WO1996000111A1 - Systemes d'administration pulsee d'agents biologiquement actifs a l'aide d'impulsions de tension electrique permettant de reguler la permeabilite membranaire - Google Patents

Systemes d'administration pulsee d'agents biologiquement actifs a l'aide d'impulsions de tension electrique permettant de reguler la permeabilite membranaire Download PDF

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Publication number
WO1996000111A1
WO1996000111A1 PCT/US1995/007951 US9507951W WO9600111A1 WO 1996000111 A1 WO1996000111 A1 WO 1996000111A1 US 9507951 W US9507951 W US 9507951W WO 9600111 A1 WO9600111 A1 WO 9600111A1
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WO
WIPO (PCT)
Prior art keywords
tissue
drug
duration
agent
pulse
Prior art date
Application number
PCT/US1995/007951
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English (en)
Inventor
Ooi Wong
Tung-Fen Chen
Russell O. Potts
Durairaj Bommi Bommannan
Original Assignee
Cygnus, Inc.
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.)
Filing date
Publication date
Application filed by Cygnus, Inc. filed Critical Cygnus, Inc.
Priority to AU29477/95A priority Critical patent/AU2947795A/en
Priority to EP95925294A priority patent/EP0766579A1/fr
Priority to JP8503326A priority patent/JPH10511008A/ja
Publication of WO1996000111A1 publication Critical patent/WO1996000111A1/fr

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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
    • A61N1/0412—Specially adapted for transcutaneous electroporation, e.g. including drug reservoirs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—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
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation
    • 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

