JPH0647096A - Electric endermal drug muti-signal applicator - Google Patents

Abstract

PURPOSE: To provide an electrical percutaneous drug applicator having a strengthened drug flow to a blood flow of a patient. CONSTITUTION: This is a percutaneous applicator 10 for fixing to a skin with a drug reservoir containing drug, and the applicator 10 has an electrical connection formed between a reservoir 12 contact with the skin and a surface interface, and a means to percutaneously move a drug through the surface and to retain percutaneous movement. A power source has terminals 24, 28, one of which is electrically connected with at least the reservoir 12 at a position away from the skin surface interface, and the other of which forms a circuit at a position away from the interface of the reservoir 12/the skin surface with a skin surface 16. The electric circuit is formed by fixing the applicator to the skin 18, and connected from one power terminal to at least one reservoir 12, until the skin surface 16 connected by the circuit within the skin through the interface of the reservoir 12/the skin surface, and then to the other power terminal, and when a current flows in a first direction of the circuit, the drug is transported through the skin 18.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention generally relates to transdermal drug electrical devices that use electrokinetic principles such as electrophoresis and electroosmosis to deliver drugs to the patient's entire body by the blood stream. More particularly, it relates to transdermal drug electrical applicators that use multiple intermediate and overlapping signals of varying potentials that extend the therapeutic drug delivery time and thereby increase the utility of the drug applicator.

[0002]

Background of the Invention References to devices or devices for the transdermal delivery of drugs by passing an electric current through the skin of humans or animals are set forth in the following US patents: 385,556. 4,243,052 486,902 4,325,367 588,479 4,367,745 2,493,155 4,419,019 2,267,162 4,474,570 2,784,715 4,406, 658 3,163,166 4,314,554 354,289,671 4,166,457 3,547,107 4,239,052 3,677,268 4,290,878 4,008,721 4,164,164 226 4,141,359 4,362,645 4,5 4,239,046 4,273,135 The following foreign patents are disclosed transdermal drugs. It describes handling equipment: EPA No. 0060452 DE No. 290
202183 DE No. 3225748 EPA No. 00
58920 EK No. 2104388 From the above, it is clear that transdermal drug delivery by application of electric current is not unknown. However, except for experimental and development purposes, such electrodermal drug applicators are not currently marketed for use by medical professionals or individuals.

[0003]

The problem with transdermal patches, and in particular with electrically driven patches, is that such devices have a steady state condition of the applied current and a stable state of drug concentration inside the drug reservoir of the device. Nevertheless, it shows a drug delivery rate that decreases over time. This phenomenon is described, for example, in the paper, In Vivo Transdermal Delivery of Insulin (IN VIVO TRAN).
SDERMAL DELIVERY OFINSULI
N), Chien et al., Anals of New York Academy of Sciences (Annals of
New York Academy of Science
es), pages 38-47 (1987). In this, fluctuations in blood glucose levels are recorded with respect to the elapsed time after insulin is transdermally delivered using an electric current in experimental animals. Several parameters are changing there.
For example, pulsed DC currents have been reported to have a stronger and more persistent effect than pure continuous DC currents in lowering blood glucose levels in experimental animals. The true amount of insulin delivered has not been measured. Rather, the effect of drugs on lowering blood glucose levels has been measured. In lowering blood glucose levels measured by both magnitude and duration of decline,
It has been found that one DC pulse repetition rate is more effective than another. Square waves provided better results than sine or trapezoidal waves.

The authors of the above article electrically assume the skin as having resistance and capacitance in parallel with an equivalent circuit. They find that the DC current polarizes the skin, ie charges the skin's capacitance, and once the skin is charged it cannot accept any more current and thus limits drug delivery. The use of a DC pulse rather than a steady current gives time for the skin capacitance to discharge, and in the next pulse current addition, capacitor charging and drug delivery can occur. However, at the preferred pulse repetition rate, an exceptional situation occurs when the repetition rate varies with the same current transfer level as in prior art tests. The higher this repetition rate, ie the higher the ratio of the ON time current to the OFF time current, the more insulin is transdermally delivered and the measured effect on blood glucose levels is corresponding. Would be more suitable and more durable. Contrary to what was expected, however, as the repetition rate increased from a 1: 1 ratio to a 1: 8 ratio, the glucose level decrease duration increased slightly, but the blood glucose level decrease itself increased. Rather less.

