[go: up one dir, main page]

WO1993003790A1 - Procede et dispositif ionotherapeutiques - Google Patents

Procede et dispositif ionotherapeutiques Download PDF

Info

Publication number
WO1993003790A1
WO1993003790A1 PCT/US1992/007221 US9207221W WO9303790A1 WO 1993003790 A1 WO1993003790 A1 WO 1993003790A1 US 9207221 W US9207221 W US 9207221W WO 9303790 A1 WO9303790 A1 WO 9303790A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical
skin
insulin
periodic
iontotherapeutic
Prior art date
Application number
PCT/US1992/007221
Other languages
English (en)
Inventor
Yie W. Chien
Wei-Min Shi
Original Assignee
Rutgers, The State University Of New Jersey
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 Rutgers, The State University Of New Jersey filed Critical Rutgers, The State University Of New Jersey
Priority to JP5504665A priority Critical patent/JPH07501238A/ja
Priority to EP92919517A priority patent/EP0604504A4/fr
Publication of WO1993003790A1 publication Critical patent/WO1993003790A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0432—Anode and cathode
    • A61N1/044—Shape of the electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A61N1/303—Constructional details
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0432—Anode and cathode

Definitions

  • This invention relates to development of an iontothera ⁇ Implantic device for regulated transdermal systemic administra- tion of ionizable pharmaceuticals (including ionizable bio- pharmaceuticals) and a novel battery device usable as an element of said device.
  • the invention also provides an iontotherapeutic process for trans ⁇ dermal administration of ionizable pharmaceuticals, particu- larly those which are otherwise transdermally absorbed to a small degree or not at all.
  • the invention also relates to a polymeric unit dose in which an ionized pharmaceutical is dispersed.
  • the unit dose is adapted to be assembled as a part of either the anode or the cathode, depending upon whether the ionized pharmaceutical is cationic or anionic, so that the ionized pharmaceutical will be delivered trans- dermally and then be absorbed systemically when the ionto ⁇ therapeutic device is in operation.
  • Many pharmaceuticals are required to be administered to patients by injection.
  • a notable example is insulin, which cannot be administered orally to be effective in lowering the elevated blood sugar levels, which are too high in diabetics (i.e., > 126 mg/dL) .
  • Other pharmaceuticals may be administered orally, but in some cases, there is inefficient absorption into the bloodstream to permit the pharmaceuti ⁇ cals to achieve their intended therapy.
  • many orally administered pharmaceu- ticals undergo a high degree of destruction by the hepato- gastrointestinal first-pass metabolism. Often the metabo- lites of the first-pass metabolism cause unwanted biological activity or toxicity.
  • transder ⁇ mal absorption of a number of pharmaceuticals particularly the macromolecular drugs such as insulin and cationic drugs like propranolol HCI.
  • the hazard and discomfort of administration of pharma ⁇ ceuticals by injection, especially if therapy is required on a frequent basis, such as the subcutaneous injection of insulin for diabetes therapy, which is required daily, are universally known.
  • a process has been found for administering transder- ally a systemically effective amount of an ionizable phar ⁇ maceutical in sterile aqueous solution using an iontothera ⁇ Commissionic device such as provided by this invention.
  • the ionized pharmaceutical solution can be contained in a unit dose form such as disposable polymeric matrix unit dose form in which a dosage amount of an ionized pharmaceutical solu ⁇ tion (pH desirably at least about 1.0, 1.5 or about 2 pH units above or below the pKa or isoelectric pH of the ionizable pharmaceutical) is intermixed with a polymer which is characterized by being compatible with the pharmaceutical as well as the skin, hydrophilic, and capable of releasing the pharmaceutical for iontotherapeutic transdermal absorp ⁇ tion.
  • a dosage amount of an ionized pharmaceutical solu ⁇ tion pH desirably at least about 1.0, 1.5 or about 2 pH units above or below the pKa or isoelectric pH of the io
  • the unit dose form can also comprise a sterile solu- tion of the ionized pharmaceutical contained within a closed reservoir unit dose form having a drug-releasing microporous membrane surface.
  • the unit dose forms are assembled with a pharmaceutical reservoir electrode and are further adapted to permit the dissolved, ionized pharmaceutical to be delivered iontophoretically to the skin of the subject treated and to provide iontotherapeutic transdermal absorp- tion of a systemically effective amount of the pharmaceuti ⁇ cal.
  • the unit dose forms are maintained covered to retain sterility until the desired time of iontotherapeutic admin ⁇ istration.
  • a pharmaceutical reservoir electrode which will receive such a unit dose form is used as a part of the iontotherapeutic device, such as provided by this invention, which is used to carry out the iontotherapeutic delivery and transdermal absorption of the ionized pharmaceutical.
  • the pharmaceutical reservoir electrode is either a cathode or an anode depending upon whether the pharmaceutical is in anionic or cationic form, respectively.
  • the iontotherapeu ⁇ tic device provides, in the process, an iontotherapeutically effective and physiologically acceptable pulse current with a specific waveform having an amplitude such as up to about 10mA based on a reservoir electrode skin-contacting area of about 5 cm 2 and an effective frequency of at least about 10
  • the pharmaceutical administered by this invention can be selected from pharmaceuticals which ordinarily are not transdermally absorbed through intact skin in an effective dosage amount, such pharmaceuticals including but not limited to insulins, vasopressin, heparin, growth hormones, glucagon, oxytocin, and other macromolecular drugs as well as a number of others which can be provided in ionized form.
  • the device is a lightweight, portable transdermal periodic iontotherapeutic device for transdermal administration of a systemically-effective amount of an ionized pharmaceutical, which is adapted to be worn by a subject being iontothera ⁇ Implantically treated, comprising
  • a DC power supply capable of providing an iontothera ⁇ Implantically effective and physiologically acceptable DC current in the range up to about 10mA;
  • a periodic waveform generator electrically connected to the DC power supply and having integrated circuitry capable of providing a) a periodic waveform in the square, triangular, sinusoidal, trapezoidal, or other acceptable geometric form or combination thereof; b) an on/off ratio of 1/50 to 10/1; and c) a repetition fre- quency from about 10 Hz to about 50 KHz;
  • an output circuit electrically connected to said wave- form generator which a) can provide a periodic DC cur ⁇ rent in a pre-selected waveform of said forms; b) moni ⁇ tors current intensity delivered; c) adjusts and main ⁇ tains the current intensity within predetermined maxi ⁇ mum and minimum levels and d) delivers the current to a reservoir electrode for iontotherapeutic transdermal administration of said ionized pharmaceutical;
  • a pharmaceutical reservoir electrode which can be pre ⁇ selected to be either the cathode or the anode depend ⁇
  • said electrode having a receptacle adapted 20 to receive a unit dose of said ionized pharmaceutical in which said ionized pharmaceutical is in aqueous solution at a pH at least 1.0 pH unit below or above 25 the isoelectric point or pKa point of said ionized pharmaceutical ; said electrode with said received unit
  • said electrode having a terminal to receive and to 35 transmit through said unit dose the said periodic DC current and said unit dose adapted to be in electrical
  • receptor electrode adapted to be in electrical contact
  • a preprogramable control element electrically inte ⁇ grated within said device to preprogram and to control said iontotherapeutic administration on an automated basis as in accordance with a physician's prescription entered into the control element, without interaction of a subject being treated with the device for said administration except to permit said subject to stop operation of the device as in the event of an emer ⁇ gency.
  • the device will ordinarily have a terminal by which the transdermal administration carried on by the device can be monitored using a computer system and a connecting line to connect the device and the computer system or by which a prescription for administration of a pharmaceutical by the device can be entered into the programmable control element by use of a computer system and a connecting line to connect the control element with the computer system.
  • the device desirably has one or more addi ⁇ tional terminals by which the control element can be con- nected by a connecting line with a sensor to sense a skin condition or with a separate sensor to sense a level of an entity in the body (which correlates with a need for admin ⁇ istration of the pharmaceutical) , the sensor(s) held in intimate contact with the subject's body and signals said control element on need for administration or skin condi- tion.
  • the signal can transmit the nature of need for insulin administration.
  • the invention provides a process for adminis ⁇ tering an ionized pharmaceutical by use of the above defined device and carrying out the following steps:
  • a dosage unit containing a pharmaceutically acceptable aqueous solution of said peptide into a receptacle of a reservoir electrode of a transdermal periodic iontotherapeutic system, which electrode is a cathode or anode depending upon whether such ionized peptide is anionic or cationic, said solution having a pH at least about 1.0 pH unit below or above the iso- electric point of said peptide;
  • a sensor is held in intimate contact with the body of subject being treated such as in intimate contact with the skin of the person being treated and said sensor trans ⁇ mits one or more signals to the control element of the device such as a physiological factor of the subject being treated which correlates with the pharmaceutical administra- tion carried out by the device or a skin condition which relates to the transdermal administration.
  • FIG. 1 is a diagram portraying a device of the inven ⁇ tion in operation to effect iontotherapeutic transdermal absorption of an ionized pharmaceutical and its uptake into the bloodstream of the subject treated.
  • FIG. 2 is a block diagram of a transdermal periodic iontotherapeutic device parent application Serial No. 07/046,984.
  • FIG. 3 is a block diagram of a transdermal periodic iontotherapeutic device coming within the invention.
  • FIG. 4 is a detailed circuit diagram for the Square-
  • FIG. 5 is a detailed circuit diagram for the Trape- zoidal-Triangular Wave Generator shown in FIGS. 2 and 3.
