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WO1999030773A1 - Regulateur avec charge artificielle permettant de maintenir un apport regule - Google Patents

Regulateur avec charge artificielle permettant de maintenir un apport regule Download PDF

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Publication number
WO1999030773A1
WO1999030773A1 PCT/US1998/026187 US9826187W WO9930773A1 WO 1999030773 A1 WO1999030773 A1 WO 1999030773A1 US 9826187 W US9826187 W US 9826187W WO 9930773 A1 WO9930773 A1 WO 9930773A1
Authority
WO
WIPO (PCT)
Prior art keywords
voltage
load
resistance
regulator
current
Prior art date
Application number
PCT/US1998/026187
Other languages
English (en)
Inventor
Paul Urbanski
Original Assignee
Alza Corporation
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 Alza Corporation filed Critical Alza Corporation
Priority to JP2000538748A priority Critical patent/JP2002508228A/ja
Priority to EP98964714A priority patent/EP1039950A1/fr
Priority to CA002314929A priority patent/CA2314929C/fr
Priority to AU19976/99A priority patent/AU1997699A/en
Priority to KR1020007006600A priority patent/KR20010033208A/ko
Publication of WO1999030773A1 publication Critical patent/WO1999030773A1/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
    • A61N1/18—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 generally to an electrotransport device for transdermally or transmucosally delivering a beneficial agent (e.g., a drug) to a patient. More particularly, the present invention relates to a portable or patient-worn electrotransport delivery device having a voltage booster and an artificial load to maintain regulated delivery of the beneficial agent.
  • a beneficial agent e.g., a drug
  • electrotransport refers generally to the delivery of an agent (e.g., a drug) through a membrane, such as skin, mucous membrane, or nails, in which the delivery is at least partially induced or aided by the application of an electric potential.
  • an agent e.g., a drug
  • a membrane such as skin, mucous membrane, or nails
  • a beneficial therapeutic agent may be introduced into the systemic circulation of an animal (e.g., a human) by electrotransport delivery through the skin.
  • the electrotransport process has been found to be useful in the transdermal administration of drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, and many other drugs.
  • drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, and many other drugs.
  • electrotransport is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates production of sweat. The sweat is then collected and analyzed for its chloride content to detect the presence of the disease.
  • Presently known electrotransport devices use at least two electrodes, positioned in intimate contact with some portion of the animal's body (e.g., the skin).
  • a first electrode called the active or donor electrode
  • delivers the therapeutic agent e.g., a drug or a prodrug
  • the second electrode called the counter or return electrode
  • a source of electrical energy such as a battery, supplies electric current to the body through the electrodes.
  • the therapeutic agent to be delivered into the body is positively charged (i.e., a cation)
  • the anode will be the active electrode and the cathode will serve as the counter electrode to complete the circuit.
  • the therapeutic agent to be delivered is negatively charged (i.e., an anion)
  • the cathode will be the donor electrode and the anode will be the counter electrode.
  • both the anode and cathode may be used to deliver drugs of opposite electrical charge into the body.
  • both electrodes are considered donor and counter electrodes.
  • the anode can simultaneously deliver a cationic therapeutic agent and act as a "counter" electrode to the cathode.
  • the cathode can simultaneously deliver an anionic therapeutic agent into the body and act as a "counter" electrode to the anode.
  • electromigration also called iontophoresis
  • electroosmosis Another type of electrotransport, electroosmosis, involves the flow of a liquid solvent from the donor reservoir, which liquid contains the agent to be delivered, under the influence of the applied electric field.
  • Still another type of electrotransport process involves the formation of transiently existing pores in a biological membrane by the application of high voltage pulses.
  • a therapeutic agent can, in part, be delivered through the skin by passive diffusion by reason of the concentration difference between the concentration of the drug in the donor reservoir of the electrotransport device and the concentration of the drug in the tissues of the patient's body.
  • electrotransport should be given its broadest reasonable interpretation so that it includes, for example, the electrically induced or enhanced transport of at least one therapeutic agent, whether charged, uncharged, or a mixture thereof.
  • load current and the current flowing through the skin are defined as the current flowing between the two electrodes.
  • Electrotransport devices generally require a reservoir or source of the agent, or a precursor of such agent, that is to be delivered into the body by electrotransport.
  • reservoirs or sources of, preferably ionized or ionizable, agents include a pouch as described in Jacobsen U.S. Patent 4,250,878, or a pre-formed gel body as disclosed in Webster U.S. Patent 4,383,529.
  • Such reservoirs are electrically connected to the anode or the cathode of an electrotransport device to provide a fixed or renewable source of one or more desired therapeutic species.
  • electrotransport delivery devices have become much smaller, particularly with the development of miniaturized electrical circuits (e.g., integrated circuits) and more powerful light weight batteries (e.g., lithium batteries).
  • miniaturized electrical circuits e.g., integrated circuits
  • light weight batteries e.g., lithium batteries
  • the advent of inexpensive miniaturized electronic circuitry and compact, high-energy batteries has meant that the entire device can be made small enough to be unobtrusively worn on the skin of the patient and under clothing. This allows the patient to remain fully ambulatory and able to perform all normal activities, even during periods when the electrotransport device is actively delivering drug.
  • the prior art transdermal electrotransport delivery devices supply set voltages indiscriminately to any skin surface, irrespective of the resistance of the skin. Further, in some other prior art transdermal electrotransport delivery devices, the voltage of the power supply and/or the boost multiple of the voltage boosting circuit, are chosen to be large enough to overcome the high skin resistance present at the start of operation. However, once operation had reached a steady state, with the attendant drop in skin resistance, the prior art devices have excess working voltage. Accordingly, by supplying a higher voltage than required, these prior art devices deliver more drug dosage than required, once the skin resistance drop from its initial high level.
  • an improved electrotransport device and method that can maintain a target drug delivery rate while the skin resistance drops from its initial value, and which can be applied to deliver the targeted drug delivery rate to different areas of the skin with different resistances.
  • One embodiment of the present invention is an electrotransport device with a drug delivery regulating apparatus which delivers the proper drug dosage rate over time by adapting to variable skin resistance values, particularly the decline in skin resistance over the time that the lectrotransport device is used, and to different skin resistances at different skin surface locations.
  • a drug delivery regulating apparatus in another embodiment, includes a voltage booster, a serially connectable artificial impedance, and a feedback sensor, which are all connected to a controller.
  • This apparatus outputs a load voltage across two electrodes.
  • the controller monitors the output of the feedback sensor to determine (a) the skin resistance, or (b) a load current, or ⁇ the load voltage, and based on the monitored value, controls the load voltage across the electrodes, so that the targeted drug dose rate is maintained even as the initial skin resistance drops over the period that the electrotransport device is used.
  • the artificial impedance is generated and applied to prevent over dose where the skin resistance falls below the battery voltage of the apparatus.
  • Figure 1 is a perspective view of an electrotransport drug delivery device of this invention.
  • Figure 2 is an exploded view of an electrotransport device of this invention.
  • Figure 3 is a graph illustrating the decline of patient skin resistance with time.
  • Figure 4 is a graph of an exemplary current-time profile of load current supplied by an electrotransport device of this invention.
  • the graph is an example of a current-time profile.
  • Figure 5 is a time line graph of a load voltage of an electrotransport device of this invention.