In summary, the application of electrical current for an extended period of time, ie, the transcutaneous transfer of more electrical energy for drug delivery, results in a continuous decrease in drug delivery. Becomes The said article addresses the problems with prior art transdermal drug applicators and delivery methods that use electrical current to deliver the drug across the skin, namely, the effectiveness of the delivered drug is both persistent and therapeutic. Is insufficient, and the problem is that the drug delivery rate decreases when the delivery current is continuously loaded for a long period of time. There is a need for a transdermal drug applicator that enhances drug delivery to a patient in terms of amount of drug delivered systemically and duration of drug efficacy.

[0006]

SUMMARY OF THE INVENTION Generally stated, in accordance with the present invention, there is provided an electrotransdermal drug applicator having enhanced drug flow into a patient's bloodstream. A plurality of electrical signals of varying potential are applied to the skin which is in circuit with the drug reservoir of the applicator. Each signal is selected for persistence, repetition rate, shape and harmonic content by dilating blood vessels proximal to the patch and inhibiting vasoconstriction associated with blood aggregation and current passage through the skin. , Maintain or enhance local blood circulation. In some cases the electrical signal will overlap with the other signal,
On the other hand, applying each signal separately would also be considered suitable, as the entire signal would be contained within the overriding repetition rate regime. A power supply and appropriate signal producing timing circuitry is provided within the built-in transdermal applicator. Multi-signal technology has been applied in conventional transdermal drug applicators and more complex devices such as those described above, which are incorporated by reference in their co-pending US patent application, entitled "
Electrodermal transdermal drug applicator with counteractor and drug delivery method ", Application No. 287, 348, 19
It contains a counteractor, as described in the application filed December 21, 88.

Accordingly, it is an object of the present invention to apply electrical selected DC and AC waveforms of selected frequency, waveform, duration, repetition rate, etc. to enhance drug flow into the patient's circulatory system. An object is to provide a transdermal drug improvement applicator. Another object of the present invention is to provide an electrotransdermal drug modification applicator that uses an electrical signal to cause the body to produce its own vasodilators and thrombolytic compounds. That is. Yet another object of the present invention is to provide an electrodermal transdermal modification applicator that applies an electrical signal to prolong fibrinogen clotting time in a patient. Another object of the present invention is to provide an electrotransdermal drug modification applicator that applies an electrical signal to enhance drug delivery from solution. Yet another object of the present invention is to provide an electrotransdermal drug modification applicator that applies signals to enhance drug delivery from the gel. Other objects and advantages of the invention will in part be obvious and will become apparent from the specification. Accordingly, the invention comprises aspects of construction, combination of elements, and assembly of elements,
They will be exemplified in the configuration described below,
The scope of the invention will be indicated in the claims.

[0008]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Referring to FIG. 1, an electrodermal drug multi-signal applicator according to the present invention is described, for example, in the gels disclosed in the text by the present inventor as an example in any of the above cited patents. It contains a reservoir 12 containing the drug dispersed in a simple suspension. Surface 14 of reservoir 12
Are placed on the surface of the user's skin 18 and fixed in position by, for example, tape (adhesive) (not shown). The electrode 20 is connected to another surface 22 of the reservoir 12, which electrode 20 is connected to an external terminal 24 of a signal generation and timing unit 26, which electrode 20 is connected to the signal generation and timing unit 26.
Is connected to the external terminal 24 of. The other external terminal 28 of this signaling and timing unit contacts the skin and is connected to the skin surface 16 by a return electrode 30 which is fixed in position by, for example, tape (adhesive) (not shown).
Connected to. The unipolar switch 32 includes an external terminal 24,
It is connected between 28. The gel and drug are contained in reservoir 12 in such a way as to prevent leakage of the substance. In addition, the skin surface 16 from the reservoir 12 to the electrode 30
There is no short circuit of current directly across.