  • FIG. 6 is a detailed circuit diagram for the Sinusoidal Signal Generator shown in FIGS. 2 and 3.
  • FIG. 7 is a detailed circuit diagram for the Output
  • FIG. 8 is a block diagram of a wristwatch-type minia ⁇ turized periodic iontotherapeutic device coming within the invention, in which the drug reservoir electrode is posi ⁇ tioned away from the main portion of iontotherapeutic device.
  • FIG. 9A and 9B are diagrams illustrating a wristwatch- type miniaturized transdermal periodic iontotherapeutic system with the drug reservoir electrode positioned directly in the lower portion of the iontotherapeutic device and with multifunctional programmability.
  • FIG. 10 is a block diagram of a portable transdermal periodic iontotherapeutic device.
  • FIG. 11 and 11A are detailed circuit diagrams of the device shown in FIG. 10.
  • FIG. 12 is a detailed circuit diagram showing an elec ⁇ tronic timer element which can be used to control the ionto ⁇ therapeutic administration.
  • FIG. 13 is a schematic diagram of a wrist-type ionto ⁇ therapeutic device coming within the invention showing a belt-type battery power supply and a sensor for blood sugar monitoring.
  • FIG. 14 is a schematic diagram showing an iontothera ⁇ Terminator device of this invention in interface with a computer system through a connecting line (e.g., interface cable/ telephone line) .
  • a connecting line e.g., interface cable/ telephone line
  • FIG. 15 is a schematic diagram of an iontotherapeutic device of this invention using a belt or band to attach to the subject being treated.
  • FIG. 16 is a graph comparing the effects of periodic wave mode and DC mode on the transdermal absorption of insu ⁇ lin and on the reduction of blood glucose level (B.G.L.) in the diabetic hairless rats.
  • FIG. 18 is a graph showing the effect of the frequency generated by the transdermal periodic iontotherapeutic sys- tern on the reduction in the blood glucose level (B.G.L.) in the diabetic hairless rates using insulin. 5
  • FIG. 19 is a graph showing the effect of the on/off ratio in the transdermal periodic iontotherapeutic system on 10 the reduction in the blood sugar level (B.G.L.) in the dia ⁇ betic hairless rats using insulin.
  • FIG. 20 is a graph showing the effect of the treatment
  • FIG. 21 is a graph showing the effect of the treatment
  • FIG. 22 is a graph showing permeation of vasopressin 35 facilitated by the transdermal periodic iontotherapeutic system compared to passive diffusion of a vasopressin solu-
  • FIG. 23A is a graph showing permeation rate of insulin solution at pH 7.1 through hairless rat skin using no ionto- 45 therapy as compared to permeation rate shown in FIG. 2IB when using iontotherapy (TIDD) .
  • TIDD iontotherapy
  • FIG. 24 is a series of graphs showing the comparative effects of the change in waveform in lowering blood glucose level (B.G.L.) in diabetic hairless rats using transdermal periodic iontotherapeutic system using insulin solution at pH 3.68.
  • FIG. 25A is a graph showing lowering of blood sugar level (B.G.L.) of hairless rats using transdermal periodic iontotherapeutic system on Day 1 using insulin solution at pH 3.68.
  • 25B is a graph showing further lowering of the blood sugar levels of the same rats on Day 3 using transder ⁇ mal periodic iontotherapeutic system without further admin- istration of insulin, indicating that the insulin delivered transdermally on Day 1 is stored in the skin tissues and can be activated to become available for absorption into systemic circulation on Day 3 by TPIS.
  • FIG. 26A is a pair of comparative graphs showing plasma immunoreactive insulin levels in diabetic rabbits after administration of insulin solution (pH 7.1) using transder- mal periodic iontotherapeutic system (TPIS) compared with corresponding levels in diabetic rabbits using subcutaneous administration (SC) .
  • TPIS transder- mal periodic iontotherapeutic system
  • SC subcutaneous administration
  • FIG. 26B is a pair of comparative graphs corresponding to those of FIG. 24A showing the respective reduction of blood glucose levels (B.G.L.).
  • the data show that blood glucose levels can be controlled at a highly constant level so as not to fall substantially, if at all, below normal levels by TPIS. 5
  • FIG. 27A is a pair of comparative graphs showing the increase in plasma insulin concentration after ad inistra-
  • TPIS transdermal periodic iontotherapeutic system
  • TIDD transdermal iontotherapeutic system
  • FIG. 27B is a pair of comparative graphs corresponding to those of FIG. 25A showing the attained lowering of blood 25 glucose levels (B.G.L.). The data show a near instantaneous reduction of blood glucose level from the hyperglycemic
  • TPIS transdermal periodic iontotherapeutic system
  • TIDD transdermal iontotherapeutic system
  • FIG. 28 is a pair of comparative graphs showing a
  • FIG. 29 is a graph showing vasopressin permeation rate enhancement when the ionic strength of the vasopressin solu ⁇
  • FIG. 30 is a graph showing enhancement of skin permea ⁇ tion of vasopressin using TPIS with a short skin permeation lag time. The graph also shows reversibility of skin per ⁇ meation within 2 hours after ceasing TPIS treatment and again enhancement of skin permeation after reinstituting TPIS.
  • FIG. 1 is a diagram portraying a device of the inven ⁇ tion in operation to deliver iontotherapeutically an ionized pharmaceutical and its uptake into the bloodstream of the subject being treated.
  • the figure shows the iontotherapeu ⁇ tic device in electrical contact with the skin.
  • the pharmaceutical reservoir electrode in contact with the skin as well as the other electrode, which is referred to as the receptor electrode.
  • the electrodes are in contact with the uppermost skin barrier, called stratum corneum.
  • the pharmaceutical is transmitted through the stratum corneum and flows into the dermo-epidermal layer.
  • the stratum corneum is the principal absorption rate limiting barrier.
  • the first portion of the dermis layer is referred to as the papillary layer, which contains a capil ⁇ lary network of the vascular system.
  • the capillary network takes up the transdermally absorbed pharmaceutical and the uptaken pharmaceutical is shown to flow from the capillary network into the main portion of the vascular system.
  • FIG. 2 is a block diagram of a transdermal periodic iontotherapeutic device coming within the invention in which the power supply is derived either from the conversion of the alternate current (AC) from a 120 V-mains (or other available AC mains) into direct current or from a suitable battery.
  • the power is turned on manually by a switch or automatically by a programmable timer.
  • the device also consists of one or a combination of several electronic multifunction generators, a drug reservoir electrode and a receptor electrode.
  • the multifunction generator is assembled with a power supply, to delivery direct current with periodic waveform of either square, triangular, trape- zoidal or sinusoidal shape, to an output circuit.
  • the desired iontotherapeutically-effective waveform can be selected manually or preprogrammed through a switch (K- j , and the frequency of the output waveform can be adjusted in the range of 10 Hz - 50 KHz.
  • the output circuit then pro- vides a physiologically acceptable current, for example, ranging up to 10 mA, to the pharmaceutical reservoir elec- trode which contains the ionized pharmaceutical to be delivered transdermally, and a receptor electrode in series.
  • the device can be operated to deliver either DC current alone (periodically or continuously) , or in com ⁇ bination with a periodic waveform.
  • FIG. 3 is a block diagram of an iontotherapeutic device of this invention. It consists of the following elements: a microprocessor, a multiple waveform generator, a waveform selector, an output circuit, a sensor signal processor, a display unit, a power supply with indicator, a reservoir electrode, and a receptor electrode.
  • the microprocessor is the center of the device. It has the following functions: a. receiving and processing the physiological signal(s) from the sensor element; b. communicating with a computer system via an interface cable; c. receiving and exercising commands from the computer system; d. storing data and transmitting data to the computer system; e. controlling operation parameters of the multiple wave- form generator, such as frequency and duty cycle of generated waveforms; f. selecting the input waveform of the output circuit; g. controlling the operation parameters of the output circuit, such as output current amplitude and treatment cycle; h. monitoring the load impedance of the device and alert ⁇ ing the user of improper operation conditions.
  • the microprocessor is made using a commercial single chip microcontroller with necessary expanded memory capa- city, additional input/output ports and signal converters.
  • a preferred microcontroller is 80C552 single chip microcon ⁇ troller made by Signetics, a subsidiary of Philips Compo- nehts. This microcontroller is very powerful and meets the requirements of the current application. It has the follow- ing important features: 16 MHz speed, 8K ROm and 256K RAM memory, 4 watchdog timer-counters, 6 I/O ports and 8 channel
  • the multiple waveform generator provides pulse-mode signals of desired waveforms. It can be realized by using the circuitry shown in FIG. 6. It can also be made by using a commercial integrated circuit ICL8038 made by Motorola
  • the waveform selector can be made using a commercial electronic analog switch, such as AD7510 made by Analog
  • the output circuit can be made by using the circuit design shown in FIG. 7 or using a three-pin constant current regulator LM334 made by National Semiconductor Corporation.
  • the function of the sensor signal processor is to fur ⁇ ther condition the physiological signals, such as blood glucose level signals. It provides necessary function, such as amplification and filtering of the signals.
  • the condi ⁇ tioned signals will be sent to the analog/digital converter of the microprocessor. They will be used for close-loop control of iontotherapeutic treatment.
  • the power supply unit consists of battery elements connected in series.
  • the batteries can be either regular ones or rechargeable ones.
  • a low-batter indicator will be used to signal the low battery condition.
  • FIG. 4 is a detailed circuit diagram for the square wave generator shown in FIG. 2. It employs a microchip 555 timer.
  • the frequency (F) of the square wave is:
  • P's are potentiometers
  • C is a capacitor
  • D's are diodes.
  • the capacitor C is charged through the potentiometer P and P 2 and the diode D for ⁇ seconds and discharged through potentiometer P ⁇ _ and diode D 2 for t 2 seconds.
  • Other circuits can be used in place there ⁇ of.
