Classifications

• • 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
  • A61N1/0432—Anode and cathode
  • A61N1/044—Shape of the electrode
• • 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
  • A61N1/0448—Drug reservoir
• • 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
  • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/02—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
  • A61N1/0432—Anode and cathode
  • A61N1/0436—Material of the electrode

Definitions

• the present invention relates to both a passive and an electricity-assisted delivery system for transporting active agents across a body surface of a mammal (e.g., the skin or mucosa of a human) .
• This system delivers active agents more efficiently than prior passive or electrotransport systems.
• Transdermal and topical dosage forms have been widely prescribed for decades in the treatment of systemic diseases and local conditions such as those involved with the skin and underlying tissues.
• an active agent is delivered into a mammal by using a concentration gradient across a barrier membrane (e.g., through passive diffusion through skin) .
• a patch containing the drug in high concentration is affixed to the skin of a patient.
• Such transdermal delivery systems have been approved in the United States for the administration of scopolamine, nitroglycerin, clonidine, 17-B-estradiol , fentanyl, nicotine, and testosterone.
• Electricity also may be employed to facilitate drug transport across the skin barrier.
• an electric potential (voltage) is applied to the skin to facilitate drug transport .
• transdermal iontophoresis an ionized drug migrates into the skin driven by an applied electric potential gradient.
• electro-osmosis a non- ionic drug to be delivered is carried by a fluid, which is driven across the skin by an applied electric potential gradient.
• Electroporation is the microscopic perforation of the skin barrier by extremely short pulses of high electric voltage and low electric current.
• an electrotransport system may actually deliver the active agent simultaneously with both iontophoresis and electro-osmosis.
• electroporation can be used first to increase the skin permeability, followed by iontophoresis to transport the active agent through the skin barrier.
• the apparatus e.g., the drug reservoir, conductive electrode, and a counter electrode
• the present invention relates to an apparatus for the delivery of an active agent through a body surface (e.g., the skin or mucosa) of a mammal (e.g., a human) comprising: a housing with a delivery orifice through the housing; an active agent reservoir within the housing for containing the active agent
• the active agent reservoir is in communication with the delivery orifice; a fluid reservoir within the housing for containing a fluid (e.g., a low electrolyte aqueous solution such as distilled water) ; and a semi-permeable membrane in communication with the active agent reservoir and the fluid reservoir for both permitting the movement of fluid (e.g., water an non-active agent ions solublized therein) between the active agent reservoir and the fluid reservoir and substantially preventing the movement of the active agent between the active agent reservoir and the fluid reservoir (e.g., preventing about 75% to about 100% , such as about 95% to about 100%, of the initial amount of active agent from leaving the active agent reservoir and entering the fluid reservoir) .
• the volume of the active agent reservoir is smaller (e.g., about five or ten times smaller) than the volume of the fluid reservoir.
• the housing further comprises an inlet (e.g., a septum for receiving a needle) to allow fluid to enter the fluid reservoir and/or an inlet to allow the active agent to enter the active agent reservoir.
• the active agent reservoir comprises an active agent.
• the semi -permeable membrane is flexible (e.g., capable of expanding) and the fluid reservoir comprises a fluid- absorbable material (e.g., a material that expands while absorbing fluid) .
• the apparatus further comprises an electrode within the fluid reservoir where the electrode is capable of being in electronic communication with a current supply unit.
• the apparatus further comprises a sensor within the housing where the sensor is capable of being in electronic communication with the current supply unit .
• the sensor may be selected from the group consisting of sensors for the measurement of pH, conductivity, impedance, the active agent, ions, and biological compounds.
• the current supply unit may be able to modify an electric parameter at the electrode based upon feedback from the sensor.
• the electric parameter is selected from the group consisting of current intensity, current mode, current waveform, voltage, and polarity.
• the apparatus further comprises protrusions (e.g., needles or straight-tipped or curved-tipped blades) proximate to the delivery orifice where the protrusions are capable of piercing the stratum corneum of the mammal .
• the protrusions are capable of piercing the stratum corneum, but are not capable of substantially piercing the dermis.
• the invention features a system for the delivery of an active agent through the body surface of a mammal comprising: a current supply unit; a first apparatus where the first apparatus comprises: (a) a first housing with a first delivery orifice through the first housing; (b) a first active agent reservoir within the first housing for containing a first active agent where the first active agent reservoir is in communication with the first delivery orifice; (c) a first fluid reservoir within the first housing for containing a first fluid; (d) a first semi -permeable membrane in communication with the first active agent reservoir and the first fluid reservoir for permitting the movement of fluid between the first active agent reservoir and the first fluid reservoir and substantially preventing the movement of the first active agent between the first active agent reservoir and the first fluid reservoir; and (e) a first electrode within the first fluid reservoir where the first electrode is in electric communication with the current supply unit; and a second electrode in electric communication with the current supply unit .
• the volume of the active agent reservoir is smaller (e.g., five times or ten times smaller) than the volume of the fluid reservoir.
• the current supply unit provides the electric voltage/potential (e.g., it can reverse the polarity) as well as the electric current needed for the electrotransport (e.g., iontophoresis, electro-osmosis, and electroporation delivery) of the active agent from the reservoir, through the orifice, and into the mammal ' s body though the mammal ' s body surface.
• the current supply unit may connected to an external current source or comprise a battery.
• the system further comprises a second apparatus where the second apparatus comprises a second housing with a second delivery orifice and a second reservoir within the second housing containing the second electrode where the second reservoir is in communication with the second delivery orifice.
• the second reservoir comprises a second active agent reservoir for containing a second active agent where the second active agent reservoir is in communication with the second delivery orifice; a second fluid reservoir for containing a fluid; and a second semi -permeable membrane in communication with the second active agent reservoir and the second fluid reservoir for permitting the movement of fluid between the second active agent reservoir and the second fluid reservoir and substantially preventing the movement of the second active agent between the second active agent reservoir and the second fluid reservoir.
• the second active agent reservoir is smaller than the volume of the second fluid reservoir.
• the first fluid reservoir and/or the second fluid reservoir comprises a fluid-absorbable material (e.g., a material that expands while absorbing fluid) .
