WO2003047689A1 - Appareil et procedes d'administration de fluide utilisant des aiguilles electroactives et des dispositifs d'administration electrochimiques implantables - Google Patents

Appareil et procedes d'administration de fluide utilisant des aiguilles electroactives et des dispositifs d'administration electrochimiques implantables Download PDF

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Publication number
WO2003047689A1
WO2003047689A1 PCT/US2001/045421 US0145421W WO03047689A1 WO 2003047689 A1 WO2003047689 A1 WO 2003047689A1 US 0145421 W US0145421 W US 0145421W WO 03047689 A1 WO03047689 A1 WO 03047689A1
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WIPO (PCT)
Prior art keywords
electrochemically active
anode
electroactive
cathode
drug
Prior art date
Application number
PCT/US2001/045421
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English (en)
Inventor
Ashok V. Joshi
Original Assignee
Microlin Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Microlin Llc filed Critical Microlin Llc
Priority to AU2002220061A priority Critical patent/AU2002220061A1/en
Priority to EP01274928A priority patent/EP1355697A4/fr
Priority to PCT/US2001/045421 priority patent/WO2003047689A1/fr
Publication of WO2003047689A1 publication Critical patent/WO2003047689A1/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
    • A61N1/306—Arrangements where at least part of the apparatus is introduced into the body
    • 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

Definitions

  • the present invention relates to apparatus and methods for delivering drugs and other beneficial agents. More specifically, the present invention relates to apparatus and methods for subcutaneous, transdermal, intravenous, and intramuscular delivery of drugs and other beneficial agents to a subject.
  • transdermal delivery means introduction of drugs or other beneficial agents through, or by way of, the skin.
  • drug delivery systems typically provide for systemic administration of drugs in that the drug is delivered throughout the body by the bloodstream.
  • passive diffusion and active transport mechanisms can be used for more localized delivery of drugs into the tissues.
  • transdermal drug delivery has its own advantages over the various other delivery technologies. Most recently, transdermal drug delivery has been shown to offer particular promise for a number of reasons. As an alternative to medicines administered orally, transdermal drug delivery avoids the "first-pass" metabolism of the liver, allowing for relatively lower doses and more controlled delivery of conventional forms of certain drugs. In contrast to the direct injection of drugs, transdermal drug delivery allows for continuous and convenient drug administration over an extended time period. Transdermal delivery techniques can, in some applications, allow a subject unrestricted mobility, a benefit not afforded by many intravenous drug administration systems.
  • the low permeability of the outer surface of mammalian (including human) skin provides a daunting barrier to the transdermal administration of drugs at therapeutic levels.
  • the skin's outermost layer, the epidermis acts as the primary resistive barrier to drug diffusion.
  • the epidermis can be most basically described as an avascular layer of stratified squamous keratinized epithelium sitting on a basement membrane.
  • the epithelium can be subdivided into four primary layers from the base to the free surface.
  • the most resistive layer of the epidermis forms a superficial water-resistant protective layer called the stratum corneum.
  • the stratum corneum is composed of layers of dead tissue, essentially consisting of flattened cells filled with cross-linked keratin together with an extracellular matrix made up of lipids arranged largely in bilayers. Underlying the stratum corneum are the further layers of the epidermis, generally comprising three layers commonly identified as the stratum granulosum, stratum spinosum, and stratum basale. These further layers of the epidermis are followed by the dermis, which contains two layers, the papillary dermis and the reticular dermis.
  • Electrotransport processes are presently used in a wide variety of therapeutic drug delivery applications.
  • iontophoresis One method of using electrotransport for transdermal drug delivery is known as "iontophoresis.”
  • an ionized drug e.g., salts of a pharmaceutical or other drug which, when dissolved, form charged ions
  • the permeation rate (or "flux") of the ionized drug compound will be directly proportional to the strength of the applied electric current.
  • Electroosmosis A second type of electrotransport process involving the transdermal flux of a liquid solvent containing an uncharged drug or pharmaceutical agent, has been recognized as a means for delivery of an uncharged drug or agent into the body. Electroosmosis, in which the solvent convectively moves through a "charged pore” in response to the preferential passage of counter ions, can be induced by the presence of an electric field imposed across the skin by the active electrode of an iontophoretic device.
  • electrotransport A third type of electrotransport is known as “electroporation.” Electroporation can be used for drug or other agent transport by altering lipid bilayer permeability through the formation of transiently existing pores in the skin membranes.
  • a typical iontophoretic system 16 similar to the iontophoretic system disclosed in U.S. Patent 5,618,265 to Meyers et al., involves the placement of two oppositely charged "donor and counter" electrodes (an anode and a cathode) 18, 20 on a subject's skin surface 30 at or around a tissue region selected for therapeutic application.
  • a reservoir 22 containing the ionized drug to be delivered is placed under the electrode bearing the same charge as the drug (the "donor electrode").
  • a positively charged drug is placed under the positively charged anode electrode 18.
  • the negative electrode (cathode) 20 would be the active electrode under which the ionized drug would be placed.
  • An ion-conducting adhesive 28 may be situated under each electrode 18, 20 for stabilization of the electrodes. Electrolytes are typically added to the solution containing the ionized drug so that current can be easily conducted.
  • a selectively permeable membrane (not shown) may further be placed under the active electrode 18 to allow for selective flow of particular types of charged and uncharged species into skin surface 30.
  • a voltage source 24, typically a battery, supplies direct electric current by conductive wires 26 extending to the electrodes. At electrodes 18, 20, the current is converted to an ionic current by a series of oxidation-reduction reactions.
  • electrodes 18, 20 are spaced apart from one another on skin surface 30 where skin surface 30 acts as a conductor to complete the electrical circuit of iontophoretic system 16.
  • the charged drug is repelled by active electrode 18 into the skin 30 (as indicated by the arrows), thereby initiating drug transport by electrostatic repulsion, ionic conduction, and other cooperating electrotransport processes.
  • Representative iontophoretic systems are disclosed in U.S. Patent 5,618,265 to
  • Peptide and protein drugs are particularly affected by pH which exerts a major influence on their isoelectric point.