  • Figure 6 is a schematic block diagram of a drug delivery regulator of this invention.
  • Figure 7 is a schematic logic circuit diagram of a drug delivery regulator of this invention.
  • Figure 8 is a timing diagram of the operation of the circuit of Figure 7.
  • Figure 9 is a schematic logic circuit diagram of another drug delivery regulator of this invention.
  • Figure 10 is a timing diagram of the operation of the circuit of Figure 9.
  • Figure 11. is a perspective view of an electrotransport drug delivery device which includes a disposable drug unit.
  • Figure 12 is an exploded view of an electrotransport device of Figure
  • Figure 13 is a schematic logic circuit diagram of another drug delivery regulator of this invention.
  • Embodiments of electrotransport drug delivery devices which include the electrotransport drug delivery regulator of the present invention are illustrated in Figs. 1-2 and 11-12.
  • Figure 1 shows a perspective view of an electrotransport delivery device 10 having an optional activation switch in the form of a push button switch 12 and an optional light emitting diode (LED) 14 which is turned on when device 10 is in operation.
  • an optional activation switch in the form of a push button switch 12 and an optional light emitting diode (LED) 14 which is turned on when device 10 is in operation.
  • LED light emitting diode
  • FIG. 2 is an exploded view of a second device 10 of this invention.
  • the device 10 of Figure 2 differs from device 10 of Figure 1 in the location of a LED 14.
  • Device 10 of Figure 2 comprises an upper housing 16, circuit board assembly 18, lower housing 20, anode electrode 22, cathode electrode 24, anode reservoir 26, cathode reservoir 28 and skin-compatible adhesive 30.
  • Upper housing 16 has lateral wings 15 which assist in holding device 10 of Figure 2 on a patient's skin.
  • Upper housing 16 can be composed of an injection moldable elastomer (e.g., ethylene vinyl acetate).
  • Upper housing 16 can also be composed of rubber or other elastomeric material.
  • Printed circuit board assembly 18 comprises an integrated circuit 19 coupled to discrete components 40 and battery 32.
  • Circuit board assembly 18 is attached to housing 16 by posts (not shown in Figure 2) passing through openings 13a and 13b, the ends of the posts being heated/melted in order to heat stake circuit board assembly 18 to housing 16.
  • Lower housing 20 is attached to upper housing 16 by an adhesive 30, an upper surface 34 of adhesive 30 being adhered to both lower housing 20 and upper housing 16 including the bottom surfaces of wings 15.
  • circuit board assembly 18 Shown (partially) on the underside of circuit board assembly 18 is a button cell battery 32. Other types of batteries may also be employed to power device 10.
  • Device 10 is generally comprised of battery 32, electronic circuitry 19, 40, electrodes 22, 24, and drug/chemical reservoirs 26, 28, all of which are integrated into a self-contained unit.
  • the outputs (not shown in Figure 2) of the circuit board assembly 18 make electrical contact with the electrodes 24 and 22 through openings 23, 23' in depressions 25, 25' formed in lower housing 20, by electrically conductive adhesive strips 42,42'.
  • Electrodes 22 and 24, in turn, are in direct mechanical and electrical contact with top sides 44', 44 of drug reservoirs 26 and 28.
  • Bottom sides 46', 46 of drug reservoirs 26,28 contact the patient's skin through openings 29', 29 in adhesive 30.
  • Lower housing 20 can be composed of a plastic or elastomeric sheet material (e.g., polyethylene) which can be easily molded to form depressions 25, 25' and cut to form openings 23,23'.
  • the assembled device 10 is preferably water resistant (i.e., splash proof) and is most preferably waterproof.
  • the system has a low profile that easily conforms to the body, thereby allowing freedom of movement at, and around, the wearing site.
  • Reservoirs 26 and 28 are located on the skin-contacting side of device 10 and are sufficiently separated to prevent accidental electrical shorting during normal handling and use.
  • agent Any agent may be used, so long as it is at least partly ionized.
  • drug and “agent” are used interchangeably and are intended to have their broadest reasonable interpretation, namely any therapeutically active substance that is delivered to a living organism to produce a desired, usually beneficial, effect.
  • drug and agents include therapeutic compounds and molecules from all therapeutic categories including, but not limited to, anti-infectives (such as antibiotics and antivirals), analgesics (such as fentanyl, sufentanil, buprenorphine, and analgesic combinations), anesthetics, antiarthritics, antiasthmatics (such as terbutaline), anticonvulsants, antidepressants, antidiabetics, antidiarrheals, antihistamines, anti-inflammatories, antimigranes, antimotion sickness preparations (such as scopolamine and ondansetron), antineoplastics, antiparkinsonisms, antipruritics, antipsychotics, antipyretics, antispasmodics (including gastrointestinal and urinary), anticholinergics, sympathomimetrics, xanthine and derivatives thereof, cardiovascular preparations (including calcium channel blockers such as nifedipine, beta-agonist
  • analgesics such as
  • the electrotransport device of the present invention can deliver drugs and/or agents including baclofen, beclomethasone, betamethasone, buspirone, cromolyn sodium, diltiazem, doxazosin, droperidol, encainide, fentanyl, hydrocortisone, indomethacin, ketoprofen, lidocaine, methotrexate, metoclopramide, miconazole, midazolam, nicardipine, piroxicam, prazosin, scopolamine, sufentanil, terbutaline, testosterone, tetracaine and verapamil.
  • drugs and/or agents including baclofen, beclomethasone, betamethasone, buspirone, cromolyn sodium, diltiazem, doxazosin, droperidol, encainide, fentanyl, hydrocortisone, indomethacin, ketoprofen
  • the electrotransport device of the present invention may also deliver peptides, polypeptides, proteins and other macromolecules.
  • Such molecules are known in the art to be difficult to deliver transdermally or transmucosally due to their size.
  • such molecules may have molecular weights in the range of 300-40,000 daltons and include, but not limited to, LHRH and analogs thereof (such as buserelin, gosserelin, gonadorelin, naphrelin and leuprolide), GHRH, GHRF, insulin, insulinotropin, heparin, calcitonin, octreotide, endorphin, TRH, NT-36 or N-[[(s)-4-oxo-2-azetidinyl]carbonyl]L- histidyl-L-prolinamide], liprecin, pituitary hormones (such as HGH, HMG, HCG, desmopressin acetate), follicile luteoids, a-AN
  • Device 10 optionally has a feature which allows the patient to self- administer a dose of drug by electrotransport.
  • the electronic circuitry on circuit board assembly 18 delivers a predetermined DC current to electrodes/reservoirs 22, 26 and 24, 28 for a delivery interval of predetermined length.
  • Push button switch 12 is conveniently located on the top side of device 10 and is easily actuated through clothing. A double press of push button switch 12 within a short time period, e.g., three seconds, can be used to activate the device for delivery of drug, thereby minimizing the likelihood of inadvertent actuation of device 10.
  • the device can transmit to the user a visual and/or audible confirmation of the onset of the drug delivery interval by LED 14 becoming lit and/or an audible sound signal from, e.g., a "beeper".
  • Drug is delivered through the patient's skin by electrotransport, e.g., on the arm, over the predetermined delivery interval.
