of a neurotoxin, not more than 30 units of a neurotoxin, not more than 40 units of a neurotoxin, not more than 50 units of a neurotoxin, not more than 60 units of a neurotoxin, not more than 70 units of a neurotoxin, not more than 80 units of a neurotoxin, not more than 90 units of a neurotoxin, not more than 100 units of a neurotoxin, not more than 110 units of a neurotoxin, not more than 120 units of a neurotoxin, not more than 130 units of a neurotoxin, not more than 140 units of a neurotoxin, not more than 150 units of a neurotoxin, not more than 160 units of a neurotoxin, not more 170 units of a neurotoxin, not more than 130 units of a neurotoxin, not more than 190 units of
  • not more than 400 units of a neurotoxin not more than 410 units of a neurotoxin, not more than 420 units of a neurotoxin, not more than 430 units of a neurotoxin, not more than 440 units of a neurotoxin, not more than 450 units of a neurotoxin, not more than 460 units of a neurotexln, not more than 470 units of a neurotoxin, not more than 480 units of a neurotoxin, not more than 490 units of a neurotoxin, not more than 500 units of a neurotexln, or the like
  • the dose of the neurotoxin is expressed in protein amount or concentration.
  • the neurotoxin can be administered in an amount of between about ,2ng and 20 ng.
  • the neurotoxin Is administered in an amount of between about .3 ng and 19 ng, about .4 ng and 18 ng, about .5 ng and 17 ng, about .6 ng and 16 ng, about 7 ng and 15 ng, about .8 ng and 14 ng, about .9 ng and 13 ng, about 1.0 ng and 12 ng, about 1.5 ng and 1 1 ng, about 2 ng and 10 ng, about 5 ng and 7 ng, and the like, Into a target tissue such as a muscle.
  • neurotoxin administration can comprise a total dose of between 5 and 7 ng, between 7 and 9 ng, between 9 and 11 ng, between 11 and 13 ng, between 13 and 15 ng, between 15 and 17 ng, between 17 and 19 ng, or the like.
  • administration can comprise a total dose of not more than 5 ng, not more than 6 ng, not more than 7 ng, not more than 8 ng, not more than 9 ng, not more than 10 ng, not more than 11 ng, not more than 12 ng, not more than 13 ng, not more than 14 ng, not more than 15 ng, not more than 16 ng, not more than 17 ng, not more than 18 ng, not more than 19 ng, not more than 20 ng, or the like.
  • neurotoxin administration can comprise a total dose of not less than 5 ng, not less than 6 ng, not less than 7 ng, not less than 8 ng, not less than 9 ng, not less than 10 ng, not less than 11 ng, not less than 12 ng, not less than 13 ng, not less than 14 ng, not less than 15 ng, not less than 16 ng, not less than 17 ng, not less than 18 ng, not less than 19 ng, not less than 20 ng, or the like,
  • administration can comprise a total dose of about 0,1 ng of a neurotoxin, 0.2 ng of a neurotoxin, 0.3 ng of a neurotoxin, 0 4 ng of a neurotoxin, 0.5 ng of a neurotoxin, 0.6 n of a neurotoxin, 0.7 ng of a neurotoxin, 0.8 ng of a neurotoxin, 0.9 ng of a neurotoxin, 1 ,0 ng of a neurotoxin, 1 1 ng of a neurotoxin, 1.2 ng of a neurotoxin, 1 .3 ng of a neurotoxin, 1 ,4 ng of a neurotoxin, 1.5 ng of a neurotoxin, 1 .6 ng of a neurotoxin, 1.7 ng of a neurotoxin, 1.8 ng of a neurotoxin, 1.9 ng of a neurotoxin, 2,0
  • administration can comprise a dose per administration of about 0.1 ng of a neurotoxin, 0.2 ng of a neurotoxin, 0.3 ng of a neurotoxin, 0.4 ng of a neurotoxin, 0.5 ng of a neurotoxin, 0.6 n of a neurotoxin, 0.7 ng of a neurotoxin, 0.8 ng of a neurotoxin, 0.9 ng of a neurotoxin, 1.0 ng of a neurotoxin, 1.1 ng of a neurotoxin, 1.2 ng of a neurotoxin, 1.3 ng of a neurotoxin, 1 ,4 ng of a neurotoxin, 1 ,5 ng of a neurotoxin, 1.6 ng of a neurotoxin, 1.7 ng of a neurotoxin, 1.8 ng of a neurotoxin, 1.9 ng of a neurotoxin, 2.0 ng of a neurotoxin, 2.0
  • Embodiments comprise injection of a volume of dermal filler, for example hyaluronic add.