  • the characteristic charge associated with an ionizable drug in conjunction with the pH of the skin may render certain drugs more susceptible to iontophoretic transport than others.
  • influencing the effectiveness of iontophoretic delivery are many complicating factors that vary with age, gender, race, site of iontophoretic delivery, and skin characteristics of particular individuals (e.g., skin quality, skin follicle density, etc.).
  • the interface between an electrode and the skin can act as a further limiting factor, such as when the surface contact of an electrode is poor or when the skin tissue is dry and clean.
  • the transdermal delivery of many drugs requires that the iontophoretic apparatus be configured to achieve a "skin breakthrough voltage" of a particular threshold to initially overcome the rigorous impedance barrier of the stratum corneum. Once the impedance barrier of the stratum corneum has been broken down by the "skin breakthrough voltage," a follow-on voltage of a much lesser intensity is capable of continuing the transdermal facilitation of the drug across the skin barrier.
  • the need for a "skin breakthrough voltage" in the transdermal application of many drugs limits the usefulness of many prior art galvanic iontophoretic devices which are typically configured as relatively low-voltage systems.
  • the invention includes apparatus and methods for electrically assisted transport ("electrotransport”) of a drug or other beneficial agent through a skin or mucosal membrane surface, wherein at least one of the cathode or anode electrodes of an electrochemical cell is configured, at least in part, as an electroactive needle adapted to be inserted all or part way through the stratum corneum of a subject's skin, resulting in direct current flowing from the electroactive needle through the tissues of the subject.
  • a "subject” will typically be a mammal.
  • a reservoir contaimng a drug or other beneficial agent may be provided in fluid communication with one or more electroactive needles, in which case the electroactive needle(s) may be configured with a hollow bore interior extending therethrough for transport of the drug or other beneficial agent directly into a subject's tissues.
  • the drug or other beneficial agent is preferably provided as a liquid or dissolved in a fluid or solvent such that it is otherwise in liquid form.
  • the electroactive needle of the present invention may be configured of a length and shape suitable for intravenous and/or intramuscular delivery of a drug or other beneficial agent.
  • An apparatus of the present invention for transdermal, intradermal and/or subcutaneous delivery of a drug or other beneficial agent includes an electrochemical cell having an electrochemically active cathode and an electrochemically active anode wherein at least a portion of at least one of the cathode and anode is configured as at least one electroactive needle.
  • the present invention also includes a method of electrically facilitating the transport of a drug or other beneficial agent through body tissues of a subject.
  • the method comprises providing an anode configured to conduct current in relation to a first skin surface, providing a cathode and an anode configured to conduct current in relation to a respective skin surface wherein at least a portion of at least one of the cathode and anode are configured as at least one electroactive needle of a predetermined length, providing at least one conductor extending between and electrically interconnecting the anode with said cathode, providing a drug or other beneficial agent reservoir disposed adjacent and in fluid communication with an electrically conducting area of at least one of the anode and the cathode, inserting the electroactive needle a predetermined distance into a skin surface to electrochemically activate the anode and cathode, electrochemically generating a voltage from the activation of the anode and the cathode, and delivering voltage to the body tissues of a subject to facilitate the transport of a drug
  • the cathode and/or anode may be formed of a plurality of electroactive needles.
  • the electrotransport apparatus of the present invention may further include a battery, power cell, or one or more additional electrochemical cells, to boost the voltage of the apparatus.
  • a resistor can be added to control the voltage flow.
  • the device can be further configured to deliver medication contained in standard medication cartridges.
  • an implantable electrotransport system wherein one of the anode or cathode of an electrochemical cell is implanted under a skin surface.
  • the implantable electrode is configured as a porous or microporous metal substrate which allows drugs or other beneficial agents to flow therethrough.
  • a battery and resistor may be provided to enhance the performance of the device.
  • the present invention also includes a porous or microporous metal substrate electrode, comprising either the anode or the cathode of an electrochemical cell, mounted on a skin surface for the electrically assisted delivery of drugs or other beneficial agents through the skin.
  • an electrotransport system having active porous electrodes wherein the electrotransport sytem is entirely implantable under a skin surface.
  • FIG. 1 is a schematic representation of an exemplary prior art transdermal drug delivery device.
  • FIG. 2 is a schematic view of a preferred embodiment of an electrochemical transdermal delivery system according to the present invention.
  • FIG. 3 is a cross-sectional representation of a preferred embodiment of an electroactive needle of the present invention.
  • FIG. 4 illustrates an embodiment of the transdermal delivery system of the present invention for use in intravenous, subcutaneous, intramuscular or similar delivery of a drug or other beneficial agent.
  • FIG. 5 is a cross-sectional representation of a further embodiment of the electroactive needle shown in FIG. 4.
  • FIG. 6 is a simplified schematic view of a voltage-enhancing embodiment of an electrochemical transdermal delivery system according to the present invention.
  • FIG. 7 is a schematic view of another voltage-enhancing embodiment of the electrochemical transdermal delivery system according to the present invention.
  • FIG. 8 is a schematic view of another preferred embodiment of an electrochemical transdermal delivery system according to the present invention.
  • FIG. 9 is schematic representation of a preferred embodiment of an electrode according to the present invention.
  • FIG. 10 illustrates a variation of the preferred electrode embodiment of FIG. 9 according to the present invention.
  • FIG. 11 illustrates a further variation of the preferred electrode embodiment of FIG. 9 according to the present invention.
  • FIG. 12 illustrates an implantable embodiment of the present invention.
  • FIG. 13 illustrates a variation of the implantable embodiment of FIG. 12.
  • FIG. 14 is a schematic representation of an embodiment of the present invention mounted on a skin surface.
  • FIG. 15 illustrates an embodiment of the present invention which is entirely implantable under the skin.
  • electrotransport refers to the facilitated migration of beneficial fluids through body tissue in response to the flow of electrons. Electroosmosis, electroporation, iontophoresis, and combinations of any of these, are thus contemplated by the use of the term “electrotransport.” In the current context, however, such "electrotransport” generally occurs beneath the stratum corneum.
  • electroactive needle 40 participates in the generation of electrical current, and then delivers that electrical current to underlying and/or surrounding tissues of a subject.
