JPH07501238A - Ionization therapy device and method - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Ionization therapy device and method [Related applications] This application is filed under U.S. Patent Application No. 07158740, filed September 25, 1990. No. 6, and U.S. Patent Application No. 071046984 filed May 5, 1987. This is a partial continuation application of No. In addition, U.S. Patent Application No. 071046984 is It is patented as Tokusho No. 5042975 and was filed on July 25, 1986. This is a continuation-in-part of U.S. Patent Application No. 890,702 (abandoned).

〔Technical field〕

The invention relates to ionizable (ionizable) agents (including ionizable biological agents). ) and an ionization therapy device for the controlled transdermal systemic treatment of The present invention relates to a novel power supply device that can be used as a component of a.

The present invention also provides a method for treating ionizable drugs, particularly those that would otherwise be absorbed transdermally in only trace amounts. Provides an ionization therapy process for transdermal administration of drugs that are poorly or not absorbed at all.

The present invention also relates to polymeric unit doses into which ionized drug is distributed. for this unit The amount is delivered transdermally and then absorbed systemically when the ionization therapy device is used. the anode or the cathode depending on whether the ionized drug is a cationic or anionic agent. It is intended to be assembled as part of any sword.

[Background technology]

Many drugs require that they be administered to patients by injection. One notable example is insulin, which is associated with high blood sugar levels (i.e., 1 (26 mg/d1 or higher) cannot be administered orally effectively. . Other drugs can be administered orally, but in some cases the drug may not be suitable for the given therapy. It does not absorb into the bloodstream sufficiently to enable it to achieve its function. Also, for oral administration Regarding this, many orally administered drugs are highly destroyed by single-phase metabolism in the liver/gastrointestinal tract. Destroyed. Metabolites of this -phase metabolism often have undesirable biological effects. may cause toxicity. For oral administration, especially for certain drugs, gastrointestinal There are variable factors that cause undesirable changes in the absorbance of Heterogeneity resulting from large initial absorption with undesirable side effects or toxicity associated problems with blood concentrations that are lower than therapeutically optimal values, and subsequent blood concentrations that are lower than therapeutically optimal values. There is a problem.

Recently, there has been increasing interest in transdermal administration. However, many drugs, especially of polymeric preparations such as insulin and cationic agents such as propranolol HCf2. It is hoped that transdermal absorption will be improved. For diabetes treatment needed every day injections, especially when treatments are required frequently, such as subcutaneous injections of insulin. Barriers and problems in administering these drugs are widely known. Avoids the need for injection treatments There has been a long-standing desire to do so.

Possibility to locally introduce certain therapeutic agents using direct current (DC) iontophoresis A lot of research has been carried out. For example, fluoride ions can aid in DC iontophoresis. It was discovered that it can be applied within the tooth tissue. Also, using direct current, pilocal Introducing sweat accelerators such as pi-o-carpine into the skin. Localized "sweating" occurred. The induced sweat is then analyzed for diagnostic purposes. Analyzed using electrodes to determine chloride ion concentration. Low chloride content in sweat Minutes indicate that the patient may have cystic fibrosis. DC iontophoresis The use of electric power applied specifically in the case of certain drugs to achieve a level of systemic treatment. It can be uncomfortable when the flow level is at high levels.

Improved ion therapy devices and processes and unit doses used therein morphology, and in this using physiologically acceptable low currents. It would be highly desirable to further provide therapeutic levels of systemically effective drugs.

[Summary of the invention]

systemically effective therapy in sterile aqueous solution using an ionization therapy device such as provided by the present invention. A process has been discovered for transdermally administering quantities of ionizable drugs. Can be ionized An ionizable drug solution (the pKa of the ionizable drug, that is, the isoelectric pH value or higher) be at least about 1.0.1.5 or about 2 pH units above or below the desired pH value) is compatible with the drug and the skin, exhibits hydrophilic properties, and a polymer capable of releasing a drug for transdermal absorption of ionization therapy. Units such as dosage forms of optionally mixed polymeric matrix units It can be maintained in a dosage form. This unit dosage form can also be used to Ionizable held in a unit dosage form in a sealed reservoir with a porous septum surface sterile solutions of pharmaceutical agents. This unit dosage form contains an electric charge in the drug reservoir cavity. combined with electrodes to further deliver the dissolved ionizable agent to the skin of the patient being treated. Transdermal absorption of iontophoretic therapy by dispersing and systemically dispersing drugs using iontophoretic techniques It is for carrying out. This unit dosage form is suitable for the required time of ionization therapy administration. It is kept sealed to maintain sterility. Unit dosage forms such as The drug reservoir cavity electrode that receives the This device is used as part of the ionization therapeutic delivery of ionizable drugs and transdermal It is used to carry out standard absorption. The drug reservoir electrodes are each in a negative state. Whether the cathode or the anode is ionic or cationic becomes. This ionization therapy device allows the patient being treated to undergo ionization during the process. approximately 5 cm' until receiving a pharmacologically effective systemic dose of the ionizable agent. Based on the area of the reservoir electrode in contact with the skin, the magnitude is up to about 10 mA and at least Ionization therapy with a specific waveform having an effective frequency of approximately 50 KHz to 50 KHz Produces a pulsed electrical current that is legally valid and physiologically acceptable.

The drugs administered according to the invention are administered transdermally in effective dosages, usually through intact skin. can be selected from drugs that are poorly absorbed. Such drugs Phosphorus, vasopressin, heparin, growth hormone, glucagon, oxytocin, and and other macromolecular drugs, as well as numerous others that can be given in ionized form. including but not limited to. occurring naturally in the human body or elsewhere Also within this group of drugs are numerous compounds that are often peptides in nature. Many of these have been created using recombinant DNA or other biological techniques. It can be produced as one or related compounds.

Also provided by the invention is an effective amount of an ionizable drug. A new ionization therapy (iontophoretic therapy) device that allows transdermal administration of drugs throughout the body. It is a place. This device is used for subjects ( A human-effective amount of an ionized drug suitable for use by a subject) Lightweight, portable, transdermal periodic ion ion therapy (ion immersion) for transdermal administration. fluorotherapy) device, 1) therapeutically effective and physiologically acceptable within a range of up to approximately 10 mA; 2) a) square, triangular, sine wave; , ladder shape, or other acceptable geometric shapes, or any combination thereof. periodic current waveform at , and C) one capable of providing a repetition frequency of about 10 KHz to about 50 KHz. A periodic waveform generator electrically connected to a DC power source with integrated circuitry and, 3) an output circuit electrically connected to said waveform generator, comprising: a) said b) providing a periodic current in a preselected waveform of the waveform; C) monitoring the strength of the current within predetermined maximum and minimum levels; regulating and maintaining said ionized ionization therapy reservoir for transdermal administration 4) an output circuit capable of delivering current to the electrode; Either the cathode or the anode, depending on whether it is an ionic or cationic agent. a drug storage electrode selected from one of a drug reservoir electrode having a container configured to receive a drug reservoir electrode; and the ionized drug is at least 1.0 mm below its isoelectric point, or pKa point. OpH is a low or high pH aqueous solution, and the electrode is and placed in electrical contact with the intact skin to be ionotherapeutically treated. the electrode is configured to receive the periodic current throughout the unit dose. the unit dose is in electrical contact with the terminal; and the unit dose is in electrical contact with the terminal. , 5) said drug reservoir in electrical contact with the intact skin to be treated; A second electrode is provided which together with the pole forms an anode and cathode electrode combination. and the electrode is electrically connected to the output circuit and is undergoing treatment. When placed on the skin of a subject (patient), it undergoes treatment. 6) provide a current path through intervening tissue of the patient; and 6) electrically interface with the device. automated system according to the doctor's prescription entered into the control element. Ionization therapy administration a preprogrammable control element for preprogramming and controlling the , when the patient being treated with this device is in danger of administering said device. No interaction by the patient except to allow movement to stop , is characterized by a pre-programmable control element.

The device includes a computer system and a connection connecting the device and the computer. The transdermal process performed by the device using a a terminal that allows administration to be monitored; or , computer systems and programmable control elements and computer systems and a connection line connecting the Terminal that allows notes to be input to the programmable control element usually has.

Additionally, the device has one or more further terminals by which the control element can be connected. The skin is connected to a sensor that senses the skin condition by a connecting line, and Another sensor that senses the level in the mouth (which correlates with the need for administration of the drug) wherein the sensor(s) maintain close contact with the patient's body. , signals the control element of the need for administration or skin condition. For example, In insulin ionization therapy, the signal characterizes the need for insulin administration. can be sent.

Furthermore, the present invention can be achieved by performing the following steps using the above-described apparatus. The present invention provides a process for administering ionized pharmaceutical drugs.

l) transmit prescriptions or other instructions to the control elements of said device using a computer system; step, 2) The pharmaceutical acceptability of the peptide is to administer a dosing unit containing an aqueous solution transdermally. Incorporated into the receptacle of the resrevoil electrode of the target ionization therapy system the electrode is a cathode or an anode, and the electrode is a cathode or an anode; The solution depends on whether the converted peptide is anionic or cationic. At least 1. Incorporated with a pH value below or above OpH step, 3) Treating the cathode electrode and the anode electrode of the percutaneous periodic ionization therapy system. 4) a) rectangular; triangle, sine, trapezoid, or other acceptable geometric form; combination periodic waveform, b) physiological acceptance of at least about 10 Hz is acceptable; using a repetition frequency and C) an on/off ratio of 1150 to/1. Ionotherapy effective up to about 10 mA based on a storage electrode/skin contact area of about 5 cm2 applying a periodic DC current of .

The process involves passive diffusion from the solution during a dosing period of at least 2 hours. a rate of at least 500 percent from that provided by skin absorption to provide systematically efficient absorption of the peptide preparation from the solution.

Said defined process preferably involves the sensor being in close contact with the body of the patient being treated. i.e., held in close contact with the skin of the person being treated. the sensor detects one or more signals, e.g. Physiological factors of the patient undergoing treatment that correlate with administration of the drug or related to transdermal administration the condition of the skin to be affected, etc., to a control element of the device.