  • FIG. 5 is a detailed circuit diagram for the triagular- trapezoidal waveform generator shown in FIG. 2. It consists of an integrator (A) and a regenerative comparator (B) con- nected in a positive feedback loop. Precise triangular waves are formed by integration of the square wave which is fed back from the output of the comparator to the input of the integrator.
  • Vo+ and Vo " are the higher and lower trip points of the comparator, respectively.
  • Resistors R- ⁇ and R 2 control the comparator trip points.
  • Capacitor C is the integration capacitor.
  • Potentiometer P- ⁇ provides adjustment of the triangular wave offset.
  • Potentiometers P 2 and P 3 adjust frequency and symmetry, respectively.
  • the third op-amp circuit (C) acts as a damper. It produces a trapezoidal wave with the same frequency as the triangular wave. Potentiometer P ⁇ sets the clamping level. 4
  • FIG. 6 is a detailed circuit diagram for the sinusoidal signal generator shown in FIG. 2.
  • the circuit of the generator uses two amplifiers: one (A) acts as a non- inverting integrator, and other (B) acts as an inverting integrator. They are connected in cascade to form a feed ⁇ back loop.
  • the frequency (F) of the sinusoidal signal is determined by:
  • FIG. 7 is a detailed circuit diagram for the Output
  • the desired waveform is selected manually or automatically from the 3 generators through a switch (K j ) and sent to the inverting amplifier, from which the signal then goes to the output stage of two transistors.
  • the output current (dose currentO is adjusted by a potentio ⁇ meter (P) , as monitored by a current meter (A) , and is delivered to the drug reservoir electrode (B) .
  • Other circuits can be used in place thereof.
  • FIG. 8 is a diagram illustrating the wristwatch-type miniaturized transdermal periodic iontotherapeutic system with multifunction programmability. It is designed to have one or more nuclear batteries and two pieces of microchips: one for the purpose of generating different waveforms, as outlined in FIGS. 4-6, and the other is for the purpose of controlling and to display the output current.
  • the nuclear batteries provide the energy needed for long-term operation.
  • the programmability may include selection of
  • the drug reservoir electrode is positioned outside the device.
  • FIG. 9 shows an embodiment of another design of ionto ⁇ therapeutic device. It shows two views of the device.
  • the first view is a cross-sectional view showing the integrated circuitry, L.C. display, battery, drug reservoir electrode positioned directly in the lower central portion of the base and the receptor electrode encircling the drug reservoir electrode.
  • the next view shows the bottom view of the device. In the center portion of the bottom view is shown the circular drug reservoir portion of the drug reservoir electrode.
  • the drug or pharmaceutical dissolved in an aqueous solution is homogeneously dispersed in a polymer matrix unit dose as described herein.
  • the pharmaceutical solution can also be contained in a reservoir-type unit dose having a microporous surface adapted to permit the drug to be transmitted.
  • the receptor elec ⁇ trode As a circular ring positioned in spaced relationship from the drug reservoir electrode.
  • a liquid crystal display At the top of the cross- sectional view is shown a liquid crystal display. It can display a number of functions, including whether or not the device is in operation, the type of periodic current and waveform being used and other pertinent information of the transdermal periodic iontotherapeutic drug delivery.
  • the battery employed as the power source for this invention can be a lithium or other nuclear battery having a voltage, for example, of from 6 to 12 volts.
  • FIG. 10 is a block diagram of a portable transdermal periodic iontotherapeutic device in which the power supply is derived from a battery source such as one or more 9V batteries.
  • the power is turned on manually by a switch.
  • the device can be equipped so that it can be turned on auto ⁇ matically by a programmable timer.
  • the device also consists of one or a combination of several electronic multifunction generators, a drug reservoir electrode and a receptor elec ⁇ trode.
  • the multifunction generator can provide periodic waveform of either square, triangular, trapezoidal or sinu ⁇ soidal shape, to an output circuit.
  • the desired iontothera ⁇ Terminally effective waveform can be selected manually and the frequency of the output waveform can be adjusted to a physiologically acceptable frequency of at least 10 Hz and up to about 50 KHz.
  • the output circuit then provides a physiologically acceptable current, ranging up to 10 mA, to the pharmaceutical reservoir electrode, which contains the solution of the ionized pharmaceutical to be delivered transdermally, and a receptor electrode in series.
  • the device can be operated to deliver either DC current alone (periodically or continuously) , or in combina ⁇ tion with a periodic waveform.
  • FIGS. 11 and 11A show a detailed circuit diagram for the portable transdermal periodic iontotherapeutic device shown in the block diagram of FIG. 10. Referring to FIG. 11, the following is a description of the circuits and their functioning:
  • R 1C 2 , R 1 -R 4 , C ⁇ , LI and diode IN914 consist of a DC- to-DC converter which is incorporated in step-up applica ⁇ tion.
  • the output voltage is elevated from 9V battery to 27V with the proper adjustment of R 4 .
  • the output voltage of the battery is monitored by a battery voltage monitor which includes a zener diode D- ⁇ R 5 -R 7 , C 4 and C106Y1.
  • IC 2 , D 2 -D 5 , T- j _, C 5 , C 6 and R 8 are components of a triangle-wave generator.
  • the charge and discharge currents for C 6 come through the diode bridge formed by D 2 -D 5 .
  • Bridge D 2 ⁇ D 5 consists of four general purpose switching diodes with low-leakage characteristics, that serve to steer current in the proper direction through the current source made up of T- j ⁇ and R g .
  • the pin 3 of IC 2 serves as a source of current for the timing network, and its state of high or low determines the direction of current flow into or out of C 6 for charge or discharge. Since both charge and discharge currents flow through the same current regulator circuit, the currents are equal, and thus times of charge and discharge are equal. As a result, triangular waves are formed across C 6 .
  • the circuit covers the frequency range of about 20 Hz to 30 KHz. The adjustment of the frequency is done with R 8 -
  • the frequency of the triangle waves can be expressed as
  • the output of the triangle-wave generator is sent to the pin 3 of IC 3 which serves as a comparator.
  • the voltage comparison is made between pin 1 and pin 3 of IC 3 .
  • the square waves are formed at pin 7 of IC 3 with a duty cycle which is determined by the voltage of the voltage divider composed of R o -R i2 - ⁇ he h i ( _ 'her tne voltage applied to pin 2 is, the shorter the "on" time of the square waves, and vice versa.
  • the duty cycle of the square waves covers the range of 1/10 to 10/1.
  • the square waves are amplified by T 2 -T 4 and sent to pin 11 of IC 4 .
  • I c g 2 3 i- s employed to serve as a current regulator.
  • the maximum output current is set as 0.6/R. This feature is adapted to form a current regulator. As soon as the condition ( v ou / R ) > ⁇ -s ⁇ ⁇ satisfied (where V Qut is the output voltage, R L , load resis ⁇ tance, and l ⁇ , output current preset), the output current will be kept at the preset level. 5
  • R 21 is the minimum current limit resistor.
  • R 22 is used to preset the desired output current.
  • C and R 20 are used 10 to eliminate high frequency noise.
  • Output current monitor 15 Intersil 7106 interfaced with a liquid crystal display is the heart of the current monitor.
  • R 23 is a shunt resis ⁇ tor.
  • C 8 and R 24 consist of an RC oscillator which runs at
  • C 10 and R 27 serve as an input filter.
  • C g is for auto-zero function.
  • the power is turned on manually by a switch or auto- 30 matically by a programmable timer.
  • the device also consists of one or a combination of several electronic multifunction 35 generators, a drug reservoir electrode and a receptor elec ⁇ trode.
  • the multifunction generator is assembled with a power supply, to deliver direct current with periodic wave- 40 form of either square, triangular, trapezoidal or sinusoidal shape, to an output circuit.
  • the desired iontotherapeuti- 45 cally effective waveform can be selected manually or pro ⁇ grammed through a switch (K ⁇ ) , and the frequency of the output waveform can be adjusted in the range of 10 Hz - 50 50
  • the output circuit then provides a physiologically acceptable current, ranging up to 10 mA, to the pharmaceuti-
  • the device can be operated to deliver either DC current alone (periodically or continuously) , or in combination with a periodic waveform.
  • FIG. 12 is a detailed circuit diagram for the timer of the multi-channel transdermal periodic iontotherapeutic device shown in the block diagram of FIG. 12.
  • FIG. 12 the following is a description of the circuit, and their functioning:
  • Timer The timer consists of ten IC chips, two relays and other components, IC g provides a system clock. IC ⁇ , IC 3 an
  • IC 5 are quad 2-input multiplexers which consist of four 2- input multiplexers with common select and enable inputs.
  • the four output pins assume the values of inputs of pin 1, 5, 14, 11, other ⁇ wise, inputs of pin 3, 6, 13, 10.
  • the inputs of the first group represent the "off” time of the timer which has a maximum value of 999 minutes.
  • the inputs of the second group represent the "on” time of the timer which has a maximum value of 99 minutes.
  • the values of both "on” and “off” time needed are set through BCD thumbwheels.
  • IC 2 , IC 4 and IC 6 are "decade-down" counters which receive preset values from multiplexers.
  • the pin 15's of these counters will become logical “o" when the minimum count is reached.
  • IC g a "AND” gate, will turn to be logical "1”.
  • This pulse is inverted by IC 10 and goes to reset the system clock, reloads counters and converts IC 7 , which consists of two Flip-Flop's.
  • the pin 3 and pin 5 turn to be logical "o", which opens two relays and turns on the red LED> AT the same time, the pin
  • the switch K 2 is used to interrupt the operation and trigger the timer.
  • IC 13 diode bridge consisting of four I 914 , T- ⁇ R 28 and C 5 -C 7 are components of a triangle wave generator.
  • the charge and discharge currents for one of c 6 ⁇ 17 come through the diode bridge formed by four TNg 14 , which serve to steer current in the proper direction through the current source made up of T- ⁇ and R 28 -
  • the pin 3 of IC 2 serves as a source of current for the timing network, and its state of high or low determines the direction of current flow into or out of the capacitor for charge or discharge. Since both charge and discharge cur- rents flow through the same current regulator circuit, the currents are equal and thus times of charge and discharge are equal. As a result, triangular waves are formed across the working capacitor C.