  • Anodic electrode 22 can be comprised of silver, and cathodic electrode 24 can be comprised of silver chloride. Both reservoirs 26 and 28 can be comprised of polymer hydrogel materials. Electrodes 22, 24 and reservoirs 26, 28 are retained within the depressions 25',25 in lower housing 20.
  • Device 10 adheres to the patient's body surface (e.g., skin) by a peripheral adhesive 30 which has upper side 34 and body-contacting side 36.
  • Adhesive side 36 has adhesive properties which assures that device 10 remains in place on the body during normal user activity, and yet permits reasonable removal after the predetermined (e.g., 24-hour) wear period.
  • Upper adhesive side 34 adheres to lower housing 20 and retains lower housing 20 attached to upper housing 16.
  • Reservoirs 26 and 28 generally comprise a gel matrix, with the drug solution uniformly dispersed in at least one of the reservoirs 26 and 28.
  • Drug concentrations in the range of approximately 1 x 10 "4 M to 1.0 M or more can be used, with drug concentrations in the lower portion of the range being preferred.
  • Suitable polymers for the gel matrix may comprise essentially any nonionic synthetic and/or naturally occurring polymeric materials. A polar nature can be implemented where the active agent is polar and/or capable of ionization, so as to enhance agent solubility.
  • the gel matrix will be water swellable.
  • suitable synthetic polymers include, but are not limited to poly(acrylamide), poly(2-hydroxyethyl acrylate), poly(2- hydroxypropyl acrylate), poly(N-vinyl-2-pyrrolidone), poly(n- methylolacrylamide), poly(diacetone acrylamide), poly(2-hydroxylethyl methacrylate), poly(vinyl alcohol) and poly(allyl alcohol).
  • Hydroxyl functional condensation polymers i.e., polyesters, polycarbonates, polyurethanes
  • suitable polar synthetic polymers are also examples of suitable polar synthetic polymers.
  • Polar naturally occurring polymers (or derivatives thereof) suitable for use as the gel matrix are exemplified by cellulose ethers, methyl cellulose ethers, cellulose and hydroxylated cellulose, methyl cellulose and hydroxylated methyl cellulose, gums such as guar, locust, karaya, xanthan, gelatin, and derivatives thereof.
  • Ionic polymers can also be used for the matrix provided that the available counterions are either drug ions or other ions that are oppositely charged relative to the active agent.
  • the polypeptide analogs of the present invention will be incorporated into the drug reservoir, e.g., a gel matrix as just described, and administered to a patient using an electrotransport drug delivery system, optionally as exemplified hereinabove.
  • Incorporation of the drug solution can be done any number of ways, i.e., by imbibing the solution into the reservoir matrix, by admixing the drug solution with the matrix material prior to hydrogel formation, or the like.
  • Figures 11-12 show another embodiment of an electrotransport drug delivery device of the present invention.
  • This embodiment includes a reusable electronic controller and a drug unit.
  • the reusable controller in Figures 11-12 usually houses a drug delivery regulator and is designed to be used in conjunction with the drug unit for transdermally delivering the drug stored in the drug unit.
  • Figure 11 is a perspective view of electrotransport device 320 having a reusable electronic controller 322 which is adapted to be coupled to and uncoupled from, drug-containing unit 324.
  • the reusable electronic controller 322 is reusable, i.e., it is adapted to be used with a plurality of drug units 324, e.g., a series of similar and/or very different drug units 324.
  • drug unit 324 typically has a more limited life and is adapted to be discarded after use, i.e., when the drug contained therein has been delivered or depleted.
  • drug unit 324 is uncoupled from reusable electronic controller 322 and replaced with a fresh drug unit 324 of the same or different structure and/or composition.
  • Reusable electronic controller 322 is designed to provide one of a plurality of different predetermined electrical outputs which can be set at the time the controller is
  • the different electrical outputs of the reusable electronic controller 322 are designed to be used with different drug units 324.
  • the reusable electronic controller 322 can be designed to be used with at least two different drug units 324, both of which units are adapted to be used with the same reusable electronic controller 322 to continuously deliver drug over a period of 12 hours.
  • the two different drug units 324 contain the same drug in their respective donor reservoirs but each contains a different amount of the drug.
  • the drug unit 324 which contains a greater amount of drug is a "high dose" drug unit which is adapted to be used with a higher DC current (e.g., 2 mA) output from the reusable electronic controller 322.
  • the drug unit 324 which contains a lesser amount of drug is a "low dose" drug unit which is adapted to be used with a lower DC current (e.g., 1 mA) output from the reusable electronic controller 322.
  • the reusable electronic controller 322 is designed to apply one of two different DC currents (i.e., 1 mA or 2mA) depending upon whether a low dose or a high dose drug unit 324 is coupled thereto.
  • the present invention signals to reusable electronic controller 322 which type of drug unit (e.g., either a high dose or a low dose drug unit) is being coupled thereto and for appropriately setting the output of the controller (i.e., setting either the high current output or the low current output) to match the coupled drug unit.
  • drug unit 324 signals reusable electronic controller 322 by an optical signal, which optical signal is automatically sent and then read (i.e., decoded) by reusable electronic controller 322 upon coupling drug unit 324 thereto (i.e., by the snap connectors 326, 328). Upon reading the signal, the controller appropriately selects the correct electrical output to apply to the coupled drug unit 324.
  • Reusable electronic controller 322 is comprised of an upper housing 368 and a lower housing 350, both typically formed of a molded plastic such as polypropylene.
  • Upper housing 368 is joined to lower housing 350 by a contiguous splash proof and preferably water proof peripheral seal. The seal can be made by heat sealing or ultrasonic welding of the joint between housings 350, 368, by gluing the housings together at their common joint using a water proof adhesive, and the like.
  • Lower housing 350 has an opening 352 for receiving battery 354.
  • Battery contacts 364, 366 are provided to make electrical contact with the respective poles of battery 354.
  • a removable cover 360 screws into the opening 352 to retain battery 354 in place.
  • Cover 360 has a slot 362 for inserting a coin or a screw driver blade to turn cover 360 and remove it from opening 352 in order to access (i.e., replace) battery 354.
  • Reusable electronic controller 322 includes a battery 354, e.g. a button cell battery, for powering the electrical circuit (not shown) on circuit board 359.
  • Circuit board 359 is formed in a conventional manner, having conductive traces patterned for interconnecting electrical component(s) thereon which control the magnitude, timing, frequency, waveform shape, etc., of the electrical output (e.g., voltage and/or current) of reusable electronic controller 322.
  • the conductive traces on circuit board 359 may be deposited with a conventional silk screen printing process or a conventional solder coated copper plated mask and etch process.
  • the insulating substrate of circuit board 359 may be made of standard FR-4 or the like.
  • reusable electronic controller 322 includes a push button switch 374 which can be used to start operation of device 310 and a liquid crystal display 356 ( Figure 11) which can display, through a window 358 ( Figure 12), system information such as the particular type of drug unit 324 that is coupled to the controller, the applied current level, the dosing level, number of doses delivered, elapsed time of current application, battery strength, etc.
  • Lower housing 350 is provided with holes 375a, 375b which hold electrically conductive receptacles 330, 332. Receptacles 330, 332 protrude through respective holes 375a, 375b in lower housing 350. The ends of receptacles 330, 332 are held in place, and make electrical contact with the outputs of the electronic circuit on circuit board 359, by respective conductive gripping fasteners 376a, 376b.