When a voltage difference of appropriate magnitude and polarity is applied across the external terminals 24, 28, current flows through the skin 18, as indicated by arrow 34, while any drug from the reservoir 12 is removed from the skin. Access to the user's body through the surface 16 is well established. Current 34 is indicated by a number and includes current flowing in the opposite direction. For example, electrode 2 for skin and electrode 30.
A positive potential on 0 will produce a current in the direction shown, whereas a negative potential on electrode 20 with respect to skin and electrode 30 will produce a current through skin 18 in the opposite direction (not shown). ). In the exemplary embodiment of FIG. 1, the current circuit is skin 18
It includes a current limiter that limits the upper limit of the current that can flow through the, thus avoiding skin burns and possible damage to skin irritation upon contact with the current.

Signal generating timing unit 26
Contains a plurality of signal generating circuits. Among them, the AC signal generator 38 outputs the AC pulse passing through the buffer amplifier 40 and the closing switch 42 at the carrier frequency, and is rectified into DC by the rectifier 44. The rectified signal passes through shaping circuit 46, where
A sinusoidal half-wave envelope is applied to provide a positive output pulse 48 as shown. No signal amplification will be necessary. It is believed that the detailed construction of the circuitry in the abbreviated form of the text is in the state of the art and does not present any obstacle to the implementation of those skilled in the art.

By-pass, schematically represented by switch 50, the rectified signal goes directly to external terminal 24, thus imparting a rather rectangular pulse rather than a half sinusoidal pulse. The AC carrier frequency inside the pulse 48 is 2500 Hz plus or minus 1000 H
z. The original AC signal from generator 38 may be a sine or square wave. The pulse 48 has a width of 6.
25 ms plus or minus 5 ms, that is, for example, this is
0 Hz, and 80 pulses per second ± 20 per second
It will have a nominal working time corresponding to the interval of pulse repetition rates. This repetitive signal lasts, for example, a time B of 1 minute ± 20 seconds, then a time C of 1 minute, for example.
Off for a period of time and then on for a period of time. After a few minutes of action, for example 30 minutes for insulin delivery, switch 50 is closed so that the square pulse replaces the sinusoidal half-wave pulse shown at 48. The time of 2 minutes (B + C) corresponds to a frequency of 0.008 Hz. Inclined and trapezoidal pulsed envelopes can also be used, and other envelope shapes will also benefit certain drugs in terms of delivery. All frequencies, pulse widths, repetition rates, amplifications, etc. used to characterize the text are nominal and are intended to include a range of values even if this range is not directly defined. It is considered.

The parallel signal generator 52 outputs a negative DC signal that passes through the buffer amplifier 54 and the switch 55 and is applied to the electrode 20. With switch 56 closed, a negative voltage of 0.8 volts ± 0.4 volts is applied to electrode 20. This causes current to flow through skin 18 in the opposite direction as shown by arrow 34. The negative voltage is applied during the C interval when the shaping pulse 48 (and other signals described below) is not applied. Parallel AC Square Wave Generator 57
Is a square wave AC to the switch 58 next to the amplifier 58.
It outputs a signal and the signal is applied to the electrode 20. The square wave section D corresponds to a frequency of 250 Hz and is, for example, 0.4 ms plus or minus 0.2.
ms. Switch 60 is actuated and during interval B, shown at 62, a single A with a repetition rate of 80 cycles per second.
Send C cycles. The second parallel AC square wave generator 66 is similar to the wave generator 57. The output of generator 66 is amplified and rectified, passes through switch 67, and is also applied to terminal 20. Signal output 6
8 is about 770Hz plus 100Hz minus 200H
It has a frequency of z and is output to the section E of 0.4 ms plus or minus 0.2 ms of the section B, for example.