  • the electrical current generated by electrochemical cell 62 facilitates the transdermal flux of drugs or other beneficial agents through selected body tissues of a subject.
  • Electroactive needle 40 will also preferably be formed with an internal passageway extending therethrough. As such, electroactive needle 40 can be used for direct delivery of drugs or other beneficial agents into body tissues underlying the skin's outer surface.
  • electroactive needle 40 is shown after insertion into a skin surface 60 of a patient.
  • a "receiving" electrode 50 is placed on a skin surface 60 at a location which is spaced apart from an upper surface of inserted active electrode 38.
  • Receiving electrode 50 is preferably constructed to be thin and flexible and to conform to the surface of a patient's skin.
  • Conductive wire 56 provides an electrical path between electrodes 38, 50, thus establishing an electrochemical cell 62.
  • underlying receiving electrode 50 is a conductive adhesive 58 for stabilizing receiving electrode 50 on skin surface 60 while preserving the electrode's ability to conduct current in relation to skin surface 60.
  • a polyacrylamide gel may be substituted for conductive adhesive 58.
  • a reservoir 52 normally containing a drug or other beneficial agent in liquid form (“beneficial fluids") 54, is positioned adjacent active electrode 38 such that the contents of reservoir 52 are in fluid communication with a hollow bore portion of electroactive needle 40.
  • liquid in the context of the drug or other beneficial agent should be understood to mean one or more drugs or beneficial agents provided in a fluid or solvent carrier or other form having a suitable rheology for gravity-assisted, electrically-assisted, and/or pressure-assisted flow through the bore of the electroactive needle of the present invention.
  • the beneficial fluids 54 in reservoir 52 are preferably provided without an ionic charge to prevent electrostatic repulsion or attraction in relation to electroactive needle 40.
  • initially-charged beneficial agents comprising the beneficial fluids 54 may have their charge neutralized by various drug carriers known to those of skill in the art.
  • Active electrode 38 including the electroactive needle 40 portion thereof which may comprise all or part of active electrode 38 can be formed as either an anode or a cathode.
  • the electrode can be comprised of any active metal, but is preferably comprised, at least in part, of Zn, Mg, Ca, Ba, Al, Sn, Fe, including alloys and mixtures of any of these.
  • the corresponding cathode electrode will then typically comprise any of the active metal oxides, halides, and chalcogenides, but will preferably comprise carbon, silver oxides, copper oxides, manganese dioxides, lithium, and mixtures thereof.
  • the electroactive needle 40 of active electrode 38 is constructed with a hollow bore interior or passageway 48 extending from external openings at both ends of electroactive needle 40 for voltage-enhanced delivery of beneficial fluids 54 through a skin surface 60 of a patient.
  • Electroactive needle 40 is preferably tapered and comprises a tip 42 for insertion into skin surface 60, a downwardly extending hollow shaft 44, and a shank end 46 which is positioned proximate skin surface 60 after insertion of electroactive needle 40 into skin 60.
  • shank end 46 is configured to be integrated with an air-tight fitting (not shown) of reservoir 52, the air-tight fitting such that the contents of reservoir 52 can flow through the external opening of shank end 46 and into a hollow bore portion of electroactive needle 40 while being completely sealed at the interface of shank end 46 and reservoir 52.
  • a fitting of reservoir 52 may comprise, for example, a connecting interface such as an O-ring configuration or other sealable arrangement known to those of skill in the art.
  • reservoir 52 may be fashioned such that a functional interface is accomplished by sealably molding or adhering a portion of reservoir 52 over an end portion of shank end 46.
  • Shank end 46 may also be configured with suitable interface fittings known in the art, as well as a sharp projecting tab (not shown) for puncturing a fluid-retaining portion of reservoir 52 during the installation of reservoir 52.
  • tip 42 is normally configured to be open-ended such that a liquid may be delivered through the hollow bore interior of shank end 46 and shaft 44 and out of tip 42.
  • Tip 42 may also be formed as a porous end or as otherwise having arranged multiple openings for various distribution patterns in the delivery of a beneficial fluid.
  • Shaft 44 may also be configured as porous, in whole or in part.
  • Shaft 44 extends to a predetermined length consistent with the desired therapeutic application.
  • shaft 44 will preferably extend through some, most, or all of the stratum corneum for delivery of beneficial fluids 54 to underlying and/or surrounding tissues.
  • shaft 44 will extend electroactive needle 40 to a length that is slightly longer than the depth of the stratum corneum.
  • the length for shaft 44 in this embodiment will be 2 mm or less so that tip 42 will not bruise capillary vessels in the vascular papillary and reticular tissue layers of the dermis.
  • Shaft 44 may also be configured of a length suitable for intravenous or intramuscular delivery of beneficial fluids 54. An example of an intravenous delivery embodiment of the present invention is shown in FIG. 4.
  • the diameter of shaft 44 may vary substantially, dependent upon the particular application used. In most applications, shaft 44 will be configured to be narrow enough such that the insertion of shaft 44 into the skin results in little or no bruising or swelling of the skin, while still permitting the voltage-enhanced delivery of beneficial fluids through the hollow passageway of shaft 44 and tip 42. Typically, shaft diameters of up to 400 ⁇ m are preferred to limit damage to skin 60. Shaft 44 may also be formed of various larger diameters or irregular diameters and with larger or varying hollow interiors therein to increase or alter the flow of beneficial fluids. In another preferred embodiment, at least a portion of shaft 44 may be electrically insulated from the skin for more focused delivery of electrochemically generated voltage, preferably with a biocompatible insulator. For example, various nontoxic polymeric resins (e.g., silicone rubber), ceramic materials or blends thereof (e.g, hydroxyapatite blends) may be used for insulating shaft 44.
  • various nontoxic polymeric resins e.g., silicone rubber
  • Shaft 44 may be alternatively coated with a microporous and microthin (preferably on the order of microns) separator material known in the art, including materials comprising microporous polymers such as polypropylenes, polyethylenes, polytetrafluoroethenes (PFTEs), and the like, to enhance the mechanical and chemical surface properties of shaft 44 by reducing friction, fretting, fatigue, and by providing corrosion resistance.