  • the volume of hyaluronic acid composition comprises, for example, .3 ml, .4 ml, .5 ml, .6 ml, .7 ml, ,8 ml, ,9 ml, 1 ml, 1.5 ml, 2 ml, 2.5 ml, 3 ml, 3.5 ml, 4 ml, 4.5 ml, 5 ml, 5.5 ml, 6 ml, 6.5 ml, 7 ml, 7.5 ml, 8 ml, 8.5 ml, 9 ml, 9.5 ml, 10 ml, 12 ml, 14 ml, 16 ml, 18 ml, 20 ml, 22 ml, 24 ml, 26 ml, 27 ml, 28 ml, 29 ml,
  • the volume of derma! filler composition comprises, for example, not more than 3 ml, not more than .4 ml, not more than .5 mi, not more than .6 ml, not more than .7 ml, not more than .8 ml, not more than .9 ml, not more than 1 ml, not more than 1 ,5 ml, not more than 2 ml, not more than 2.5 ml, not more than 3 ml, not more than 3,5 ml, not more than 4 ml, not more than 4.5 ml, not more than 5 ml, not more than 5 5 ml, not more than 6 ml, not more than 6.5 ml, not more than 7 ml, not more than 7.5 ml, not more than 8 ml, not more than 8.5 ml, not more than 9 ml, not more than 9.5 ml, not more than 10 ml, not more than 12 mi, not
  • the volume of derma! filler composition comprises, for example, not less than .3 ml, not less than .4 ml, not less than .5 ml, not less than ,6 ml, not less than .7 ml, not more than .8 ml, not more than .9 ml, not less than 1 ml, not less than 1.5 mi, not less than 2 ml, not less than 2,5 mi, not less than 3 ml, not less than 3,5 ml, not less than 4 ml, not less than 4.5 ml, not less than 5 ml, not less than 5.5 ml, not less than 6 ml, not less than 6.5 ml, not less than 7 ml, not less than 7,5 ml ⁇ not more than 8 mi, not less than 8 5 ml, not less than 9 mi, not less than 9 5 ml, not more than 10 ml, not less than 12 ml, not less than 14
  • the treatment device or devices applying the electric charge, field, or current is applied surrounding or to the treatment area for, for example, 30 seconds, 45 seconds, 60 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 83 minutes, 34 minutes, 35 minutes, 36 minutes, 37 minutes, 38 minutes, 39 minutes, 40 minutes, 41 minutes, 42 minutes, 43 minutes, 44 minutes, 45 minutes, 46 minutes, 47 minutes, 48 minutes, 49 minutes, 50 minutes, 51 minutes, 52 minutes, 53 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58 minutes, 53 minutes, 60 minutes, 61 minutes, 62 minutes, 63 minutes, 63 minutes, 64 minutes, 65 minutes, 66 minutes, 67 minutes
  • the treatment device or devices applying the electric charge, field, or current is applied surrounding or to the treatment area for, for example, not less than 30 seconds, not less than 45 seconds, not less than not less than 60 seconds, not less than 1 minute, not less than 2 minutes, not less than 8 minutes, not less than 4 minutes, not less than 5 minutes, not less than 6 minutes, not less than 7 minutes, not less than 8 minutes, not less than 9 minutes, not less than 10 minutes, not less than 11 minutes, not less than 12 minutes, not less than 13 minutes, not less than 14 minutes, not less than 15 minutes, not less than 16 minutes, not iess then 17 minutes, not less than 18 minutes, not less than 19 minutes, not less than 20 minutes, not less than 21 minutes, not less than 22 minutes, not less than 23 minutes, not less than 24 minutes, not less than 25 minutes, 26 minutes, not less than 27 minutes, not less then 28 minutes, not less than 29 minutes, not less than 30 minutes, not less than 31 minutes, not less than 32 minutes, not less than 33 minutes, not less than