  • Drug unit 324 is configured to be removably coupled to reusable electronic controller 322, with the top of drug unit 324 adjacent to and facing the bottom of reusable electronic controller 322.
  • Top drug unit 324 is provided with the male parts of two snap type connectors, the male parts being posts 326 and 328 which extend upwardly from drug unit 324.
  • Receptacle 330 is positioned and sized to receive donor post 326 and receptacle 332 is positioned and sized to receive counter post 328.
  • One snap connector pair for example receptacle 332 and post 328, may be made larger than the other snap connector pair (i.e., receptacle 330 and post 326) in order to provide a polarity specific connection of drug unit 324 to reusable electronic controller 322.
  • Receptacles 330, 332 and posts 326, 328 are made from an electrically conductive material (e.g., a metal such as silver, brass, stainless steel, platinum, gold, nickel, beryllium-copper, etc., or a metal coated polymer, e.g., ABS with a silver coating).
  • Donor post 326 is electrically connected to donor electrode 390, which in turn is electrically connected to donor reservoir 401 which typically contains a solution of the therapeutic agent (e.g., a drug salt) to be delivered.
  • Counter post 328 is electrically connected to counter electrode 388, which in turn is electrically connected to counter reservoir 399 which typically contains a solution of a biocompatible electrolyte (e.g., buffered saline).
  • a biocompatible electrolyte e.g., buffered saline
  • Electrodes 388 and 390 are typically comprised of electrically conductive materials, which can be a silver (e.g., silver foil or silver powder loaded polymer) anodic electrode and a silver chloride cathodic electrode.
  • Reservoirs 399 and 401 typically include hydrogel matrices which hold the drug or electrolyte solutions and are adapted to be placed in contact with the body surface (e.g., skin) of a patient (not shown) when in use. Electrodes 388, 390 and reservoirs 399, 401 are isolated from each other by foam member 396.
  • the bottom (i.e., patient contacting) surface of foam member 396 can be coated with a skin contact adhesive in order to secure drug unit 324 on the patient's body.
  • a release liner 402 covers the body contacting surfaces of the two reservoirs 399 and 401 and the adhesive coated surface of foam member 396 before drug unit 324 is put in use.
  • Release liner 402 in one embodiment is a silicone coated polyester sheet. Release liner 402 is removed when device 320 is applied to the skin of a patient (not shown).
  • post 326 and receptacle 330 comprise a snap type connector which electrically connects an output 378a of the circuit on circuit board 359 to electrode 390 and reservoir 401.
  • post 328 and receptacle 332 comprise a snap type connector which electrically connects an output 378b of the circuit on circuit board 359 to electrode 388 and reservoir 399.
  • the two snap connectors also provide a separable (i.e., not permanent) mechanical connection of drug unit 324 to reusable electronic controller 322.
  • electrically conductive snap connectors 326, 330 and 328, 332 simultaneously provide the functions of (i) mechanically coupling drug unit 324 to connector 322, and (ii) electrically connecting electrical output of reusable electronic controller 322 to drug unit 324.
  • drug unit 324 provides an optical signal to reusable electronic controller 322 in order to properly set the electrical output of the controller to a predetermined output which is appropriate for the specific drug unit 324 and the specific drug unit 324 and the specific drug contain therein.
  • the mating surface of drug unit 324 has two surface areas 340, 342.
  • Surface area 340 is shown as "white” for high light reflectivity while surface area 342 is shown as "black” for low light reflectivity.
  • Areas 340, 342 may be provided (e.g., by printing or painting) directly on backing layer 344 of drug unit 324 or alternatively on a thin strip of paper or mylar 343 which is mounted on backing layer 344 by a suitable adhesive.
  • Reusable electronic controller 322 has a pair of light reflection switches 334, 336 mounted on circuit board 359 and oriented so as to project through holes 337a, 337b in lower housing 350. Switches 334, 336 are directed toward and adjacent to drug unit 324. Reflective areas 340, 342 are positioned on drug unit 324 such that areas 340, 342 are located closely adjacent to reflection switches 336, 334, respectively, when reusable electronic controller 322 and drug unit 324 are coupled.
  • Light reflection switches 334, 336 are arranged to illuminate the light reflective areas 340, 342 respectively. Reflective areas 340, 342 are arranged such that the illumination from switch 334 is independently reflected by area 342 back to switch 334. Similarly, the illumination from switch 336 is independently reflected by area 340 back to switch 336.
  • switches 334 and 336 are each provided with a respective illumination source in the form of a photo emitter, 346a and 346b, and a respective matching light sensitive photodetector in the form of a phototransistor, 348a and 348b, such as the SFH901 or SFH902 available from Siemens Optoelectronics Division, Cupertino, CA.
  • the phototransistors 348a and 348b are connected in a circuit (described below) which generates signals responsive to incident light.
  • Switches 334, 336 are mounted on circuit board 359 and respective traces (not shown) by conventional means such as through holes and solder connections.
  • Flexible backing layer 344 which can be made of a material (e.g., polyethylene sheet) which is impermeable to the passage of liquid water, forms the top-most layer of drug unit 324.
  • Holes 384a, 384b are provided through backing layer 344 and perforations 382a, 382b through strip 343 in an aligned arrangement.
  • Conductive base rivets 326a, 328a project through openings 384a, 384b and perforations 382a, 382b, respectively, and engage posts 326, 328 to fix backing layer 344 therebetween.
  • Electrodes 388, 390 are composed of electrically conductive materials such as a carbon powder/fiber loaded polymer matrix, a metal powder loaded polymer matrix or a metal foil. Electrodes 388, 390 make contact with the base rivets 326a, 328a. A carbon filled or silver particle filled conductive adhesive is used to bond electrodes 388, 390 to base rivets 326a, 328a. Electrodes 388, 390 are in electrical contact with reservoirs 399, 401 , respectively.
  • An insulating closed cell foam layer 396 has cavities 398, 400 therein, which cavities contain reservoirs 399, 401 , respectively.
  • one of reservoirs 399, 401 is the donor reservoir which contains a liquid solution of the therapeutic agent to be delivered by electrotransport while the other is the counter reservoir which contains a solution of a bio-compatible electrolyte (e.g., saline).
  • the matrix of reservoirs 399, 401 can be a gel. Transmitting information about drug unit 324, via the optical signal transmitted to reusable electronic controller 322, is accomplished by providing reflective areas 340, 342 with different levels of reflectivity.
  • area 340 may be a standard white having about 90% reflectivity
  • area 342 may be a flat black having between about 10 to 15% reflectivity at the wavelength of illumination from the switches 334, 336.
  • drug unit 324 may transmit to reusable electronic controller 322 up to four differently coded optical signals based on following "reflectivity code"; (1) a first optical signal when both areas 340 and 342 have low reflectivities; (2) a second optical signal when both areas 340 and 342 have high reflectivities; (3) a third optical signal when area 340 has a low reflectivity and area 342 has a high reflectivity; and (4) a fourth optical signal when area 340 has a high reflectivity and area 342 has a low reflectivity.
  • the areas 340, 342 may be encoded by simply painting with a paint having suitable reflectivity.