Definitions

  • the present invention relates to transdermal delivery of biologically active agents and other substances in a controlled manner.
  • Constant drug delivery with steady state rates has been used in many controlled release devices such as transdermal patches and oral tablets (osmotic pump) .
  • Iontophoresis has been used for delivery of substances across tissues.
  • the rate of substance delivery is limited by the iontophoretic mechanism, such as the nature of the substance, the nature of the delivery site on the tissue, the structure and composition of the substance reservoir, etc.
  • the ability to control the iontophoretic delivery rate to transfer increased levels of the substance for short periods of time on demand or according to a preset schedule is limited.
  • pulsatile drug delivery with variable delivery rates during the therapy treatment offers better therapeutic advantages.
  • Many mechanisms have been studied to generate pulsatile types of delivery profiles, including iontophoresis, magnetically modulated drug delivery systems, temperature responsive controlled drug delivery, pH sensitive gels by swelling mechanism, and solubility dependent controlled release systems.
  • Sibalis U.S. Patent No. 5,013,293 an iontophoretic system that can purportedly deliver a drug through a patient's skin in pulses.
  • Sibalis apparently accomplishes the pulsatile delivery profile by changing the amount of current applied to the skin, i.e., by changing the magnitude of the driving force transporting the drug through the skin.
  • An innovative way to achieve pulsatile drug delivery is to maintain the release rate of the drug device substantially constant while altering the membrane permeability at will in a controlled manner. In this way, the drug delivery rate can be altered at any time.
  • Chemical enhancers are not suitable to alter the membrane permeability in an on-demand fashion since their actions are slow and not easily controllable.
  • Pope et al. U.S. Patent No. 4,723,958 describes a pulsatile drug delivery system in which alternatinv layers of drug and spacer and placed in a tube, and the tube is placed in a fluid environment within the patient .
  • a delivery force is applied to one end of the stack.
  • the drug layers respond to exposure to the fluid to deliver the drug.
  • the spacer layers respond only to the delivery force.
  • the timing of drug pulses depends on the delivery force and the size of the layers, and the duration of a pulse is determined by teh rate of expansion or dispersion of the active layer into the fluid environment.
  • the invention is directed to a method for pulsed transport of a substance through tissue, the method comprising the steps of (a) applying at least one electrical pulse to the tissue to cause electroporation of the tissue region, the electrical pulse being applied for an electroporation pulse duration, the electroporation pulse duration being shorter than the driving force duration; (b) applying a driving force to the region of tissue whereby the driving force causes the substance to be transported through the tissue for a driving force duration; and (c) repeating step (a) during the driving force duration.
  • the invention is a method for pulsatile type of delivery of a substance through tissue by using electroporation, combined with either passive diffusion or iontophoresis or both.
  • the invention uses a single pulse of voltage in the range of about 100 to about 1000 volts and having a duration of about 10 ⁇ sec to about 50 msec, followed by similar additional pulses up to about 8 hrs later or even as long as about 7 days.
  • This novel method maintains the permeability of the treated skin high over an extended period of time to permit the transfer of a substance passively by iontophoresis and/or passive diffusion. Iontophoresis can provide a constant skin flux. After the first pulse, the delivery flux can be increased dramatically (spiked) . When the skin permeability reverts to normal after a period of time, the flux will drop to the iontophoretic flux. Subsequent pulsing will give another spike of skin flux.
  • the spikes of delivery rates can be controlled in a pre-determined manner to generate a pulsatile delivery profile for a substance such as a drug.
  • the method of the invention provides either on demand pulsatile drug delivery/or pre-programmed delivery of a substance such as a drug and faster onset of action. It can also be used to provide a drug delivery spike in response to a measured or detected parameter.
  • the electroporative pulses change the tissue's resistance to iontophoretic transport without causing tissue damage.
  • the magnitude and duration of the electroporative pulse are selected so that the additional current provided to the tissue by the electroporative pulse is less than 0.1% of the total current delivered by both electroporation and iontophoresis over a 30 minute period.
  • the method is therefore a substantially constant current method of providing pulsatile drug delivery or pre-programmed delivery of a substance.
  • the method avoids or at least minimizes skin damage caused by high current densities.
  • the magnitude and duration of the electroporative pulse is such that the tissue's resistivity to substance transport can be lowered, and total substance flux increased, without damaging the tissue.
  • the method of the invention is useful for delivering insulin for patients with diabetes mellitus, antiarrhythmic to patients with heart rhythm disorders, nitrates to patients with angina pectoris, selective beta-blockade, birth control and general hormone replacement therapy, immunization, cancer chemotherapy, long-term immunosuppression and the like.
  • Figure 1 is a graph of the delivery of fentanyl through human cadaver skin in vi tro .
  • Figure 2 is a graph of the results of transdermal iontophoretic delivery of luteinizing hormone-releasing factor (LHRH) using human cadaver skin in vi tro with or without an electroporative pulse.
  • LHRH luteinizing hormone-releasing factor
  • Figure 3 is a graph of the results of passive delivery of LHRH using a single application of a 1000 v pulse and a duration of 5 msec.
  • Figure 4 is a graph of the results of iontophoretic delivery of neurotensin through human skin in vi tro with or without electroporative pulse.
  • Figure 5 is a graph of the results of the delivery of salmon calcitonin (sCT) .
  • Figure 6 is a graph of the delivery of sCT.
  • Figure 7 is a graph of the delivery of LHRH through porcine skin.
  • Figure 8 is a graph of the results of delivery of molsidomine.
  • Electroporation means the use of an electric field to create a temporary decrease in resistance to the transport of substances through a tissue such as a lipid-based barrier or skin. Electroporation is applied in vivo (on living tissue) or ex vivo (on excised tissue) or in vi tro (on artificial tissue) .
  • an apparatus comprising a plurality of electrodes, usually of planar steel or other metal such as silver/silver chloride electrodes, disposed on a tissue surface generates an electrical field in the tissue to provide molecular transport of a desired substance from a substance donor res-ervoir through the tissue into a patient or conversely from a patient through the tissue to a receiver reservoir.
  • the method utilizes means for controlling at least one member selected from the group consisting of the time of initiation of an electroporation pulse, the pulse voltage, the duration of the pulse, the density of the pulse, the interval of time between multiple pulses, the initiation of iontophoresis.
  • the first electroporative pulse can be initiated any time after application of the electroporation apparatus on the tissue surface, followed by iontophoresis.
  • the subsequent pulsings after the first pulsing can be made at any time after the previous pulsing, continuing up to 24 hours or more.
  • the magnitude of each electro voltage pulsing ranges from about 10 to about 1000 V, with a duration (pulse width) of about 1 ⁇ sec to about 50 msec.
  • the iontophorectic current density ranges from 0 (i.e., passive delivery) to about 10 mA/cm 2 .
  • the invention uses a single pulse of voltage in the range of about 10 to about 1000 V, a duration of about 10 ⁇ sec to about 20 msec, with an iontophoretic current density of about 0.05 to about 10 mA/cm 2 , followed by similar additional pulses up to about every 8 hours thereafter, especially about every 4 to about every 8 hours or even about every 7 days.
  • Iontophoresis as used herein means the application of electrical energy to tissue to drive a substance from a reservoir into the tissue.
  • an iontophoretic method and apparatus could use two electrodes placed in contact with the tissue.
  • One of the electrodes is conveniently a pad of absorbent material containing the substance being administered.
  • a voltage is applied between the two electrodes drives the substance from the absorbent material into the tissue.
  • the voltage is preferably in the range of 0.1-50V.