[Brief explanation of the drawing]

Figure 1 shows the transdermal ionization therapy of ionizable (ionizable) drugs. The invention in use for absorption and uptake into the bloodstream of the patient to be treated A diagram showing the device of FIG. 2 shows the transdermal periodicity of the parent application, U.S. Patent Application No. 0,710,46984. Block diagram of ionization therapy device, FIG. 3 is a block diagram of a transdermal periodic ionization therapy device according to the present invention, and FIG. is a detailed circuit diagram for the power supply shown in Figures 2 and 3; Figure 5 is a detailed circuit diagram for the power supply shown in Figures 2 and 3; The detailed circuit diagram for the square wave generator shown in Figure 6, Figure 6, is shown in Figures 2 and 3. The detailed circuit diagram for the sine wave signal generator shown, FIG. 7, is shown in FIGS. 2 and 3. A detailed circuit diagram for the output circuit shown, FIG. 8, shows the main parts of the ionizable drug device. A small wristwatch-shaped periodic ionization device according to the present invention in which storage electrodes are placed apart from each other. The block diagram of the therapy device, Figures 9A and 9B, shows that the block diagram of the ionization therapy device is A wristwatch-shaped compact periodic device with a multifunctional programmable drug storage electrode. A diagram showing a transcutaneous ionization therapy device, FIG. 1O is a block diagram of a portable transcutaneous ionization therapy device according to the present invention; 1 and IIA are detailed circuit diagrams of the apparatus shown in FIG. 1O, and FIG. 12 is an ionization therapy Detailed circuit showing electrical timer elements that can be used to control regimen administration figure, Figure 3 shows a belt-style battery power supply and sensor for blood glucose monitoring. A schematic diagram of a wrist watch type ionization therapy device according to the invention shown in FIG. connection (e.g. Inter7Ace cable, telephone line) to the computer system. a schematic diagram illustrating an ionization therapy device of the invention interfacing with; Figure 15 uses a belt or band for attachment to the patient undergoing treatment. A schematic diagram of the ionization therapy device of the present invention, Figure 16 shows the transdermal absorption of insulin in diabetic hairless rats. and turbid wave mode in decreasing blood glucose levels (B, G, L) Figure 17 is a graph comparing the effects of the 40-minute square wave mode ( 7 cycles of cyclic transcutaneous ionization therapy at 1mA, 0N10FF=l/l, frequency -2KHz). The system allows injection from a drug storage electrode containing 250 fU of insulin with a pH value of 3.6. Blood glucose in diabetic hairless mice as a result of transdermal administration of insulin - a graph showing the time course of the decline in level (BGL); Figure 18 shows blood glucose levels in diabetic hairless mice using insulin. Frequencies produced by periodic transcutaneous ionization therapy systems in reducing levels (BGL) Graph showing the effect of numbers, Figure 19 shows blood glucose and ON1 in periodic transcutaneous ionization therapy system in decreasing level (BGL) A graph showing the effect of 0FF ratio, Figure 20 shows blood glucose levels in diabetic hairless mice using insulin. Cyclic therapy with pH 3,6 drug reservoir electrode in decreasing BGL level (BGL) A graph showing the effect of treatment duration with a skin ionization therapy system, Figure 21, is Blood glucose levels (BGL) in diabetic hairless mice using insulin ) Cyclic transcutaneous ionization therapy/splash with pH 7.1 drug storage electrode Graph showing the effect of duration of treatment with TEM, Figure 22 shows the effect of hairless mouse skin. Cyclic diffusion compared to passive diffusion of a pH 5.0 vasopressin solution at Graph showing vasopressin penetration facilitated by skin ionization therapy system , Figure 23A shows the immersion shown in Figure 23B when using ionization therapy (TIDD). pH 7.1 in hairless mouse skin without ionization therapy compared to permeation rate. Figure 24 is a graph showing the permeation rate of In/Nirin at pH 3.68. Diabetic hairless mice using turbid transcutaneous ionization therapy system using turin solution shows the comparative effect of waveform changes on blood glucose levels (BGL) in A series of graphs, FIG. Graph showing decrease in blood sugar level (BGL) in diabetic hairless mice, 2nd Figure 5B shows that insulin introduced transcutaneously on day 1 is stored in the skin tissue and Absorbed in the circulation by the periodic transcutaneous ionization therapy system (TPIS) in 3. Further administration of insulin, which has been shown to be able to be activated so that it can be used to Blood of the same mouse on day 3 using a periodic transcutaneous ionization therapy system without Graph 26A shows that sugar levels further decrease after subcutaneous administration (SC) Cyclic transcutaneous ionization therapy compared to corresponding levels in diabetic rabbits using Sugar after administration of insulin solution (pH 7,1) using stem (TPIS) A pair of ratios showing plasma insulin levels that produce an immune response in urinary rabbits. The comparison graph, Figure 26B, shows that if the data were substantially lower than the normal level due to TPIS, Control the blood glucose level (BGL) to a high constant level so that it does not drop. FIG. 24A shows each decrease in blood glucose level showing that blood glucose levels can be reduced. A pair of comparison graphs corresponding to Figure 27A shows a more rapid acquisition of increased plasma insulin concentrations with TPIS. A transcutaneous ionization therapy system using four times the current strength and twice the administration time ( The use of a cyclic transcutaneous ionization therapy system (TPIS) compared to the use of a TIDD) ) Plasma insulin concentration after administration of insulin solution (pH 7, 10) using A pair of comparative graphs illustrating the increase in intensity, Figure 27B, shows the transcutaneous ionization therapy The drop using the stem (TIDD) is below the euglycemic level, but the data are Hyperglycemia in diabetes management using periodic transcutaneous ionization therapy system (TP　r　S) blood glucose level (BGL) indicating an almost instantaneous drop in blood glucose level (BGL) from Figure 25A and corresponding pairwise comparison showing the achieved reduction in fluid glucose levels graph, Figure 28 shows that the corresponding graph shows that TPIS is more effective than TIDD in reducing urine output. Periodic transfusions to administer vasopressin solution (pH 5,0) indicating that demonstrated by urine osmotic measurements in rabbits anesthetized using a skin ionization therapy system. A pair of comparative graphs, FIG. 29, showing the required reduction in urine output such as TP When the ionic strength of the vasopressin solution used in IS decreases, vasopressin Graph showing the increase in penetration rate of TPIS, Figure 30, after stopping the TPIS geography. The ability to reverse skin penetration within 2 hours and the ability to reduce skin penetration after resetting the TPIS. bath using TPIS with a short skin penetration lag time, which also shows a state of enhanced penetration. Graph showing the state of enhanced skin penetration of Pressin.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS FIG. The present invention is in an active state for therapeutic delivery and ingestion into the bloodstream of the patient being treated. FIG. The figure shows an ionization therapy device in electrical contact with the skin. It shows.

The figure also shows what are called drug storage electrodes and response electrodes that are in contact with the skin. Other electrodes are also shown. These electrodes connect to the top protective wall of the skin called the stratum corneum. in contact. The drug is transmitted through this stratum corneum and flows into the epidermal layer of the skin. do. The stratum corneum is the major absorption rate limiting barrier. The first layer of skin is the papillary layer It contains the capillary network of the vascular system. This capillary network absorbs transdermally absorbed drugs. drug is shown flowing from the capillary network into the main part of the vascular system. There is.

FIG. 2 is a block diagram of a periodic transcutaneous ionization therapy device according to the present invention, in which the power source is 1. of alternating current (AC) from a 20 volt mains (or other available AC mains) It can be converted to direct current or obtained from a suitable battery. Power is supplied by a switch Dosed manually or automatically by a programmable timer. This device It also includes one or several electronic multifunction generators, drug storage electrodes and It consists of a combination of receiving and receiving electrodes. Multifunction generators can be rectangular, triangular, or trapezoidal. Alternatively, a direct current having a periodic waveform in the form of a sine wave can be supplied to the output circuit. It is combined with a power supply to The desired ionotherapy-effective waveform can be manually selected. or the frequency of the output waveform. cannot be adjusted within the range of IOHz to 50KHz. This output circuit Next, a drug reservoir electrode and a receiver in series containing an ionizing drug to be delivered percutaneously are used. Provides a physiologically acceptable current in the range of up to 10 mA to the electrode .

If necessary, the device supplies only DC current (periodically or continuously). or in combination with periodic waveforms. Multifunction generator The data has a periodic waveform that is either square, triangular, trapezoidal or sinusoidal. Waveforms can be selected manually or programmed via a switch. Also, the frequency of the output waveform can be adjusted within the range of 10Hz to 50KHz. Can not. This output circuit is in turn connected to a drug containing an ionizing drug that is delivered transdermally. Physiologically acceptable range of up to 10mA for the reservoir electrode and the receive electrode in series Provides current that can be If necessary, the device can supply only DC current (periodic (continuously) or in combination with periodic waveforms. Can be done.

FIG. 3 is a block diagram of the ionization therapy device of the present invention. This device consists of the following: Consists of elements. i.e. microprocessor, multi-waveform zeor router, waveform selection device , output circuit, sensor signal processing device, display device, power supply device with indicator, storage They are a retaining electrode and a receiving electrode.

The microprocessor is the heart of this device. It has the following features: Ru. That is, a. receiving and processing physiological signals from the sensor element;

b. Communicates with the Combicoater system via an interface cable.

C. Receives and executes instructions from a computer system.

d. storing and transmitting data to a computer system;

e0 Multiple waveform parameters, such as the frequency and duty cycle of the generated waveform. Controls the nerator's operating parameters and nota.

f. Select the input waveform to the output circuit.

g. Control operating parameters of the output circuit, such as output current value and processing cycle. .

h. Monitor the load impedance of the device and alert the user of improper operating conditions. .

This microprocessor uses a commercially available Ninguruchibu microcontroller. by adding the necessary expanded memory capacity, additional input/output ports, and signal converters. Made. A suitable microcontroller is manufactured by Shida Futake and is manufactured by Phillip. 80C552 single touch secondarily supplied by Puss Combo It is a knob microcontroller. This microcontroller is very powerful It meets the requirements of this application. It has the following important features: Immediately It has an operating speed of 16 MHz, 8 ROM and 256 RAM memory capacity, Visual timer/counter function, 6 I10 ports and 8 channels of 12-bit A /D function, UART and T2C interface function, and 6 external interrupts It is a function.

A multiple waveform generator provides pulse mode signals of the desired waveforms. This generale The data is realized using the circuit shown in FIG. This circuit is manufactured by Motorola It is made using a commercially available integrated circuit +ct, 8038.

The waveform selection device is a commercially available analog device such as the AD7510 manufactured by Analog Devices. Made using analog switches.

The output circuit may use the circuit design shown in Figure 7 or may be manufactured by National Semiconductor. It is made using a 3-pin constant current regulator LM334 manufactured by Kogyo Co., Ltd.

The functionality of the sensor signal processor further conditions physiological signals, such as blood glucose signals. That's true. This provides necessary functions like signal amplification and filtering . The conditioned signal is sent to the microprocessor's analog-to-digital converter. Ru. These are used for closed loop control in ionization therapy.

The power supply consists of battery elements connected in series. These bags The telly may be a regular one or a rechargeable one. to signal a drop in voltage , using a brownout indicator.