• the second active agent may be the same or different than the first active agent.
• the first apparatus further comprises a first sensor within the first housing where the first sensor is in electric communication with the current supply unit and where the current supply unit can modify an electric parameter (e.g., electric parameters such as polarity, current intensity and current mode or waveforms) at the first electrode based upon feedback from the first sensor.
• the second apparatus further comprises a second sensor within the second reservoir where the second sensor is in electric communication with the current supply unit and where the current supply unit can modify an electric parameter at the second electrode based upon feedback from the second sensor.
• the system comprises three or more electrodes (e.g., between three and ten electrodes) in electric communication with the current supply unit .
• the invention features a method for delivering an active agent through a body surface of a mammal, the method comprising affixing the orifice of the above mentioned apparatus to a body surface of the mammal (e.g., the skin of a human) .
• the invention features a method for delivering an active agent through a body surface of a mammal, the method comprising the steps of: affixing the first orifice of the above mentioned system to the body surface (e.g., the skin) of the mammal; and attaching the second electrode of the above mentioned system (e.g., proximate to the first orifice) to the body surface of the mammal such that current passes from the first electrode to the second electrode through the body of the mammal .
• the body surface e.g., the skin
• the second electrode of the above mentioned system e.g., proximate to the first orifice
• FIG. 1 is a schematic diagram of an embodiment of a passive delivery apparatus according to the present invention.
• FIG. 2 is a schematic diagram of an embodiment of an electrotransport apparatus according to the present invention.
• FIG. 3 is a schematic diagram of another embodiment of a drug delivery system comprising one pair of electrotransport apparatuses according to the present invention.
• FIG. 4 is a schematic diagram of another embodiment of an electrotransport apparatus including two fluid reservoirs and one active agent reservoir according to the present invention.
• FIG. 5 is a schematic diagram of another embodiment of an electrotransport apparatus including one storage capsule according to the present invention.
• FIG. 6 is a schematic diagram of another embodiment of an electrotransport apparatus including two storage capsules according to the present invention.
• FIG. 7 is a schematic diagram of another embodiment of a passive apparatus including two storage capsules according to the present invention.
• FIG. 8 is a schematic diagram of another embodiment of an electrotransport active agent delivery system comprising five pairs of apparatuses as an example of the multi-pair electrotransport delivery system according to the present invention.
• FIG. 9 is a schematic diagram of another embodiment of an electrotransport active agent delivery system comprising three apparatuses according to the present invention. DETAILED DESCRIPTION OF THE INVENTION
• the present invention relates to an improved passive and electrotransport delivery system comprising a semi-permeable membrane within the delivery apparatus of the system.
• a passive delivery process the active agent in the reservoir immediately adjacent to the body surface is delivered through the body surface into the mammal by a concentration gradient between the reservoir and the body of the mammal .
• a fluid- absorbing material e.g., a swellable polymer
• the delivery of the active agent in the active agent reservoir immediately adjacent to the body surface is enhanced by the electric repulsive force applied by the electric potential at an electrode.
• the addition of a semi-permeable membrane within the reservoir, separating the fluid and active agent reservoir reduces the competing ion concentrations in the active agent reservoir.
• This improvement allows for the direct use of injectable pharmaceutical products, which typically contain electrolytes such as buffers, antioxidants, chelating agents, preservatives, and salts for tonicity adjustment.
• injectable pharmaceutical products typically contain electrolytes such as buffers, antioxidants, chelating agents, preservatives, and salts for tonicity adjustment.
• these non-drug electrolytes act as competing ions, resulting in greater competition for transport of drug ions and hence lower the iontophoretic drug delivery.
• the presence of the semi-permeable membrane of the present invention permits for the transport of these competing into the fluid reservoir, thus reducing their concentration, as compared to the active agent, in the active agent reservoir.
• the passage of electric current through the apparatus results in certain compositional changes within the fluid, such as an increase or decrease of certain ions (e.g., hydrogen ions, hydroxyl ions, halide ions, etc.) or gases (e.g., oxygen, hydrogen, chlorine, etc.) .
• ions e.g., hydrogen ions, hydroxyl ions, halide ions, etc.
• gases e.g., oxygen, hydrogen, chlorine, etc.
• the addition of sensors within the apparatus can detect these changes and relay the signals to the current supply unit, which in one embodiment reverses the electric polarity of the conductive electrodes according to preset limits, in order to minimize the negative competing ion effect on iontophoretic delivery.
• the relayed signals from the sensors may also assist the current supply unit to modify the current mode and intensity to achieve the desired delivery rate.
• the waveforms of electric current for iontophoretic delivery include, but are not limited to, conventional direct current (DC) , superimposed signals such as combining DC with conventional alternating current (AC) and that disclosed in U.S. Patent No. 5,135,478, pulsed DC such as that disclosed in U.S. Patent No. 5,042,975, and DC and pulsed DC with periodically reversed polarity as those described by Sun, et al . , Proceed . Intern . Symp . Control . Rel . Bioact . Ma ter. 17:202-203, 1990, and U.S. Patent Nos. 5,224,927 and 5,013,293.
• DC direct current
• AC alternating current
• the electric current or potential waveforms may be tapered at any changing points (i.e., to avoid the abrupt and drastic current/potential changes) in order to reduce the associated discomfort and undesirable skin sensation.
• the waveform of the electric current in the present invention is DC, or pulsed DC, with periodically reversed polarity.
• the current density e.g., current intensity per unit are of skin
• the sensors is maintained at less than about 0.5 mA/cm 2 (e.g., less than about 0.4 mA/ cm 2 ) .
• active agents refers drugs for treating diseases locally or systemically, nutrients or other biologically active compounds or herbal extracts, and minerals to improve general health or local skin/mucous tissue conditions.
• Active agents which may be delivered with this apparatus include, but are not limited to, any material capable of exerting a biological effect on a human body, such as therapeutic drugs, including, but not limited to, organic and macromolecular compounds such as polypeptides, proteins, and nucleic acid materials comprising DNA; and nutrients.