  • PFTEs polytetrafluoroethenes
  • surface modification technologies such as diffusion, laser and plasma processes, chemical plating, grafting or bonding, hydrogel encapsulation, and bombardment with high-energy particles, may be used in the application of such coatings.
  • Antimicrobial and antibacterial treatments and coatings known in the art may also be employed in addition to each of the coatings previously described. Antimicrobial and antibacterial treatments and coatings may also be applied directly to shaft 44.
  • electroactive needle 40 into skin surface 60, in conjunction with placement of receiving electrode 50 over a second skin or mucosal membrane surface, closes the electrical circuit between electrodes 38, 50, thus activating electrotransport system 32.
  • the substratum corneum tissue layer provides a portion of the electroconductive pathway of the electrochemical cell.
  • electrotransport system 32 Upon activation of electrotransport system 32, a voltage is generated by the electrochemical interaction of electrodes 38, 50, causing electrons to be released from anode electrode 38 and consumed at cathode electrode 50.
  • electroactive needle 40 forms at least a portion of active electrode 38, electroactive needle 40 participates in the electrochemical generation of voltage in electrotransport system 32. A steady direct current is thus applied between electrodes 38, 50.
  • the voltage generated by electrodes 38, 50 increases the rate of transdermal, intradermal and/or subcutaneous flux by reducing the physical resistance and/or enhancing the permeability of underlying and/or surrounding tissue layers.
  • the current path facilitates the movement of beneficial fluid 54 through the desired underlying and/or surrounding tissues of the patient, and in some instances, facilitates the movement of beneficial fluid 54 into the systemic circulation.
  • shaft 44 extends downwardly through skin surface 60 to a predetermined distance such that tip 42 of electroactive needle 40 pierces and resides in a vein 64.
  • Electroactive needle 40 is preferably designed to be inserted with the use of light or mild manual compression. Prior to insertion, of course, the skin surface will be properly cleaned and otherwise prepared for needle insertion. As shown in FIG. 5, electroactive needle 40 can be further configured with a platform portion 66 preferably formed of the same electrochemically active materials as electroactive needle 40.
  • platform portion 66 may be formed of various other suitably rigid, but not electrochemically active, materials.
  • Platform portion 66 of electroactive needle 40 surrounds shank end 46 and the external opening therein to provide a planar supporting surface for the exertion of manual compression leading to the insertion of electroactive needle 40 into skin 60.
  • Platform portion 66 may be coplanar with a top surface of shank end 46, or may extend outwardly from a more distal surface portion of shank end 46 in parallel or substantially parallel fashion, depending upon the intended angle of insertion of electroactive needle 40, the length and diameter of electroactive needle 40, and the like. Platform portion 66 thus remains on the exterior of skin surface 60 after the insertion of electroactive needle 40 into skin surface 60.
  • platform portion 66 When formed of the same electrochemically active materials as electroactive needle 40, platform portion 66 forms an electrochemically active portion of active electrode 38.
  • Platform portion 66 can also be configured as a basement portion of a housing adapted as an enclosure for electrode 38, reservoir 52, and/or the entire electrotransport apparatus 32.
  • platform portion 66 can perform a supportive and/or interconnective function with regard to reservoir 52. It should be further recognized that conductive wires 56 can be attached to platform portion 66 to provide an electrical path between electrodes 38, 50. Platform portion 66 also helps the user insert the electroactive needle 40 to the proper depth beneath the skin. Moreover, platform portion 66 tends to press against the skin at the insertion site of electroactive needle 40, which substantially eliminates or reduces any bleeding which might result from the insertion.
  • a plurality of electrochemically active cells 62, 72, 74, 76, etc. may be provided and connected in series for higher voltage across the skin 60, as shown in electrotransport system 34 (FIG. 6).
  • By “connected in series” it is meant that an anode electrode 38 of one or more electrochemical cells 62, 72, 74, 76 is electrically connected to a cathode electrode 50 of one or more other electrochemical cells 62, 72, 74, 76 such that the electrochemical cells 62, 72, 74, 76 are connected to one another by positive terminal (anode) to negative terminal (cathode), or vice versa.
  • the voltage generated is drawn from an electrochemical cell (e.g., an electrically interconnected anode electrode 38 and cathode electrode 50) at the end of the series string.
  • Electrochemical cells 62, 72, 74, 76 connected in series supply the same current but produce a higher voltage.
  • a conductive adhesive 58 may be provided under each electrode 38, 50 on a skin surface 60 to stabilize the electrodes 38, 50.
  • the multiplied voltage resulting from the series of additional electrochemical cells 62, 72, 74, 76, etc., is ultimately relayed to electroactive needle 40 and receiving electrode 50 of electrochemical cell 62, wherein the increased resultant voltage can be delivered through the deeper layers of the skin, the tissues, and/or the systemic circulation.
  • the increase in transport voltage will be proportional to the enhancement of delivery of the beneficial fluids.
  • Varying numbers of cathodes and anodes may be arranged in series to produce a desired voltage, thus more readily facilitating the delivery of high molecular weight drugs or agents, and providing for controlled and tailored delivery of various concentrations of medicaments in beneficial fluids.
  • the electromotive force of the cell may further be enhanced by the choice of metals, composites and the like for the electrodes wherein the anode material and the cathode material are selected from materials having maximum difference in potentials according to the electromotive series.
  • the invention as described hereinabove has involved an electrochemical cell wherein voltages, driving forces and successful operation are derived from the device acting as a galvanic cell.
  • electrotransport system 32 further includes a power source 68 (typically a battery or power cell) interposed between electrodes 38, 50 to assist electrochemical cell 50 by delivering additional direct current to electrodes 38, 50 via conductive wires 56.
  • a power source 68 typically a battery or power cell
  • power source 68 acts to increase the voltage delivered at electroactive needle 40 while supplying the same current.
  • the increased transport voltage allows for increases in the electrotransport of the drugs or other beneficial agents in beneficial fluids 54.
  • the size and profile of the power source (e.g., battery) 68 can be greatly reduced, resulting in smaller over-all size of the electrotransport system of the present invention in comparison to conventional iontophoretic systems.