  • the circuit covers the frequency range of about 10 Hz to 30 KHz.
  • the adjustment of the frequency is done by the selection of the proper capacitor through a multi-stop switch.
  • the frequency of the triangle waves can be expressed as
  • the output of the triangle wave generator is sent to the pin 3 of IC 14 which serves as a comparator.
  • the voltage comparison is made between pin 2 and pin 3 of IC 14 .
  • the square waves are formed at pin 7 of IC 14 with a duty cycle which is determined by a voltage-divider composed of R 32 -
  • the square waves are amplified by T 2 and T 3 and then sent to three voltage followers T 4 ⁇ g.
  • Ic i5 ⁇ Ic i7 provide three-channel current outputs.
  • Three IC g23 are employed to serve as current regulators.
  • IC g23 is originally designed to be a voltage regulator with an output current limit resistor R across pin 10 and pin 3. 31
  • the maximum current is set as 0.6/R. This feature is adapted to form a current regulator. As soon as the condi ⁇
  • R 51 are used to preset the desired current.
  • c i9 -c 21 are used to eliminate high frequency noise.
  • the output currents are monitored by a current meter A.
  • the switch K- j _ is used to select DC or pulse output. Other circuits can be used in place thereof.
  • FIG. 13 is a schematic diagram of a device of this invention. It shows a wristwatch-type device which houses
  • the display unit emergency on/off switch, the input/output port, the interface cable to
  • This device can be comfortably worn by a patient during the
  • the weight of such device of this invention will ordinarily be 5 oz. or less, preferably 3 oz. or less.
  • FIG. 14 is a schematic diagram of a wrist-type ionto ⁇
  • therapeutic device of this invention showing a connection with a computer patient data and control system such as at a
  • the communication between the iontotherapeutic device and a computer system serves two purposes. It allows the commands and data according to the physician's prescription to transfer to the iontotherapeutic device via an interface cable. It also allows the physician to read and assess the important data of treatment using the device. By using telephone lines, the communication can be to a remote site.
  • FIG. 15 is the schematic diagram of an iontotherapeutic device of this invention using a belt or band to attach to the subject being treated.
  • bat ⁇ tery elements connected in series. These batteries can be either regular ones or rechargeable ones.
  • the battery belt can also be made into a shape of jewelry.
  • the battery belt can be designed to house different numbers of battery ele- ments to power different treatment periods.
  • the belt can be made of suitable material such as plastic or leather mate ⁇ rials or metals or combinations of materials. Its length can be adjusted as needed.
  • FIG. 17 is a graph showing the time course for the reduction of the elevated blood glucose level (% change in
  • FIG. 18 is a graph showing the effect of the frequency generated by the Transdermal Periodic Iontotherapeutic Sys ⁇ tem on the reduction of the elevated blood glucose level (% change in B.G.L.) in the diabetic hairless rats.
  • the fre ⁇ quency of 2000 Hz produces a greater magnitude and a longer duration of reduction than the 1000 Hz.
  • FIG. 19 is a graph showing the effect of the on/off ratio in the Transdermal Periodic Iontotherapeutic System on the reduction of the elevated blood glucose level (% change in B.G.L.) in the diabetic hairless rats. By regulating the ratio, the magnitude and the duration of reduction in B.G.L. in the diabetes can be controlled as desired.
  • FIG. 20 is a graph showing the effect of the treatment duration by the Transdermal Periodic Iontotherapeutic System on the reduction of the elevated blood glucose level (% change in B.G.L.) in the diabetic hairless rats.
  • pH 3.6 which is lower than the isoelectric point of insulin (pH 5.3)
  • the dose current of 1 mA, on/off ratio of 8/1 and at a frequency of 2000 Hz the treatment duration of 20-40 minutes appears to be equally effective.
  • FIG. 21 is a graph showing the effect of the treatment duration by the Transdermal Periodic Iontotherapeutic System on the reduction of the elevated blood glucose level (% change in B.G.L.) in the diabetic hairless rats.
  • AT pH 7.1 which is higher than the isoelectric point of insulin (pH
  • the treatment duration produces a difference in the rate and the duration, but with equal effectiveness.
  • FIG. 22 (Example 11) ; FIGS. 23A and 23B (Example 12) ; FIG. 24 (Example 14) ; FIG. 25 (Example 15) ; FIGS. 26A and 26B (Example 16) ; FIG. 27 (Example 17) ; FIG. 28 (Example 18) ; FIG. 29 (Example 19) ; FIG. 30 (Example 20) .
  • the pH either below or above the pKa or isoelectric point.
  • the pH below the pKa or isoelectric point such as to about 1.0 pH units or lower below, which for commercial insulins is about pH 5.3.
  • the formed unit dose is placed in the receptacle por ⁇ tion provided in the pharmaceutical reservoir electrode, so that the ionized pharmaceutical can be transdermally absorbed. If the unit dose form is a preformed self-con ⁇ tained unit dose, it can be held in the receptacle portion of the reservoir electrode by customary means such as clamp ⁇ ing, snapping into position, adhesive, or the like.
  • One convenient form of the unit dose for the ionized pharmaceutical solution is to disperse uniformly the aqueous solution of the ionized pharmaceutical in a polymeric matrix.
  • the polymeric -unit dose must be characterized by being able to release the ionized pharmaceutical, when the iontotherapeutic device is in operation, so that the ionized pharmaceutical can be absorbed transdermally.
  • the unit dose is in electrical contact with the skin of the subject being treated when the iontotherapeutic device is in operation.
  • the pharmaceuticals suitable for delivery by this poly ⁇ mer disc can be the anti-diabetic drugs, such as insulins or sulfonyl ureas; the anti-diuretic peptide drugs, such as vasopressin; the calcium-channel blocker-type anti-hyperten ⁇ sive drugs, such as verapamil ; the beta-blocker type anti- hypertensive drugs, such as propranolol; narcotic analgesic drugs, such as hydrocodone; non-steroidal anti-arthritic drugs, such as indomethacin; anti-bacterial antibiotics, such as tetracyclines, penicillins and cephalosporins; anti- neoplastic drugs, such as methotrexate; and the peptide hormones, such as luteinizing hormone-releasing hormone (LHRH) , oxytoxin, and the like.
  • the anti-diabetic drugs such as insulins or sulfonyl ureas
  • Pharmaceuticals suitable for use in the process of this invention can be selected from the following or other ionizable pharmaceuticals which are capable of being trans ⁇ dermally absorbed in the iontotherapeutic process, the fol ⁇ lowing systemically-effective pharmaceuticals expected to be capable of delivery by an iontotherapeutic device as developed in this invention: Propranolol HCI, Ibuprofen,
  • Ampicillin sodium Amantadine HCI, Acetohexamide, Haloperi- dol, Doxepin, Cyclobenzaprine HCI, Sucralfate, Cephalaxin,
  • Captopril Triazolam, Chlordiazepoxide, Amitryptilline, Dobutamide, Sulfamethoxazole, Trimethoprin, and the like.
  • the ionizable peptide pharmaceuticals used in the processes and the unit doses of this invention and adminis- tered by the devices of this invention are those which are pharmaceutically effective and transdermally absorbable.
  • the peptides have at least five amino acid units and more desirably at least nine amino acid units.
  • the appropriate unit dose containing the pharma ⁇ ceutical required for the desired therapy is assembled in the receptacle portion of the pharmaceutical reservoir elec- trode.
  • the pH of the insulin solution in the dose unit is pH 3.6
  • insulin is a cationic and therefore the dosage unit is assembled as a part of pharmaceutical reservoir electrode, which is the anode.
  • the desired waveform is selected and preprogrammed, such as a square waveform.
  • the pharmaceuti ⁇ cal reservoir electrode used preferably is adapted to receive a disposable unit dose, e.g., a polymeric matrix unit dose, and to make electric contact with the skin of the subject being treated. Such means is assembled in place.
  • the other variables are selected and preprogrammed, such as the frequency, the dose current and on/off ratio.
  • the device is attached to the subject being treated as by a band attached to the device and adapted to be attached to and detached from the subject.
  • the switch of the device is turned to "on" position and the device commences operation of the iontotherapeutic process, which causes the ionized pharmaceutical of reservoir electrode to be administered transdermally and lontotherapeutically to provide a systemic dosing.
  • the particular waveform, mA, pharmaceutical reser- voir electrode (i.e., cathode or anode), frequency, length of treatment and other factors will be selected and prepro- grammed depending upon the pharmaceutical being admin ⁇ istered, the subject being treated and others.
  • Some pharmaceuticals can be iontotherapeuti- cally administered using either periodic DC mode or periodic wave mode.
  • the periodic DC mode can be "on” for about 0.5 to about 10 minutes, preferably about 1 to about 5 minutes per hour. During the intervening period during the hour, the device is in "off” position.
  • the "on" period can be more frequent or less frequent, if desired, to provide effective treatment, such as one "on" period every
  • Example 5 it is shown that hydrocodone can be administered following this general procedure.
  • the dose currents, the on/off ratios, the dosage units and the devices described above can be used or adapted to be used in the practice of the periodic DC mode process.
  • a few hours duration of treatment each day following either procedure is ordinarily adequate, for example, 2 to 10 hours, depending upon factors such as the pharmaceutical, the subject being treated, the iontotherapeutic factors selected and the like.
  • aqueous solution of insulin at concentration of 250 IU/ml is prepared by dissolving 96.9 mg (25.8 IU/mg) of pure insulin in 10 ml of double-distilled, sterile water and adjusted to pH 7.1 with 0.5N NaOH. Two ml of the insulin solution so prepared is filled into a refillable dosage unit having a microporous membrane as the drug-releasing surface.
  • the results on the reduction in blood glucose level are shown and compared in FIG. 16.
  • Example 2 An amount of 200 mg (25.8 IU/mg) of pure insulin is dissolved in 10 ml of double-distilled, sterile water and the pH is adjusted to 3.6 with 0.5N HCI. An amount of 200 mg of hydroxypropylmethylcellulose is well dispersed in another 10 ml of double-distilled sterile water using a magnetic stirrer with a stirring bar (5 cm in length) at a rotation speed of 600 rp . The temperature is controlled at about 80°C. After the hydroxypropylmethylcellulose is dis ⁇ persed homogeneously, the stirring is continued while the mixture is cooled to about 40°C.