A sequence timer 64 including a microprocessor controls the switches 42, 55, 60 and 67 to generate a total waveform signal at a desired timing with a sequence of desired signal components. FIG. 2a shows an exemplary sequence and timing of signals, where the initial signal is a negative 0.8 volt signal 56.
, Followed by a rectified 770 Hz square wave signal 68, followed by a pulse 48. Pulse 48 has a single AC cycle, signal 62
7 illustrates an exemplary sequence and timing of signals as follows. In the embodiment according to the invention, the negative signal 56 is applied for 1 minute. Signals 68,
56 and 62 are 1/80 second, that is, 12.5 ms
Occurs within 1 minute and repeats for 1 minute (4800 repetitions), then
The minus 0.8 volt signal 56 is applied again for 1 minute. Applicator 10 always has negative DC signal 5
Start at 6 is preferred. The first pulse 56 is either longer or shorter in duration than the nominal one minute used below.

Additional signal generators 70, 72
Is shown (FIG. 1), indicating that the number of signals applied to the electrodes 20, 30 is not limited. When the switch 32 is closed, it creates a short circuit between the electrodes 20, 30 and uses any charge stored inside the skin 18 within the drive time to move in the same direction as that produced by the signal 56. An electric current is generated inside the capillaries. Such short circuit current is an aid to the application of negative DC signal 56. It is anticipated that the entire applicator, including the electrical components including the reservoir, electrodes, and power supply for its operation, will use steady state circuitry so that it can operate with small unit equipment.

In the drug applicator of the present invention of FIGS. 1 and 2, each signal is generated by an independent signal generating circuit. After selecting the desired signals for a particular drug and requiring special "tuning" for many drugs and their combinations, the respective signal-generating circuits are eliminated to provide such equipment. It should be appreciated that could be replaced with digital signals stored in memory 78 (FIG. 3). The signals are read in a suitable sequence under the control of microprocessor 80 and converted to analog signals by digital-to-analog converter 82, which are applied to external terminals 24, 28. For example, the total waveform of FIG. 2 is generated without requiring the actual circuitry for signal generation in the drug applicator.
On the other hand, in experiments in which drugs were adapted for use in electrodermal applicators, signals from each generating circuit were overlapped with desired sequence and repetition rate, etc. It is useful to drive "onsite" by overlapping until obtained.

It should be understood that several drugs can be contained in the same reservoir and delivered simultaneously. However, if one drug is carried by a voltage of one polarity and another drug is carried by the opposite polarity, both drugs will be isolated according to the invention having the second reservoir shown in FIG. Can be carried with one drug applicator. Electrode 30
The circuit system and concept are the same as those in FIG. 1 except for the addition of the second reservoir 74 related to. The drug in reservoir 12 is delivered to skin 18 when electrodes 20 and 30 are positive to the skin, while at the same time reservoir 74
The drug therein is delivered to the skin 18 when the electrode 30 is negative with respect to the skin and the electrode 20.

Another embodiment of an electrodermal transdermal multi-signal applicator according to the present invention is shown in FIG.
Electrodes 20, 30 and reservoir 12 are as described above. However, the electrodes interact with the rectified AC signals and the minus 0.8 volt signal. This 0.8 volt signal initiates the cycle and pre-prepars the skin as described below and is applied, for example, during Section C for 1 minute. The rectified AC signal is then applied to terminals 24, 28 at frequencies in the range 10 Hz to 200 KHz. This frequency range can be continuous, as is known in electronic timekeeping, or can be steps as imparted by a high frequency oscillator and the following series of frequency divider operations (not shown). . Different frequencies are selected by tapping the output at different stages in the divider network. The time spent at each frequency can be selectively varied and the signal amplification can be adjusted at different frequencies. In one embodiment according to the invention, the frequency spectrum is swept in the range of 12 to 100 times per second, after which a minus 0.8 volt DC signal is applied, for example for 1 minute. In this way, any frequencies important in enhancing drug delivery from the applicator 10 are applied along with the harmonics generated from those frequencies.

With respect to the circuit of FIG. 1 and the signals of FIG. 2, in another embodiment of the present invention, the rectified AC signal within pulse 48 varies from pulse 48 to pulse 48. If there are 4,80 repetitions of pulse 48 per minute
If zero, each such pulse represents an opportunity to apply a different selected frequency. Also within the pulse 48, the frequency band can be swept as described above. Each pulse 48 will include, for example, the entire spectrum of 10 Hz to 200 KHz and its harmonics, or the entire spectrum will be split between the sequences of pulses 48.