  • the treatment device or devices appiying the eiectric charge, field, or current is applied surrounding or to the treatment area for, for example, not more than 30 seconds, not more than 45 seconds, not more than not more than 60 seconds, not more than 1 minute, not more than 2 minutes, not more than 3 minutes, not more than 4 minutes, not more than 5 minutes, not more than 6 minutes, not more than 7 minutes, not more than 8 minutes, not more than 9 minutes, not more than 10 minutes, not more than 11 minutes, not more than 12 minutes, not more than 13 minutes, not more than 14 minutes, not more than 15 minutes, not more than 16 minutes, not more than 17 minutes, not more than 18 minutes, not more than 19 minutes, not more than 20 minutes, not more than 21 minutes, not more than 22 minutes, not more than 28 minutes, not more than 24 minutes, not more than 25 minutes, not more than 26 minutes, not more than 27 minutes, not more than 28 minutes, not more than 29 minutes, not more than 30 minutes, not more than 31 minutes, not more than 32 minutes, not
  • dermal fillers can be localized via the disclosed methods. For example, in embodiments, at physiological pH values, hyaluronic acid carries a net negative charge. In embodiments, by applying a positive source charge to a location, the dermal filler can be “fixed” in that location. Similarly, by applying a negative source charge, for example around part or all of the perimeter of a treatment site, the dermal filler can be excluded or repelled from a location.
  • Dermal fillers suitable for use with disclosed methods and systems include, for example, those containing Hyaluronic Add (HA), Calcium Hydroxyapatite (CaHA), Po!y-L-lactic Add, Polymethylmethacrylate (PMIVIA), Autologous fat injections (facial fat grafting), and combinations thereof.
  • HA Hyaluronic Add
  • CaHA Calcium Hydroxyapatite
  • PMIVIA Polymethylmethacrylate
  • Autologous fat injections facial fat grafting
  • Disclosed embodiments can be used to limit the amount of non-therapeutic materials to be injected into a patient.
  • the vessel containing the material to be Injected Is subjected to an electromagnetic field that attracts the therapeutic material, and the Injection material is withdrawn from the vessel in the vicinity of the attractive electromagnetic field.
  • Disclosed embodiments comprise methods of controlling release from “depot” drug administration.
  • “depot” drug administration refers to an injection formulation of a medication which releases slowly over time to permit less frequent administration of a medication. They are designed to increase medication adherence and consistency, especially in patients who commonly forget to take their medicine. Depot injections are available for many types of drugs, including antipsychotics and hormones. By controlling dissipation of a depot injection via the use of disclosed attractive and repellent forces, the time-release curve of the drug can be controlled.
  • the administered can comprise pharmaceutical compositions.
  • suitable pharmaceutical compositions can comprise any materials typically administered via Injection (to Include needle-less injection).
  • Such compositions can comprise, for example, biologies such as neurotoxins or components thereof, anesthetics, analgesics, dermal fillers, and the like.
  • Botulinum neurotoxins suitable for use with disclosed methods and systems include, for BoNT/A, BoNT/B, BoNT/C, BoNT/D, BoNT/E, BoNT/F, BoNT/G, BoNT/H, and combinations thereof, both as the “complex” such as the 90Gkd BoNT/A complex or the 15Qkd neurotoxin component of the 9G0kd BoNT/A complex.
  • FIG. 14 groups together exemplary botullnum toxins suitable for use in disclosed methods and compositions:
  • neurotoxins can comprise the “light chain” of a botullnum toxin.
  • Embodiments can comprise a combination of neurotoxins, for example BoNT/A and BoNT/E.
  • Embodiments can comprise the dissociation of the heavy chain and the light chain, either prior to or following administration.