  • the areas 340, 342 may also be encoded by printing or by applying adhesive tape with suitable reflectivity.
  • An apparatus e.g., electronic circuitry, which implements the method of regulating the drug delivery of the present invention is installed in the electrotransport drug delivery devices of the present invention described above. More specifically, electronic circuitry fabricated on circuit board assembly 18 of Figure 2, or circuit board 359 of Figure 12, is implemented to regulate the drug delivery of the present invention.
  • the electronic circuitry is referred as a regulator hereinafter. The regulator initiates the drug delivery only if the delivery device is attached to the patient's skin surface and when the push button switch is pressed in a particular sequence, e.g., a double click.
  • the regulator then starts a step-up period T 0 during which the regulator supplies an initial current (i) with a boosted voltage to overcome the high initial skin resistance.
  • the regulator during the step-up period T 0 , maintains the voltage seen at the skin to be between a maximum (24 V) and a minimum (O V) to reduce the irritation patient's sensation of the initial applied current.
  • the voltage is supplied by the regulator between two electrodes, for example, 22 and 24 of Figure 2 or 388 and 390 of Figure 12.
  • the regulator controls the boosted voltage to maintain a delivery current (id) during a delivery period (T d ).
  • the anode voltage (V a ) may fall below the battery voltage (V b ). This causes the regulator to enter, at time T1 , into an over dose mode during which an excess load current flows through the skin even when the battery voltage is supplied without the boosted voltage.
  • This is shown in Figure 5, where the anode voltage, V a , is shown on the y-axis, and time (t) is shown on the x axis.
  • a control enabler that is an artificial impedance, is serially connected to the skin surface.
  • the control enabler's impedance value is sufficiently high, it lowers the current supplied to the skin and also enables the regulator to control the load current by the boosted voltage.
  • the regulator cuts off the voltage supplied to the electrodes.
  • a regulator 50 includes a controller 53 connected to a battery 51. Controller 53 is also connected to a voltage booster 55, an impedance connecting switch 77, and two terminals of a regulating resistor 59.
  • an artificial impedance 57 e.g., a resistor
  • an artificial impedance 57 and impedance connecting switch 77 can be serially connected between voltage booster 55 and an anode electrode assembly 63. This structure is not shown in Figure 6.
  • Impedance connecting switch 77 connects artificial impedance 57 serially between electrode assembly 65 and regulating resistor 59 only during an over dosage mode, otherwise switch 77 connects electrode assembly 65 directly to resistor 59.
  • controller 53 activates voltage booster 55 to supply boosted voltage across two electrodes 63 and 65 which are attached to a skin surface 61.
  • the boosted voltage is required because, initially, skin surface 61 inhibits the current flowing between electrodes 63 and 65 by having a high resistance value.
  • a load current flows from electrode assembly 63, through skin 61 , to the electrode assembly 65, to regulating resistor 59, and to a system ground port 73.
  • a feedback input port
  • controller 53 is designed to determine the current flowing through regulating resistor 59. The determined current is an accurate approximate of the load current.
  • controller 53 regulates voltage booster 55 to supply sufficient voltage to maintain the dose current. This is accomplished by boosting the supplied voltage by turning on voltage booster
  • the target voltage can be set to be equal to the voltage across regulating resistor 59 when the load current is equal to the dose current.
  • the regulator When the feedback voltage is higher than a preset voltage, then the regulator enters into an over dose mode.
  • the preset voltage can be set such that it precisely determines when the skin resistance is too low to cause the anode voltage to drop below the battery voltage. As an example, the preset voltage can be set to 10% over the target voltage.
  • controller 53 cuts off the voltage supplied to electrode assembly 63.
  • a voltage limiter 79 is connected between electrode assembly 63 and a terminal of regulating resistor 59 as a safety measure. When the voltage booster builds up more than a safe level, e.g., 25 V, voltage limiter stops further boosting of the voltage supplied to electrode 63.
  • the apparatus described above with reference to Figure 6 can be implemented in an ASIC or using logic circuits. Further, the embodiment depicted in Figure 6 is only one embodiment, hence the components, controller 53, voltage booster 55, artificial impedance 57, and regulating resistor 59, can be implemented in one integrated circuit or using separate integrated circuits. Implementing the functions of each of the above described components as software modules and programming them into a microprocessor may also embody this invention.
  • FIG. 7 illustrates a detailed schematic diagram of one embodiment depicted in Figure 6.
  • a regulator 100 is electrically connected to a power source in the form of a battery 102, and a voltage controlled electrical junction 104 which is connected to an electrode assembly 108.
  • the electrode assembly 108 is attached to one region of a skin surface 110 by conventional devices such as adhesive, straps, belts or the like.
  • the skin surface is shown schematically as a variable resistance load, R v , to indicate the variation of load resistance typical of the skin when applying electric current l L , there through.
  • An electrode assembly 112 is similarly attached to another region of skin surface 110.
  • Electrode assembly 112 is serially connected to a regulating resistor 114. Electrodes 108 and 112, skin surface 110 and regulating resistor 114 form a load current path for conducting the load current, l L .
  • a voltage booster 141 includes an energy storage inductor 118 being connected between battery 102 and the anode of rectifying diode 120.
  • the cathode of diode 120 is connected to voltage controlled electrical junction 104.
  • Voltage booster 141 further includes a filter capacitor 122 being connected to junction 104 and a controlled switch 124, having a control input 126.
  • Controlled switch 124 has one terminal 128 connected to the junction of the anode of diode 120 and inductor 118, and another terminal 130 connected to the system ground.
  • Control input 126 can alternately open and close switch 124 creating a low resistance connection between terminals 128 and 130, thereby connecting or disconnecting the inductor 118 through a low resistance path to the system ground.
  • Switch 124 may be an electronic switch device such as a bipolar or field effect transistor (FET).
  • a control circuit 132 has a control output 134 connected to switch control input 126.
  • Control circuit 132 includes a feedback input 133 for controlling the control output 134 and a ground input 136.
  • Regulator 100 is provided with a microcontroller 138.
  • Microcontroller 138 is idle until a threshold voltage is seen at regulating resistor 114. This threshold voltage develops when the controller is attached to a patient and a variable skin resistance develops between electrode assemblies 108 and 112.
  • Microcontroller 138 uses an internal counter and software routine to time a low current delivery, e.g., 0.1mA. This time duration is programmable. After this time has expired, microcontroller 138 then delivers a dose current, e.g., 0.5mA, for a second programmable time period.
  • Microcontroller 138 can deliver another dose current, e.g., 0.1mA, for a third programmable time period. The time periods may vary from 0 seconds to a time determined by the limitations of microcontroller 138 memory or battery life.
  • microcontroller 138 receives feedback at input 140 which senses the current l L through the skin 110, by sensing voltage drop of regulating resistor 114, and compares the sensed voltage drop against a preset limit therefor.
  • Microcontroller 138 also receives an input 142 which senses the voltage drop accross the skin 110 and compares the sensed voltage against a preset maximum limit therefor.
  • An artificial impedance includes a control enabling resistor 123, which is serially connected between a control enabling switch 127 and electrode assembly 112. Control enabling switch 127 is controlled by load control output 135 of microcontroller 138.