  • the materials selected for the anode and cathode may be different than for purely galvanic cells, since less internal generation of electromotive force is required.
  • resistor may be interposed in the forward electron flow path of conductive wires 56, as opposed to the return path, to control the flow of current from power source 68.
  • the collective arrangement of resistor and power source 68 thus forms a "voltage controller,” as may be referred to hereinafter.
  • an electrotransport system 132 of the present invention is shown configured with two or more electroactive needles 140, 142 as cathodes and anodes
  • electroactive needles 140, 142 are formed and configured as described in relation to FIGs. 2, 3, 4 and/or FIG. 5, wherein one or both electroactive needles 140, 142 of cathode and anode 138, 150 include a hollow bore passageway extending through shank, shaft and tip portions of the needles for transdermal delivery of beneficial fluids 154 contained within reservoir 152.
  • a conductive wire 156 extending between electroactive needles 140, 142 of cathode and anode 138, 150 electrically interconnects electroactive needles 140, 142, thus establishing electrochemical cell 162.
  • Reservoir 152 is in fluid communication with one or both of electroactive needles 140, 142 of cathode and anode 138, 150 such that delivery of beneficial fluids 154 can be effected through one or both of electroactive needles 140, 142.
  • Electrotransport system 132 is activated upon insertion of each of electroactive needles 140, 142 into the skin 160, wherein the transdermal delivery of beneficial fluids 154 is facilitated by the electron path resulting from the varying electromotive potentials of electroactive needles 140, 142. Since each of electroactive needles 140, 142 is inserted some, most, or all the way through the stratum corneum of skin 160, significant reductions in the innate resistance of the skin 160 result.
  • the level of voltage required to be electrochemically generated by electroactive needles 140, 142 for facilitated transport of beneficial fluids 152 is minimal.
  • the voltage produced by electrotransport system 132 can be increased by the inclusion of additional electrochemical cells arranged in series or by the introduction of an assisting additional power source, such as a battery.
  • One advantage of the use of multiple needles is that larger quantities of beneficial fluids can be delivered over a shorter period of time.
  • Other advantages include larger diffusion areas for drug (beneficial fluid) delivery, increased material for longer lasting cathode or anode performance, and minimization of skin damage caused by the width of any one particular electroactive needle shaft.
  • FIG 9 represents another preferred embodiment of an electrotransport system 232, wherein at least one electrode of electrodes 238, 250 of an electrochemical cell 262 is comprised of a plurality of electroactive needles 240.
  • a conductive wire 256 provides an electrical path between active electrode 238 (comprising electroactive needles 240) and a receiving electrode 250 of a varying electromotive potential, thus establishing electrochemical cell 262.
  • Receiving electrode 250 is constructed and configured as previously described with regard to FIG. 2.
  • Electroactive needles 240 together comprise a single active electrode 238 and are thus electrically interconnected by integral construction, conductive bridges, and the like. Accordingly, each of electroactive needles 240 is formed of like materials suitable for the respective use of electrode 238 as a cathode or anode (as previously described with regard to FIG. 2). In terms of design and function, each of electroactive needles 240 is constructed consistently with one or more of the embodiments described in FIGs. 2, 3, and 4. Electroactive needles 240 are thus each configured for the electrically- assisted transdermal, intradermal and/or subcutaneous delivery of beneficial fluids 254.
  • a reservoir 252 containing beneficial fluids 254 interfaces with each of electroactive needles 240 such that beneficial fluids 254 are in fluid communication with the interior passageways with each electroactive needle 240.
  • Electrotransport system 232 is activated upon the insertion of electroactive needles 240 into the skin 260 in conjunction with placement of electrode 250 on a spaced apart skin surface. Insertion of electroactive needles 240 takes place by manual compression.
  • electroactive needles 240 are distributed spatially along on a flexible material, such tape or a pliable resin, to allow electroactive needles 240 to be pressed into skin 260 sequentially, or in small groups, such that the ratio of force (i.e., compression) per unit area of skin is maximized.
  • electroactive needles 240 Various patterns and spatial arrangements of electroactive needles 240 are contemplated, however, dependent upon the particular therapeutic application.
  • electrochemical cell 262 Upon activation of electrotransport system 232, electrochemical cell 262 generates a current which is applied under skin 260 by the plurality of electroactive needles 240. The electrochemically-generated current then facilitates the transdermal, intradermal and/or subcutaneous transport of beneficial fluids 254 from electroactive needles 240 into the underlying and/or surrounding tissues of the patient's body.
  • an additional power source e.g., a battery
  • additional electrochemical cells arranged in series may be easily incorporated into electrotransport system 232 to increase the system voltage.
  • receiving electrode 250 may also be constructed as a plurality of electroactive needles 242, as well as interfaced with reservoir 252 for delivery of beneficial fluids 254 as is shown in electrotransport system 233 depicted in FIG. 10.
  • electrotransport system 234 (FIG. 11).
  • some of the electroactive needles comprising electrode 238 have been formed so as to be of solid construction, rather than as having hollow passageways as described in relation to FIG. 9.
  • the solidly formed electroactive needles 248 are positioned peripherally in relation to electroactive needles 240 formed with hollow passageways therethrough.
  • each of electroactive needles 248 and 240 is configured to be electrochemically active and to distribute current into the skin 260 of a patient, only electroactive needles 240 formed with hollow passageways are in fluid communication with beneficial fluids 254 within reservoir 252.
  • FIG. 12 illustrates an embodiment of an implantable electrotransport system 332.
  • one of an anode and cathode electrode 338, 350 is surgically implanted under a skin surface 360 of a subject, preferably to a depth just exceeding that of the stratum corneum 364.
  • electrodes 338, 350 are electrochemically active and are of differing electromotive potentials so as to form an electrochemical cell 362. Representative materials for the composition of both electrodes 338, 350 have been previously described in relation to the electrotransport system of FIG. 2.
  • electrode 338 is configured as an anode (“anode 338"). As shown in FIG.
  • anode 338 is implanted while cathode 350 remains extracorporeally on skin surface 360.