  • Disclosed embodiments can comprise use of an electric charge, field, or current to dissociate a neurotoxin from accessory proteins or formulation components, for example HSA, either prior to or following an administration, for example an injection.
  • Embodiments comprise aligning the dipole of a botullnum toxin to provide the correct orientation for binding.
  • the complex when the neurotoxin complex is injected, the complex dissociates under physiological pH to release the neurotoxin component. In such cases the strength and orientation of the attractive and repellent forces can be determined based on the properties (such as pi) of the neurotoxin component itself.
  • Dermal fillers suitable for use with disclosed methods and systems include, for example, those containing Hyaluronic Acid (HA), Calcium Hydroxylapatite (CaHA), Poly-L-!actic Acid, Polymethylmethacrylate (PMMA), Autologous fat injections (facial fat grafting), and combinations thereof.
  • Embodiments can also comprise adjusting the isoelectric point (pi) of an injected material, for example using recombinant technologies.
  • disclosed embodiments comprise an engineered clostridial toxin comprising at least one amino acid modification, wherein said at least one amino acid modification increases the isoelectric point (pi) of the engineered clostridial toxin to a value that is at least 0.2 (for example, at least 0.2, 0.3, 0.4, 0.5, 0.8, 0.7, 0.8, 0,9 or 1) pi units higher than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification.
  • said at least one amino acid modification increases the pi of the engineered clostridial toxin to a value that is at least 0.4 pi units higher than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification. In one embodiment, said at least one amino acid modification increases the pi of the engineered clostridial toxin to a value that is at least 0.5 pi units higher than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification. In one embodiment, said at least one amino acid modification increases the pi of the engineered clostridial toxin to a value that is at least 0.6 pi units higher than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification.
  • said at least one amino acid modification increases the pi of the engineered clostridial toxin to a value that is at least 0.8 pi units higher than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification. In one embodiment, said at least one amino acid modification increases the pi of the engineered clostridial toxin to a value that is at least 1 pi unit higher than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification.
  • Further disclosed embodiments comprise an engineered clostridial toxin comprising at least one amino acid modification, wherein said at least one amino add modification decreases the pi of the engineered clostridial toxin to a value that is at least 0.2 (for example, at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1) pi units lower than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification.
  • said at least one amino acid modification decreases the pi of the engineered clostridial toxin to a value that is at least 0.4 pi units lower than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification.
  • said at least one amino acid modification decreases the pi of the engineered clostridial toxin to a value that is at least 0.5 pi units lower than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification, in one embodiment, said at least one amino acid modification decreases the pi of the engineered clostridial toxin to a value that is at least 0.8 pi units lower than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification, in one embodiment, said at least one amino acid modification decreases the pi of the engineered clostridial toxin to a value that is at least 0.8 pi units lower than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification, in one embodiment, said at least one amino acid modification decreases the pi of the engineered clostridial toxin to a value that is at least 1 pi unit lower than the pi of an otherwise identical clostridial toxin lacking said at least one amino acid modification.
  • compositions can be administered using iontophoresis
  • iontophoresis is a process of transdermal drug delivery by use of a voltage gradient on the skin.
  • a small electric current is applied to an iontophoretic chamber placed on the skin, containing a charged active agent and its solvent vehicle.
  • Another chamber (or a skin electrode) carries the return current.
  • the positively charged chamber called the anode
  • the cathode will repel a negatively charged species into the skin
  • iontophoresis techniques can safely “drive” molecules over 1cm into tissue, for example beneath the skin, using safe, well-tolerated voltages and currents. Such depths are suitable for methods disclosed herein, as many administered, for example injected, materials are administered just below the skin or at a minimum depth intramuscularly. Therefore, these safe, well-tolerated voltages and currents used in iontophoresis can also be used to control material dissipation by, rather than using a repellent force to drive a material into the skin, using that repellent force to “fence”, drive, or limit the material to a desired treatment area. In addition to the repellent force, an attractive force can also be used to localize an administered material, as well as providing a “return” for any currents produced,
  • FIG. 2 For example, the Iontophoresis patch Is employed with a disclosed administered material, with the patch employing an electrode comprising a repellent charge to drive the material Into the skin, and a return electrode forming at least part of the perimeter of the device. After the material is substantially or completely driven Into the skin, the polarity of the device reverses, such that the repellent electrode then forms the perimeter, thus containing the area of dissipation of the material.