  • the insulin solution prepared above is then added to the dispersion of hydroxypropylmethylcellulose with inter ⁇ mittent stirring to avoid any denature of insulin molecules, using the same stirring mechanism as described above, at the same stirring rate of 600 rpm for a period of two minutes.
  • the insulin/hydroxypropylmethylcellulose solution is then placed in a refrigerator for congealing to occur.
  • the insu ⁇ lin-containing polymer matrix is cut into disc-shaped parts with the appropriate dimensions, such as 2.5 cm in diameter and 0.2 cm in thickness.
  • the insulin-containing discs are stored at 5°C.
  • the concentration of insulin in the discs is about 250 IU/gm.
  • the insulin-containing polymeric matrix dosage forms are removed as needed and assembled into the pharmaceutical reservoir electrode.
  • Application of this insulin-containing polymeric matrix unit dose is made onto the abdominal skin of 3 diabetic hairless rats.
  • the transdermal periodic iontotherapeutic system is then operated at 1 mA using an on/off ratio of 1/1, a frequency of 2000 Hz and a square wave mode, for 40 minutes. The result on the reduction in blood glucose level is shown in FIG. 17.
  • 250 IU/ml is prepared by dissolving 193.8 mg (25.8 IU/mg) of pure porcine insulin in 20 ml of citrate buffer at pH 3.6. Two ml of the insulin solution so prepared is filled into a refillable dosage unit having a microporous membrane as the drug-releasing surface.
  • This insulin-containing reservoir- type dosage unit is then assembled as a part of the pharma ⁇ ceutical reservoir electrode of the iontotherapeutic device and applied successively on the abdominal skin of 9 diabetic hairless rats with the transdermal periodic iontotherapeutic system operating at 1 mA with square waveform mode to study the effect of frequency, on/off ratio and treatment duration on the reduction of blood glucose level. The results are shown and compared, respectively in FIGS. 18, 19 and 20.
  • the same insulin solution is prepared in the same way as in Example 1, except that a phosphate butter at pH 7.1 is used to replace the double-distilled water.
  • Two ml of the insulin solution so prepared is filled into a refillable dosage unit having a microporous membrane as the drug- releasing surface.
  • This unit dose is applied to 3 diabetic hairless rats following the same operation procedures as in Example 3 to study the effect of treatment duration on the reduction of blood glucose level. The results are shown in FIG. 21.
  • a saturated solution of hydrocodone 9pKa 8.56), a narcotic analgesic drug, is prepared in citrate buffer at pH 4.0 and in phosphate buffer at pH 7.5. An aliquot of 3.5 ml of this hydrocodone solution is filled into the reservoir compartment, which is in contact with the stratum corneum surface of the hairless rat abdominal skin, of each Valia-
  • a saturated solution of methotrexate, an anti-neoplas- tic drug is prepared in double-distilled water and adjusted to pH 8.0, which is higher than the pKa values of metho ⁇ trexate (4.8 and 5.5) .
  • An aliquot of 3.5 ml of this metho- trexate solution (2 mg/ml) is filled into the donor compart ⁇ ment, which is in contact with the stratum corneum surface of the hairless rat abdominal skin, of each Valia-Chien skin permeation cell with the receptor compartment containing equal volume of a pH 7.4 buffered isotonic (drug-free) saline solution.
  • the transdermal periodic iontotherapeutic system is then mounted with its electrodes immersed in the skin permeation cell, one electrode in each of the two solu- tion compartments.
  • a DC current of 1 mA is applied for 10 minutes periodically on the hour for 5 hours with a fre- quency of 2000 Hz, a square wave form, and an on/off ratio of 4/1.
  • Table II Enhancing Effect of Transdermal Periodic Iontotherapeutic System (TPIS) on the Skin Permeation of Methotrexate - An Anti-Neoplastic Drug
  • a saturated solution of propranolol (pKa 9.45), a beta-blocker type anti-hypertensive drug, is prepared in 30 citrate buffer at pH 3.68.
  • the enhancing effect of the transdermal periodic iontotherapeutic system is studied under the same conditions as that outlined in Example 6.
  • TPIS applied a DC current of 1mA periodically at 10 min/hr, a frequency of 2000 Hz and an on/off ratio of 4/1.
  • a saturated solution of verapamil (pKa 8.9), a cal ⁇ cium-channel blocker-type anti-hypertensive drug, is pre ⁇ pared in citrate buffer at pH 3.68.
  • the enhancing effect of the transdermal periodic iontotherapeutic system is studied under the same conditions as that outlined in Example 6.
  • Table IV Enhancing Effect of Transdermal Periodic Iontotherapeutic System (TPIS) on the Skin Permeation of Verapamill f l ⁇ - A Calcium-Channel Blocker-Type Antihypertensive Drug
  • TPIS applied a DC current of 1 mA periodically at 10 min/hr, a frequency of 2000 Hz and an on/off ratio of
  • TPIS Iontotherapeutic System
  • TPIS applied a DC current of 1 mA periodically at 10 min/hr, a frequency of 2000 Hz, a square waveform and an on/off ratio of 4/1.
  • vasopressin 50 mcg/ml containing 1. 7 mcCi/ml H 3 ⁇ vasopressin ) is prepared in citrate-phosphate buffer at pH 5.0. An aliquot of 3.5 ml of this vasopressin solution is filled into the refillable dosage unit having a microporous membrane as the drug- releasing surface. The dosage unit is then assembled as a part of the pharmaceutical reservoir electrode of the ionto- therapeutic device and membrane surface thereof is applied to the stratum corneum side of hairless rat skin mounted in the Valia-Chien skin permeation cell at 37 0 C.
  • TPIS transdermal periodic iontophoretic system
  • aqueous solution of insulin (5.3 IU/ l containing 0.3 mcCi of I 125 -insulin) is prepared and adjusted to pH 7.1 using naOH.
  • An aliquot of 3.5 ml of this insulin solution is filled into the refillable dosage unit having a micro ⁇ porous membrane as the drug-releasing surface.
  • the dosage unit is then assembled as a part of the pharmaceutical reservoir electrode of the iontotherapeutic device and mem ⁇ brane surface thereof is applied to the stratum corneum side of hairless rat skin mounted in the Valia-Chien skin permea- tion cell at 37 0 C.
  • FIG. 23B shows comparison of insulin permeation data in FIG. 23A using no iontotherapy (0) over a 7-hr. period with permeation data of same insulin solution using TIDD iontotherapy.
  • aqueous solution of insulin (5.3 IU/ l containing 0.3 mcCi of I 125 -insulin) is prepared and adjusted to pH
  • Permeabiity coefficient is the ratio of the steady state rate of skin permeation of the pharmaceutical which is transdermally absorbed/the concentration of the pharmaceuti ⁇ cal solution which is applied transdermally.
  • the pharmaceu ⁇ tical in this experiment is insulin.
  • the skin permeation profiles are enhanced with skin permeability coefficient increased to a range from
  • aqueous buffer solution of insulin (250 IU/ml) is prepared in citrate-phosphate buffer at pH 3.68. An aliquot of 2.5 ml of this insulin solution is filled into the refillable dosage unit having a microporous membrane as the drug-releasing surface. The dosage unit is then assembled as a part of the pharmaceutical reservoir electrode of the iontotherapeutic device and membrane surface thereof is applied to the skin at abdominal region of 3 groups of anesthetized, diabetic hairless rats. Blood samples are withdrawn at regular time intervals and glucose levels are measured by glucose analyzer. The reduction in glucose level from hyperglycemic state is the pharmacodynamic response to the insulin absorbed transdermally.
  • aqueous buffer solution of insulin (250 IU/ml) is prepared in citrate-phosphate buffer at pH 3.68. An aliquot of 2.5 ml of this insulin solution is filled into the refillable dosage unit having a microporous membrane as the drug-releasing surface.
  • the dosage unit is then assembled as a part of the pharmaceutical reservoir electrode of the iontotherapeutic device and membrane surface thereof is applied to the skin at abdominal region of 5 anesthetized, diabetic hairless rats. Blood samples are withdrawn at regular time intervals and glucose levels are measured by glucose analyzer. The reduction in glucose level from hyperglycemic state is the pharmacodynamic response to the insulin absorbed transdermally.
  • TPIS transdermal periodic iontophoretic system
  • the blood glucose levels are reduced sub- stantially (FIG. 25A) .
  • the diabetic rats are treated again with TPIS with no insulin in the pharmaceuti- cal reservoir electrode (placebo formulation) , the blood glucose is also reduced, indicating that part of the insulin delivered transdermally on Day 1 forms a depot in the skin tissue and can be triggered to be systemically absorbed on Day 3 (FIG. 25B) .
  • Example 16 An aqueous buffer solution of insulin (500 IU/ml) at pH 8.
  • FIG. 24B shows that by using the TPIS system of this invention the blood glucose level (B.G.L.) can be appropriately
  • the dosage unit is then assembled as a part of the pharmaceutical reservoir electrode of the iontotherapeutic device and mem-
  • 25A and B show that the TPIS system of this invention provides both a more rapid increase in plasma insulin concentration after administration and a more rapid reduction in blood glucose level than use of TIDD even though the corresponding current intensity in the TIDD system is 4 times as much (4 mA vs. 1 mA) and administration is 2 times as great (80 minutes vs. 40 minutes) as in the TPIS system.
  • vasopressin 40 IU/ml
  • aqueous buffer solution of vasopressin (40 IU/ml) is prepared in citrate-phosphate buffer at pH 5.0.
  • Vasopressin is an anti-diuretic pharmaceutical, which is used by patients which have an excessive urine output. Vasopressin caused a reduction of urine output and an increase in ion content, such as sodium ion content. Ion content in the urine is determined by using osmolarity measurement. An aliquot of 3.5 ml of this vasopressin solution is filled into the refillable dosage unit having al microporous mem ⁇ brane as the drug-releasing surface. The dosage unit is then assembled as a part of the pharmaceutical reservoir electrode of the iontotherapeutic device and membrane sur- face thereof is applied to the abdominal skin of 2 groups of anesthetized rabbits. Blood samples are withdrawn and urine
  • TPIS transdermal periodic iontophoretic system
  • the urine osmolarity increases from the basal levels more rapidly and substantially than with transdermal iontophoretic delivery
  • vasopressin 50 mcg/ml containing 1.7 mcCi/ml H 3 -vasopressin
  • Passive diffusion to the range of 65.9 (+13.1) to 632 (+65.0) ng/cm 2 /hr, depending upon the ionic
  • vasopressin 50 mcg/ml containing 1.7 mcCi/ml H 3 ⁇ vasopressin
  • citrate-phosphate buffer pH 5.0 at ionic strength