  • control enabling switch 127 When the feedback voltage sensed by microcontroller 138 at feedback input 140 is higher than the preset voltage limit for longer than a predetermined time, then control enabling switch 127 connects control enabling resistor 123 to regulating resistor 114. When the high feedback voltage condition persists even after connecting control enabling switch 127 is closed, then microcontroller shuts down control circuit 132 and also stops load current l L . At other times, load switch connects electrode assembly 112 directly to regulating resistor 114.
  • the microcontroller 138 monitors the resistance of the skin 110 by the voltage input 142 and the current input 140 and shuts down the voltage boosting function of regulator 100 when the resistance of skin 110 exceeds a predetermined upper limit or decreases below a predetermined lower limit in accordance with stored programs.
  • the first maximum low load detection period and the second maximum low load detection period mentioned above are measured by microcontroller 138, e.g., by tracking the number of timer overflow interrupts.
  • Microcontroller 138 also monitors system events. A low battery signal from control circuit 132 (not shown in Figure 7) notifies microcontroller 138 of a low battery condition. Microcontroller 138 then causes an LED (light emitting diode, not shown in Figure 7) to flash notifying the caregiver.
  • control circuit 132 is adapted to first connect input 136 to system ground. This enables regulating resistor 114 to begin conducting load current, l L , from load 110.
  • Control circuit 132 is configured to toggle control output 134 so that switch 124 connects the one end of inductor 118 to ground for a period of time T1.
  • the inductor current Ii driven by battery 102
  • T1 is a part of the set-up period.
  • the control circuit is adapted to change output 134 to toggle switch input 126 again which opens switch 124 for a time period, T2.
  • T2 the inductor current, ⁇ allocate to switch 124.
  • Filter capacitor 122 provides a low impedance path for the instantaneous current, I*, which then decays toward zero during the time period T2, as the voltage at electrical junction 104 is boosted by the charging of capacitor 122.
  • T2 is another part of the set-up period.
  • inductor 118 stores energy by charging with the current.
  • inductor 118 discharges energy into filter capacitor 122 through diode 120.
  • Inductor 118 thereby transfers energy from battery 102 into capacitor 122 with low loss, limited only by the voltage drop across diode 120 and the negligible series resistance of inductor 118, battery 102 and the electrical connections.
  • the energy source for load current l L is not directly the battery 102 but rather either capacitor 122 (i.e., during time T1) or a combination of the capacitor 122 and inductor 118 (i.e., during time T2).
  • Control circuit 132 is adapted to repeat the T1 , T2 cycle indefinitely or when stopped as described below.
  • the voltage, Vw, at junction 104 is thereby boosted to an adjustable multiple of battery 102 voltage depending on the values of the time periods T1 and T2.
  • the voltage boost thus can be adjusted by adjusting the values of T1 and T2.
  • Dotted lines in Figure 8 indicate missing or delayed pulses as controlled by the control circuit 132. This may occur when pulses are not necessary to replace charge depleted from the capacitor 122, for example, when the therapeutic current, l L , demanded is relatively low.
  • the dotted lines in Figure 8 indicate that the voltage boost control may be by pulse width modulation (PWM), pulse frequency modulation (PFM), pulse skipping, or some combination thereof.
  • PWM pulse width modulation
  • PFM pulse frequency modulation
  • Vw causes the load current l L to flow through skin surface 110, through regulating resistor 114 to the system ground at switch input 136.
  • Feedback input 133 senses the voltage across regulating resistor 114 caused by the load current, l L .
  • Control circuit 132 is adapted to respond to feedback input 133 to regulate the working voltage either boosting, Vw, by adjusting the time periods, T1 and T2 or connecting load resistor 123 by controlling loading switch 127. This is accomplished by comparing the voltage sensed at input 133 with set reference voltages within control circuit 132, e.g., the target voltage.
  • control circuit 132 opens and closes switch 124 at a high frequency until Vw is boosted to the appropriate level.
  • the longer switch 124 is closed i.e., the longer is T1
  • Battery 102 voltage can be boosted by reason of inductor 118.
  • the voltage (Vind) developed in inductor 118 is equal to the inductance value (L) multiplied by the rate of change of the current flow through the inductor:
  • a higher voltage (which is determined in part by the inductance value of inductor 118 and in part by the rate of change of current flow through inductor 118, which is controlled by the values of T1 and T2) is output from inductor 118 at a lower current, since the power into inductor 118 must equal the power out of inductor 118.
  • Electrode assemblies 108 and 112, and thus skin surface 110 are not exposed to high peak voltages, but instead experience only the minimum, constant value sufficient to drive the desired load current l L .
  • the time periods T1 and T2 are adjusted by the control circuit 132 to boost Vw to the minimum absolute value to provide the load current l L , to maintain a desired predetermined value. If the resistance of the skin surface 110 is too high to allow the predetermined value of l L to be attained without having Vw exceed a safe level, then a voltage limiting device, such as a zener diode 116 connected across the electrode assemblies 108 and 112, limits the voltage applied to skin 110.
  • a typical safe maximum limiting value for Vw is about 24 volts. Other values of limiting voltage can be achieved by zener diodes 116 having different breakdown voltages, or by using other protection as described further below.
  • control circuit 132 will respond to the feedback at feedback input 133 and will adjust T1 and T2 to boost Vw to a multiple just sufficient to maintain the current at the predetermined level. Further, when the skin resistance becomes too low so that the load voltage falls below the battery voltage, control enabling resistor 123 is serially connected to allow controller to regulate the load voltage using voltage booster 141.
  • the working voltage, Vw, at the controlled electrical junction 104 is thus boosted to a boost multiple of the battery 102 voltage just sufficient to maintain the load current, l L , at the predetermined value as long as the load voltage is less than the limiting voltage set by the zener diode 116.
  • the low loss transfer of energy from the battery 102 to the skin 110 and capacitor 122 maximizes the useful life of the battery 102, for a given battery capacity. This allows smaller batteries to be used for a given therapeutic regimen, or extends the lifetime of therapeutic treatment at a given cost.
  • the predetermined current applied across skin 110 may be constant or varying with time in accordance with a current-time profile. In either event, the control circuit 132 establishes a predetermined current-time profile to be applied.
  • control circuit 132 is additionally adapted such that, in combination with the values of inductor 118, the value of the load resistance across skin 110, the capacitance value of capacitor 122, the time periods, T1 , T2, and load resistor 123 are arranged in response to the voltage at feedback input 133 such that filter capacitor 122 smooths and adjusts the voltage Vw, to
  • FIG. 13 is a schematic diagram of an alternate drug delivery regulator circuit 400.
  • Regulator 400 is similar to the drug delivery regulator circuit 100 described above with reference to Figure 7, where like elements are numbered similarly.
  • microcontroller 138 detects a decrease in the skin resistance between electrodes 108 and 112.
  • switch 127 is activated to couple resistance 123 in series with electrode 112 and resistor 114.
  • this combined resistance can be further reduced below the first pre-determined minimum resistance.
  • the skin resistance may decrease to substantially zero ohms.
  • Regulator circuit 100 is shut off when this condition is experienced.
  • An alternate embodiment of a drug delivery regulator 400 ( Figure 13) compensates for skin resistance which is reduced below the first pre-determined minimum resistance.
  • the drug delivery regulator circuit 400 includes battery 102, voltage booster circuit 141 , electrodes 108 and 112, microcontroller 138 and control circuit 132.