• polypeptide and protein active agents examples include thyrotropin-releasing hormone (TRH) , vasopressin, gonadotropin-releasing hormone (GnRH or LHRH) , melanotropin-stimulating hormone (MSH) , calcitonin, growth hormone releasing factor (GRF) , insulin, erythropoietin (EPO) , interferon alpha, interferon beta, oxytocin, captopril, bradykinin, atriopeptin, cholecystokinin, endorphins, nerve growth factor, melanocyte inhibitor-I, gastrin antagonist, somatotatin, encephalins, cyclosporin and its derivatives (e.g., biologically active fragments or analogs) .
• TRH thyrotropin-releasing hormone
• vasopressin vasopressin
• GnRH or LHRH gonadotropin-releasing hormone
• MSH melanotropin-
• active agents include anesthetics; analgesics (e.g., fentanyl and salts thereof such fentanyl citrate) ; drugs for treating psychiatric disorders, epilepsies, and migraine; drugs for stopping drug additions and abuses; anti-inflammatory agents; drugs to treat hypertension, cardiovascular diseases, gastric acidity and ulcers; drugs for hormone replacement therapies and contrceptives; antibiotics and other antimicrobial agents; antineoplastic agents, immunosuppressive agents and immunostimulants; and drugs acting on blood and the blood forming argans including hematopoietic agents and anticoagulants, thrombolytics, and antiplatelet drugs.
• analgesics e.g., fentanyl and salts thereof such fentanyl citrate
• drugs for treating psychiatric disorders, epilepsies, and migraine drugs for stopping drug additions and abuses
• anti-inflammatory agents drugs to treat hypertension, cardiovascular diseases, gastric acidity and ulcers
• Staphylococcus aureus See, e.g., R. Ulrich, et al in Vaccine, Vol. 16, No. 19, pages 1857-1864, 1998.
• An example of a vaccine against staphylococcus intoxication is described in PCT Patent Application WO 00/02523.
• other cationic and anionic active agents such as those described in M. Roberts, et al . , "Solute Structure as a Determinant of Iontophoretic Transport", Mechanisms of Transdermal Drug Delivery, R.O. Potts and R.H. Guy, Ed., Marcel Dekker, pages 291-349, 1997, may be delivered with this apparatus, e.g., by iontophoresis or passive diffusion. Active agents that are non-ionized or with a net charge equal to zero may also be delivered with this apparatus by electro-osmosis or passive diffusion.
• the apparatus 100 comprises a housing 102 having a removable release-liner 104 covering delivery orifice 134.
• the removable release- liner 104 will be removed prior to an electrotransport delivery exposing orifice 134, and the apparatus 100 will be affixed to the skin surface 106 with the adhesive layer 132.
• the housing 102 may be comprised of a silicone rubber, synthetic rubber, or natural rubber, such as poly (isoprene) , poly (butadiene-co-styrene) , poly (isobutene-co-isoprene) , and poly (chloroprene) ; polyurethane; nylons; polystyrene; polycarbonate; and acrylic polymers.
• the housing 102 may be any shape (e.g., circular, oval, or rectangular) and size (e.g., dependent upon the volume of active agent to delivered and convenience if the device is to be worn by a patient) .
• the contact surface of housing 102 to the skin surface 106 may be any shape (e.g., circular, oval, or rectangular) which an area of from about 1 to about 50 cm 2 (e.g., from about 5 to about 30 cm 2 or about 12 cm 2 ) .
• the orifice 134 may be any shape (e.g., circular, oval, or rectangular) .
• the housing 102 comprises more than one orifice 134, e.g., various small holes within said housing in communication with the active agent reservoir 120 and the skin surface 106 (Not Shown) .
• the adhesive layer 132 affixes the apparatus to the body surface during delivery.
• the adhesive in the adhesive layer may be a polymeric, pressure sensitive and/or nonconductive and remain adherent even after prolonged exposure to water.
• the adhesive has a broad working temperature range .
• Suitable adhesive materials include, but are not limited to, silicones, polyisobutylenes and derivatives thereof, acrylics, natural rubbers, and combinations thereof.
• Suitable silicone adhesives include, but are not limited to, Dow Corning * 355 (available from Dow Corning of Midland, MI); Dow Corning X7-2920; Dow Corning ® X7-2960; GE 6574 (available from General Electric Company of Waterford, NY) ; and silicone pressure sensitive adhesives, such as those disclosed in U.S. Patent Nos.
• acrylic adhesives include, but are not limited to, vinyl acetate-acrylate multipolymers , including, such as Gelva " 7371 (available from Monsanto Company of St. Louis, MO) ; Gelva 7881; Gelva 2943; 1-780 medical grade adhesive available from Avery Dennison of Painesville, OH; and acrylic pressure sensitive adhesives, such as those disclosed in U.S. Patent Nos. 4,994,267, 5,186,938, 5,573,778, 5,252,334, and 5 , 780 , 050.
• vinyl acetate-acrylate multipolymers including, such as Gelva " 7371 (available from Monsanto Company of St. Louis, MO) ; Gelva 7881; Gelva 2943; 1-780 medical grade adhesive available from Avery Dennison of Painesville, OH; and acrylic pressure sensitive adhesives, such as those disclosed in U.S. Patent Nos. 4,994,267, 5,186,938, 5,573,778, 5,252,334, and 5 , 780
• a removable release-liner 104 is adhered to the adhesive layer 132 during storage.
• the selection of the removable release-liner 104 is dependent on the type of the adhesive in use, and is well known to a person skilled in the art.
• the release-liner 104 is typically a polymer sheet or a paper coated with a polymer, which has rather weak adhesion toward the adhesive layer 132, therefore allowing itself to be easily removed prior to electrotransport delivery without damaging the adhesive layer 132.
• the apparatus 100 may be fastened to the body surface with an elastic band, a band with a buckle (similar to a leather watch band) , or a Velcro band or the like (Not Shown) .
• the skin surface 106 (e.g., the human skin) may be intact in which case the active agents are delivered through the skin appendages (e.g., sweat glands and hair follicles) and intercellular spaces between keratinocytes of the stratum corneum.