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Electrotherapy Devices (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Harvester Elements (AREA)
  • Catching Or Destruction (AREA)
  • Filters For Electric Vacuum Cleaners (AREA)

Abstract

Cette invention concerne un dispositif ionothérapeutique portatif et léger permettant l'administration régulée à l'organisme de composés pharmaceutiques ionisables par voie transdermique. Le dispositif comprend un élément de commande préprogrammable qui commande l'administration ionothérapeutique en fonction de la prescription et d'autres instructions introduites dans l'élément de commande par l'interface au moyen d'un système informatique qui peut communiquer des données relatives à l'ionothérapie par l'interface avec un système informatique. Cette invention concerne également un procédé ionothérapeutique permettant l'administration transdermique automatisée de produits pharmaceutiques ionisés à l'aide de ce dispositif. Une nouvelle ceinture pour les piles est également prévue, laquelle peut s'adapter pour être utilisée avec ledit dispositif.
PCT/US1992/007221 1991-08-26 1992-08-26 Procede et dispositif ionotherapeutiques WO1993003790A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5504665A JPH07501238A (ja) 1991-08-26 1992-08-26 電離療法装置及び方法
EP92919517A EP0604504A4 (fr) 1991-08-26 1992-08-26 Procede et dispositif ionotherapeutiques.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US74992891A 1991-08-26 1991-08-26
US749,928 1991-08-26