  • the regulator circuit also includes a variable resistor 402, and resistor control circuit 404.
  • the variable resistor can be, in one embodiment, a field effect transistor (FET) having a channel resistance and the resistor control circuit 404 can be an operational amplifier (op-amp) coupled to a gate electrode of the FET.
  • FET field effect transistor
  • op-amp operational amplifier
  • regulator 400 includes a variable resistance 402.
  • a voltage drop is provided across resistor 114.
  • a resistor divider circuit is provided by the skin resistance, variable resistor 402 and resistor 114.
  • Operational amplifier 404 receives an input voltage from microcontroller 138 via output node 135. When a voltage at node 408 exceeds the voltage provided at node 135, the operational amplifier adjusts a control voltage provided to variable resistor 402.
  • variable resistor 402 is a field effect transistor
  • operational amplifier 404 reduces the gate voltage such that a resistance across the transistor source and drain is increased.
  • the regulator of Figures 7, 9 and 13 include a variable resistance circuit 101. This circuit allows the regulator to vary a resistance path through the electrodes. Each embodiment allows the control circuitry 132 and 138 to control a series resistance. In Figures 7 and 9 include different resistance paths, while the embodiment of Figure 13 includes a variable resistance circuit.
  • the variable resistance circuit 101 is shown in Figure 7 as having either a low resistance path (essentially zero ohms) or resistor 123 coupled in series with the load resistance.
  • Figure 9 illustrates a variable resistance circuit 101 which has both the low resistance path (through switch 274) and resistor 272 coupled in parallel to form a low resistance path.
  • a regulator circuit 200 includes a battery 202, an inductor 204, a diode 206, a voltage controlled electrical junction 207, a low resistance filter capacitor 208, and electrode assemblies 210, 212 which are attached by conventional means to spaced apart regions of skin surface 213.
  • Skin surface 213 is represented schematically as a variable load resistance Rv to emphasize the fact that the resistance of the skin 213 does vary with time and current.
  • At least one of the electrode assemblies 210, 212 contains a therapeutic agent in a form suitable for electrotransport delivery into skin surface 213.
  • Regulator 200 includes an N-channel field effect transistor (FET) switch 218, for switching inductor current Ii, an inductor current sense resistor 220, and a regulating resistor 214.
  • the circuit also includes a high efficiency, adjustable DC-DC step-up controller 216.
  • An adjustable DC-DC step-up controller 216 can be the Maxim
  • the MAX773 controller 216 includes a reference voltage pin 256, a ground pin 258, a feedback input 264, a shut down input 266, a current sense input 268, and a power bus input 270.
  • MAX773 controller 216 also includes a first two-input comparator 230 having an output 231, a second two-input comparator 232 having an output 233, a first reference voltage 242, a second (e.g., 1.5 volt) reference voltage 244, a PFM/PWM driver circuit 240 having a switch control output 252, and a switch control output 254.
  • regulator 200 includes a boost monitoring comparator 273, an over voltage monitoring comparator 275, control enabling switch 274, a control enabling resistor 272, and a cut-off switch 276.
  • a microcontroller (not shown in Figure 9) is also included in regulator 200.
  • a boost monitoring signal 277, an over voltage monitoring signal 279, a feedback signal 265 and a pair of reference voltages (not shown in Figure 9) are connected to the microcontroller as inputs thereto.
  • the microcontroller controls the control enabling switch 274, cut-off switch 276, and a shut-down signal 271.
  • a microcontroller for the present invention can be the PIC16C620- SSOP microcontroller, available from Microchip Technology, Inc. of Chandler, AZ. This microcontroller is discussed in more detail in the PIC 16/17 Microcontroller Data Book, May 1995, pages 2-203 through 2-212, which are incorporated herein by reference. Normal operation of regulator 200 can be understood by reference to Figure 9 and Figure 10.
  • the circuit 200 uses the MAX773 controller 216 to provide a high efficiency conversion of energy from the battery 202 into an adjustably boosted voltage Vw at the voltage controlled electrical junction 207, and simultaneously control the load current l L .
  • MAX773 controller 216 is connected to use regulating resistor 214 to generate an error voltage to control the average load current l L .
  • MAX 773 controller 216 also operates with high frequencies, (up to 300 kHz) allowing the use of small external components.
  • MAX773 controller 216 is an integrated circuit having internal components connected by conductive traces formed during the integrated circuit manufacturing process. External pins are provided for electrical connection to external components by conventional printed circuit features such as plated or deposited copper or other conductors deposited and formed on insulating substrates. Reference to electrical connections in the description herein are understood to be internal or external as shown in Figure 9. References to the components of the MAX773 controller 216 circuit are illustrative for the purposes of describing the function of circuit 216.
  • regulating resistor 214 One terminal of regulating resistor 214 is connected to feedback input 264. This same terminal of regulating resistor 214 is also connected to electrode assembly 212 for receiving the load current l L . The other terminal of regulating resistor 214 is connected to the system ground. Input 264 connects to the inverting input of comparator 232. Non-inverting input of comparator 232 is connected to reference voltage 244. Output 233 of comparator 232 is connected to PFM/PWM driver circuit 240.
  • Output 231 of comparator 230 is connected to PFM/PWM driver circuit 240. Inverting input of comparator 230 is connected to reference voltage 242. Non-inverting input of comparator 230 connects to current sense input 268. Input 268 is connected to one terminal of inductor current sense resistor 220. The other terminal of resistor 220 connects to the system ground. The ground pin 258 of the MAX773 controller 216 is also connected to the system ground.
  • PFM/PWM driver circuit 240 connects to output 252.
  • Input 270 is connected to one terminal of battery 202.
  • the other terminal of the battery 202 is connected to the system ground.
  • One output of PFM/PWM driver circuit 240 connects output 254.
  • Outputs 252 and 254 are both connected to the gate of the external N-channei switch 218.
  • the drain of the switch 218 is connected to a joint connection of one end of energy storage inductor 204 and the anode of rectifying diode 206.
  • the source of switch 218 is connected to the one terminal of inductor current sense resistor 220 which is connected to current sense input 268.
  • the other terminal of the inductor 204 is connected to power bus input
  • a filter capacitor 276 is connected between input 270 and the system ground.
  • a filter capacitor 278 is connected between voltage pin 256 and the system ground. Filter capacitors 276 and 278 have low dynamic impedance at the pulse frequencies of interest.
  • Cathode of diode 206 is connected to an electrical junction 207.
  • Junction 207 is also connected to one terminal of a filter capacitor 208, the cathode of a zener diode 280 and electrode assembly 210.
  • the anode of zener diode 280 and the other terminal of capacitor 208 are connected to ground.
  • Junction 207 completes circuit 200 which boosts the working voltage, Vw, at junction 207 by an adjustable multiple of the voltage of the power source, i.e., battery 202.
  • Zener diode 280 limits the peak voltage across the electrode assemblies 210 and 212, and thus the maximum voltage experienced by the skin 213.
  • regulator 200 normal operation of regulator 200 can be understood.
  • the MAX773 controller 216 and the microprocessor begin operating.
  • switch 218 is not turned on until voltage comparator 232 senses that the output current is out of regulation.