• the body surface may also be damaged, such as in certain skin diseases
• the disruptions of the body surface may also be carried out purposely by attaching protrusions to the skin contacting surface of the device (e.g., proximate of adjacent to the orifice (s) of the device) in order to improve skin permeation of active agents (e.g., as disclosed in U.S. Patent Nos. 3,964,482 and 5,250,023, PCT Patent Applications W096/17648, W097/48441, W097/48442, WO 98/11937, WO 98/46124, and WO98/28037, and Henry, et al .
• active agents e.g., as disclosed in U.S. Patent Nos. 3,964,482 and 5,250,023, PCT Patent Applications W096/17648, W097/48441, W097/48442, WO 98/11937, WO 98/46124, and WO98/28037, and Henry, et al .
• the housing comprises multiple orifices and multiple blades.
• the orifices and blades are formed from a single sheet of material (e.g., a thin sheet of metal such as stainless steel) .
• the channels are formed by using a penetrator (e.g., a round or flat- sided awl) to pierce the sheet.
• the penetrator stretches the sheet until it pierces through the sheet, creating an orifice and tapered, tipped blades (e.g., the width of the resulting blades are wider at the bottom of the blade than at the top or tip of the blade, and the thickness of the edge of the blade is greater at the bottom than at the top of the blade) .
• the blades thus, surround the perimeter of the orifice.
• the number of blades created will depend on the shapes of the penetrator (e.g., a penetrator with four side will create four blades) .
• the blades may also be curved towards the channel (e.g., if a conical or pyramidal penetrator is used) .
• the manufacture of such orifices and blades are described in PCT Application No. W098/11937.
• a semi -permeable membrane may be present between the active agent reservoir 120 and the removable release-liner 104 or the skin surface 106 during use.
• a semi-permeable membrane allows the active agent to pass freely into the skin during passive of electrotransport delivery, but retains any other ingredients (e.g., a suspending agent) in the active agent reservoir 120.
• the fluid reservoir 110 may contain a suspending material for holding the fluid.
• Suitable suspending materials include hydrophilic, highly absorbent, porous materials.
• suitable porous materials include, but are not limited to, cotton-based gauze; non-woven pad made of rayon or a mixture of rayon, polyester and/or other polymer fibers; foam and spongelike materials comprised of polyurethane, polyester and/or other polymers; and cross-linked and non-cross- linked gelling materials, such as polyacrylamide, polyvinyl alcohol, gelatin, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose .
• a fluid-absorbing material is present in the fluid reservoir 110 that is capable of absorbing the fluid from the adjacent active agent reservoir 120 through the semi -permeable membrane 108, thereby causing a reduction in the volume of the drug reservoir 120 by mechanical or osmotic pressure.
• the fluid-absorbing material may be a polymer.
• the semi-permeable membrane 108 is not permeable to the fluid-absorbing material nor to the active agent, but is permeable to the fluid and other small non-active species (e.g., electrolytes) .
• the semi- permeable membrane 108 has enough flexibility or elasticity so that it can change its shape or dimension without compromising its integrity and permeation properties.
• the semi -permeable membrane 108 changes its shape to accommodate the reduced drug reservoir volume and increased fluid reservoir volume.
• the reduction in the drug reservoir volume leads to an increase in the concentration of the active agent in the drug reservoir 120, resulting in a delivery enhancement of the active agent into the barrier membrane .
• fluid-absorbing material examples include, but are not limited to, those cross-linked and non-cross- linked polymers as described by N.A. Peppas in " Hyrogels in Medicine and Pharmacy” , CRC Press, Inc., Volume I, 1986, Volumes II & III, 1987, swellable polymers such water-swollen cellulose derivatives, such as methylcellulose (MC) , hydroxyethyl methylcellulose (HEMA) , hydroxypropyl methylkcellulose (HPMC) , ethylhydroxyethyl cellulose (EHEC) , hydroxyethylcellulose (HEC) , hydroxypropylcellulose (HPC) , carboxymethlcellulose (CMC) and its sodium salt (NaCMC) ; polyvinyl alcohol (PVA) ; polyvinylpyrrolidone (PVP) ; polyethylene oxide (PEO) ; polymers prepared by monomers such as hydroxyethyl methacrylate (HEMA) , hydroxye
• the fluid-absorbing material may also be a clay or other swellable minerals, including but not limited to bentonite and montmorillonite .
• the active agent reservoir 120 contains active agents in a solution during delivery and is separated with the semi-permeable membrane 108 from the fluid reservoir 110.
• the aforementioned suspending material to hold the fluid in the fluid reservoir 110 may also be present in the active agent reservoir 120.
• the semi-permeable membrane 108 is permeable to solvents and low molecular weight excipients, such as low molecular weight buffer species and tonicity adjusting ions, but not permeable to the active agent to be delivered. In one embodiment, only particles which have less than half (e.g., less than about a quarter) of the molecular weight of the active agent are able to permeate through the semi-permeable membrane 108.
• the semi -permeable membrane 108 may be comprised of cellulose; cellulose derivatives, such as Spectra/Por dialysis membranes (available from Spectrum of Houston, TX) , regenerated cellulose, cellulose acetates, and cellulose nitrate; mixtures of cellulose with other polymeric materials, such as cellulose/polyesters and cellulose/propylene; polyethylene; polypropylene; Teflon ; polytetrafluoroethylene; polyvinylidene fluoride; nylon; polysulfone; polyethersulfone; cuprophan; polymethyl methacrylate; ethylene vinyl alcohol; polysulfone; and polyacrylonitrile .
• cellulose derivatives such as Spectra/Por dialysis membranes (available from Spectrum of Houston, TX) , regenerated cellulose, cellulose acetates, and cellulose nitrate
• mixtures of cellulose with other polymeric materials such as cellulose/polyesters and cellulose/propylene
• electrode 112 is introduced within the fluid reservoir 110.
• the electrode 112 may be made of a conductive material such as a noble metal such as platinum or gold, titanium, carbon, or made by plating the conductive material onto a substrate.
• Conductive polymers may also be used in the electrode 112. Suitable conductive polymers include, but are not limited to, conductive filler-embedded polymers, such as carbon-embedded silicone rubbers, carbon- embedded natural rubbers, and silver halide powder- embedded polymers .