  • the activation of electrotransport system 332 results in electrochemical generation of power (voltage) by electrochemical cell 362 that is capable of facilitating the diffusion of fluids through the tissues of a subject, the fluids and voltage delivered by way of anode 338.
  • An additional power source 368 (typically a battery) is preferably added to the circuit in furtherance of increased and/or sustained voltage.
  • a resistor 370 will preferably be interposed between power source 368 and anode 338 to control the flow of current through anode 338.
  • an implantable electrotransport system 332 comprises an implanted electrode (in this case, anode 338) wherein the implanted electrode is configured as a porous metal substrate of a predetermined thickness.
  • the implanted electrode 338 will be microporous throughout and comprise a substrate formed of an active metal oxide configured in a finely interwoven "wool"- or “mesh” for reasons to be discussed hereinafter.
  • the implanted electrode 338 may also be formed of other active materials, including halides, sulfides, alloys, and various mixtures of metal oxides, halides, sulfides, and alloys.
  • a reservoir 352, containing beneficial fluids 354 therein, is implanted with anode 338 and in fluid communication therewith.
  • anode 338 is configured with a microporous external surface and having a rasp-like surface 340, comprising a plurality of sharp, raised, pointed projections, situated thereon.
  • Rasp-like surface 340 may be integral to anode 338 or provided as a separate component which is sealably interfaced with anode 338.
  • rasp-like surface 340 and anode 338 are otherwise interfaced with one another in a sealable arrangement with respect to beneficial fluids 354 in reservoir 352 and the surrounding tissue of a subject.
  • the porous or sieve-like nature of anode 338 is preferably adapted to be substantially uniform throughout anode 338, allowing beneficial fluids 354 to flow or percolate into interior portions of anode 338 and to flow or percolate out of one or more exterior surfaces of anode 338 in a fairly evenly distributed manner.
  • beneficial fluids 354 entering the porous anode 338 the porosity of anode 338 will allow beneficial fluids 354 to progress therethrough in a flow-retarded fashion.
  • the flow rate of beneficial fluids 354 will thus vary according to the thickness and porosity of anode 3 8, the rheology of beneficial fluids 354, and increases in diffusion of beneficial fluids 354 caused by the electrical current applied to adjacent tissue areas by anode 338.
  • delivery flow rates for a particular concentration of drugs or other beneficial agents contained in beneficial fluids 354 can thus be optimized in terms of dosage over time by adjustment of any of these parameters.
  • anode 338 may be configured of a size and shape known in the art (e.g., provided in thin small outline form) which allows anode 338 to remain in an implanted state for an indefinite period of time without interfering with the normal daily activities of the subject, and with little or no discomfort and physiological reaction to the implanted device. Furthermore, it is preferable that anode 338 be coated for the protection and biocompatibility of anode 338 and/or for focused delivery of beneficial fluids 354. Methods and materials suitable for coating anode 338 have been previously described with respect to shaft 44 of electroactive needle 40 (see discussion of FIG. 3). Benefits of electrotransport system 332 with implantable anode 338 include substratum corneum transfer of beneficial fluids 354, as well as a relatively large diffusion area for beneficial fluids 354 owing to the porous fluid delivery surface area of anode 338.
  • FIG. 13 shows an alternate embodiment 334 of the electrotransport system of FIG. 12.
  • the configuration is similar except that reservoir 352 is placed on a skin surface 360 overlying anode 338 and in fluid communication with porous anode 338 by means of a fluid transport intermediary, shown as a catheter 380, which extends through skin surface 360.
  • catheter 380 sealably attaches to reservoir 352 at one end, where catheter 380 and reservoir 352 may be interfaced in a detachable manner.
  • Catheter 380 is sealably attached to a second reservoir 382 of reduced size in relation to reservoir 352, at a second catheter end. Catheter 380 thus allows transfer of beneficial fluids 354 from reservoir 352 to second reservoir 382.
  • catheter 380 and second reservoir 382 are integrally fashioned as a single component.
  • Reservoir 382 is provided immediately adjacent anode 338 and is thus implanted under the skin surface of a subject along with anode 338.
  • Reservoir 382 is configured to store and deliver beneficial fluids 354 over a porous surface region of anode 338 for percolation therethrough as previously discussed.
  • This embodiment is additionally advantageous in that the diameter of catheter 380 provides another means for controlling dosage and that reservoir 352 can be readily exchanged or refilled with additional beneficial fluids 354.
  • an electrotransport system 432 comprises an electrochemically active porous anode electrode 438, conceptually similar to anode 338 of FIG. 12, placed on the skin surface 460 via a skin contact area 442 of anode 438.
  • An electrochemically active cathode electrode 450 is also provided on skin surface 460 in a spaced-apart relationship with anode 438. Materials for the composition of electrochemically active electrodes 438, 450 have been previously described in relation to the electrotransport systems of FIGs. 2 and 12.
  • a connecting wire 456 electrically interconnects electrodes 438, 450, creating an electrochemical cell 462.
  • anode 438 may be formed of a porous metal substrate of a predetermined thickness, such as a finely interwoven metal oxide wool or mesh.
  • anode 438 may be formed of a porous and active metal oxide-filled polymer or adhesive.
  • a microporous and active metal oxide-filled polymer tape may be used as anode 438.
  • Anode 438 is preferably provided with a relatively thin cross-section relative to cathode 450.
  • the active metal oxide filler will preferably comprise materials such as Zn, Mg, Ca, Ba, Sn, Fe, as well as their alloys and mixtures.
  • a conductive adhesive (not shown) may be supplied under anode 438 and/or cathode 450.
  • the innate material composition provided for the porous and active metal oxide-filled polymer or adhesive will provide sufficient adherence for anode 438 to be stabilized with respect to skin 460.
  • a reservoir 452 containing beneficial fluids 454 is provided adjacent a reservoir mounting surface 440 of anode 438 and in fluid communication with pores or micropores thereof. Reservoir 452 is otherwise fitted to anode 438 in a sealed and airtight arrangement by methods known in the art.
  • An additional power source 468 typically a battery
  • Power source 468 will preferably provide sufficient voltage, alone or in combination with the electrochemical generation of power from anode 438 and cathode 450, to establish a "skin breakthrough voltage" which overcomes the resistive properties of the stratum corneum.