Publications (1)

Publication Number Publication Date
WO1993003790A1 true WO1993003790A1 (fr) 1993-03-04

Family

ID=25015812

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/007221 WO1993003790A1 (fr) 1991-08-26 1992-08-26 Procede et dispositif ionotherapeutiques

Country Status (5)

Country Link
EP (1) EP0604504A4 (fr)
JP (1) JPH07501238A (fr)
AU (1) AU2563292A (fr)
CA (1) CA2122150A1 (fr)
WO (1) WO1993003790A1 (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006497A1 (fr) * 1993-09-03 1995-03-09 Alza Corporation Diminution de l'irritation cutanee et de la resistance de la peau dans un dispositif d'electrotransport
US5415629A (en) * 1993-09-15 1995-05-16 Henley; Julian L. Programmable apparatus for the transdermal delivery of drugs and method
FR2724115A1 (fr) * 1994-09-02 1996-03-08 Elf Aquitaine Dispositif d'ionophorese pour l'administration transcutanee d'un principe actif a un sujet assurant un controle precis de la posologie
WO1996030078A1 (fr) * 1995-03-24 1996-10-03 Alza Corporation Affichage pour un dispositif d'administration par electrotransport
US5624415A (en) * 1995-04-24 1997-04-29 Alza Corporation Reduction of skin irritation and resistance during electrotransport
WO1998000107A3 (fr) * 1996-07-02 1998-06-11 Massachusetts Inst Technology Dispositifs d'administration de medicaments sur microplaquettes
WO1998028038A1 (fr) * 1996-12-24 1998-07-02 Alza Corporation Procede et dispositif de regulation du cycle reproducteur des mammiferes
US5876368A (en) * 1994-09-30 1999-03-02 Becton Dickinson And Company Iontophoretic drug delivery device having improved controller
US5941844A (en) * 1997-11-17 1999-08-24 Alza Corporation Method and device for controlling mammalian reproductive cycle
WO1999052590A1 (fr) * 1998-04-09 1999-10-21 Paedipharm Arzneimittel Gmbh Systeme d'application transdermal (tds) dote d'un reseau d'electrodes
US6035234A (en) * 1995-06-02 2000-03-07 Alza Corporation Electrotransport delivery device with voltage boosting circuit
WO2001041736A3 (fr) * 1999-12-10 2002-01-31 Massachusetts Inst Technology Dispositifs a puces pour l'administration de molecules et procedes de fabrication correspondants
US6527762B1 (en) 1999-08-18 2003-03-04 Microchips, Inc. Thermally-activated microchip chemical delivery devices
US6551838B2 (en) 2000-03-02 2003-04-22 Microchips, Inc. Microfabricated devices for the storage and selective exposure of chemicals and devices
US6730072B2 (en) 2000-05-30 2004-05-04 Massachusetts Institute Of Technology Methods and devices for sealing microchip reservoir devices
US6757560B1 (en) 1999-04-09 2004-06-29 Novosis Pharma Ag Transdermal delivery system (TDS) with electrode network
US6773429B2 (en) 2000-10-11 2004-08-10 Microchips, Inc. Microchip reservoir devices and facilitated corrosion of electrodes
US6895271B2 (en) 1998-09-15 2005-05-17 Biophoretic Therapeutic Systems, Llc Iontophoretic drug delivery electrodes and method
US6976982B2 (en) 2001-01-09 2005-12-20 Microchips, Inc. Flexible microchip devices for ophthalmic and other applications
US7070590B1 (en) 1996-07-02 2006-07-04 Massachusetts Institute Of Technology Microchip drug delivery devices
US7226442B2 (en) 2000-10-10 2007-06-05 Microchips, Inc. Microchip reservoir devices using wireless transmission of power and data
WO2009000262A1 (fr) * 2007-06-25 2008-12-31 Acino Ag Système d'administration transdermique électrophorétique
US7488316B2 (en) 2005-01-25 2009-02-10 Microchips, Inc. Control of drug release by transient modification of local microenvironments
US7497846B2 (en) 2001-06-28 2009-03-03 Microchips, Inc. Hermetically sealed microchip reservoir devices
US7534241B2 (en) 2002-09-23 2009-05-19 Microchips, Inc. Micro-reservoir osmotic release systems and microtube array device
US7537590B2 (en) 2004-07-30 2009-05-26 Microchips, Inc. Multi-reservoir device for transdermal drug delivery and sensing
EP1688132A3 (fr) * 1999-12-10 2009-10-07 Massachussetts Institute of Technology dispositifs à puces pour l'administration de molécules et procédés de fabrication correspondants
US7604628B2 (en) 2004-09-01 2009-10-20 Microchips, Inc. Multi-cap reservoir devices for controlled release or exposure of reservoir contents
US7937142B2 (en) 2004-04-30 2011-05-03 Eyegate Pharma S.A.S. Irritation-reducing ocular iontophoresis device
DE102010024558A1 (de) 2010-06-22 2011-12-22 Amw Gmbh Transdermales therapeutisches System mit Elektroden
CN103768707A (zh) * 2013-12-28 2014-05-07 陈宁飞 一种具有渗透感测导入的装置
US9180292B2 (en) 2008-12-31 2015-11-10 Eyegate Pharmaceuticals, Inc. System and method for ocular iontophoresis with buffering

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2869531B1 (fr) * 2004-04-30 2006-07-14 Optis France Sa Sa Dispositif de iontophorese oculaire diminuant les irritations

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986007269A1 (fr) * 1985-06-10 1986-12-18 Drug Delivery Systems Inc. Commande programmable et systeme de montage d'un applicateur de medicaments transdermiques
WO1986007268A1 (fr) * 1985-06-10 1986-12-18 Drug Delivery Systems Inc. Systeme et procede de regulation de la vitesse de liberation electrocinetique d"un medicament
US4722726A (en) * 1986-02-12 1988-02-02 Key Pharmaceuticals, Inc. Method and apparatus for iontophoretic drug delivery
US4931046A (en) * 1987-05-15 1990-06-05 Newman Martin H Iontophoresis drug delivery system
US4942883A (en) * 1987-09-29 1990-07-24 Newman Martin H Drug delivery device
US5013293A (en) * 1987-05-28 1991-05-07 Drug Delivery Systems Inc. Pulsating transdermal drug delivery system
US5042975A (en) * 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
US5135479A (en) * 1983-08-18 1992-08-04 Drug Delivery Systems, Inc. Programmable control and mounting system for transdermal drug applicator

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5135479A (en) * 1983-08-18 1992-08-04 Drug Delivery Systems, Inc. Programmable control and mounting system for transdermal drug applicator
WO1986007269A1 (fr) * 1985-06-10 1986-12-18 Drug Delivery Systems Inc. Commande programmable et systeme de montage d'un applicateur de medicaments transdermiques
WO1986007268A1 (fr) * 1985-06-10 1986-12-18 Drug Delivery Systems Inc. Systeme et procede de regulation de la vitesse de liberation electrocinetique d"un medicament
US4722726A (en) * 1986-02-12 1988-02-02 Key Pharmaceuticals, Inc. Method and apparatus for iontophoretic drug delivery
US5042975A (en) * 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
US4931046A (en) * 1987-05-15 1990-06-05 Newman Martin H Iontophoresis drug delivery system
US5013293A (en) * 1987-05-28 1991-05-07 Drug Delivery Systems Inc. Pulsating transdermal drug delivery system
US4942883A (en) * 1987-09-29 1990-07-24 Newman Martin H Drug delivery device