• Various carbon-based electrodes may be constructed from glassy carbon, reticulated vitreous carbon, graphite/epoxy composites, pyrolytic graphite, carbon pastes, carbon powders, and carbon fibers.
• Electrode 112 Other materials that may be used as the electrode 112 include, but are not limited to, silver halide-coated silver (e.g., AgCl-Ag, AgBr-Ag, Agl-Ag) , corrosive resistant alloys (e.g., stainless steels and Ti-containing alloys) .
• the electrode 112 may also be made with a combination of any of the foregoing materials.
• the conductive electrodes should be electrochemically inert, e.g., a platinum electrode.
• Fluid reservoir 110 serving as the electrode chamber to house the electrode 112, is in communication with the electrode 112, the sensor 118, and active agent reservoir 120 (through a semi -permeable membrane 108) .
• Cable 116 establishes electronic communication between the electrode 112 and the current supply unit (Not Shown) .
• cable 114 establishes the communication between the sensor 118 and the current supply unit (Not Shown) .
• electrode mediums should have low or no ionic charge.
• the electrode medium comprises an aqueous solution containing less than 1% (e.g., less than 0.1% or less than 0.01% by weight of electrolyte) .
• the electrode medium is water.
• the electrode medium may also contain from about 0.1 to about 90% by weight of other nonionic solvents, including, but not limited to, glycerin, propylene glycol, hexylene glycol, polyethylene glycol, polypropylene glycol, and low carbon-chain alcohols (such as ethanol and isopropyl alcohol) .
• the volume ratio between the active agent reservoir 120 and the fluid reservoir 110 the more of the competing ions are forced from the active agent reservoir 120 and into the fluid reservoir 110. Consequently, the active agent delivery efficiency increases as the volume ratio decreases.
• the competing ion concentration in the active agent reservoir 120 after the competing ions permeate through the semi -permeable membrane 108 to reach equilibrium with the fluid reservoir 110, will be 1/lOth the concentration in the same apparatus without the semi-permeable membrane 108 and the separate fluid reservoir 110 with such as a volume ratio. If the volume ratio is 1:49, the competing ion concentration in the active agent reservoir 120 will be reduced by l/50th. Therefore, it is preferable to minimize the volume ratio of the active agent reservoir 120 to the fluid reservoir 110. In one embodiment, the volume ratio is less than about 1:1
• ionic active agents are known to participate in the electrochemical reactions at the surface of the electrode 112.
• the electrochemical reaction of the active agent often results in the degradation of the active agent or deposition of the active agent on the surface of the electrode 112, thus reducing or eliminating the therapeutic effect of the active agent.
• the semi-permeable membrane 108 also inhibits the active agent from contacting the surface of the electrode 112, thereby preventing degradation of the active agent or the loss of the active agent due to deposition of the active agent on the surface of the electrode 112.
• the injectable drug preparations usually contain ionic excipients including preservatives such as cresol , chlorocresol , benzyl alcohol, methyl p- hydroxylbenzoate, propyl p-hydroxybenzoate, phenol, thimerosal, benzalkonium chloride, benzethonium chloride, and phenylmercuric nitrate; stabilizing agents; antioxidants such as ascorbic acid, ascorbic acid esters, butylhydroxy anisole, butylhydroxy toluene, cysteine, N-acetylcysteine, sodium bisulfite, sodium metabisulfite, sodium formaldehydesulfoxylate, acetone sodium bisulfite, tocopherols, and nordihydroguaiaretic acid; buffers; chelating agents such as ethylenediaminetetraacetic acid and its salts; buffers such as acetic acid, citric acid, phosphoric acid, sodium bicarbonate, sodium phosphat
• ionic excipients compete with the active agent ions for carrying the electric current. Because the competing ions (i.e., the ionic excipients) are usually smaller and weigh less than the active agent ions, they can carry a significant amount of the electric current. Consequently, much of the electric current is diverted to moving the ionic excipients instead of the active agent ions resulting in lower delivery efficiency of active agents.
• the electrotransport apparatus of the present invention can significantly reduce the competing ion concentration in the active agent reservoir 120, thus increasing electrotransport delivery of the active agent even when an injectable preparation in the market is used.
• the competing ions from the drug preparation in the active agent reservoir 120 can easily pass through the semi- permeable membrane 108 into the electrode medium containing no electrolyte or a very low concentration of electrolyte in the fluid reservoir 110.
• the active agent reservoir 120 thus, will have a much smaller number of competing ions. Consequently, a great fraction of the electrical current into the body surface is carried by the active agent ions instead of competing ions, resulting in greater delivery of the active agent.
• the current supply unit 200 connects to one pair of the electrotransport apparatuses, 100a and 100b, to form a electrotransport active agent delivery system 300.
• the electric polarities applied from the current supply unit 200 to the conductive electrodes 112a and 112b in the first electrotransport apparatus 100a and the second electrotransport apparatus 100b, respectively may be reversed periodically by the current supply unit 200 based upon feedback from sensors 118a and 118b.
• Sensors 118a and 118b communicate with current supply unit 200 through cables 114a and 144b, respectively.
• the two active electrodes can simultaneously or sequentially deliver either the same active agent or different agents using simple direct current (DC) or pulsed DC.
• insulin molecules carry positive charges in a solution at pH of 3, and carry negative charges at pH of 7.
• Simultaneous electrotransport delivery of insulin can be conducted at both electrodes when an insulin solution of pH of 3 is placed under the positive electrode, and another insulin solution of pH of 7 is placed under the negative electrode.
• an insulin solution of the same pH value e.g., pH of 7
• an insulin solution of the same pH value may be placed under both electrodes, so that at a given time, only one electrode (i.e., the cathode) is delivering insulin.
• the other electrode When the electric polarity is reversed, the other electrode will be delivering insulin until the next electric polarity reversal .
• two different active agents carrying either the same charge or the opposite charge in their respective solutions, may be delivered by the delivery system according to the present invention, by placing the solutions under the two electrodes and conducting iontophoresis with the aforementioned reversed polarity method.
• the reversed polarity reverses the directions of the electrochemical reactions concomitantly occurring at each electrode surface (i.e., the surface of the conductive material), hence neutralizing the hydrogen ions and hydroxyl ions generated at each electrode surface as a result of electrolysis of water, and preventing the undesirable pH shifting.
• H + hydrogen ions
• OH " hydroxyl ions
• the accumulation of access hydrogen ions at the anode during the first time interval shifts the pH of the electrode medium toward acidic (i.e., to a lower pH value), where as the accumulation of access hydroxyl ions at the cathode shifts the pH of the electrode medium toward alkaline (i.e., to a higher pH value) .
• the iontophoresis technique of reversing polarity with a fixed frequency (i.e., with a constant time interval between each polarity reversal as described in the example above and in the prior art) , however, works only in an ideal situation, and is problematic under real-life circumstances faced by drug delivery device products.
• There are many factors influencing a reverse- polarity iontophoresis process which causes the solution pH to drift away from the initial pH value, and eventually diminishes electrotransport delivery of the drug.
• other components of the composition in the electrotransport delivery system also participate the electrochemical reactions on the conductive electrode surfaces, which alter the amount of hydrogen ions or hydroxyl ions produced at each electrode, leading to the pH drifting.
• chloride ions can be oxidized into chlorine gas at the anode.
• Antioxidants in the composition can also be oxidized. This problem is more serious when two different compositions are exposed to the electrodes such as when two active agents are delivered under each electrode, or when the electrochemical reactions occur in two different pH ranges.
• the impurities in the drug formulation and in the electrode components, as well as the difference in the fluid volumes between the two electrodes, will also lead to the drift from the original point or from an optimal electrotransport condition.
• the electrotransport apparatus of the present invention is incorporated with one or more sensors .
• the sensors are in communication with the fluid, either the electrode medium in the fluid reservoir 110, as shown in FIG. 2, or the active agent solution in the active agent reservoir 120 (not shown) .
• the sensors 118a and 118b detect the compositional or electrical changes resulting from current passage through the apparatus, and relay the signal to the current supply unit 200.
• the current supply unit 200 acts to reverse electric polarities on electrodes 112a and 112b in apparatus 100a and apparatus 100b, respectively. In this way, the current supply unit 200 dictates the length of the time interval between each reversal to assure the system is always operating under an optimal condition.
• the current supply unit 200 may also adjust the current intensity and current waveform to achieve the desired delivery rate.
• composition changes in the fluid include but not limited to the changes in the solution pH, solution conductivity, the active agent (s) , halide ions, anions of various acids and salts (e.g., sulfuric acid, nitric acid, phosphoric acid, acetic acid and citric acid), metal ions (e.g., sodium, potassium, lithium, strontium, calcium, zinc, magnesium and aluminum) , compounds with amine functional groups, compounds with carboxylic acid functional groups, gases (e.g., oxygen, hydrogen, chlorine, carbon dioxide, ammonia) , changes in color, viscosity, density, temperature, pressure, and the reactants and products of oxidation and reduction process on the conductive electrodes (e.g., metal and non-metal species of various valences) .
• various acids and salts e.g., sulfuric acid, nitric acid, phosphoric acid, acetic acid and citric acid
• metal ions e.g., sodium, potassium, lithium, strontium, calcium
• the sensors may also detect the biological/chemical species from the mammal that enter the apparatus from its body surface, such as urea, lactic acid, creatinine, glucose, prostaglandins, electrolytes, amino acids, peptides and polypeptides, proteins and protein fragments, fatty acids and their esters, enzymes, hormones, and other metabolic products.
• the sensors of the present invention may be capable measuring any aforementioned changes in the contents of housing 102, and relay these information as signals to the current supply unit .
• sensors include, but are not limited to, conductivity and impedance sensors, ion- selective electrode sensors, sensors based on potentiometry such pH sensor and ion-selective electrodes (e.g., chloride, fluoride, sulfate, silver, sodium, potassium, lithium, and ammonium) , sensors based amperometry or voltametry (e.g., oxygen and various amines) , sensors based on colorimentry and spectrophotometry, pressure sensors, and temperature sensors. Examples of such sensors are disclosed in Biosensors . Theory and Applications, by D.G. Buerk, Lancaster, PA, Technomic Publishing Company (1993), Ion- Selective Micro-Electrodes .
• buffering agents may be placed in the fluid reservoir 110 to maintain the pH of electrode medium within a given pH range during iontophoresis.
• Buffering agents include, but are not limited to, polymeric buffers, and solid materials which have a buffering effect to the surrounding liquid.
• these buffering agents can not pass through the semi- permeable membranel08 to the active agent reservoir 120, because of the large molecular size of the polymeric buffer and the large particle size of the solid buffering materials (e.g., greater than about twice molecular weight cut-off of the semi-permeable membrane 108) .
• the polymeric buffer may be any polymer that ionizes at a given pH by consuming hydrogen ions or hydroxyl ions and maintains the pH of the solution in the fluid reservoir 110.
• the solid buffering materials may be water insoluble or have only limited aqueous solubility. Suitable solid buffering materials include, but are not limited to, calcium carbonate and zinc oxide.
• the polymeric buffer may be water-soluble or water-insoluble .
• the water-insoluble polymeric buffers are in the form of fine particles to maximize their surface area. Small particles of the polymeric buffer may be suspended in a gel matrix in which the active agent to be delivered is dissolved or suspended.
• the water insoluble polymeric buffer is formed into a porous or non-porous polymer membrane that covers the electrode 112 and/or the internal wall of the fluid reservoir 110. The porous polymer membrane may also be used as the semi -permeable membrane 108.
• Polymers with acidic functional groups may be used to prevent an increase in the pH of the electrode medium in the fluid reservoir 110 during cathodic iontophoresis (i.e., a negatively charged active agent delivered by a negative electrode) .
• Suitable anionic polymers include, but are not limited to, copolymers of methacrylic acid and methacrylate, such as Eudragit L, S, RS and RL available from Rohm Tech, Inc.
• the anionic polymer is of a pharmaceutical grade.
• Eudragit S100 One such anionic polymer is Eudragit S100. Below a pH of 7, Eudragit S100 is a solid. At a pH of 7 and above, Eudragit S100 dissolves due to ionization of its carboxyl groups. The ionization of the carboxylic acid functional groups leads to neutralization of the excess hydroxyl ions generated by the electrochemical reaction during cathodic iontophoresis.