With respect to FIG. 2, different signals 4
It is to be understood that 8, 62, 68 can occur in any order, and that they actually occur at the same time, i.e. one signal occurs to some extent overlapping another signal. In addition, other signals 48, 62, 68
Can be applied with all or any of the signals. Also,
It should be appreciated that within the pulse 48, the carrier frequency can come from a sinusoidal or square waveform. The square waveform can have unequal repetition rates that impart a dual frequency effect. Figure 2a shows ON / OFF
A square wave carrier in pulse 48 with a ratio of 1/3 is shown. The low repetition rate reduces power consumption and also reduces the likelihood of skin damage. As mentioned above,
The envelope for the pulse 48 can be a sinusoidal half-wave shape or a square waveform or the like as illustrated.

Natural vibration phenomena exist in biological systems. Supplying energy above the critical velocity causes various oscillatory systems to collapse to their lowest energy state, resulting in strong interfering single-mode oscillations, an extremely efficient mechanism for targeted energy propagation. . Biopiezoelectric semiconductors, such as enzymes, amplify lattice vibrations by lowering the energy barrier at optimal frequencies. Low frequencies increase the penetration depth of the electric field and thus the drug delivery rate when so applied. Low frequencies carry energy over large molecular distances. The cell membranes expand and contract alternately, and take in and out the drug molecules carried under the influence of a fluctuating electric field.

The dielectric constant reflects the degree to which the local charge distribution is distorted or polarized by the electric field. The dielectric constant is related to the electrical double layer, solvated macromolecules and polar molecules on the surface of the membrane. The polarization effect is fully realized at low frequencies. The decrease in the relative permittivity at high frequencies due to the rotational motion of protein molecules greatly contributes to the polarization of the solutions. Dielectric dispersion depends on the effective mobility of ions on the surface of macromolecules. At low frequencies, the interior of the cell is shielded from the electric field. All collagenous tissue (skin) is piezoelectric. The skin relaxation process observed at 80 Hz and 2K to 3KHZ is associated with relaxation of counterions and "ice-like" water bound to skin proteins. Alternating currents change the concentration of ions in cell bilayers and cell channels; these phenomena are frequency-specific. For example, known frequency selective cellular ion channels are 300 Hz for K ions, 200 Hz for Na ions, and 11 Hz for Ca ions.
And 16 Hz.

It is possible that particular frequencies cause the stimulation of particular enzymes and consequently enhance the specific transport of certain active compounds through the cell layer. The drug concentration difference across the cell membrane is frequency dependent. The square waveform is
It will increase the selectivity of the cell adsorption process. The repetition rate of the waveform and the amount of overlapping DC determine the degree of mechanical coupling of electrochemical surface events. The repetition rate in the range 2-30 Hz seems to be less significant at high frequencies. Sudden waveform, that is, repetition rate 1 (ON / O
An amplified modified square wave below FF) causes the cell bilayer to widen and produce an effective pulse. Low repetition rate pulses have poor drug specificity. A carrier frequency of 160 KHz changes the permeability of cell membranes to drugs and also acts as a vasodilator. This carrier also enhances electroosmosis.

Some frequencies useful for particular drug formulations are: 140 KHz-oil suspensions;
100 KHz-colloidal suspensions; 80 KHz-aqueous solutions and 10 Hz-dispersants. Low relaxation frequencies are found by permittivity measurements; conductivity data reflect high frequency phenomena. Extremely low frequencies (10 ^-2 H
z) is related to the hopping electronic mechanism and pressure relaxation. The side chains of biomolecules cause a relaxation effect at low frequencies and a moderating effect in the piezoelectric electron relaxation reaction at high frequencies (100 Hz). 0.025Hz-1
Frequencies in the 0 Hz range are also natural voltage fluctuations associated with active cell transport, which the present invention tunes and enhances.