  • the device of FIG. 9 (comprising an attractive and a repellent electrode placed opposite each other at either end of the long axis) Is placed on the skin on one side of the face of each of two subjects, providing a test side (with electrodes) and control side (without electrodes). 20 U of BoNT/A Is injected in the gap region between the two electrodes.
  • FIG. 10 shows the results of the Injections as quantified with a starch test performed two days after injection.
  • the white areas show where the toxin has limited perspiration, the dark areas indicate perspiration.
  • Subject 1 left; low power electrodes (creating minimal muscle contractions) were used on right side of the face (left side of image).
  • the test injection shows better spread as well as migrating “up” toward the attractive electrode as compared to the negative control (no electrodes) injected in the same horizontal plane.
  • Subject 2 (right); medium power electrodes used on left side of the face (right side of image.
  • the test injection shows better spread as well as migrating “down” toward the attractive electrode as compared to the negative control (no electrodes) injected in the same horizontal plane (the electrodes were reversed on the two subjects).
  • FIG. 11 shows results follow up starch test results from Subjectl (left) and Subject 2 (right) approximately 20 weeks after the study conducted with the electrode configuration of FIG. 9 confirming the localized toxin remained in its targeted position.
  • the doctor Injects 5 sites with 4 U of the BoNT/A to the typical glabellar lines treatment sites.
  • the patient wears the embodiment producing the electric field for 30 minutes.
  • the patient experiences no ptosis.
  • a 54 year old female patient Is going to be treated to minimize glabellar lines with BoNT/A.
  • the doctor Prior to administering the toxin via needle Injection, the doctor applies a disclosed embodiment that generates a repeilant electric charge between the Intended injection sites and the patient’s eyes. An attractive charge is established toward the patient’s hairline. An electric field is established between trie two charges.
  • the doctor injects 5 sites with 4 U of the BoNT/A to the typical glabellar lines treatment sites. The patient wears the embodiment producing the electric field for 20 minutes The patient experiences no ptosis.
  • the doctor Injects 5 sites with 4 U of the BoNT/B to the typical glabellar lines treatment sites.
  • the patient wears the embodiment producing the electric field for 45 minutes The patient experiences no ptosis.
  • the doctor injects 7 sites with 3 U of the BoNT/A to the typical glabellar lines treatment sites.
  • the patient wears the embodiment producing the electric field for 45 minutes. The patient experiences no ptosis.
  • the doctor injects 5 sites between the charges with 4 U of the BoNT/A to the trapezius.
  • the patient wears the embodiment producing the positive electric field for one hour.
  • the patient experiences no neurotoxin dissipation toward the midiine, and the effect onset of the neurotoxin Is accelerated by the applied electric field.
  • a 33 year old female patient Is going to be treated to minimize crows feet with BoNT/A.
  • the doctor Prior to administering the toxin via needle injection, the doctor applies a disclosed embodiment comprising a zinc electrode that generates a positive electric field in a perimeter between the Intended Injection sites and the eyes. Then, the doctor Injects 5 sites with 4 U of the BoNT/A to the typical crow's feet treatment sites.
  • the doctor applies a disclosed embodiment comprising a sliver electrode that generates a negative electric field toward the hairline.
  • the patient wears the embodiments producing the electric field for 30 minutes. The patient experiences no ptosis.
  • a 54 year old female patient Is going to be treated to minimize crows feet with BoNT/A.
  • the doctor Prior to administering the toxin via needle injection, the doctor applies a disclosed embodiment comprising a electrode that generates a positive electric charge In a perimeter surrounding the intended injection sites. Then, the doctor injects 5 sites with 5 U of the BoNT/E to the typical crows feet treatment sites Following the Injections, the doctor applies a disclosed embodiment comprising an electrode that generates a negative electric field directly on top of the injection sites. The patient wears the embodiments producing the positive and negative charges for 30 minutes. The patient experiences no ptosis.