FIG. 4 is a detailed circuit diagram for the square wave generator shown in FIG. this The generator uses a Microchip 555 timer. Square wave frequency (F )teeth, 1 t 1-0.693 (PH+p)) C1, +t2 t, -0,693P+ C However, P is a potentiometer, C is a capacitor, and D is a diode. Ru.

During operation, capacitor C connects potentiometer P, and P2 and die for t1 seconds. Charged via Ord D, t! Second potentiometer P, and diode island is discharged through. Other circuits can also be used.

Figure 5 is a detailed circuit diagram for the triangular/trapped waveform generator shown in Figure 2. be. This generator consists of an integrator (A ) and a regenerative comparator. The exact triangular waveform is the output of the comparator. It is formed by integrating a square wave that is fed back from the force to the input of the integrator.

The frequency (F) of the triangular wave is 1, +1° Rt / C (R2a + P1 b) Ry / C (R2b+P, a) However, ■, 3''' and Vo- are relatively high or relatively high of the comparator, respectively. It is a low moving point. Resistors R1 and R2 control the moving point of this comparator. Ru.

Capacitor C is an integrating capacitor. Potentiometer P1 is a triangular wave Adjust the offset. The potentiometers P and P are the frequency and and adjust symmetry.

The third operational amplifier circuit C acts as an attenuator, which has the same frequency as the triangular wave. This produces a trapezoidal wave. Potentiometer P1 sets the clamp level.

Other circuits can also be used.

FIG. 6 is a detailed circuit diagram for the sine wave signal generator shown in FIG.

The circuit of this generator uses two amplifiers, one (A) with a non-inverting integral the other (B) as an inverting integrator. These are the feeds connected in cascade to form a back loop. Frequency of sine wave signal The wave number (F) is determined by the following formula. That is, F disorder □ C.P. C and P are an integrating capacitor and a variable resistor, respectively. Resistance R + li It is feedback resistance. Capacitor C1 is used to prevent high frequency oscillation. I can stay. Other circuits can also be used.

FIG. 7 is a detailed circuit diagram for the output circuit shown in FIG. 2. The required waveform is , manually or automatically from three generators via one switch (K1) is selected and sent to an inverting amplifier, from where the signal is then passed to the outputs of the two transistors. Go to the stairs. The output current (dose current) is controlled by the potentiometer as monitored by the ammeter (A). It is regulated by the shomeometer (P) and sent to the drug storage electrode (B).

Other circuits can also be used.

Figure 8 shows a wristwatch-shaped miniature periodic transcutaneous ionization therapy with multi-function programmability. FIG. 1 is a diagram showing a system. This system consists of one or more nuclear batteries and two Designed with a microchip. That is, one is summarized in Figures 4 to 6. The other controls and displays the output current for the purpose of producing different waveforms as shown. It is for a purpose. Nuclear batteries provide the energy needed for long-term operation do. For example, programmability may include DC only or in combination with periodic waveforms. The combination may include selecting a dose current for a specifically designated period of time. certain use odor Therefore, when using the device of the present invention, the periodic current waveform is It may be advantageous to maintain a constant DC level. This kind of ionization therapy device In some designs, the drug reservoir electrode is placed on the outside of the device.

FIG. 9 shows an embodiment of another design of an ionization therapy device falling within the scope of the present invention. are doing. The figure shows two views of the device. The first diagram shows an integrated circuit, liquid crystal Drug reservoir electrode centrally located directly below the display, battery, and base , and a cross-sectional view showing a receiving electrode surrounding a drug storage electrode. The following illustration shows the main packaging. The bottom view of the unit is shown. At the center of this bottom view is the circular drug reservoir of the drug reservoir electrode. It is shown. Drugs or agents dissolved in aqueous solutions are evenly distributed in unit doses of mer matrix. A solution of the drug also Can be held in unit doses in a reservoir form with a porous surface to enable transport. can. Next, a circular ring is placed in a spaced relationship from the drug storage electrode. The receiving electrode is shown. At the top of the cross-sectional view, a liquid crystal display is shown.

This display shows whether the device is in operation and the periodic current being used. and waveform type, and other relevant information of cyclic transcutaneous ionization therapy drug delivery. View many features including: The battery used as a power source of the present invention is, for example, It may be a lithium or other nuclear battery with a voltage of 6 to 12 ports.

FIG. 1O shows a block diagram of a portable periodic transcutaneous ionization therapy device falling within the scope of the present invention. is a locking diagram in which the power source is one or more batteries, such as a 9-port battery. Supplied from. Power is applied manually via a switch. This device is programmed It can be equipped so that it can be dispensed automatically by a timer that can be programmed. Book binding The system also includes a combination of one or several electronic multifunction generators, drug reservoirs, Consists of an electrode and a receiving electrode. Multifunction generators can be rectangular, triangular, or trapezoidal. Alternatively, a periodic waveform in the form of a sine wave can be applied to the output circuit.

The desired ionotherapy-effective waveform can be manually selected and the frequency of the output waveform can be The wavenumber is at least 1 OHZ and up to approximately 50 KHz, a physiologically acceptable frequency. It can be adjusted to the wave number. Therefore, the output circuit is connected to a percutaneously delivered ionizable The lomA Provides a range of physiologically acceptable electrical currents. If necessary, the device Provides DC current alone (periodically or continuously) or in combination with periodic waveforms It can be operated to supply

Figures 11 and IIA are portable periodic transdermal devices shown in the block diagram of Figure 1O. FIG. 3 is a detailed circuit diagram for the ionization therapy device. Regarding Figure 11, the following is the circuit and This is an explanation of its function.

(DC/DC converter and battery voltage monitor) IC, R, -RC , -C3, Ll and diode IN914 are DC/DC included in boost applications. Consists of a current converter. The output voltage can be reduced to 9 port batts by proper adjustment of R4. The voltage is increased from 1 to 27 volts. The battery output voltage is determined by the Zener diode Monitored by a battery voltage monitor containing D, , C, and Cl06Yl.

When the output of a 9-port battery drops below the minimum allowable voltage of 8.3 volts, the LE D lights up to indicate the need for recharging.

(Pulse generator and constant current output stage) ICz, Dz, Ds, T5, Cs, CI and R1 are the components of the triangular wave generator. In this circuit Then, the charging and discharging currents for C6 are D.

-D, through a diode bridge formed by. Bridge D.

Ds directs the current in the proper direction through the current source consisting of T, and R8. Four general-purpose switching diodes with anti-leakage characteristics that work to It will be.

Pin 3 of the IC, serves as a current source for the timing circuit and its high or The low state of C determines the direction of current for C6 for charging or discharging. charging and discharge open current flow through the same current regulation circuit, these currents are equal, and therefore Therefore, the charging and discharging times are equal. As a result, a triangular wave is generated across C6. Ru.

This circuit covers a frequency range of approximately 20Hz to 30KHz. frequency key The adjustment is performed by R. The frequency of the triangular wave can be expressed by the following formula.

That is, The output of the triangle wave generator is sent to pin 3 of the IC, which acts as a comparator. . A voltage comparison is made between pins 2 and 3 of IC1. The square wave is R, , −R, □ with a duty cycle determined by the voltage of the voltage divider consisting of Formed at pin 7 of IC3. The higher the voltage applied to pin 2, the more The "on" time of the shaped wave becomes shorter and vice versa. Square wave duty size covers a range of l/10 to 10/l. The square wave is generated by TI T4. It is amplified and sent to pin 11 of IC4.

In the constant current output stage, IC52s is used as a current regulator. ■ Initially, C, , j is the current due to the output current limiting resistor R across bins 10 and 3. Designed as a pressure regulator. Maximum output current is set as 0.6/R .

This feature is for forming a current regulator. Condition (V,,,/RL )>I, is satisfied. (However, ■, 1. is the output voltage, Rt is the load resistance, and 1. is the preset output current) and immediately the output current reaches the preset level. will be retained.

R2+ is the minimum current limiting resistance. R22 presets the required output current used for this purpose. , C7 and R3° are used to remove high frequency noise. It will be done.

(Output current monitor) Intersil interfaced with LCD display 7106 is the heart of the current monitor. R13 is a shunt resistor. C, and The R21 and R21 operate at approximately 48KHz and are clocked at 48KHz before being used as the system clock. It consists of an RC oscillator divided by . C1° and R27 act as input filters. Ku. C11, CI2 and Ls determine display sensitivity. C9 is automatic return It's for zero functionality.

Power is applied manually via a switch or on a programmable timer. It will be added automatically. This device also supports several electronic multifunction generators. one or a combination of the following: a drug reservoir electrode, and a receptor electrode. multifunction ze The generator can be combined with a power supply to provide a square, triangular, trapezoidal or sinusoidal output circuit. It sends out direct current with a periodic waveform of either waveform. Required ionization therapy The effective waveform can be manually selected or preprogrammed using the switch (K,). The frequency of the output waveform can be adjusted within the range of IOHz to 50KHz. can do. Therefore, the output circuit carries the prescription drug delivered transdermally. For drug reservoir electrodes and receptor electrodes in series, physiological to give an acceptable current. If necessary, the device (periodic or continuous) ) operated to supply DCt flow alone or in combination with a periodic waveform. be able to.

FIG. 12 shows the multi-channel periodic transcutaneous ionization therapy shown in the block diagram of FIG. FIG. 3 is a detailed circuit diagram of a timer of the device. With reference to Figure 12, the following describes the circuit and its is a description of the function of That is, (timer) This timer consists of 10 IC chips, 2 relays, and other components. The IC provides the system clock. I(:l, IC3 and Ice are , a circuit consisting of four two-person multiplexers with common selection and enable inputs. It is a two-person multi-flexor. When the selection input is a logical value “o”, the four outputs bin takes the value of the input in bin 1.5.14.11, otherwise bin 3.6, 13. Take the input value of lO. The first group of inputs has a maximum value of 999 minutes. 2) represents the time of the timer. The input for the second group is the maximum value of 99 minutes. represents the ``on'' time of a timer with . “On” and “Off” required Both time values are set via the BCD knob.

IC, , IC, and Ice receive preset values from the multiplexer. This is an “IO hex subtraction” counter. Bin 15 of these counters is the minimum count When it reaches , the logical value becomes "0". When all three counters reach their minimum values, I C, ie, the rANDJ gate becomes the logical value rlJ. This pulse is generated by the IC, . is inverted, resets the system clock, reloads the counters, and Converts an IC consisting of 7 lips and 70 pieces. At the end of the "on" time, Bin 3 and Bin 5 go to logic '0', which opens the two relays and turns the red line on. Turn on ED. At the same time, bin 2 and bin 6 become logical value 'l', which A value representing the r on time for bins 4, 7, 9.12 of the three multiplexers. Load it and turn off the edge LED. At the end of the "off" time, Bin 3 and bin 5 becomes a logic value '1', which causes bins 4 and 7 of the three multiplexers to ゜For 9.12, load the value representing the off time and turn on the edge LED. Ru.

The entire cycle, both "on" and "off", is repeated for the required length of time .

The switch is used to interrupt this operation and trigger a timer. It will be done.

(Pulse generator and constant current output stage) 4 INs, T, R,, IC, which is a diode bridge consisting of C5-C, and C5-C, is a triangular wave generator. It is a component of the controller. In this circuit, charging for one of C, -C, The current and discharge current are connected to a diode bridge formed by four IN, 14 , which directs the current in the proper direction through a current source consisting of T and R2M. Work to direct the flow.

Bin 3 of IC2 acts as a current source for the timing circuit and its high or low state indicates whether current flows in or out of the capacitor for charging or discharging. Determine the direction. Because both charging and discharging currents flow through the same current regulation circuit, the current are equal, so the charging and discharging times are not equal. As a result, the triangular wave It is formed across the operating capacitor C.

This circuit covers a frequency range of approximately 10Hz to 30KHz. frequency key Adjustment is performed by selecting the appropriate capacitor via a multi-point switch. triangle wave The frequency of can be expressed by the following formula. That is, the output of the triangular wave generator is , as a comparator (is sent to bin 3 of running ICI4. The voltage comparison is ,. This is done between bins 2 and 3. The square wave consists of Ryu2R34 In the bin 7 of the IC, 4, the duty cycle is determined by the pressure regulator. will be accomplished. The higher the voltage applied to bin 2, the more "on" the square wave is. time becomes shorter and vice versa. The duty cycle of the square wave is I/1 Covers the range from 0 to 10/1. The square wave is amplified by I2 and T, , then sent to three voltage followers T, -T,.

During the “on” time of the timer, the two relays are closed and the emitter of I4 T# is closed. is connected to the bin 11 of IC+s IC:+y. ICII IC+a, Provides three channels of current output. Three ICezs work as current regulators It is used like this. ICI23 first controls the output current between bin IO and bin 3. It is designed to be a voltage regulator with a limiting resistor R. The maximum current is 0.6/R is set.

This feature is for forming a current regulator. Condition (V,,,/RL )＞■, is satisfied (however, VI@l is the output voltage, RL is the load resistance and I, is the preset output current), then this output current reaches the preset level. It will be held by the bell. R3゜+R4fi and R6゜ are respectively maximum It is a current limiting resistor. Rllr R468 and R5I preset the required current used for C+s C21 is used to remove high frequency noise. I can stay.

The output current is monitored by ammeter A. 1 to switch, DC or pulse output Used to select.

FIG. 13 is a schematic diagram of the apparatus of the invention. The illustration shows a belt-type battery package. The figure shows a wristwatch-like device connected to the camera and containing an ionization therapy device in the center. Dis play unit, emergency on/off switch, input/output boat, computer The interface cable to the data system and sensor input board are also shown. It is. The device can be comfortably worn by the patient during treatment. of the present invention The weight of such attachments is usually 5 ounces or less and 3 ounces or less. It is preferable that the weight is also light.

FIG. 4 is a schematic diagram of a wristwatch-type electrotherapy device of the present invention, and a computer patient data and connections with control systems in hospital rooms, doctor's offices, etc.

Communication between the ionization therapy device and the computer system serves two purposes. the Communication is via an interface cable that transmits commands and data according to the doctor's prescription. to the ionization therapy device via. In addition, communication may be handled by the doctor. Read and access data important to treatment using the device. enable. Telephone lines can be used to communicate with remote locations.

A wide variety of computers, including personal computers and large computers, can be Can be used in computer systems. A wide variety of suitable programs can be used to communicate It can be used as

FIG. 15 shows the present invention using a belt or band for attachment to the patient being treated. 1 shows a schematic diagram of an ionization therapy device. Inside the belt are batteries connected in series. There is an element. These batteries can be regular or rechargeable. That's it. Battery belts can also be made into jewelry. The battery belt is Accommodates different numbers of battery elements to power different treatment times It can be designed as follows. Belts can be made of plastic materials, leather materials, metal, It can be made of any suitable material, such as a combination of several materials. belt length The height can be adjusted as necessary.

Figure 16 shows the drug storage electrode (pH Transdermal delivery of insulin from 7,1 (containing 2501 U of insulin) in diabetic hairless mice as a result of the current supplementation mode and as a result of the effect of the current supplementation mode. lowering of elevated blood glucose levels (% change in BGL) It is a graph showing the passage of time. Key: (○) DC mode (2mA), (・) Circular Regular square wave mode (2mA, 0N10FF=4/l, frequency -2000Hz) .

Figure 17 shows the periodic square wave mode (1 mA, 0N10FF-1/l, frequency -2 000 Hz) periodic transcutaneous ionization therapy system with a drug storage electrode (pH 3, 6). Results of transdermal delivery of insulin from (holding 2501U of insulin) As a reduction in elevated blood glucose levels in diabetic hairless mice It is a graph showing the passage of time versus (% change in BGL).

Figure 18 shows elevated blood glucose levels in diabetic hairless mice. The decrease (% change in BGL) caused by the cyclic transcutaneous ionization therapy system 2 is a graph showing the effect of frequency. The frequency of 2000Hz is 1ooOHz It also produces large size and long duration.

Figure 19 shows elevated blood glucose levels in diabetic hairless mice. 0 in cyclic transcutaneous ionization therapy system for reduction (% change in BGL) It is a graph showing the effect of N10FF ratio. By adjusting this ratio, sugar The magnitude and duration of BGL decline in urinary patients should be controlled as necessary. can be done.

Figure 20 shows elevated blood glucose levels in diabetic hairless mice. Treatment with periodic transcutaneous ionization therapy system for reduction (% change in BGL) It is a graph showing the effect of period. Lower than the isoelectric point of insulin (pH5, 3) At pH 3,6, the dose current 1mA10N10FF ratio is 8/1 and the frequency For several 2000 Hz, treatment durations of 20-40 minutes seem to be equally effective. It will be done.

Figure 21 shows elevated blood glucose levels in diabetic hairless mice. Treatment with periodic transcutaneous ionization therapy system for reduction (% change in BGL) It is a graph showing the effect of period. Higher than the isoelectric point of insulin (pH 5.3) At pH 7.1, the dose current 1mA%0N10FF ratio is 1/l and the frequency For 1000 Hz, treatment periods vary in speed and duration, but The effect is equal.

For a more detailed explanation of the background to the remaining drawings, please refer to the examples shown. sea bream. That is, FIG. 22 (Case 11), FIG. 23A, and FIG. 23B (Case 12) , Figure 24 (Case 14), Figure 25 (Case 15), Figure 26A and Figure 26B. (Case 6), Figure 27 (Case 17), Figure 28 (Case 18), Figure 29 (Case 19), Figure 30 (Case 20).

For administering systemically measured ionizable drug compounds by transdermal means When carrying out the ionization therapy process, the first thing that must be done is to ensure that the drug is present in an aqueous solution. The objective is to provide a unit dose containing the drug. The pH of the aqueous solution is the pK of the drug. a, that is, the effective pH value is adjusted to either above or below the isoelectric point. This pH value is the p of the drug. The p of the drug is preferably at an effective level of about 1 pH above or below the Ka or isoelectric point. to an effective pH level of at least 2 pH units above or below the Ka or isoelectric point. It is desirable to adjust the H value. For certain drugs, the pH value is defined as pKa, or It is desirable to adjust either below or above the electrical point. For example, Regarding phosphorus, commercially available insulin has a pH value of about 5.3, which is the isoelectric point. It is desirable to adjust the pH value to less than about 1.0 units below the isoelectric point. stomach.

The prepared unit dose contains a drug reservoir such that the ionisable drug can be absorbed transdermally. Place it in the container part provided on the retention electrode. If this unit dosage form is If the unit dose is stored, customary means such as gripping, snapping into place, adhesive, etc. It can be held in the container part of the storage electrode by.

One convenient form of unit dose for ionisable drug solutions is polymer matrix The aim is to evenly disperse an aqueous solution of an ionizable drug in the form of a box. polymeric The unit dose of the ionization therapy device is such that the ionizable drug can be absorbed transdermally. It must be characterized by the ability to release ionizable agents during use. unit dose is in ionizing contact with the skin of the patient being treated during use of the ionization therapy device.

For unit doses in the form of polymer matrix dose units, There are many polymers that can be used to form a unit dose of matrix.

In general, polymers can be used with substantially non-ionic, hydrophilic and ionized drugs and skin. They must be able to coexist. Pores used in matrix formation The remer must release the drug in an ionized state during use of the ionization therapy device.

Polymers suitable for forming the matrix are usually woody polymers or It is considered to fall under the category of Drogel. These include the example sections below. Includes ululose-type polymers and other polymers. That is, polyhydroxyethyl methacrylate, hydroxypropylcellulose, polyhydroxypropylmethacrylate, Tacrylate, hydroxypropyl methylcellulose, polyglyceryl methacrylate rate, polyacrylamide, polymethacrylamide, polyvinyl alcohol , poly-N vinyl-2-pyrrolidone.

When preparing polymer matrix unit doses, the viscosity of the drug reservoir is increased. Certain viscosity generators may also be included to increase the viscosity. For example, polyethylene that creates viscosity It was found appropriate to use ren glycol. 1500 to 800 Polyethylene glycols with a molecular weight in the range of 0 are good. polymer· In preparing dosage units of the matrix, an amount of the appropriate polymer is taken and this Suitably, this is mixed with water, such as sterile distilled water, to form a gel. used The amount of polymer used depends on the type of polymer used and the water/polymer combination. It depends on the viscosity produced. Retains sufficient structural integrity during storage and use Sufficient polymer must be used to provide a matrix. for example , hydroxypropyl methylcellulose was used as the matrix-forming polymer. When water is used, an amount of about 1.5 to 10% based on the amount of water used is sufficient. It turns out. It is appropriate to use approximately 2% hydroxypropyl methylcellulose. It turned out to be. The amount of other polymers used depends on the type of polymer used and and molecular weight, and the properties of the final matrix disc required. become

The discs are first made by double-vaporizing a polymer commonly referred to as a hydrogel-forming polymer. Dispersed in water such as distilled sterile water or in a suitable aqueous solution such as an aqueous drug solution. It is made by letting. Buffers may be included to maintain the desired pH level. good. If the required pH is on the acidic side, especially within the pH range of about 3 to 5. It has been found possible to use citrate buffers. If the desired pH is For example, if the pH value is between about 7 and 9, it is advisable to use a phosphate buffer. It turned out to be appropriate. Generally, optionally adding HCQ or NaOH It was found that simple adjustment of solution pH was carried out well. For example, 0°5 A molar amount of HCQ or NaOH has been found to be suitable. Other conventional methods known to those skilled in the art Means can be used to adjust the pH level.

For example, hydroxypropyl methylcellulose is used in the preparation of hydrokels. When the water and polymer are mixed, the mixture of water and polymer is rapidly stirred to ensure homogeneity of the polymer in the water. Perform proper dispersion to form a gel. 500 to 11,000 rpm, suitably about 60°r A high speed stirrer, such as one capable of rotating at pm, can be used. Includes stirring magnet It has been found that any stirring mechanism can be used. Depending on the polymer used, approx. It is generally desirable to conduct the dispersion at slightly elevated temperatures, such as 50 to 100°C.

When dispersing hydroxypropyl methylcellulose, a temperature of approximately 80°C is appropriate. I found out something. Once dispersed, stirring may be continued while the dispersion cools. desirable. This dispersion allows the drug dissolved in water at an appropriate concentration to form a drug reservoir. The polymer must be cooled to a temperature slightly above the gelling temperature of the polymer before incorporation. Must be. In the case of insulin, approximately 2 grams of insulin is stirred twice. The pH of the insulin solution is, for example, 0. Preferably about 3.6 using 5N HCQ or other suitable acidic pH adjuster. It was found that the pH could be adjusted to be acidic. Adequate amount of acidified insulin is added to the dispersed phase of the polymer in water before the solution is cooled to the gelling temperature. It will be done. In the case of insulin, a 2% insulin solution is It is a good concentration to add to a 2% dispersion of mer. This material is then stored in the refrigerator. Suitable cooling to about 5°C results in solidification of the insulin-containing polymer dispersion.

The ionic strength of the ionized drug solution is reduced to a low level, such as not greater than about 0.5 or 0.3. It was found that it is desirable to maintain this level at a high level. These low levels of ions If the intensity is relatively large, such as from a peptide solution from a vasopressin solution, It was found that transdermal absorption can occur.

A polymer disk containing a drug suitably used in an ionization therapy device has a rectangular shape. It may be of any suitable shape, such as round, circular, or rectangular, and the size may be approximately The desired size may be in the range of 5 to 30 cm with 0.05 to 0.4 cm. has a surface area of up to about 25 cm and a thickness of 0.1 to 1.3 cm, and The desirable size is 10cm to 20cm in area! and the thickness is O,l~0.2cm It is. The disc is suitably placed in a container which conforms to the suitably adapted form, and this The container is then sterilized, such as by using a removable seal that covers the surface of the disc. sealed in condition. The formed unit dose is then optionally added to the reservoir electrode container. It can be submitted to the department. The unit dose is the lead wire from the output circuit to the reservoir electrode. It must have a means of making electrical contact with the termination.

Drugs suitable for delivery by such polymer discs include insulin or Diabetic preparations such as sulfonylurea, urinary peptide preparations such as vasopressin , calcium channel pro-7ka such as verapamil blocker-type antihypertensive preparations, and base-based drugs such as propranolol. Beta-blocker type antihypertensive preparation, hydrocodone narcotic analgesic preparations such as, non-steroidal arthritis preparations such as indomethatin, Non-antibacterial antibiotics such as tetracyclines, penicillins and cephalosporins antitumor agents such as methotrexate, and luteinizing hormone-releasing hormone (LHRH), peptide hormones such as oxytocin, etc.

Agents suitable for use in the process of the invention include transdermal treatment in ionization therapy processes. may be selected from the following or other ionizable agents that can be absorbed: The following systemically effective drugs can be administered using an ionization therapy device such as that developed in this invention. expected to be available. That is, Propranolol HC (1, Ibuprofen, Indomethatin (In domethacin) HCQ, tel-Lorazep am), Thioridazine HCl2. ) Lazamide (T o Iazamide), Doxycycline, Furla Flurazepam, Minocifrin (Minocycle 1n) e), Disopyramide, Metoclopramide (Me toclopromide) HC(!, Cephalothin ) Sodium, Thiothixene, Vincristine (V incrist 1ne), oxazepam, palpro Va1 roic acid, Tematsu epan am), Hydralizine HC:ff, Ampicillin ( Ampicillin Sodium, Amantadine H Cl2, Acetohexamide, Haloperidol ( ) (al.

periodol), doxepin, cyclobenzapri Cyclobenzaprine HC (!s Sucralfate (Suc) ralfate), Cephalaxin (Cephalaxin), Cefazolin ( Cefaz.

1in) Sodium, Ampicillin, Cefadrox Cefadroxi, Hydralizine HC l2, reserpine and hydrochlorthiazide (Hydrochlorthia talindamycin (C), talindamycin (C), HCQ, Ka - Penicillin sodium, biloxican (Pi) roxicam), fenoprofen calcium, Artiazene (Dialtiazem) HCQ, Chlorpropamide (Ch lorpropamide), Sulindac (Sulindac), 1 f-7 Nefedipine, Cimetidine 1ne), Naproxen, Biloxy Power”y (Pirr ox i cam) % Ranitidine HCQ1 Nadra Ndolal, Alprozolam, Captogli Captopril, Triazolan (Tr i azo I am), Chlordiazepoxide, amitributi AmiLryptilline, Dobutamide , sulfamethoxyazole (Sulfamsthoxazo!e), trimeth Purine (Trimethoprin), etc.

used in the process and unit dose of the invention and laid down by the apparatus of the invention. The ionizable peptide substance administered should be pharmaceutically effective and transdermally absorbable. It's something you get. The peptide substance may have at least 5 amino acid units. Preferably, it has at least 9 amino acid units.

For example, the present process may use a wristwatch-type ionization therapy device such as that provided by the present invention. When using a drug, an appropriate unit dose containing the drug required for the desired therapy is stored in the drug reservoir. Attached to the container part of the electrode. For example, if you have to administer insulin However, if the pH value of the insulin solution in the dosage unit is pH 3.6, Insulin is a cationic drug and therefore the dosage unit is the anode drug reservoir Assembled as part of the pole. The desired waveform is selected, such as a square waveform. Use is The preferred drug storage electrode is a flexible unit dose, e.g. polymer matrix. receives a unit dose of the drug and makes electrical contact with the skin of the patient being treated. ing. Such means are assembled in place. Frequency, administered current S and 0 Other variables may be selected or preselected, such as the N10FF ratio. Book The device is attached to the patient by means of a strip, etc., which is attached to the patient in a removable manner. Attached to the patient being treated. Switch the device to the “on” position. is detected and the device begins to operate the ionization therapy process, which is a systemic In order to carry out the administration, the ionizable drug of the reservoir electrode is administered transdermally and ionotherapy. Ru.

specific waveform, mA, drug reservoir electrode (i.e. cathode or anode), frequency, The length of the procedure and other factors are selected according to the drugs being administered, the patient being treated, etc. will be done.

Some drugs, especially those with relatively small molecular weights, can be used in either periodic DC mode or periodic wave mode. It can be administered iontotherapeutically using any of the following modes: For example, period DC mode for about 0.5 to 10 minutes, preferably about 1 to 5 minutes per hour. can be “on” for a while. During periods intervening during this time, the device In the "off" position. The on-j period is one on-off every 30 minutes or every 9 minutes. If necessary, more frequent can be done less frequently. In case 5, this general procedure It is indicated that hydrocodone can be subsequently administered. Administration current mentioned in the text, 0N 10FF ratio, dose unit and equipment during the implementation of the process in cyclic DC mode. available or intended to be used.

The duration of daily treatment following any procedure is determined by the drug, patient being treated, Several hours are usually appropriate depending on factors such as ionization therapy factors, e.g. It will be 10 hours.

The following examples are illustrative of the invention, but should not be considered limiting.

(Case 1) An aqueous solution of insulin with a concentration of 25QIU/ml was distilled twice to 0.5N Na Add 96.9ml of pure insulin to 10ml of sterile water adjusted to pH 7.1 with OH. g (25,810/mg). Prepared like this Refill with 2 ml of insulin solution with microporous membrane as drug release surface Fill into any possible dosing device. This storage-type administration device that holds insulin is , which was then assembled as part of a drug storage electrode and placed in the abdomens of three diabetic hairless mice. DC mode or periodic square wave mode (ON10FF ratio -4/L frequency) on the skin of Using a periodic transcutaneous ionization therapy system operating at 2 mA according to It is applied by The result of the drop in blood glucose level is shown in Figure 16. shown and compared.

(Case 2) 200 mg of pure in/niline is dissolved in 10 ml of double-distilled sterile water, Adjust the pH to 3.6 with 0.5NH (l). Chilled cellulose was mixed with a stirring bar (5 cm in length) with a rotation speed of 600 rpm. Thoroughly disperse in another 10 ml of double-distilled sterile water using a magnetic stirrer. . The temperature is controlled at approximately 80°C. Hydroxypropyl methylcellulose is After uniform dispersion, stirring is continued while the mixture is cooled to about 40°C.

Same stirring speed of 600 rpm for a period of 2 minutes to avoid denaturation of the in/niline molecules. The previously prepared insulin was stirred intermittently using the same stirring mechanism described above. The solution is then added to the dispersion of hydrogin propyl methylcellulose. next, This solution of in/niline and hydroxypropyl methylcellulose produces coagulation. It is placed in a freezer to keep it cool. Polymer matrix containing yne/niline Cut into disk-shaped parts of appropriate dimensions, such as 2.5 cm in diameter and 0.2 cm in thickness. be done. The discs containing this in/niline are stored at 5°C. This di The insulin concentration in the bloodstream is approximately 2501 U/mg.

Dosage forms of polymeric matrix containing in/niline can be removed as needed. and incorporated into a drug storage electrode. unit dose of this insulin-containing polymer The shaped drug reservoir electrode is inserted into the polymer matrix delivery device. I) H value 3 where the phosphorus molecule is lower than the isoelectric point of yne/niline (pHi 5o = 5.3) ．． Since it is a cationic agent of No. 6, it is an anode.

A unit dose of this in/niline-containing polymer matrix was administered to 3 non-diabetic animals. It is applied to the belly skin of hairy mice. Cyclic transcutaneous ionization therapy/stem is then applied to l/ Using a 0N10FF ratio of 1, a frequency of 2000 Hz, and a square wave mode It is operated at 1 mA for 40 minutes. The consequences of the drop in blood glucose levels are This is shown in Figure 17.

(Case 3) An aqueous solution of in/niline with a concentration of 25010/ml was prepared in a citrate buffer at pH 3.6. 193.8 mg of pure porcine insulin in 20 mI (25.8 IU/mg ) prepared by dissolving. The insulin solution prepared in this way was m11 in a refillable dosing device with a microporous membrane as a drug release surface. Fill it up. This in/niline-containing reservoir-type dosing control is then applied to the drug reservoir of the ionotherapy device. A periodic phase integrated as part of the retention electrode and operated at ImA in square wave mode. Continuously applied to the abdominal skin of nine diabetic hairless mice using a skin ionization therapy system frequency, 0N10FF ratio and and the effectiveness of the treatment period. The results are shown in Figures 18, 19 and 20. are shown and compared.

(Case 4) Same as above, except that a pH 7.1 phosphate buffer is used instead of double-distilled water. A diine/niline solution is prepared in the same manner as in case 1. The thus prepared i Refillable with 2 ml of Ntuyurin solution and a microporous membrane as a drug release surface. Fill into a suitable dosing device. This unit dose follows the same operating procedure as in case 3. It was applied to three diabetic hairless mice and showed a decrease in blood glucose levels. Examine the effect of treatment duration on The results are shown in FIG.

(Case 5) A saturated solution of hydrocodone (pKa -8,56), a narcotic analgesic drug, has a p Prepared in citrate buffer at H4.0 and phosphate buffer at pH 7.5 . 3.5 ml of this hydrocodone solution was filled into the storage compartment. A receiver containing an equal volume of buffered isotonic (drug-free) saline at pH 7.4. Belly skin of a hairless mouse in each Valia-Chien skin penetration cell with a volume compartment. placed in the stratum corneum plane. The periodic transcutaneous ionization therapy system then connects its electrodes to the skin. Attach one electrode in each of the two solution compartments by immersing it into the skin's infiltrating cells. I get kicked. ImA current can be set in DC mode or periodic square wave mode (frequency 20 00Hz, 0N10F F ratio 1/l) for 1 hour for 12 hours is added periodically for 2 minutes. The results are shown in Table ■.

Table ■ Hydrocodone, a narcotic analgesic drug, is removed from the skin by a periodic transcutaneous ionization therapy system. Enhancement of the rate of temporal lag and decline in skin penetration rate (hours) Control 4.75±1.70 3,10 5.17 DC mode 7.61±2.7 4 37.5 0.72 period waveform mode 7. O1±1.16 59.4 0. 90 (Case 6) A saturated solution of methotrexate, an antitumor drug, was prepared in double-distilled water. and pH 8°0, which is greater than the pKa value of methotrexate (4, 8 and 5.5). Adjust to A 3.5 ml aliquot of this methoxate solution (2 mg/ml ) is loaded into the supply compartment, which contains a buffered isotonic (drug) solution at pH 7.4. ) each Va　1a-Ch　i with a receiving compartment containing an equal volume of saline solution The skin-penetrating cells are in contact with the stratum corneum surface of the abdominal skin of hairless mice. next , a cyclic transcutaneous ionization therapy system uses its electrodes immersed into the permeating cells of the skin. one electrode in each of the two solution compartments. ImA DC current but with a frequency of 2000 Hz, a square wave form and an ON10F ratio of 4/1 is added periodically for 10 minutes over 5 hours. The results are shown in Table II. That is, , Table 11 Periodic transcutaneous ionization therapy for skin penetration of methotrexate, an anti-inflammatory drug Strengthening the effectiveness of the system (TPIS) Cumulative amount of drug absorbed (mcg/cm2) (hrs) TP IS Using TPIS 1.33 0.0086 0.08202.33 0.024 7 0.13733.33 0.0471 0.42234.16 0.074 5 0.57055.16 0.1398 1.0835 (Case 7) A saturated solution of propranolol (pK a-9,45) is prepared in citrate buffer at pH 3,68. periodic sutra The reinforcing effect of the skin ionization therapy system was observed under the same conditions as summarized in case 6. be done. The results are shown in Table II+. That is, Table II+ Effects on skin penetration of propranolol, an anti-high plate pressure beta-blocker drug Periodic Transcutaneous Ionization Therapy/Strengthening Effects of Stem (TP　r　S)　Absorbed Drugs Cumulative amount (mcg/am2) (hrs) TP Without IS Using TPIS 1. 5 0.0691 0.5970 2.5 0.2615 1.5950 3.5 0.5845 3.3650 4.5 0.9955 5.2150 5.5 2.0800 9.0700 (Note) 1) In skin-permeating cells of Va l i a-Ch i en, pH 3, Supply containing 13.3 mg/ml of propranolol (pKa”J, 45) of 68 The solution was applied topically to the skin of hairless mice at 37°C.

2) TPIS is 10 minutes/hour, frequency 2000Hz; and ON10F A DC current of ImA was applied periodically at an F ratio of 4/l.

(Case 8) Wearing of veelapamil, an antihypertensive drug of the Cal/Rum channel blocker type, A solution (pKa-8,9) is prepared in citrate buffer at pH 3,68. . The reinforcing effect of the periodic transcutaneous ionization therapy system was outlined in Case 6. was examined under the same conditions. The results are shown in Table IV. That is, Table I■ Veelapamil (1 Enhancement effect of periodic transcutaneous ionization therapy system (TPIS) on skin penetration of )14 M Cumulative amount of drug absorbed (mcg/cm2) (hrs) T P I S Using TPIS 1.42 <0.0001 0.2972.42 <0.00 01 0.4453.42 - 0.695 4.17 0.973 5.17 <0.0001 1.945 (note) 1) In the skin-penetrating cells of Valia-Chien, Vuela at pH 3.68 A feed solution containing 23.95 mg/ml of Bamil (pKa 78.9) was It was applied topically to hairless mice at °C.

2) TPI511.1097 hours, frequency 2000Hz, 1: and ON10F A DC current of ImA was periodically applied at an F ratio of 4/1.

(Case 9) A saturated solution of the antibiotic drug tetranculin HCQ (pKa-3,3,7-8 and 9,7) were prepared in phosphate buffer at pH 9.0. periodic transcutaneous ionization The reinforcing effect of the therapy system is examined under the same conditions outlined in Case 6.

The results are shown in Table V. That is, Table V Periodic transcutaneous ionization therapy for skin penetration of the antibiotic drug tetraphthalin HC4 Strengthening time of the effect of the legal system (TPIS) Cumulative amount of absorbed drug (mc g/cm2) (hrs) T P I S None TPT5 used 1.25 0.0 180 0.17652.25 0.0550 0.25553.25 0.0 650 0.78154.25 0.1450 1.32355.25 0.3 040 3.5600 (note) 1) In skin-penetrating cells of Valia-Chien, tetracycline at pH 9.0 Contains Furin HC at 6.2 mg/ml (pKa-3, 3, 7, 8 and 9.7). The feeding solution was applied topically to hairless mice at 37°C.

2) TPIS is 1097 hours, frequency 2000Hz, square wave, and 0N10 A DC current of ImA was applied periodically at an FF ratio of 4/1.

(Case 10) Saturated solution of indomethacin, a non-steroidal arthritis drug (pKa-4,5) is 2 pH below the pKa, pH 2,5, and 1 pH unit above the pKa. prepared in a buffer solution at a pH of 5.5 and a pH value of 4.5 with a pKa of It was. The reinforcing effect of the periodic transcutaneous ionization therapy system is similar to that outlined in Case 6. evaluated under the same conditions. The results are shown in Table Vl.

Table Vl Periodic transdermal treatment of indomethacin, a non-steroidal arthritis drug, through the skin. Strengthening effect of ionization therapy system (TPIS) YE S O, 760, 446, 3 0 (Note) *TP IS is 7 hours at 5 minutes/hour, frequency 2000Hz, square wave and 0N10FF ratio 2/ A DC current of 1.2 mA was applied periodically at 1.

(Case 11) A buffered aqueous solution of vasopressin (1.7 mcCi/mI H' of vasopressin) (50 mcg/ml) prepared in citrate phosphate buffer at pH 5.0. It was.

3.5 ml of this vasopressin solution was separated into microporous pores as a drug release surface. Filled into a refillable dosing device with a diaphragm. This dosing device then It is incorporated as a part of the drug storage electrode of the separation therapy device, and its septum surface is kept at 37°C Va. The stratum corneum side of the skin of a hairless mouse attached to the skin-penetrating cells of lia-Chien attached to. Samples are removed at regular intervals and the radioactivity is scintillated. Measured by a counter to determine the amount of vasopressin absorbed transdermally .

The results showed that the skin of hairless mice was absorbed at a constant but slow rate (0.94 ± 0.62 ng /cm2/hr) for 30 hours (Figure 22).

Skin: 05 and current strength of 1mA, frequency of 2KHz, ON/○F of l/l F ratio and cyclic transcutaneous ionization therapy cycles at a rate of 10 minutes per 40 minutes for 4 hours. When treated with stem (TPTS), the permeability properties of the skin are 9.94 (±0 ．． 62) ng/cm”/hr (called “passive diffusion” in Figure 22)? et al., 116.2 (±10.7) and 178.0 (±25) ng/cm, respectively. Enhanced by speed increase to 2/hr. In Table Vll below, “Positive activity ratio After treatment with a periodic transcutaneous ionization therapy system called "Phase", the release of vasopressin Skin penetration rates were only 0.7 (±0.4) and 5.3 (±0.5), respectively. It is reduced to a base rate of ng/cm2/hr. The results of this experiment are shown in Figure 22. and shown in Table V11 below.

Table Vl+ Effect type of TPIS on the skin penetration rate of vasopressin - current strength delay time consideration (hr) (ng/cm2/hr) Without TPIS 0.0mA 9.12 ( U-06) 0.94 (+0.62) with TPIS a) Active phase (2) 0.5 mA < 0.5 116.2 (10,7) b) Post-activation Sexual aspect 0. OmA 0.7 (+0.4) a) Active phase (2) ], , OmA < 0.5 178.0 (+25.0) b) Post-activation phase Q, QmA 5-3 (±0 ．． 5) (Note) 1) Trial of hairless mouse skin attached to Val 1a-Chien infiltrated cells Penetration in test tube 2) 40 min period of treatment repeated in 6 40 min cycles 0N10 of l/l by a multi-channel TPTS device (shown in Figure 22) for a minute. Applying DC with FF ratio and frequency of 2KHz (Case 12) Aqueous solution of insulin/niline (r 125 insulin (containing L3mcCi 5.3 IU/ml) is adjusted to pH 7.1 using NaOH. This insulin A 3.5 ml aliquot of the liquid was refilled with a microporous diaphragm as the drug release surface. into a fillable dosing device. This dosing device then in turn Va　1　1a-Ch　i is incorporated as a part of the retention electrode, and its diaphragm surface is at 37℃. The skin-penetrating cells of en are attached to the stratum corneum side of hairless mouse skin.

Samples are taken at regular intervals and the radioactivity is detected using a scintillation counter. to determine the amount of insulin absorbed transdermally.

The results showed that the skin of hairless mice was covered with a constant but slow velocity (3,94 ± 0.29 mc lU/cm2/hr) for 48 hours (Figure 23A).

The skin has a current strength of 1mA, a frequency of 0KHz, and an ON10F ratio of l/l. and transdermal therapy system (TID) at a rate of 5 minutes per 60 minutes for 7 hours. D), the permeability properties of the skin are 3.94 (, ±0.29) mc From IU/cm”/hr to 37.5 (±4.5) me IU/cm”/hr Enhanced by increased speed. Figure 23B shows that using TIDD ionization therapy Ionization therapy over a 7 hour period for the same insulin solution permeation data. Figure 23A shows a comparison of insulin penetration data without (0) .

(Case 13) Insulin aqueous solution (5.31U containing Q, 3mCi of Insin/Niline) /ml) using solutions of HCQ or NaOH at pH values 3.7, 5.2 or 7. The temperature is adjusted to 1°. A 3.5 ml aliquot of this insulin solution is used to release the drug. Filled into a refillable dosing device with a microporous membrane as a surface. this The dosing device is then incorporated as part of the drug reservoir electrode of the ionization therapy device and its septum Hairless rats attached to skin-penetrating cells of Valia-Chien at 37°C It is attached to the stratum corneum side of the skin. Samples are taken at regular time intervals and released. The radiation activity was measured using a scintillation counter and Determine the amount of urin.

The results showed that it penetrated the skin of hairless mice at a constant but slow rate for 48 hours, and that the penetration rate increased. The numbers are 6.50 (±], 42) to 10.02 (±L 94)XIO-'c m/hr (Table Vl11). The osmotic coefficient is the osmotic coefficient for drugs that are absorbed transdermally. is the ratio of the constant rate of skin penetration to the concentration of a transdermally administered drug solution. . The drug in this experiment is insulin.

The skin has a current strength of ImA, a frequency of 0 KHz, and an ON10F ratio of l/1. and transdermal therapy system (TID) at a rate of 5 minutes per 60 minutes for 7 hours. When treated with D), the permeation properties of the skin are 70.76 (±8.56)XI From O-'cm/hr, 242.59 (±18-43)XI O-'cm/h This is enhanced by the increased skin permeability coefficient, which is dependent on the pH of the solution. Show degree. If the pH solution is low (pH 3, 7), the skin effect facilitated by TPIS Presenting a greater increase in penetration capacity.

Table Vll+ Insulin skin penetration coefficient (hairless mouse) 3.7 6.50 (±1.42) 242.59 (118,43) 5.2 10.02 (±1.94) 120.0 7 (Sat 22.86) 7.1 7.43 (±0.54) 70.76 (±8.56 ) (Note) (1) Mie decision (Case 14) A buffered aqueous solution of insulin (2501 U/ml) was mixed with citric acid at pH 3.68. prepared in phosphate buffer. A 2.5 ml fraction of this insulin solution was filled into a refillable dosing device with a microporous membrane as a drug release surface. Ru. The dosing device is then incorporated as part of the drug reservoir electrode of the ionization therapy device; The skin of the abdominal region of anesthetized diabetic hairless mice in three groups whose septal surface Attached to the skin. Blood samples are taken at regular time intervals and glucose The glucose level is measured by a glucose analyzer. Glucose from hyperglycemic symptoms ・The decrease in levels is a pharmacological response to transdermally absorbed insulin. be.

The result is a current strength of ImA at the skin, a frequency of 2 KHz, and an ON10 of l/l. Treated with cyclic transcutaneous ionization therapy system (TPTS) for 40 minutes at FF ratio. indicates that blood glucose levels are substantially lowered when Data is , blood glucose levels in diabetic mice depending on the type of waveform used. Fig. 24 shows the process and degree of the decrease in .

(Case 15) A buffered aqueous solution of insulin (250 IU/ml) was mixed with citric acid at pH 3.68. prepared in phosphate buffer. A 2.5 ml fraction of this insulin solution was filled into a refillable dosing device with a microporous membrane as a drug release surface. Ru. The dosing device is then incorporated as part of the drug reservoir electrode of the ionization therapy device; The septum surface was applied to the skin in the abdominal region of five anesthetized diabetic hairless mice. attached. Blood samples are taken at regular time intervals and glucose levels glucose is measured by a glucose analyzer. Glucose levels from hyperglycemic symptoms is a pharmacological response to transdermally absorbed insulin.

The result is a current strength of ImA at the skin, a frequency of 2KHz, a square wave, 1/1 0N Periodic transcutaneous ionization with insulin in the drug storage electrode for 40 minutes at a 10FF ratio. When treated on day 1 by the therapy system (TPIS), blood glucose (Figure IJ25A) showing that the source level is substantially reduced. day 3 smell Then, diabetic mice were again treated with insulin-free TPIS in the drug storage electrode. (Branpo effect), blood glucose also decreases and Some of the insulin delivered cutaneously forms depots in the skin tissue, causing EJ3 to (Figure 25B).

(Case 16) An aqueous solution of insulin (5001 U/ml) with a pH of 7.10 is used. child A 2.5 ml aliquot of insulin solution was transferred to a microporous membrane as a drug release surface. into a refillable dispensing device with a This dosing device then uses ionization therapy. It is incorporated as part of the device's drug storage electrode, and its septum surface is attached to three diabetic mice. attached against the skin in the dorsal area of the body. Blood samples are taken at regular time intervals Insulin concentrations and glucose that produce an immune response are determined using labeled immunoassays. The glucose level is analyzed by a glucose analyzer. Guru from hyperglycemic symptoms The reduction in course levels is due to the pharmacological effect on transdermally absorbed insulin. It is a response.

The result is that the skin is ON10F with a current strength of ImA and a frequency of 1/l at 2KHz. by the Periodic Transcutaneous Ionization System (TPIS) for 40 minutes at F ratio and square wave. When treated, insulin levels rapidly increase causing a plasma immune response and Indicates that glucose levels are substantially reduced. This plasma insulin (Figure 26A) shows a decrease in blood glucose levels in diabetic mice. from conventional subcutaneous administration of insulin, as well as the course and extent (Figure 26B). The results are compared. This data includes plasma insulin concentrations and blood glucose levels. can be effectively controlled using the periodic transcutaneous ionization therapy system of the present invention. Show that. FIG. 26B shows that by using the TPIS system of the present invention, Prevents blood glucose levels (BGL) from falling below normal levels. As shown, BGL is appropriately lowered by the V-implanted method than by daily SC administration. Show what you can do.

(Case 17) An aqueous solution of insulin (5001 U/ml) with a pH of 7.10 is used.

A 2.5 ml fraction of this in/niline solution was used to form a microporous barrier as a drug release surface. Filled into a refillable dosing device with a membrane. This administration device then It is incorporated as part of the drug storage electrode of the device, and its septum surface is connected to two groups of sugars. Attached to the abdominal skin of a urinary mouse. Blood samples are taken at regular time intervals The concentration of insulin that produces an immune response using a labeled immunoassay, and Analyzed for glucose levels by a lucose analyzer. From hyperglycemic symptoms The lowering of glucose levels in insulin is associated with a medicinal effect on transdermally absorbed insulin. This is a scientific response.

The result is that the skin is ON10F at a current strength of ImA, a frequency of 2KHz, and I/l. by the Periodic Transcutaneous Ionization System (TPIS) for 40 minutes at F ratio and square wave. When treated, insulin levels rapidly increase causing a plasma immune response and Glucose levels were determined by transdermal iontophoresis at a current strength of 4 mA for 80 minutes ( TIDD). Figure 27A and The data in Figure 27B are shown in Figure 27B, even if the corresponding current strength in a TIDD system is 4 times (4 mA vs. 1 mA) and the dose was 2 times higher than in the TPIS system. Even twice as much (80 minutes vs. 40 minutes), the TPIS system of the present invention Increases intuulin concentration more rapidly and lowers blood glucose levels than the use of TIDD. shows that both lead to a more rapid decline in the level.

(Case 18) A buffered aqueous solution of vasopressin (40 IU/ml) was prepared by phosphorus citrate at pH 5.0. Prepared in acid salt buffer. Vasopressin can be used in patients with excessive urine output. It is an antidiuretic drug used in many cases. Vasopressin causes decreased urine output and This resulted in an increase in ionic components such as sodium ion components. Ionic components in urine , determined by using permeability measurements. 3° of this vasopressin solution A 5 ml aliquot is placed in a refillable dosage form with a microporous membrane as a drug release surface. filled into a feeding device. This administration device then becomes part of the drug reservoir electrode of the ionization therapy device. The diaphragm surface was inserted into the abdomen of two groups of anesthetized rabbits. Skin I: Attached. Blood samples are taken and floor samples are collected at regular intervals. The urine is collected and its permeability is measured using an osmometer. Increase in permeability from base level vasopressin is a pharmacological response to transdermally absorbed vasopressin.

The results show that the periodic transcutaneous ionization system (TPIS) allows the skin to receive 0-22 mA/ current strength of cm”, frequency of 2KHz, 0N10FF ratio of 1/l and When treated with a square wave for 40 minutes, the permeability of urine was lower than that of transdermal ions under the same experimental conditions. Increases from the base level more quickly and substantially than with the introduction method TIDD. (Figure 28).

(Case 19) Buffered aqueous solution of vasopressin (1.7mcCi/ml H”) 50 mcg/m+) was added to citric acid at pH 7.4 using varying ionic strength. Prepared in phosphate buffer. 3.5ml fraction of this vasogressin solution is filled into a refillable dosing device with a microporous membrane as a drug release surface. be done. This delivery device is then incorporated as part of the drug reservoir electrode of the ionization therapy device. , and its diaphragm surface reaches the skin-penetrating cells of Va l i a-Ch i en at 37°C. It is attached to the stratum corneum side of the skin of a hairless mouse. sample at regular time The radioactivity is measured using a scintillation counter and the transdermal Determine the amount of vasopressin absorbed.

The results showed that vasopressin moved the skin of hairless mice at a constant but slow rate (1°3 2±0-38 ng/cm"/hr) for 30 hours.

The skin is 0.5mA current strength, 2KHz frequency, l/l 0N10FF ratio and cyclic transcutaneous ionization therapy system at a rate of 10 minutes per 40 minutes for 4 hours. When treated with (TPIS), the permeation properties of the skin are According to the ionic strength of 1.32 (±0.38) ng/cm”/hr 632.6 (±65.0) ng/cm”/hr Enhanced by speed increase to Experimental results are shown in Table IX below.

Table XI Effect of ionic strength on the skin penetration rate of vasopressin Ionic strength Skin penetration Speed l) Strengthening factor 2) (ng/c/hr thSD) 0.488 65.9 (±13.l) 49.9 (±18.0) 0.244 1 01.4 (±9.1) 76.8 (±6.9) 0.122 244.6C±26 ．． 3) 185.3 (±19.9) 0.061 632.6 (465,0) 4 72.8 (±59.0) (Note) 1) Delay in the range of 0.48 (=1=0.21) to 0.86 (i, 15) time Velocity determined in the active phase with extended time 2) Vasopressure due to passive diffusion Compare with the skin penetration M degree (1-32ng/am”/hr) of The rate of skin penetration facilitated by TPIS appears to depend on the ionic strength of the drug solution. It looks like As the ionic strength decreases, the rate of skin penetration increases and the extent of skin penetration decreases. strengthened (Figure 29).

(Case 20) Buffered aqueous solution of vasogressin (1.7mcCi/ml N3 vasopressin containing 50mcg/ml) at pH 5.0 with an ionic strength of 0.064. prepared in phosphate buffer. A fraction of 3.5 ml of this vasopressin solution [was , filled into a refillable dosing device with a microporous diaphragm as a drug release surface. It will be done. This dosing device is then incorporated as part of the drug reservoir electrode of the ionization therapy device. , whose septal surface was attached to a Valia-Chien skin-penetrating cell at 37°C. It is attached to the stratum corneum side of the skin of hairless mice. Samples taken at regular time intervals The radioactivity was measured using a scintillation counter and absorbed transdermally. Determine the amount of vasopressin.

The results showed that vasopressin moved the skin of hairless mice at a constant but slow rate (0°9 8±0.26ng/cm'/hr) for 30 hours.

When the skin is 0.3mA current strength, 16KHz frequency, l/l ON10F When treated with a cyclic transcutaneous ionization system (TPIS) for 60 minutes at a ratio of The skin penetration characteristics are 0.89 (±0.26) ng/cm”/hr (r passive expansion). increase from 757.3 (±53.2) ng/cm”/hr It is strengthened by the added speed, but the time delay period is 0.40 (±0.06) hours. (Figure 30). The data in Figure 30 is based on TPIS. showed a return of skin permeability within 2 hours after treatment with TPIS. Return to the previous speed. Therefore, TPIS facilitates the skin penetration of vasopressin. It can be used again.

Nene Toya FIG.4 −　−１ −2 Periodic far F gun stem 1 claw jig support matatakem (TPIS) 10th edict ■×to! 0:LD Tadashi- Engraving (no changes to the content) (%)　HSlI/3 lights'7/, u4　Y()弘】So4゛fuso-(%)! ';l )': IX-E 7/LAI! (%) 11fuk) γ-[:l Takasa ltsu (%) -T';I)I M-[1/, l, 纂W 1 yi i Haruma (HR) (%) Gowara”, I, i-Y-C1/J/Ichigoka’IV, (, ==< with n F fallen )1 wave 4<(+r-<<pt:,”’+b”i”z”5it (convex x/uso)i N soft M Stone brush 1 ■ Fusuma dΔ near the brush (2uO15riu-1)Tih*:1Jr-Last1, display of incident PCT/US92107221 1993 Patent Application No. 504665 2. Name of the invention Ionization therapy device and method 3. Person who makes corrections Relationship to the incident: Patent applicant address Name: Rutgers, The State University of Yunyan - 4. Agent Address: Shin-Otemachi Building, 206-ku, 2-2-1 Otemachi, Chiyoda-ku, Tokyo 5. Date of amendment order: August 30, 1994 (shipment date) 6. Subject of amendment (1) Domestic document stating the applicant's representative pitch name (2) Power of attorney and translation (3) Description printed by type printing 0 Continuation of translated text front page (72) Inventor Shi, Weimin Lincoln, New Jersey, 08854, United States avenue

Claims (1)

[Claims] 1. A lightweight, portable, transdermal periodic ion ionization therapy (iontophoresis) device. suitable for use by subjects being treated with iontophoretic therapy (iontophoretic therapy). A device for transdermally administering an effective amount of an ionized drug to a subject. At the location, 1) Therapeutically effective and physiologically acceptable within a range of up to approximately 10 mA 2) a DC power supply capable of generating a pulsed current of a high power; and 2) an electrical connection to said DC power supply. connected periodic waveform generators comprising: a) square, triangular, sinusoidal, ladder shapes; , or in any other acceptable geometric shape, or any combination thereof. b) an on/off ratio of about 1/50 to about 1/10, and c) integrated that can provide a repetition frequency of about 10KHz to about 50KHz 3) a periodic waveform generator comprising a circuit; and 3) electrically connected to said waveform generator. an output circuit comprising: a) a period in a preselected waveform of said waveform; b) monitor the strength of the supplied current, and c) maintain a predetermined maximum level. adjusting and maintaining the strength of said current within a minimum level and d) said ionization; electrical current to a reservoir electrode for transcutaneous administration of ionization therapy , an output circuit, and 4) the ionized drug is an anionic agent or a cationic agent. The drug storage electrode is selected as either a cathode or an anode, depending on the Thus, the drug reservoir electrode is configured to receive a unit dose of the ionized drug. the ionized drug in the container has an isoelectric is an aqueous solution with a pH at least 1.0 pH lower or higher than the pKa point; The electrode, along with the received unit dose, is attached to the intact skin to be ionotherapeutically treated. configured to be placed in electrical contact with the skin, the electrodes being configured to be placed in electrical contact with the skin; a terminal for receiving and transmitting the periodic DC current; is in electrical contact with the terminal, 5) said drug reservoir in electrical contact with the intact skin to be treated; A second electrode is provided which together with the pole forms an anode and cathode electrode combination. and the electrode is electrically connected to the output circuit and is undergoing treatment. the intervening assembly of the object being treated when positioned on the skin of the object being treated. 6) a preprogrammed electrically integrated with said device; a control element capable of displaying a doctor's prescription entered into the control element; The ionization therapy administration (admin stratiom) (dosing) in advance, and for said dosing. Stopping the operation of the device when the object being treated by the device is in a dangerous situation. Control elements on which said object cannot act except to enable A device characterized by comprising: 2. 2. The apparatus of claim 1, wherein the apparatus comprises: A device characterized in that it is electrically connected to a sensor. 3. 3. The apparatus of claim 2, wherein the sensor is a physiological component of the subject's body. Detects and correlates the level of radiation and correlates it with transcutaneous ionization therapy-controlled parameters. and configured to communicate that information to said control element. A device used as a sign. 4. 3. The apparatus of claim 2, wherein the sensor detects a predetermined skin condition of the subject's body. and configured to detect the information and communicate that information to the control element. A device characterized by: 5. The apparatus of claim 1, wherein the apparatus interfaces with a computer system. The computer system is pre-programmed into the control element. enter prescripts and other instructions or An apparatus configured to receive data based on a function of the apparatus. 6. The device of claim 1, wherein the device is of the wristband type that is worn around the arm. A device characterized by: 7. Suitable for use by subjects being treated with iontophoretic therapy transdermal administration of an effective amount of ionized drug to a subject. Ion ionization therapy is a skin periodic ion ionization therapy (iontophoretic therapy). , suitable for transdermal treatment, and capable of transdermal absorption using the device according to claim 1. in a manner that allows 1) transmit prescriptions or other instructions to the control elements of the device using a computer system; step, 2) transdermally administering a dosage unit containing a pharmaceutically acceptable aqueous solution of said peptide; Incorporating into a receptacle of a reservoir electrode of a cyclic ionization therapy system, the step comprising: , the electrode is a cathode or an anode, which means that the ionized peptide Depending on whether the peptide is anionic or cationic, the solution is having a pH value of at least 1.0 pH below or above; 3) Treating the cathode electrode and the anode electrode of the percutaneous periodic ionization therapy system. 4) placing it in electrical contact with the intact skin to be treated; 4) approximately 5 cm2; ionotherapeutically effective cyclic up to about 10 mA for the reservoir electrode/skin contact area of applying a DC current in a) square, triangular, sinusoidal, trapezoidal, or periodic waveforms of other acceptable geometric forms, or combinations thereof, b ) a physiologically acceptable repetition frequency of at least about 10 Hz, and c) A step that supplies DC current with an on/off ratio of 1/50 to 1/10. P Consisting of The method includes passively diffusing transdermal treatment from the solution during an administration period of at least 2 hours. from that provided by absorption, in a proportion of at least 500%. characterized in that it provides a systematically effective absorption of said peptide preparation from solution. Method. 8. 8. The method of claim 7, wherein the ionized drug is ionized. A method characterized in that it is a peptide drug. 9. 8. The method of claim 7, wherein the solution of the drug is at an isoelectric point of the drug, i.e. A method characterized in that the pH is at least 1.5 pH lower or higher than the pKa point. 10. 8. The method of claim 7, wherein the pH of the solvent for the drug is or at least 2.0 pH lower or higher than the pKa point. How to do it. 11. 8. The method of claim 7, wherein the ionized drug is The pH is at least 1.5 to 1.0 lower than the electric point or pKa point. How to do it. 12. 8. The method of claim 7, wherein the ionized solvent is Moreover, the pH of the insulin solvent is in the range of approximately pH 3.0 to 4.0. A method characterized by: 13. 8. The method of claim 7, wherein the pH of the insulin solvent is about pH 3.6. 14. 8. The method of claim 7, wherein the current intensity is approximately 5 cm2 at a reservoir electrode. /Skin contact area must be set not to exceed approximately 5 mA. A method characterized by: 15. 8. The method of claim 7, wherein the current intensity is approximately 5 cm2 at a reservoir electrode. /Skin contact area must be set not to exceed approximately 2 mA. A method characterized by: 16. 8. The method of claim 7, wherein the current intensity is approximately 5 cm2 at a reservoir electrode. /Skin contact area must be set not to exceed approximately 1 mA. A method characterized by: 17. 8. The method of claim 7, wherein the solvent is an insulin solvent; The pH of the agent is at least about 1.5 pH below or above the isoelectric point of the solvent. and the current strength is approximately 2 mA for a reservoir electrode/skin contact area of approximately 5 cm2. The administration time is set to no greater than 40 minutes. and the periodic frequency is at least 1000 Hz. 18. A battery belt that is structured to be wrapped around the arm or body of an object, and that is In a battery belt for supplying power to electronic devices used in bunt for storing ponds, 2) the batteries connected in series; 3) connected to the series-connected batteries, and connecting the batteries to the electronic device via a connecting line; terminal for electrical connection to the A battery belt characterized by comprising: 19. 19. The battery belt according to claim 18, wherein the battery belt comprises the battery belt according to claim 1. A battery belt configured for use with a device.