  • Passive diffusion refers to the movement of a substance from a reservoir into tissue using a concentration gradient as the driving force.
  • Transport delivery or sampling/extraction according to the method of the invention is a non- invasive method to transport substances into and through tissue of a subject/patient, including for diagnostic assay, forensic evaluation and drug delivery through skin.
  • the tissue or dermis can be natural or artificial tissue and can be of plant or animal nature, such as natural or artificial skin, blood vessel tissue, intestinal tissue and the like.
  • the term "artificial” as used herein means an aggregation of cells of monolayer thickness or greater which are grown or cultured in vivo or in vi tro and which functions as a tissue but are not actually derived, or excised, from a pre-existing source or host.
  • the subject/host can be an animal, particularly a mammal, such as dogs, cats, cattle, horses, sheep, rats, mice, and especially is a human being.
  • Substances that can be transdermally delivered include a wide variety of drugs and diagnostic materials.
  • the term "pharmaceutical” or “drug” is broadly defined to include any chemical agent that affects or prevents processes in a living organism.
  • Non- limiting suitable examples of drugs includes those used for therapy, such as antibiotics, drugs intended for prevention, such as vaccines, drugs intended for diagnosis, such as natural and therapeutically introduced metabolites, hormones, enzymes, proteins and the like.
  • Other substances that can be transdermally delivered include enzymes, vitamins, nutrients, DNA, RNA and the like into living organisms.
  • Suitable substances include antiinflammatory drug, analgesics, antiarthritic drugs, antispasmodics, antidepressants, antipsychotic drugs, tranquilizers, antianxiety drug, narcotic antagonists, antiparkinsonism agents, cholinergic agonists, anticancer drugs, immunosuppression agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistaminics, antimigraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptive agents, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs, opioids and the like.
  • the substances are capable of - 10 -
  • Examples of specific drugs include steroids such as estradiol, progesterone, demegestone, promegestone, testosterone, and their esters, nitro- compounds such as nitroglycerine, and isosorbide nitrates, nicotine, chloropheniramine, terfenadine, triprolidine, hydrocortisone, oxicam derivatives such as piroxicam, ketoprofen, mucopolysacccharides such as thiomucase, buprenorphine, fentanyl, fentanyl analogs, naloxone, codeine, dihydroergotamine, pizotiline, salbutamol, terbutaline, protaglandins such as misoprostol and emprostil, omeprazole, imipramine, benzamides such as metoclopramide, scopolamine, peptides such as growth releasing factor and somatostatin, clonidine, dihydroxypyridines such as nif
  • the substance can be administered in a physiologically acceptable carrier.
  • physiologically acceptable carriers include buffers such as isotonic phosphate buffered saline (PBS) , carriers for topical application, and the like.
  • PBS isotonic phosphate buffered saline
  • permeability enhancers conventionally known in the art can also be present. Suitable permeability enhancers include fatty acid esters or fatty alcohol ethers of C 2 _ 4 alkanediols, alcohols such as ethanol, dimethyl sulfoxide, dimethyl lauramide, polyethylene glycol monolautrate (PEGML) and the like.
  • the dose and frequency of transdermal administration of a substance by the method of the invention depends on a number of factors, including the drug being used, the intended use, potential skin irritation side effects, the lifetime of the substance, the tissue to which it is administered, the age, weight and sex of any subject or patient.
  • a prior art rate control delivery device is designed to release a substance at a rate lower than that obtainable through skin of average permeability and to contain sufficient drug such that unit activity (saturation concentration) is maintained throughout the steady state delivery.
  • the method can include a step of analyzing a sample obtained from a subject to determine the presence or absence of a substance, the quantity or quality thereof. This can be by the use of specific electrodes or electronic biosensors that utilize a bioactive molecule as the sensing signal-transducing element.
  • the method can also include the step of automatically administering a drug to the subject in response to a predetermined level of a target substance in the sample or automatically alerting an operator to administer a drug or other treatment in response to a predetermined level of a target substance in the sample, for example orally, dermally, rectally, buccally, intravenously or the like.
  • Example 1 The following examples are provided to illustrate the invention and should not be regarded as limiting the invention in any way.
  • Example 1
  • Flux studies were conducted using split thickness human cadaver skin.
  • a piece of skin (0.78 cm 2 ) separated the donor compartment from the receiver compartment of the diffusion cell assembly.
  • the donor solution contained fentanyl citrate dissolved in isotonic phosphate buffered saline (PBS) at pH 7.4.
  • the receiver solution was PBS at pH 7.4.
  • Fentanyl citrate has a pKa of 7.9. Hence, fentanyl is positively charged at pH 7.4. Therefore, the donor solution contained the anode to ensure electrophoretic mobility.
  • Silver and Ag/AgCl electrodes were used as anodes and cathodes respectively.
  • Receiver solution (1 ml) was withdrawn and replaced with an equal volume of PBS at 30 minute intervals (15 minutes during the pulsing episodes) .
  • the withdrawn sample was analyzed for fentanyl content using HPLC.
  • Figure 1 shows the fentanyl flux as a function of time.
  • the up arrowheads indicate the start and the down arrowheads indicate the cessation of the electrical treatment -- open arrowheads indicate iontophoresis and solid arrowheads represent electroporation.
  • FIG. 2 is a graph of the results of transdermal delivery of luteinizing hormone-releasing factor (LHRH) using human cadaver skin in vi tro with or without a single electroporation pulse.
  • the open squares represent flux with iontophoresis alone and the solid squares represent flux with iontophoresis after pulsing.
  • the solid arrowhead indicates the initiation of pulsing.
  • Figure 3 is a graph of the results of delivery of LHRH using a single electroporative pulse of a 1000 V pulse and a duration of 5 msec in the absence of iontophoretic current.
  • the solid arrowhead indicates the initiation of pulsing.
  • Figure 4 is a graph of the results of iontophoretic delivery of neurotensin through human skin in vi tro with or without electroporative pulse.
  • the solid squares represent the electroporative single pulsing at 1000 V and 7 msec.
  • the open squares represent the control without application of electroporative pulsing.
  • sCT salmon calcitonin
  • Cells 1-3 black diamonds where subjected to iontophoretic treatment at 1 mA/cm 2 ( 0.385 mA) for two hours, cells 4-6 (black squares) were subjected to a 500V electroporation single pulse and a 1 mA/cm 2 iontophoretic treatment for two hours, and cells
  • Example above the delivery of sCT was determined.
  • the experimental conditions were the same (1.0 mA/cm 2 ) except that the pH of the donor and receiver solutions was 4.0 instead of 7.4.
  • Figure 6 is a graph of the delivery of sCT.
  • the solid squares represent passive delivery only, the open squares represent iontophoresis treatment only and the solid diamonds represent the application of electroporative single pulsing with iontophoresis.
  • transdermal delivery of LHRH was determined.
  • the electroporative conditions to initiate each iontophoresis treatment were 500 V amplitude and 10 msec pulse width.
  • Figure 7 is a graph of the delivery of LHRH to porcine skin.
  • the solid squares represent iontophoresis treatment alone and the open squares represent the treatment by iontophoresis and single pulse electroporation.
  • the open arrowheads represent when iontophoresis started and the solid arrowheads represent when iontophoresis was discontinued.
  • the electroporative effects on passive permeation of molsidomine through human cadaver epidermis were 500 V amplitude with a time constant of about 20 msec pulse width.
  • Results of this experiment are set forth in Figure 8.
  • the open squares represent the control .
  • the solid diamonds represent the treatment with a single electroporative pulse of 500 V amplitude.
  • the passive flux of molsidomine from aqueous pH 7.4 was very low. With a single pulse at the beginning of the experiment, the passive flux was increased over 10 times initially.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
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  • Public Health (AREA)
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Abstract

Procédé d'entraînement pulsé d'une substance dans un tissu, consistant: (a) à soumettre le tissu à au moins une impulsion électrique afin de provoquer l'électroporation de la zone tissulaire, la durée de l'impulsion électrique étant égale à la durée d'impulsion d'électroporation, et la durée d'impulsion d'électroporation étant inférieure à la durée d'une force motrice; (b) à soumettre la zone tissulaire à une force motrice de sorte que celle-ci provoque l'entraînement pulsé de la substance dans le tissu, et ce pendant la durée de la force motrice; et (c) à répéter l'étape (a) pendant la durée de la force motrice.
PCT/US1995/007951 1994-06-24 1995-06-23 Systemes d'administration pulsee d'agents biologiquement actifs a l'aide d'impulsions de tension electrique permettant de reguler la permeabilite membranaire WO1996000111A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU29477/95A AU2947795A (en) 1994-06-24 1995-06-23 Pulsatile delivery systems of biologically active agents using electro voltage pulsing for controlling membrane permeability
EP95925294A EP0766579A1 (fr) 1994-06-24 1995-06-23 Systemes d'administration pulsee d'agents biologiquement actifs a l'aide d'impulsions de tension electrique permettant de reguler la permeabilite membranaire
JP8503326A JPH10511008A (ja) 1994-06-24 1995-06-23 膜透過性制御のための電子電圧パルスを用いた生物学的活性因子のパルス使用送達システム

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US26530694A 1994-06-24 1994-06-24
US08/265,306 1994-06-24

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WO1996000111A1 true WO1996000111A1 (fr) 1996-01-04

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EP (1) EP0766579A1 (fr)
JP (1) JPH10511008A (fr)
AU (1) AU2947795A (fr)
CA (1) CA2194010A1 (fr)
WO (1) WO1996000111A1 (fr)

Cited By (19)

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WO1999012606A1 (fr) * 1997-09-08 1999-03-18 Becton Dickinson And Company Administration par iontophorese de buprenorphine
WO1999022809A1 (fr) * 1997-11-04 1999-05-14 Genetronics, Inc. Appareil d'electroporation et d'iontophorese combinees pour l'apport de medicaments et de genes
US5968006A (en) * 1997-11-04 1999-10-19 Genetronics, Inc. Method and apparatus for a combination of electroporation and iontophoresis for the delivery of drugs and genes
US6009345A (en) * 1992-08-17 1999-12-28 Genetronics, Inc. Method and apparatus for a combination of electroporation and iontophoresis for the delivery of drugs and genes
WO2000009205A1 (fr) * 1998-08-14 2000-02-24 Genetronics, Inc. Appareil et procede d'administration de medicaments et de genes dans les tissus
WO2000047274A1 (fr) * 1999-02-10 2000-08-17 Gmp Drug Delivery, Inc. Ionophorese, electroporation et dispositifs a patch combines pour administration locale de medicaments
WO2001043817A1 (fr) * 1999-12-15 2001-06-21 University Of South Florida Dispositif d'electroporation
EP1128870A1 (fr) * 1998-11-09 2001-09-05 Elecsys Ltd Apport de medicaments et extraction d'analytes par voie transdermique
EP1222932A1 (fr) * 1999-10-14 2002-07-17 Pola Chemical Industries, Inc. Compositions d'electroporation
US6528315B2 (en) 1997-06-30 2003-03-04 Aventis Pharma S.A. Method for transferring nucleic acid into multicelled eukaryotic organism cells and combination therefor
WO2003046170A1 (fr) * 2001-11-27 2003-06-05 Cellectricon Ab Procede d'administration parallele combinee d'agents et d'electroporation pour structures cellulaires et utilisation associee
US6778853B1 (en) 1997-12-17 2004-08-17 University Of South Florida Electroporation device
WO2004089299A2 (fr) * 2003-04-02 2004-10-21 Advancis Pharmaceutical Corporation Antigenes et adjuvants a administration transdermique pulsatile
US6939862B2 (en) 1997-06-30 2005-09-06 Aventis Pharma S.A. Method for transferring nucleic acid into striated muscles
WO2005089728A2 (fr) * 2004-03-19 2005-09-29 Pfizer Health Ab Dispositif d'administration transdermique de la nicotine
EP1682217A2 (fr) * 2003-11-13 2006-07-26 ALZA Corporation Systeme et methode d'administration transdermique
US8232074B2 (en) 2002-10-16 2012-07-31 Cellectricon Ab Nanoelectrodes and nanotips for recording transmembrane currents in a plurality of cells
US8281675B2 (en) 2007-10-17 2012-10-09 Syneron Medical Ltd Dissolution rate verification
JP2013099586A (ja) * 1996-12-31 2013-05-23 Altea Therapeutics Corp 生物活性薬剤送達のための組織微穿孔

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WO1993010854A1 (fr) * 1991-12-03 1993-06-10 Alza Corporation Dispositif d'administration iontophoretique et son alimentation
EP0625360A1 (fr) * 1992-08-28 1994-11-23 Katsuro Tachibana Appareil a elements de dosage de medicaments et de collecte de fluides corporels

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WO1993010854A1 (fr) * 1991-12-03 1993-06-10 Alza Corporation Dispositif d'administration iontophoretique et son alimentation
EP0625360A1 (fr) * 1992-08-28 1994-11-23 Katsuro Tachibana Appareil a elements de dosage de medicaments et de collecte de fluides corporels

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6009345A (en) * 1992-08-17 1999-12-28 Genetronics, Inc. Method and apparatus for a combination of electroporation and iontophoresis for the delivery of drugs and genes
JP2013165967A (ja) * 1996-12-31 2013-08-29 Altea Therapeutics Corp 生物活性薬剤送達のための組織微穿孔
JP2013099586A (ja) * 1996-12-31 2013-05-23 Altea Therapeutics Corp 生物活性薬剤送達のための組織微穿孔
US6528315B2 (en) 1997-06-30 2003-03-04 Aventis Pharma S.A. Method for transferring nucleic acid into multicelled eukaryotic organism cells and combination therefor
US6939862B2 (en) 1997-06-30 2005-09-06 Aventis Pharma S.A. Method for transferring nucleic acid into striated muscles
WO1999012606A1 (fr) * 1997-09-08 1999-03-18 Becton Dickinson And Company Administration par iontophorese de buprenorphine
WO1999022809A1 (fr) * 1997-11-04 1999-05-14 Genetronics, Inc. Appareil d'electroporation et d'iontophorese combinees pour l'apport de medicaments et de genes
US5968006A (en) * 1997-11-04 1999-10-19 Genetronics, Inc. Method and apparatus for a combination of electroporation and iontophoresis for the delivery of drugs and genes
AU741399B2 (en) * 1997-11-04 2001-11-29 Genetronics, Inc. Combined electroporation and iontophoresis apparatus for drug and gene delivery
US8338150B2 (en) 1997-11-06 2012-12-25 Cellectricon Ab Method for combined parallel agent delivery and electroporation for cell structures an use thereof
US6778853B1 (en) 1997-12-17 2004-08-17 University Of South Florida Electroporation device
AU769758C (en) * 1998-08-14 2007-09-06 Genetronics, Inc. Apparatus and method for the delivery of drugs and genes into tissue
US6192270B1 (en) 1998-08-14 2001-02-20 Genetronics, Inc. Apparatus and method for the delivery of drugs and genes into tissue
US7395110B2 (en) 1998-08-14 2008-07-01 Genetronics, Inc. Electrode apparatus and method for the delivery of drugs and genes into tissue
AU769758B2 (en) * 1998-08-14 2004-02-05 Genetronics, Inc. Apparatus and method for the delivery of drugs and genes into tissue
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JPH10511008A (ja) 1998-10-27
AU2947795A (en) 1996-01-19
CA2194010A1 (fr) 1996-01-04
EP0766579A1 (fr) 1997-04-09

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