• a drug formulation that is intended to be administered by iontophoresis at a pH ranging from 6.5 to 7 may utilize Eudragit S100 as a buffering agent. At a pH of 6.5 to 7, Eudragit S100 is a solid and therefore does not interfere with the active agent delivery process. As the iontophoresis process at a cathode progresses, hydroxyl ions begin to build up in the solution of the fluid reservoir 110, which causes the Eudragit S100 polymer to dissolve and therefore the pH of the electrode medium is maintained.
• Polymers with basic functional groups i.e., cationic polymers such as polymers with amine groups, may be used to prevent a decrease in pH during anodic iontophoresis (i.e., a positively charged active agent delivered by a positive electrode) .
• Suitable cationic polymers include copolymers of dimethylaminoethyl methacrylate and methacrylic acid esters, such as Eudragit E available from Rohm Tech, Inc.
• the cationic polymer is of a pharmaceutical grade.
• Eudragit E is solid above pH 5 and dissolves below pH 5. As the concentration of hydrogen ions increases due to the anodic electrochemical reaction, the Eudragit E is ionized by absorbing the hydrogen ions, thereby maintaining the pH of the electrode medium.
• the electrode medium in the fluid reservoir 110 may also contain other adjuvants, including, but not limited to, saccharides, polysaccharides, such as cyclodextrins, non-ionic surfactants, chelating agents, antioxidants, and antimicrobial agents.
• adjuvants including, but not limited to, saccharides, polysaccharides, such as cyclodextrins, non-ionic surfactants, chelating agents, antioxidants, and antimicrobial agents.
• the fluid reservoir 110 is split into two or more reservoirs that may be separated by another semi-permeable membrane (s) of different pore size(s) to allow only selected material to pass through.
• another semi-permeable membrane s
• FIG. 4 The presence of the second semi -permeable membrane 107 creates another fluid reservoir 115, which is in communication with both the fluid reservoir 110 (through the second semi -permeable membrane 107) and the active agent reservoir 120 (through semi -permeable membrane 108) .
• the fluid reservoir 115 may contain the aforementioned polymeric buffers and solid buffers, as well as ion-exchange resins, and optionally, the aforementioned suspending material.
• the fluid reservoir 115 may serve to remove the competing ions and to prevent them reaching active agent reservoir 120.
• Additional reservoirs may also included in the electrotransport apparatus to serve other purposes, for example, to remove the gases and other "wastes" generated from the electrochemical reactions on the conductive electrodes.
• the additional fluid reservoirs may be positioned between the top of the housing 102 (the side opposite the delivery orifice) and the conductive electrode 112.
• the current supply unit 200 in FIG 2 may be of any shape and size, and typically will be small if the system is intended to be worn by a patient.
• the current supply unit may receive its energy from an external source (e.g., the current supply unit is plugged into a standard wall outlet) or it may comprise a battery (e.g., if it is to be worn by a patient) .
• the current supply unit, the apparatus, and the second electrode are all contained within the same container. Examples of such systems and the circuits for such systems are well known in the art, e.g., U.S. Patent Nos.
• an inlet 128 permits introduction fluids (e.g., the electrode medium) into the fluid reservoir 110 through a inlet 128.
• the inlet 128 is adapted to receive electrode medium contained in capsule 130.
• Capsule 130 may be any shape (e.g., cylindrical or spherical) .
• Capsule 130 may be made of any pharmaceutically acceptable material such as glass, plastic, or metal.
• a plunger 124 may be pressed against the capsule 130 in the chamber 122 to break the capsule 130 by crushing or piercing through the capsule wall. The solution in the capsule 130 then flows through the inlet 128 into the fluid reservoir 110.
• the inlet 128 may optionally contain a filter to prevent broken pieces of the capsule 130, such as glass debris, from entering the fluid reservoir 110 and contacting the skin of the mammal.
• the active agents with this embodiment may be preloaded in the active agent reservoir 120 either as powder immobilized in the aforementioned suspending material, for example, porous material (e.g., non-woven pad or polyurethane foam) or in a lyophilized form (i.e., by freeze-drying) with or without the porous material.
• the solid-state drug is dissolved as the electrode medium enters the active agent reservoir 120 through the semi-permeable membrane 108 from fluid reservoir 110.
• the pharmaceutical excipients necessary for drug stability during lyophilization process and storage, rapid dissolution, and solubilization may be present in the active agent reservoir 120.
• the examples of the excipients include, but are limited to, phosphoric acid, citric acid their pharmecutically acceptable salts, antioxidants, chelating agents, preservatives, human serum albumin, gelatin and carbohydrates such as dextrose, mannitol , dextran, and cyclodextrins.
• first capsule 130 and second capsule 140 are inserted into chamber 122.
• Second capsule 140 contains a solution containing the active agent.
• First capsule 130 contains a fluid, such as a low ionic or non-ionic liquid (e.g., distilled water) as the electrode medium.
• the partition membrane 135 separating the two capsules is impermeable to liquid, but is elastic enough (e.g., diaphragm-like) or movable (e.g., piston-like) to allow the force exerted by the plunger 124 to break both first capsule 130 and second capsule 140.
• the plunger is pressed into the chamber 122 to break the first capsule 130 and second capsule 140.
• the drug solution from second capsule 140 enters the active agent reservoir 120 from the inlet 138, and the electrode medium from first capsule 130 enters the fluid reservoir 110 through the inlet 128.
• the non-drug ions from the active agent reservoir 120 enter the fluid reservoir 110 through the semi -permeable membrane 108, the competing ion concentration in the drug reservoir is significantly reduced for the reasons described above, and the efficiency of electrotransport delivery is significantly increased.
• the aforementioned fluid-absorbing material may also be present in fluid reservoir 110, which upon expansion causes a reduction in the volume of the active agent reservoir 120 and an increase in the concentration of the active agent as fluid flows from the active agent reservoir 120 into fluid reservoir 100. The increase in active agent concentration leads to further enhanced drug delivery.