  • anode 438 will have uniform porosity throughout and will be insulatively coated or otherwise sealed on its exterior surfaces excluding, of course, the fluid transporting regions of reservoir mounting surface 440 and skin contact area 442.
  • the porosity of anode 438 will allow beneficial fluids 454 to advance and percolate, in a flow-retarded fashion from reservoir 452, through anode 438, and out the bottom surface of skin contact area 442.
  • the entirety of the electrotransport apparatus of FIG. 14 can be adapted to be implanted below the skin surface of a subject, as is illustrated in FIG. 15.
  • Like reference numerals are provided in FIG. 15 for the like components previously shown in FIG. 14.
  • each of anode 438, cathode 450, reservoir 452, insulated connecting wire 456, power source 468, and resistor 470 of electrotransport apparatus 432 may be subcutaneously implanted under the skin surface 460.
  • electrotransport apparatus 432 is implanted to a depth which is at least below the depth of the stratum corneum layer of the skin 460.
  • the transdermal flux of beneficial fluids 454 is enhanced as both anode 438 and cathode 450 may advantageously deliver electrical current without hindrance from the stratum corneum barrier layer.
  • anode 438 can be provided as a porous metal substrate of a predetermined thickness and configured as previously described in relation to implantable electrode 338 of FIG. 12.
  • the reservoir 452 and anode 438 are also preferably interfaced as previously described in relation to FIG. 12.
  • a unitary housing (not shown) made of biocompatible material will preferably be provided over anode 438, cathode 450, reservoir 452, insulated connecting wire 456, power source 468, and resistor 470.
  • the unitary housing may serve to position anode 438 and cathode 450 a predetermined separation distance from one another, as well as function to protect and stabilize electrotransport system 432 during handling, implantation, and while functioning under the skin 460.
  • the unitary housing which may be molded by processes known in the art for a secure fit over the components of electrotransport system 432, is configured to not interfere with the electrical flow from anode 438 and cathode 450 to the tissues under the skin.
  • the unitary housing will also preferably be configured of a size and shape known in the art (e.g., provided in thin small outline form) which allows electrotransport system 432 to remain in an implanted state for an indefinite period of time without interfering with the normal daily activities of the subject, and with little or no discomfort and physiological reaction to the implanted device.
  • the above-described apparatus and methods according to the present invention represent an improvement over conventional iontophoretic systems.
  • the electroactive needle of the present invention extends all or part way through the stratum corneum of a skin surface, the keratinous and bilipid barriers of the outermost skin layer can be breached, resulting in a substantial reduction in impedance to the voltage electrochemically generated by the apparatus.
  • the electrochemically generated voltage from the electrodes of the system thus facilitates the flow of the beneficial agents into patient tissue which underlies and/or surrounds the electroactive needle without the need for a "skin breakthrough voltage.”
  • the apparatus and methods according to the present invention bypass potential alterations to the charge of a beneficial substance which may otherwise occur as a result of the relatively low pH on the outer surface of the skin.
  • the apparatus and methods of the present invention are particularly suited for the delivery of therapeutic proteins and peptides.
  • the apparatus of the present invention can be easily adapted to accept standard medication cartridges (a type of reservoir) which are pre-loaded with fluids comprising drugs and other beneficial agents.
  • the reservoir may also be configured to be interfaced with one or both of the electrodes of the present invention in various orientations.
  • a semipermeable membrane preferably permeable to a nonionic form of the therapeutic agent in the beneficial fluid reservoir, is also contemplated for use in the present invention.
  • the semipermeable membrane could be interposed, for example, between the beneficial fluid reservoir and the shank end of the electroactive needle.
  • the electroactive needles of the present invention can be sterilized between uses by sterilization techniques known in the art. Alternatively, the electroactive needles may be disposed of after a single use. Additionally, the skin surface may be conditioned with bromelain, papain or similar skin conditioners which remove or alter the stratum corneum whereby electroactive needle penetration may be facilitated, the electrotransport circuit more easily realized, and the flow of delivered fluids more readily transported along solid needles to a substratum corneum delivery site. Skin-piercing microparticles known in the art could likewise be used in conjunction with the electroactive needles, skin conditioners, and other device embodiments disclosed herein to further reduce the resistive properties of the stratum corneum.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Electrotherapy Devices (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un appareil et des procédés permettant d'électrotransporter un médicament ou un autre agent bénéfique à travers une surface membraneuse de la peau ou des muqueuses. Dans un mode de réalisation, l'électrode cathode (38) ou l'électrode anode (50) au moins d'une cellule électrochimique est configurée sous forme d'aiguille électroactive (40) destinée à être insérée à travers la couche cornée de l'épiderme de la peau du patient. Un réservoir (52) contenant un agent bénéfique peut être en communication fluidique avec au moins une aiguille électroactive (40), cette/ces aiguille(s) électroactives(s) (40) comportant une partie intérieure à alésage destinée à transporter l'agent bénéfique directement dans les tissus du sujet. Dans un autre mode de réalisation, une aiguille électroactive (40) est configurée pour une utilisation intraveineuse et/ou intramusculaire. L'invention concerne également un système d'électrotransport (32) comprenant un substrat poreux actif électrochimiquement. Un autre mode de réalisation concerne un système d'électrotransport comprenant au moins une électrode poreuse active implantable (338).