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0604504A4 *

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5533971A (en) * 1993-09-03 1996-07-09 Alza Corporation Reduction of skin irritation during electrotransport
AU681447B2 (en) * 1993-09-03 1997-08-28 Alza Corporation Reduction of skin irritation and resistance during electrotransport
WO1995006497A1 (fr) * 1993-09-03 1995-03-09 Alza Corporation Diminution de l'irritation cutanee et de la resistance de la peau dans un dispositif d'electrotransport
US5415629A (en) * 1993-09-15 1995-05-16 Henley; Julian L. Programmable apparatus for the transdermal delivery of drugs and method
FR2724115A1 (fr) * 1994-09-02 1996-03-08 Elf Aquitaine Dispositif d'ionophorese pour l'administration transcutanee d'un principe actif a un sujet assurant un controle precis de la posologie
WO1996007449A1 (fr) * 1994-09-02 1996-03-14 Elf Aquitaine Dispositif d'ionophorese pour l'administration transcutanee d'un principe actif a un sujet assurant un controle precis de la posologie
US5876368A (en) * 1994-09-30 1999-03-02 Becton Dickinson And Company Iontophoretic drug delivery device having improved controller
US5843014A (en) * 1995-03-24 1998-12-01 Alza Corporation Display for an electrotransport delivery device
WO1996030078A1 (fr) * 1995-03-24 1996-10-03 Alza Corporation Affichage pour un dispositif d'administration par electrotransport
US5624415A (en) * 1995-04-24 1997-04-29 Alza Corporation Reduction of skin irritation and resistance during electrotransport
US6035234A (en) * 1995-06-02 2000-03-07 Alza Corporation Electrotransport delivery device with voltage boosting circuit
US7708731B2 (en) 1995-06-02 2010-05-04 Alza Corporation Electrotransport delivery device with voltage boosting circuit
US6842640B2 (en) 1995-06-02 2005-01-11 Alza Corporation Electrotransport delivery device with voltage boosting circuit
US7070590B1 (en) 1996-07-02 2006-07-04 Massachusetts Institute Of Technology Microchip drug delivery devices
US6123861A (en) * 1996-07-02 2000-09-26 Massachusetts Institute Of Technology Fabrication of microchip drug delivery devices
WO1998000107A3 (fr) * 1996-07-02 1998-06-11 Massachusetts Inst Technology Dispositifs d'administration de medicaments sur microplaquettes
WO1998028038A1 (fr) * 1996-12-24 1998-07-02 Alza Corporation Procede et dispositif de regulation du cycle reproducteur des mammiferes
US5941844A (en) * 1997-11-17 1999-08-24 Alza Corporation Method and device for controlling mammalian reproductive cycle
US7383083B2 (en) 1998-04-09 2008-06-03 Novosis Pharma Ag Transdermal delivery system (TDS) with electrode network
WO1999052590A1 (fr) * 1998-04-09 1999-10-21 Paedipharm Arzneimittel Gmbh Systeme d'application transdermal (tds) dote d'un reseau d'electrodes
US6895271B2 (en) 1998-09-15 2005-05-17 Biophoretic Therapeutic Systems, Llc Iontophoretic drug delivery electrodes and method
US6757560B1 (en) 1999-04-09 2004-06-29 Novosis Pharma Ag Transdermal delivery system (TDS) with electrode network
US6669683B2 (en) 1999-08-18 2003-12-30 Microchips, Inc. Thermally-activated microchip chemical delivery devices
US6527762B1 (en) 1999-08-18 2003-03-04 Microchips, Inc. Thermally-activated microchip chemical delivery devices
US6808522B2 (en) 1999-12-10 2004-10-26 Massachusetts Institute Of Technology Microchip devices for delivery of molecules and methods of fabrication thereof
EP1688132A3 (fr) * 1999-12-10 2009-10-07 Massachussetts Institute of Technology dispositifs à puces pour l'administration de molécules et procédés de fabrication correspondants
WO2001041736A3 (fr) * 1999-12-10 2002-01-31 Massachusetts Inst Technology Dispositifs a puces pour l'administration de molecules et procedes de fabrication correspondants
US7070592B2 (en) 1999-12-10 2006-07-04 Massachusetts Institute Of Technology Medical device with array of electrode-containing reservoirs
US6849463B2 (en) 2000-03-02 2005-02-01 Microchips, Inc. Microfabricated devices for the storage and selective exposure of chemicals and devices
US6551838B2 (en) 2000-03-02 2003-04-22 Microchips, Inc. Microfabricated devices for the storage and selective exposure of chemicals and devices
US7445766B2 (en) 2000-03-02 2008-11-04 Microchips, Inc. Medical device and method for diagnostic sensing
US7985386B2 (en) 2000-03-02 2011-07-26 Microchips, Inc. Implantable medical device for diagnostic sensing
US6730072B2 (en) 2000-05-30 2004-05-04 Massachusetts Institute Of Technology Methods and devices for sealing microchip reservoir devices
US7226442B2 (en) 2000-10-10 2007-06-05 Microchips, Inc. Microchip reservoir devices using wireless transmission of power and data
US6773429B2 (en) 2000-10-11 2004-08-10 Microchips, Inc. Microchip reservoir devices and facilitated corrosion of electrodes
US6976982B2 (en) 2001-01-09 2005-12-20 Microchips, Inc. Flexible microchip devices for ophthalmic and other applications
US7879019B2 (en) 2001-01-09 2011-02-01 Microchips, Inc. Method of opening reservoir of containment device
US7582080B2 (en) 2001-01-09 2009-09-01 Microchips, Inc. Implantable, tissue conforming drug delivery device
US7776024B2 (en) 2001-01-09 2010-08-17 Microchips, Inc. Method of actuating implanted medical device
US7497846B2 (en) 2001-06-28 2009-03-03 Microchips, Inc. Hermetically sealed microchip reservoir devices
US7534241B2 (en) 2002-09-23 2009-05-19 Microchips, Inc. Micro-reservoir osmotic release systems and microtube array device
US7937142B2 (en) 2004-04-30 2011-05-03 Eyegate Pharma S.A.S. Irritation-reducing ocular iontophoresis device
US8306613B2 (en) 2004-04-30 2012-11-06 Eyegate Pharma S.A.S. Irritation-reducing ocular iontophoresis device
US8611994B2 (en) 2004-04-30 2013-12-17 Eyegate Pharma S.A.S. Irritation-reducing ocular iontophoresis device
US7537590B2 (en) 2004-07-30 2009-05-26 Microchips, Inc. Multi-reservoir device for transdermal drug delivery and sensing
US7604628B2 (en) 2004-09-01 2009-10-20 Microchips, Inc. Multi-cap reservoir devices for controlled release or exposure of reservoir contents
US8403915B2 (en) 2004-09-01 2013-03-26 Microchips, Inc. Multi-opening reservoir devices for controlled release or exposure of reservoir contents
US7488316B2 (en) 2005-01-25 2009-02-10 Microchips, Inc. Control of drug release by transient modification of local microenvironments
WO2009000262A1 (fr) * 2007-06-25 2008-12-31 Acino Ag Système d'administration transdermique électrophorétique
US9180292B2 (en) 2008-12-31 2015-11-10 Eyegate Pharmaceuticals, Inc. System and method for ocular iontophoresis with buffering
DE102010024558A1 (de) 2010-06-22 2011-12-22 Amw Gmbh Transdermales therapeutisches System mit Elektroden
CN103768707A (zh) * 2013-12-28 2014-05-07 陈宁飞 一种具有渗透感测导入的装置

Also Published As

Publication number Publication date
EP0604504A1 (fr) 1994-07-06
EP0604504A4 (fr) 1995-05-17
JPH07501238A (ja) 1995-02-09
AU2563292A (en) 1993-03-16
CA2122150A1 (fr) 1993-03-04

Similar Documents

Publication Publication Date Title
WO1993003790A1 (fr) Procede et dispositif ionotherapeutiques
US5042975A (en) Iontotherapeutic device and process and iontotherapeutic unit dose
US5961482A (en) Iontotherapeutic device and process and iontotherapeutic unit dose
KR100376723B1 (ko) 전기수송전달장치
US8328788B2 (en) Methods and systems for electrokinetic delivery of a substance
US5415629A (en) Programmable apparatus for the transdermal delivery of drugs and method
CA2650412C (fr) Methodes et systemes transdermiques d'administration de composes anti-migraine
KR950008026B1 (ko) 피부를 통한 의약 투여장치
US7069073B2 (en) Electrokinetic delivery of medicaments
US5658247A (en) Ionosonic drug delivery apparatus
US5795321A (en) Iontophoretic drug delivery system, including removable controller
Parasrampuria et al. Percutaneous delivery of proteins and peptides using iontophoretic techniques
CA2201378A1 (fr) Systeme d'administration d'un medicament par ionophorese, comprenant un timbre a usage unique et un dispositif de commande amovible, reutilisable
AU2012261753B2 (en) Transdermal methods and systems for the delivery of anti-migraine compounds
AU2015203213A1 (en) Transdermal methods and systems for the delivery of anti-migraine compounds
JPH0767971A (ja) イオントフォレーシス用デバイス

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA DK ES FI JP KR NO

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE

WWE Wipo information: entry into national phase

Ref document number: 1992919517

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2122150

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 1992919517

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1992919517

Country of ref document: EP