  • the MAX773 controller 216 uses the combination of the peak inductor current limit sense resistor 220, reference voltage 242 and comparator 230 along with the maximum switch on-time and minimum switch off-time generated by PFM/PWM driver circuit 240; there is no oscillator.
  • the typical maximum switch on-time, T1 is 16 micro seconds.
  • the typical minimum switch off-time, T2 is 2.3 micro seconds.
  • the switch 218 either (1) stays off if the output current l L , is in regulation, or (2) turns on again if the output current l L , is out of regulation. While switch 218 is off, the inductor current I, flows through diode 206 into capacitor 208 at junction 207, replenishing any charge drawn off by skin 213. It can be seen that this method of switching the charging current l L provides an adjustable boost multiple of battery 202 voltage to a working voltage Vw at junction 207, just sufficient to supply the desired constant current l L .
  • the peak voltage delivered by inductor 204 will be just that required to overcome the diode drop of the diode 206 and the working voltage Vw and thus minimizes energy loss from the battery 202.
  • the MAX773 controller 216 circuitry allows circuit 200 to operate in continuous-conduction mode (CCM) while maintaining high efficiency with heavy loads.
  • CCM continuous-conduction mode
  • the average load current l L is equal to the value of reference voltage
  • PFM/PWM driver circuit 240 will automatically adjust the on time T1 and off time T2, and alternately turn the switch 218 on and off, until load current l L is at or above the desired value.
  • the current flows from the boosted voltage at electrode assembly 210 through the variable skin resistance Rv to electrode assembly 212, through control enabling switch 274 to cut-off switch 276, and finally, to regulating resistor 214.
  • both switches 274 and 276 are closed and current flows through control enabling switch 274, bypassing control enabling resistor 272.
  • the current delivered through electrode assemblies 210 and 212 is regulated by the MAX773 controller 216 maintaining a voltage, e.g., 1.5V, across regulating resistor 214.
  • a voltage e.g. 1.5V
  • Max773 controller 216 does not provide a boosted voltage and thus the current is not regulated and causes the entire battery voltage (battery 202) minus voltage drop of diode 206 to be applied to electrode assembly 210 causing boost monitoring comparator 273 to be activated.
  • Regulator 200 then goes into an over dose mode. When the over dose mode continues longer than a preset period, e.g., the first maximum low load detection period, measured by the microcontroller, the microcontroller turns off control enabling switch 274.
  • the current is then forced to flow through the additional impedance of control enabling resistor 272.
  • This additional (or artificial) load added in series with the variable skin resistance, insures a regulated current from electrode 210 to electrode 212 even if the skin resistance falls to 0W.
  • the microcontroller opens the cut-off switch 176 thereby cutting off the load current l L .
  • the current l L may be programmed to follow a predetermined profile by programming the value of the load current through regulating resistor 214.
  • Regulating resistor 214 value may be programmed by switching additional resistors in parallel or series with the load current l L .
  • the electrotransport controller may also be disposable.
  • the functions executed in the embodiments herein by circuits may alternatively be done by software in programmable components, in a digital environment.

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Abstract

L'invention concerne un dispositif d'électrotransport comportant un appareil de régulation de l'apport de médicaments permettant d'administrer une dose de médicament adéquate dans le temps tout en s'adaptant à des valeurs de résistance de la peau variables. Le dispositif d'électrotransport s'adapte à une baisse de la résistance de la peau durant la période d'utilisation de ce dispositif, ainsi qu'à différents niveaux de résistance de la peau à différents emplacements à la surface de la peau. Un des dispositifs de régulation de l'apport de médicaments comporte un amplificateur de tension, une impédance artificielle connectable en série et un capteur à rétroaction, tous connectés à un contrôleur. Cet appareil permet d'appliquer une tension de charge sur deux électrodes. Le contrôleur surveille la sortie du capteur à rétroaction afin de déterminer soit la résistance de la peau, soit un courant de charge, soit la tension de charge. La tension de charge dans les électrodes est régulée en fonction de la valeur surveillée, de façon à maintenir une dose de médicament voulue, même lorsque la résistance initiale de la peau baisse durant cette période d'utilisation du dispositif d'électrotransport. L'impédance artificielle est sélectivement régulée de façon à éviter une surdose là où la résistance de la peau est inférieure à un niveau prédéterminé, situation dans laquelle une tension de charge supérieure à une tension d'alimentation risquerait d'entraîner une surdose.
PCT/US1998/026187 1997-12-16 1998-12-09 Regulateur avec charge artificielle permettant de maintenir un apport regule WO1999030773A1 (fr)

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JP2000538748A JP2002508228A (ja) 1997-12-16 1998-12-09 調整された投与を維持する人為的負荷を備えた調整器
EP98964714A EP1039950A1 (fr) 1997-12-16 1998-12-09 Regulateur avec charge artificielle permettant de maintenir un apport regule
CA002314929A CA2314929C (fr) 1997-12-16 1998-12-09 Regulateur avec charge artificielle permettant de maintenir un apport regule
AU19976/99A AU1997699A (en) 1997-12-16 1998-12-09 Regulator with artificial load to maintain regulated delivery
KR1020007006600A KR20010033208A (ko) 1997-12-16 1998-12-09 조정된 이송을 유지하기위해 인공 부하를 갖는 조정기

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US60/069,745 1997-12-16

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WO2009021128A1 (fr) * 2007-08-08 2009-02-12 Alza Corporation Dispositif de libération de médicament par électrotransport adaptable au changement de résistance cutanée
WO2008027218A3 (fr) * 2006-08-29 2009-04-16 Alza Corp Électrotransport de médicament avec une mesure d'hydratation d'un réservoir hydratable
WO2009149226A1 (fr) * 2008-06-05 2009-12-10 Alza Corporation Dispositif de distribution de fentanyl par électrotransport à courant réglable
US7708731B2 (en) 1995-06-02 2010-05-04 Alza Corporation Electrotransport delivery device with voltage boosting circuit
WO2010078313A1 (fr) * 2008-12-30 2010-07-08 Nupathe, Inc. Régulation électronique d'un système de distribution de médicament
WO2013176728A1 (fr) * 2012-05-21 2013-11-28 Incline Therapeutics, Inc. Essai automatique pour un produit analgésique
WO2013187951A1 (fr) * 2012-06-11 2013-12-19 Incline Therapeutics, Inc. Régulation de courant pour administration de médicaments par transport électrique
US9327114B2 (en) 2010-11-23 2016-05-03 Teva Pharmaceuticals International Gmbh User-activated self-contained co-packaged iontophoretic drug delivery system

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GB201414695D0 (en) * 2014-08-19 2014-10-01 Femeda Ltd Electrostimulation related devices and methods
KR101725087B1 (ko) 2014-12-29 2017-04-26 주식회사 효성 Ｍｍｃ 컨버터의 서브모듈용 전원제어장치
CA3085193A1 (fr) * 2017-12-12 2019-06-20 Radio Systems Corporation Procede et appareil pour appliquer, surveiller et ajuster un stimulus a un animal de compagnie
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CN1154525C (zh) 2004-06-23
EP1039950A1 (fr) 2000-10-04
AU1997699A (en) 1999-07-05
CA2314929C (fr) 2008-09-02
CN1282261A (zh) 2001-01-31
KR20010033208A (ko) 2001-04-25

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