  • the doctor injects 5 sites with 4 U of the BoNT/B to the treatment sites.
  • the patient wears the embodiments producing the electric field for 30 minutes.
  • the patient experiences no spread of the toxin from the treatment site.
  • a 54 year old male patient Is going to be treated with hyaluronic acid.
  • the doctor Prior to administering the filler via needle Injection, the doctor applies a disclosed embodiment that generates a repellent electric charge In a perimeter surrounding the intended Injection sites.
  • the patient wears the embodiment producing the electric field for an hour. The patient experiences no diffusion of the filler.
  • a 43 year old female patient is going to be treated with hyaluronic acid Prior to administering the filler via needle Injection, the doctor applies a disclosed embodiment that generates a repellent electric field in a perimeter surrounding the Intended Injection sites. Following the injections, the doctor appiies a disclosed embodiment that generates an attractive electric field directly on top of the Injection sites. The patient wears the embodiments producing the attractive and repellent electric fields for 30 minutes. The patient experiences no diffusion of the filler.
  • a 33 year old female patient Is going to be treated to minimize crows feet with BoNT/A.
  • the doctor Prior to administering the toxin via needle Injection, the doctor applies a EMS device to minimize spread of the neurotoxin.
  • positive electrodes of the EMS Prior to Injection, positive electrodes of the EMS are applied to repel the toxin from beyond the treatment area, while the negative electrode Is placed toward the ears. The Intensity of the EMS is Increased until the patient reports a tingling sensation.

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Abstract

L'invention concerne des dispositifs et l'utilisation de ces derniers pour diriger la dissipation d'une composition chargée après l'njection, le dispositif ayant deux électrodes espacées l'une de l'autre sur un substrat flexible de telle sorte qu'un champ électrique directionnel peut être généré entre les deux électrodes, le substrat souple étant configuré pour être placé contre la peau d'un sujet et ayant soit un espace traversant positionné entre les deux électrodes qui est dimensionné pour permettre le passage d'un dispositif d'injection; soit un moyen pour former un espace de passage entre les deux électrodes qui est dimensionné pour permettre le passage d'un dispositif d'injection.
PCT/US2022/036147 2021-07-09 2022-07-05 Dispositifs et utilisation de ces derniers pour diriger la dissipation d'une composition chargée après administration WO2023283203A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8903485B2 (en) * 2009-08-06 2014-12-02 Incube Labs, Llc Patch and patch assembly for iontophoretic transdermal delivery of active agents for therapeutic and medicinal purposes
US20140356704A1 (en) * 2012-04-16 2014-12-04 Lg Chem Ltd. Electrode assembly including cathode and anode having different welding portion shapes and secondary battery including the same
US20190030329A1 (en) * 2016-03-28 2019-01-31 Ichor Medical Systems, Inc. Method and apparatus for delivery of therapeutic agents
WO2021062109A1 (fr) * 2019-09-27 2021-04-01 Liberate Medical, Llc Dispositifs et procédés de réglage et de suivi d'électrodes stimulant la respiration
US20210205609A1 (en) * 2019-02-20 2021-07-08 Regresar Medical, Inc. Methods and devices for localizing compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8903485B2 (en) * 2009-08-06 2014-12-02 Incube Labs, Llc Patch and patch assembly for iontophoretic transdermal delivery of active agents for therapeutic and medicinal purposes
US20140356704A1 (en) * 2012-04-16 2014-12-04 Lg Chem Ltd. Electrode assembly including cathode and anode having different welding portion shapes and secondary battery including the same
US20190030329A1 (en) * 2016-03-28 2019-01-31 Ichor Medical Systems, Inc. Method and apparatus for delivery of therapeutic agents
US20210205609A1 (en) * 2019-02-20 2021-07-08 Regresar Medical, Inc. Methods and devices for localizing compositions
WO2021062109A1 (fr) * 2019-09-27 2021-04-01 Liberate Medical, Llc Dispositifs et procédés de réglage et de suivi d'électrodes stimulant la respiration

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