Activation and inactivation of electrochemically switched ligands is a mechanism of transport of drug cations across water-immiscible biomolecules.
This ligand complex formation and release is triggered by a pulsed current. Hydroxyl compounds form molecular complexes by hydrogen bonding, which results in increasing their dipole moment values. The dipole concentration is maximum near the isoelectric point for amino acids, which means that
Pulsed current stimulation is optimal for electroosmotic drug delivery, but since dissolved ions increase the relaxation frequency,
Not optimal for ion penetration mode. Therefore, it is desirable to minimize the concentration of free ions.

Water bound to biological macromolecules is "ice-like"
It has a structure. This system is characterized by peaks related to the maximum dielectric loss spectrum of ice, that is, from 10 ³ Hz to 10 ⁴ H.
It is beneficial to excite depending on the hydrated molecular radius during z. When water fuses with collagen, a relaxation time of approximately 10 ⁻⁵ seconds is obtained due to the electret behavior of bound water.

Large Maxwell-Wagner (Maxw
The ell-Wagner) dispersion exists at low frequencies such as 7 × 10 ⁻³ Hz. This Maxwell-Wagner polarization effect creates the appearance of integrated dielectric boundary charges and ion migration. The pulsed field forms and collapses molecular complexes between molecules with permanent dipoles and nonpolar molecules that are polarized by induction. The loose bond between the donor and acceptor molecules forms a wide range of adsorption frequencies. This effect is C. Combined with the field effect, it enables efficient transdermal drug delivery of compounds, especially those that bind to body tissues.

The complex waveform with constant amplification and power level distribution within the frequency range is similar to group elements for certain drugs delivered transdermally, as determined by Fourier group analysis. Provides augmentation. This gives the circuit designer the option of achieving the same effect while minimizing waveform complexity. The amplified modulation signal is more important than the carrier frequency in pulse 48 of Figure 2a. This makes it possible, after selecting the modulating signal (envelope), to select a carrier frequency which itself has the desired effect. Signal 48 in Figure 2a
At, the carrier frequency shown has a frequency of about 2500 Hz, selected to stimulate the response described above, and the ON / OFF repetition rate is less than one. at the same time,
The envelope shows a third, much lower frequency of particular concern. The simultaneous use of different frequencies with low repetition rates can have a synergistic effect in addition to being energy efficient.

Reversing the electric field is what causes it to "repute" large molecule complexes (long chains meander in the pores, and molecules follow the same path in a "single file"). It is also crucial for transdermal drug delivery as it induces; their mobility becomes independent of size.

From the above, the above-described objects can be efficiently achieved among those clarified from the reference specification, and certain modifications can be made without departing from the spirit and scope of the present invention. It will be understood that all that is done to the present invention, and that all matters contained in the above specification or shown in the accompanying drawings are to be understood as being illustrative and not limiting. Also, the following claims are intended to cover all and all specific aspects described in this text, and all statements regarding the scope of the present invention are to be placed in the middle in terms of terms. It should be understood that this should be considered.

[0030]

As described above, according to the electrodermal transdermal drug multi-signal applicator of the present invention, the selected frequency, waveform, duration, repetition rate, etc. can be selected.
Applying C and DC waveforms enhances drug flow into the patient's circulatory system, causing the body to produce its own vasodilators and thrombolytic compounds, and also to the patient. In, there is an effect of prolonging the fibrinogen coagulation time, enhancing the drug delivery from the solution, and improving the drug delivery from the gel.

[Brief description of drawings]

1 is a schematic representation of an electrodermal transdermal multi-signal applicator.

2 a is a waveform of a composite signal generated by the electrodermal transdermal multi-signal applicator of FIG.
b is an enlarged portion of FIG. 2a.

FIG. 3 is a schematic diagram of another transdermal drug multi-signal applicator.

FIG. 4 is a partial schematic view of another transdermal drug multi-signal applicator.

FIG. 5 is a schematic diagram of another transdermal drug multi-signal applicator.