PCT/US2001/045421 2001-11-29 2001-11-29 Appareil et procedes d'administration de fluide utilisant des aiguilles electroactives et des dispositifs d'administration electrochimiques implantables WO2003047689A1 (fr)

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AU2002220061A AU2002220061A1 (en) 2001-11-29 2001-11-29 Apparatus and methods for fluid delivery using electroactive needles and implantable electrochemical delivery devices
EP01274928A EP1355697A4 (fr) 2001-11-29 2001-11-29 Appareil et procedes d'administration de fluide utilisant des aiguilles electroactives et des dispositifs d'administration electrochimiques implantables
PCT/US2001/045421 WO2003047689A1 (fr) 2001-11-29 2001-11-29 Appareil et procedes d'administration de fluide utilisant des aiguilles electroactives et des dispositifs d'administration electrochimiques implantables

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PCT/US2001/045421 WO2003047689A1 (fr) 2001-11-29 2001-11-29 Appareil et procedes d'administration de fluide utilisant des aiguilles electroactives et des dispositifs d'administration electrochimiques implantables

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WO2007030415A3 (fr) * 2005-09-07 2007-09-20 The Foundry Inc Appareil et procede permettant de desintegrer des structures sous-cutanees
US7967763B2 (en) 2005-09-07 2011-06-28 Cabochon Aesthetics, Inc. Method for treating subcutaneous tissues
US8167280B2 (en) 2009-03-23 2012-05-01 Cabochon Aesthetics, Inc. Bubble generator having disposable bubble cartridges
US8439940B2 (en) 2010-12-22 2013-05-14 Cabochon Aesthetics, Inc. Dissection handpiece with aspiration means for reducing the appearance of cellulite
US8518069B2 (en) 2005-09-07 2013-08-27 Cabochon Aesthetics, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US9011473B2 (en) 2005-09-07 2015-04-21 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US9248317B2 (en) 2005-12-02 2016-02-02 Ulthera, Inc. Devices and methods for selectively lysing cells
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US9358033B2 (en) 2005-09-07 2016-06-07 Ulthera, Inc. Fluid-jet dissection system and method for reducing the appearance of cellulite
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WO2007030415A3 (fr) * 2005-09-07 2007-09-20 The Foundry Inc Appareil et procede permettant de desintegrer des structures sous-cutanees
US7967763B2 (en) 2005-09-07 2011-06-28 Cabochon Aesthetics, Inc. Method for treating subcutaneous tissues
US9179928B2 (en) 2005-09-07 2015-11-10 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US8348867B2 (en) 2005-09-07 2013-01-08 Cabochon Aesthetics, Inc. Method for treating subcutaneous tissues
US8366643B2 (en) 2005-09-07 2013-02-05 Cabochon Aesthetics, Inc. System and method for treating subcutaneous tissues
US9011473B2 (en) 2005-09-07 2015-04-21 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US8518069B2 (en) 2005-09-07 2013-08-27 Cabochon Aesthetics, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US9005229B2 (en) 2005-09-07 2015-04-14 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US9486274B2 (en) 2005-09-07 2016-11-08 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US9364246B2 (en) 2005-09-07 2016-06-14 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US9358033B2 (en) 2005-09-07 2016-06-07 Ulthera, Inc. Fluid-jet dissection system and method for reducing the appearance of cellulite
WO2007040938A1 (fr) * 2005-09-30 2007-04-12 Tti Ellebeau, Inc. Systemes, dispositifs et procedes d'apport de medicament transdermique a micro-aiguilles fonctionnalisees
US9272124B2 (en) 2005-12-02 2016-03-01 Ulthera, Inc. Systems and devices for selective cell lysis and methods of using same
US9248317B2 (en) 2005-12-02 2016-02-02 Ulthera, Inc. Devices and methods for selectively lysing cells
US10548659B2 (en) 2006-01-17 2020-02-04 Ulthera, Inc. High pressure pre-burst for improved fluid delivery
US10220122B2 (en) 2007-10-09 2019-03-05 Ulthera, Inc. System for tissue dissection and aspiration
US9039722B2 (en) 2007-10-09 2015-05-26 Ulthera, Inc. Dissection handpiece with aspiration means for reducing the appearance of cellulite
US8167280B2 (en) 2009-03-23 2012-05-01 Cabochon Aesthetics, Inc. Bubble generator having disposable bubble cartridges
US9078688B2 (en) 2009-08-07 2015-07-14 Ulthera, Inc. Handpiece for use in tissue dissection
US9757145B2 (en) 2009-08-07 2017-09-12 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US8979881B2 (en) 2009-08-07 2015-03-17 Ulthera, Inc. Methods and handpiece for use in tissue dissection
US8920452B2 (en) 2009-08-07 2014-12-30 Ulthera, Inc. Methods of tissue release to reduce the appearance of cellulite
US8906054B2 (en) 2009-08-07 2014-12-09 Ulthera, Inc. Apparatus for reducing the appearance of cellulite
US9358064B2 (en) 2009-08-07 2016-06-07 Ulthera, Inc. Handpiece and methods for performing subcutaneous surgery
US8900262B2 (en) 2009-08-07 2014-12-02 Ulthera, Inc. Device for dissection of subcutaneous tissue
US8900261B2 (en) 2009-08-07 2014-12-02 Ulthera, Inc. Tissue treatment system for reducing the appearance of cellulite
US9510849B2 (en) 2009-08-07 2016-12-06 Ulthera, Inc. Devices and methods for performing subcutaneous surgery
US9044259B2 (en) 2009-08-07 2015-06-02 Ulthera, Inc. Methods for dissection of subcutaneous tissue
US8894678B2 (en) 2009-08-07 2014-11-25 Ulthera, Inc. Cellulite treatment methods
US10271866B2 (en) 2009-08-07 2019-04-30 Ulthera, Inc. Modular systems for treating tissue
US10485573B2 (en) 2009-08-07 2019-11-26 Ulthera, Inc. Handpieces for tissue treatment
US10531888B2 (en) 2009-08-07 2020-01-14 Ulthera, Inc. Methods for efficiently reducing the appearance of cellulite
US11337725B2 (en) 2009-08-07 2022-05-24 Ulthera, Inc. Handpieces for tissue treatment
US11096708B2 (en) 2009-08-07 2021-08-24 Ulthera, Inc. Devices and methods for performing subcutaneous surgery
US10603066B2 (en) 2010-05-25 2020-03-31 Ulthera, Inc. Fluid-jet dissection system and method for reducing the appearance of cellulite
US11213618B2 (en) 2010-12-22 2022-01-04 Ulthera, Inc. System for tissue dissection and aspiration
US8439940B2 (en) 2010-12-22 2013-05-14 Cabochon Aesthetics, Inc. Dissection handpiece with aspiration means for reducing the appearance of cellulite

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AU2002220061A1 (en) 2003-06-17
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