• the drug-containing solutions suitable for this electrotransport apparatus may be standard liquid preparations for parenteral administration.
• various stabilizing agents many ionic in nature, are formulated in the preparation, such as buffers, antioxidants, chelating agents, and preservatives.
• Electrolytes such as sodium chloride, are often added to the injectable preparations to make them isotonic.
• the electrotransport apparatus of this embodiment enables the direct use of the injectable preparations with a much enhanced delivery efficiency.
• the electrode medium and/or active agent solution is injected into the fluid reservoir 110 and active agent reservoir 120, respectively, with a syringe through an inlet (e.g., a self-sealing inlet such as a septum) .
• there may be one or more small orifices (e.g., with a diameter smaller than 100 ⁇ m on the wall of housing 102), which serves as air outlet when filling the liquid reservoir.
• the small orifice may be sealed after the liquid reservoirs are filled.
• the small orifices may also be used to release the gasses generated during electrotransport (e.g., by using a valve) .
• the apparatus and a second electrode (e.g., a second apparatus of the present invention) needs to connected to a current supply unit to form an active agent delivery system, .
• the current supply unit is the source of current to the electrode in the apparatus.
• the current supply unit can also modify various electric parameters at the electrode (e.g., modify the intensity of the current or the polarity at the electrode) based upon feedback from the sensor.
• the system comprises a pair of aforementioned apparatuses during delivery operation as shown in FIG. 8.
• the current supply unit 200 is capable of operating each pair separately from the others, but is still capable of controlling the overall delivery of the whole drug delivery system.
• the arrangements and shapes of the combined pairs may vary, such as a square, circle, oval, rectangle, or triangle.
• One such an example in a rectangular configuration is shown in FIG. 8. Since several pairs of electrotransport apparatuses (e.g., lOOal and lOObl) form a single electrotransport delivery system 400, the individual size of each apparatus's deliver orifice (i.e., the size of the apparatus's orifice) may be smaller than the orifice of a single-pair delivery system.
• a 5 -pair system as shown in FIG. 8 may provide the same skin coverage, i.e., 10 cm 2 , under five apparatuses (i.e., lOOal through 100a5) .
• the orifice under each individual electrode (e.g., lOOal) in the five pair system only covers 2 cm 2 skin rather than 10 cm 2 of the skin in the single pair system.
• the advantages of a multi -pair system are improved control of electric current distribution, improved drug delivery, and reduced risk of the tissue injuries such as burn over the total delivery area.
• the resultant current distribution over the delivery area is more homogenous since the current supply unit can control each pair (e.g., a fraction of the total delivery area) separately, and can make necessary adjustment on applied electric potential in reference to its adjacent pairs. For example, if the skin area under a particular pair of apparatuses is damaged and the skin resistance drops or if the apparatus itself malfunctions due to damage or defect to one of its components, the current supply unit can, based on the signals from the sensors, modify the current intensity or polarity reversal interval, or even stop the electric current of this particular apparatus, to avoid any potential injury to the skin tissue. The current supply unit can also adjust the other apparatus (es) to compensate for the change caused by the failing apparatus thus improving the overall drug delivery.
• each pair e.g., a fraction of the total delivery area
• the current supply unit can, based on the signals from the sensors, modify the current intensity or polarity reversal interval, or even stop the electric current of this particular apparatus, to avoid any potential injury to the skin tissue.
• a drug delivery system 500 comprises three aforementioned apparatuses (i.e., apparatuses 100a, 100b, and 100c).
• apparatuses 100a and 100b contain active agents
• apparatus 100c contains no active agents and is filled with a buffer solution or buffer suspension
• the fluid reservoir of 100c is filled with a buffer-containing liquid (e.g., the aforementioned polymeric buffer or solid buffer)
• the active agent reservoir contains only electrolyte-containing liquid.
• the current supply unit 200 is in communication with the electrode of apparatuses 100a, 100b, and 100c and the sensors in apparatuses 100a and 100b.
• the current supply unit 200 is also in electronic communication with the sensor of apparatus 100c.
• the third apparatus 100c is then electrically paired up with either the electrotransport apparatus 100a or 100b to adjust its ionic composition of the fluid in the reservoir of apparatus 100a or 100b to optimal electrotransport condition (e.g., a certain pH value) through the electrochemical reactions (e.g., electrolysis of water) on the respective electrode.
• electrotransport condition e.g., a certain pH value
• electrochemical reactions e.g., electrolysis of water
• apparatus 100c. may be electrically paired up with either the electrotransport apparatus 100a or 100b to adjust its ionic composition by enhancing the electrochemical reactions in the apparatus involved (i.e., by simply increasing the current passage through that apparatus) without suspending the electrotransport delivery operation between the electrotransport apparatus.
• both the electrotransport apparatuses 100a and 100b are simultaneously paired with the apparatus 100c that serves as a common counter electrode .
• the electrotransport delivery of the whole system is carried out by reversing the polarity periodically between the apparatuses 100a and 100c and between the apparatus 100a and 100c.
• the length of each reversal interval is determined by the sensors and current supply unit 200 to assure the drug compositions in the both 100a and 100b are always in the optimal range for electrotransport delivery.
• the presence of the buffer solution e.g., the aforementioned polymeric buffers and/or solid buffers, maintains the composition in the apparatus 100c in a biologically compatible condition to avoid any undesirable side effects such as skin irritations. Any number of drug- containing apparatuses may be paired to apparatus 100c to operate in this mode of electrotransport (e.g., from one to ten apparatuses) .
• each one of them represents the electrotransport delivery system 500 in
• FIG. 9 may be assembled together to form a multi-three- apparatus drug delivery system.

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• 2000
  • 2000-04-13 WO PCT/US2000/009933 patent/WO2000062856A1/en not_active Application Discontinuation
  • 2000-04-13 JP JP2000611991A patent/JP2002541934A/ja active Pending
  • 2000-04-13 EP EP00922160A patent/EP1171194A1/de not_active Withdrawn
  • 2000-04-13 CA CA002366900A patent/CA2366900A1/en not_active Abandoned
  • 2000-04-13 AU AU42389/00A patent/AU4238900A/en not_active Abandoned

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