[Explanation of symbols]

 10 Applicator 12 Reservoir 14 Reservoir Surface 16 Skin Surface 18 Skin 20 Electrode 22 Reservoir Surface 26 Signal Generation and Timing Unit 24, 28 External Terminal 30 Return Electrode 32 Unipolar Switch 34 Arrow 34 Current 38 AC Signal Generator 40 Buffer Amplifier 42 Closed switch 44 Rectifier 46 Shaping circuit 48 Positive output pulse (shaping pulse) 50 Switch 52 Parallel signal generator 54 Buffer amplifier 55, 56 Switch 57 Parallel AC square wave generator 58 Amplifier 60 switch 62 Section B 64 Sequence timer 66 Parallel AC square wave Generator 67 Switch 68 Signal output 42, 55, 60, 67 Switches 48, 56, 62, 68 Signal 70, 72 Signal generator 74 Second Reservoir 78 memory 80 microprocessor 82 digital-to-analog converter

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[Procedure amendment]

[Submission date] February 23, 1993

[Procedure Amendment 1]

[Document name to be corrected] Drawing

[Correction target item name] All drawings

[Correction method] Change

[Correction content]

[Figure 4]

[Figure 1]

[Fig. 2]

[Figure 3]

[Figure 5]

Claims (6)

[Claims] 1. A transdermal applicator for delivering at least one drug to the blood circulation system of a patient through the skin for a long period of time, which has means for attachment to the skin of the patient, A drug reservoir for containing at least one drug for making an electrical connection therewith at an interface therebetween, an electrical terminal electrically connected to the drug reservoir remote from the interface, and the applicator A power source of various potentials for delivering the drug into the patient's blood when in use, wherein the applicator has a second terminal disengageable from the interface and in circuit with the interface when in use. Means connected to the reservoir, the first terminal when the second terminal is electrically connected to the patient's skin in the power supply at various potentials,
Different corrugations provided through the reservoir and the interface,
Includes means for repeatedly generating complex complex pulse signals consisting of negative DC lead test pulses according to pulsed DC pulse sequence of amplification, frequencies, and repetition rate, including current flow inside the patient's capillaries Current flow,
The complex composite pulse signal is a complex total waveform signal with a sequence of waveform components effective to cause and maintain the same direction as the current flow of a DC read pulse of the complex pulse signal and at different time intervals. A transdermal applicator comprising: a timing means for providing a composite pulse signal. 2. The transcutaneous applicator of claim 1, wherein the timing means selectively delivers a time interval of the sequence to the patient's blood circulatory system through the skin for a long period of time. A transcutaneous applicator comprising a spectrum timing means consisting of a timer and a microprocessor for varying. 3. The transdermal applicator of claim 1, wherein the various potential power supplies alternate polarity of the power supplies to deliver at least one drug through the skin to the blood circulation of a patient over a long period of time. A transdermal applicator consisting of means for 4. The transcutaneous applicator of claim 1, wherein the transdermal applicator of the present invention conveys at least one drug through the skin to the blood circulation system of a patient for a long period of time between the one terminal and the second terminal. A transdermal applicator including means for creating. 5. A transdermal applicator according to claim 1, which delivers at least one drug through the skin to the blood circulation system of a patient over a long period of time, selectively the complex signal pulse component in the sequence. A transdermal applicator including a means for interrupting. 6. A transdermal applicator for delivering at least one drug to the blood circulation system of a patient through the skin for a long period of time, which has means for attachment to the patient's skin and A drug reservoir containing at least one drug that makes an electrical connection therewith at an interface between, an electrical terminal electrically connected to the drug reservoir remote from the interface, and when using the applicator The reservoir containing a power source of various potentials for delivering the drug into the patient's blood when the applicator is used, having a second terminal displaceable from the interface and in circuit with the interface, the second terminal disposed on the patient skin surface. The first terminal when the second terminal is electrically connected to the patient's skin in the power supply at various potentials.
Different corrugations provided through the reservoir and the interface,
A means for repeatedly generating a complex composite pulse signal consisting of a negative DC lead test pulse according to a pulsed DC pulse sequence of amplification, frequencies, and repetition rate, and a waveform component effective for Timing means for providing said complex composite pulse signal as a composite total waveform signal with selected sequences at different time intervals, a current flow comprising a current flow inside a capillary of a patient,
Timing means for providing said complex composite pulse signal as a composite total waveform signal with a sequence of waveform components effective to generate and maintain a desired co-direction and with selected sequences at different time intervals. A transdermal applicator characterized by: