An electrotransport delivery device with voltage boosting circuit

The invention relates to an electrotransport delivery device for delivering a therapeutic agent through the body surface of a living being, with an electrical voltage source (V +) of a predetermined output voltage, a voltage amplifier circuit connected to it that amplifies this output voltage to a working voltage, and with two electrodes for conduction that can be connected to it the electrotransport current through the body surface, wherein the voltage amplifier circuit contains a control circuit which regulates the working voltage via a sensor as a function of a parameter of the body surface (electrical resistance or voltage drop between the attached electrodes, current strength of the electrotransport current). Such an iontophoresis device has become known, inter alia, from EP 0 558 409 A1. EP 0 308 572 A2 and EP 0 547 482 A1 also deal with more or less sophisticated circuits for the constant and skin-friendly delivery of medicaments by means of electrical transport. A relevant application device emerges from DE 40 28 125 A1, for example.

The term “electrotransport” used here generally refers to the delivery of an agent (e.g. a drug) through a membrane, such as the skin, a mucous membrane or nails, which delivery is induced or supported by the application of an electrical potential. For example, a therapeutic drug can be introduced into the circulation of a living being (e.g., a human) by electrotransport delivery through the skin.

The electrotransport process has proven useful in the transcutaneous administration of drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, and other drugs. Perhaps the most common use of electrotransport in diagnosing cystic fibrosis is through the iontophoretic administration of pilocarpine salts. Pilocarpine stimulates sweat production; the sweat is collected and analyzed with regard to its chloride content in order to determine the occurrence of the disease.

In the currently known electrotransport devices, at least two electrodes are used which are brought into intimate contact with an area of ​​the body (for example the skin). The first electrode, called the active or donor electrode, delivers the therapeutic drug (e.g., a drug or prodrug) into the body by electrotransport.

The second electrode, called the counter or return electrode, closes an electrical circuit through the patient's body with the first electrode. A source of energy, such as a battery, supplies electrical power to the body through the electrodes. If z. For example, if the therapeutic agent to be administered to the body is positively charged (ie, cationic), the anode is the active electrode, with the cathode serving as the counter electrode to close the circuit. When the therapeutic agent being administered is negatively charged (ie, anionic), the cathode is the donor electrode and the anode is the counter electrode.

Alternatively, both the anode and the cathode can be used to deliver drugs of opposite electrical charges into the body. In this situation, both electrodes are to be regarded as donor and counter electrodes. For example, the anode can simultaneously release a cationic therapeutic agent and act as a “counter electrode” to the cathode. In the same way, the cathode can simultaneously deliver an anionic therapeutic agent to the body and act as a "counter electrode" to the anode.

A widespread electrotransport process is electromigration (also called iontophoresis), in which charged ions are transported by electrical induction. In another type of electrotransport, electroosmosis, a liquid solvent flows from the donor reservoir, which contains the agent to be administered, under the influence of an applied electric field. Another electrotransport process, electroporation, involves the formation of temporary pores in a biological membrane through the application of high-voltage pulses. In this way, a therapeutic agent can be partially released through the skin by passive diffusion because of the concentration difference between the concentration of the agent in the donor reservoir of the electrotransport device and the concentration of the agent in the tissues of the patient's body. In any of the specified electrotransport processes, more than one of these processes can occur simultaneously to some extent. Accordingly, the term "electrotransport device" used here should be interpreted in the broadest possible sense, so that it denotes electrically induced or amplified transport

AT 408 616 B comprises at least one therapeutic agent, whether charged or uncharged, or a mixture of such agents

The terms “drug” and “therapeutic agent” are used interchangeably and are to be interpreted in the broadest sense, namely to mean any therapeutically active substance that is administered to a living organism to achieve the desired, usually beneficial effect. This includes therapeutic agents in all therapeutic areas, including, but not limited to: Antiinfectants such as antibiotics and antiviral agents, analgesics including fentanyl, sufentanil, buprenorphine and analgesic combinations, anesthetics, anorexigens, antiarthritics, antiasthmatic agents such as terbutaline, anticonvulsants, antidepressants, antidiabetic agents, anti-diarrheal drugs, anti-inflammatory drugs, anti-inflammatory drugs, anti-diarrheal drugs such as scopolamine, ondansetron, anti-nausea agents, antineoplastic agents, Drugs for Parkinson's disease, drugs for skin inflammation and eczema, drugs for psychoses, antipyretics, antispasmodics, including gastrointestinal and urinal, anticholinergics, sympathomimetics, xanthine derivatives, preparations for the coronary arteries, including calcium channel blockers such as nifedipine, beta-blockers, Beta agonists such as dobutamine and ritodrine, antiarrhythmics, antihypertensive agents such as atenolol, ACE inhibitors such as ranitidine, diuratics, vasodilators, including general, coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, anti-hyperaemic agents, diagnostic agents, hormones such as parathyroid hormones, hypnotics, immunosuppressants, muscle relaxants, parasympatholytics, prostaglandins, proteins and peptides, prostaglandins, proteins and peptides .

Electrotransport is also useful in the controlled delivery of peptides, polypeptides, proteins, and other macromolecules. These macromolecular substances typically have a molecular weight of at least 300 Daltons and more typically a molecular weight of 300-40,000 Daltons.

Specific examples of peptides and proteins in this size range include, without limitation, the following: LHRH, LHRH analogs such as buserelin, gonadorelin, nafarelin and leuprolide, insulotropin, calcitonin, octreodide, endorphin, TRH, NT-36 (chemical name N = [[(s) -4-oxo-2-azetidinyl] coarbonyl] - L-histidyl-L-prolimanid), liprecin, mucous hormones such as HGH, HMG and desmopressin acetate, follicular celluteoid, aANF, growth factors such as a growth factor releasing factor (GFRF or GHRH), bMSH, somatostatin, bradykini, somatotropin, platelet- derived growth factor, asparaginase, chymopapain, Cholecystokinin, chorionic gonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, HCG, hirulog, hyaluronidase, interferon, interleukins, menotropins (urofollitropin (FSH and LH), desmopressin activators, plasmopressin-activators, plasmopressin-activators, LH), oxytocinase, , ACTH analogs, ANP, ANP clearance inhibitors, angiotensin II antagonists, antagonists for antidiuretic hormones, bradykinin antagonists, CD-4, Ceredase, CSF, enkaphalin, FAB fragments, IgR peptide suppressors, IGF-1, neutrophil factors, colony-stimulating factors, parathyroid hormones and agonists, parathyroid hormone antagonists, prostaglandin antagonists, pentigetide, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytic drugs, TNF, vacconists -analogue, alpha-1 antitrypsin (recombination) and TGF-beta.

Electrotransport devices generally require a reservoir or source of the beneficial agent or a precursor to such an agent to be delivered to the body by electrotransport. Examples of such reservoirs or sources of the preferably ionized or ionizable agent include a pouch as described in U.S. Patent 4,250,878 (Jacobson) or a preformed gel body as described in U.S. Patent 4,383,529 (Webster). Such reservoirs are electrically connected to the anode or cathode of an electrotransport device to provide a fixed or renewable source of one or more desired therapeutic species.

Recently, a number of US patents have been issued in the field of electric transportation indicating continued interest in this type of drug delivery. For example, U.S. Patent 3,991,755 (Vernon et al), U.S. Patent 4,141,359 (Jacobson et al), U.S. Patent 4,398,545 (Wilson), and U.S. Patent 4,250,878 (Jacobson) describe examples of electrotransport Facilities and some uses thereof.

Recently, electrotransport facilities have become much smaller, especially with the

AT 408 616 B

Development of miniaturized electrical circuits (e.g. integrated circuits) and stronger, lighter batteries (e.g. lithium batteries). The advent of cheap miniaturized electronic circuitry and compact, powerful batteries has meant that the entire device can be made small enough to be inconspicuously worn on a patient's skin or under clothing. This enables the patient to be completely mobile and to carry out normal activities even during the duration of the active delivery of the drug by the electrotransport device.

Nonetheless, there are still some limitations that limit the wider application of these available methods. One such limitation is the size and cost of the electrotransport delivery devices. In particular, the batteries required to power the electrotransport devices add significantly to the overall size and weight as well as the cost of these smaller portable electrotransport delivery devices. Reducing the number and / or cost of these batteries would enable smaller and cheaper electrotransport drug delivery devices to be manufactured.

One method of determining the number of batteries used to power an electrotransport device is to use a voltage booster circuit. Amplifier circuits are well known in the electrical arts. Conventional amplifier circuits work with an input voltage (e.g. 3.0 V) and amplify this by a predetermined multiple (e.g. x 2) and emit an "amplified" output voltage (e.g. 6.0 V = 3 , 0 V x 2). Voltage booster circuits have been used in electrotransport delivery devices, see U.S. Patent 5,254,081 (Maurer et al, Sp. 2 / Z 34-39).

These circuits allow an electrotransport device to deliver a predetermined level of electrical current with fewer batteries or a lower voltage battery or batteries than would otherwise be required without the use of an amplifier circuit. Thus, conventional amplifier circuits help reduce the size and cost of an electrotransport delivery device. by requiring fewer batteries and / or lower voltage batteries to power the device.

The problem of reducing the cost of powering an electrotransport delivery device is complicated by the fact that the electrical resistance of the surface (e.g., skin) of a patient is not constant during electrotransport delivery. Since the voltage (V) required to flow a given level of electrical current (i) through a patient's skin is proportional to the resistance (R) of the skin (ie, according to Ohm's law, where V = iR_Huht), the voltage requirements for the energy supply are not constant during the electric transport. For example, the patient's initial skin resistance at the start of electrotransport administration is relatively high, so the power supply must generate a relatively high voltage in order to deliver a predetermined level of electrotransport current. After a few minutes (ie after about 1 to 30 minutes after applying the current to the skin) the skin resistance drops, so that the voltage required to deliver a certain level of electrical current is considerably lower than the voltage that was required at the beginning of the electrotransport delivery. See e.g. B. U.S. Patent 5,374,242 (Haak et al) which describes variable skin resistance and the use of two or more batteries in either parallel or series to accommodate changing skin resistance.

Although conventional voltage booster circuits can provide the output voltage necessary to accommodate the high initial skin resistance, they reduce the effectiveness of the device and require a larger battery output voltage during periods when the skin resistance is lower than the initial stage, resulting in reduced efficiency and increased battery size and costs.

U.S. Patent 4,141,359 (Jacobsen et al), incorporated herein by reference, describes a DC-to-DC converter having a transformer to inductively convert periodic current fluctuations in the primary winding into current pulses in the secondary winding at a fixed voltage multiple of the primary supply to implement. These current pulses from the secondary winding are passed through the patient's skin by means of therapeutic electrodes. The middle resp. The direct current value of the secondary current is controlled by means of an error voltage and a feedback circuit, so that the mean value of the secondary current is kept constant

AT 408 616 B becomes. A disadvantage of the Jacobsen circuit is that the peak value of the fixed and multiplied voltage occurs directly at the electrodes. The peak voltage is unnecessary in circumstances where the skin resistance is low and results in unnecessarily high current pulses of the therapeutic current and possible deleterious effects on the skin.

As already mentioned, the initially high skin resistance can drop to almost zero in the course of iontophoresis, whereby the current becomes too high even when the voltage amplifier circuit is switched off. This results in both skin burns and the delivery of an overdose of the drug.

The aim of the invention is to avoid the above-mentioned problem.

This goal is achieved with an electrotransport delivery device of the type mentioned according to the invention in that the voltage amplifier circuit is assigned a current limiting circuit for limiting the amperage of the electrotransport current, which responds by increasing its resistance when the current flowing through it exceeds a predetermined value.

Due to the varying resistance of the current limiting circuit, the total current through the skin is controlled, even if the voltage booster circuit is not giving any amplification and the working voltage has a fixed value which corresponds to the battery voltage.

In order to ensure an optimal response of the current limiting circuit, it is advantageous if it has a sensor resistor connected in series into the electric transport current.

It has proven to be most expedient if the current limiting circuit contains a transistor, the drain and source of which are connected in series in the circuit of the electrotransport current, whereas the gate which regulates the impedance of the transistor is connected to the output of an operational amplifier which has an input for the voltage tapped at the sensor resistor and connected to a reference voltage with the second input.

In order to obtain reliable interaction between the voltage amplifier circuit and the current limiting circuit, it is advantageous if a limiting resistor for the induction current is connected in series for this purpose.

The invention is explained in more detail below with reference to exemplary embodiments illustrated in the drawing: FIG. 1 shows a diagrammatic view of an electrotransport drug delivery device, FIG. 2 shows an exploded view of this electrotransport device, FIG Time, FIG. 4 is a schematic circuit diagram of an adjustable voltage amplifier circuit, FIG. 5 4 shows a time diagram of the operation of the circuit according to FIG. 6, FIG. 6 shows a schematic circuit diagram of a further adjustable voltage amplifier circuit, FIG. 7 shows a time diagram of the operation of the circuit according to FIG. 6 and FIG. 8 shows a schematic circuit diagram of an adjustable voltage amplifier circuit according to the invention with an associated current limiting circuit.

The electronic circuit according to the invention can be used in essentially any electrotransport delivery device, although the circuit is particularly useful for devices which are designed to deliver transdermal medicaments by electrotransport. Examples of electrotransport delivery devices that can be used with the circuit of the present invention are shown in FIGS. Fig. 1 shows a diagrammatic view of an electrotransport device 10 with an optionally provided on-switch in the form of a push-button switch 12 and an optionally provided light-emitting diode (LED) 14, which is switched on when the device 10 is in operation.

Fig. 2 is an exploded view of a second device 10 'according to the invention. The device 10 'according to FIG. 2 differs from the device 10 according to FIG. 1 in the arrangement of the LED 14', which in this embodiment of the invention is arranged next to the push-button switch 12 at one end of the device 10 '. The device 10 'consists of an upper housing 16, a circuit board unit 18, a lower housing 20, an anode 22, a cathode 24, an anode reservoir 26, a cathode reservoir 28 and a skin-friendly adhesive pad 30. The upper housing 16 has lateral wings 15, which aid in holding the device 10 'against the skin of a patient. The upper housing 16 is preferably made from an injection moldable elastomer (e.g., ethylene vinyl acetate). The circuit board unit 18 has a

AT 408 616 B integrated circuit 19, which is connected to individual components 40 and a battery 32. The circuit board unit 18 is attached to the housing 16 with feet (not shown in FIG. 2) which protrude through openings 13a and 13b and the ends of which are heated or melted in order to hold the circuit board unit 18 on the housing 16 at a distance therefrom. The lower housing 20 is attached to the upper housing 16 by means of the adhesive pad 30, the top 34 of which is adhered to both the lower housing 20 and the upper housing 16 including the underside of the blades 15.

A button battery 32 is (partially) shown on the underside of the circuit board unit 18. Other types of batteries can also be provided for supplying the device 10 '.

The device 10 'generally consists of the battery 32, the electronic circuit 19, 40, the electrodes 22, 24 and medicament / chemical reservoirs 26, 28, which are all combined into an independent unit. The outputs of the circuit board unit 18 (not shown in FIG. 2) are in contact with the electrodes 22, 24 through openings 23, 23 'in recesses 25, 25' formed in the lower housing 20 by means of electrically conductive adhesive strips 42, 42 '. The electrodes 22, 24, on the other hand, are in direct mechanical and electrical contact with the upper sides 44, 44 'of the medicament reservoirs 26, 28. The undersides 46, 46' of the medicament reservoirs 26, 28 contact the patient's skin through openings 29, 29 'in the adhesive pad 30th

After pressing the push button switch 12, the electronic circuit on the circuit board unit 18 delivers a predetermined direct current to the electrodes / reservoirs 22, 26 and 24, 28 for a delivery interval of a predetermined length. Preferably, the device transmits to the user a visible and / or audible confirmation of the activation of the drug delivery by means of the LED 14 ', which is illuminated, and / or an audible tone signal e.g. B. a "beeper". A medicament is now delivered from one of the reservoirs 26, 28 through the patient's skin by means of electrotransport.

The anode 22 is preferably made of silver and the cathode is preferably made of silver chloride. Both reservoirs 26 and 28 are preferably made of a polymeric hydrogel. The electrodes 22, 24 and the reservoirs 26, 28 are held in the lower housing 20. One of the reservoirs 26, 28 is the “donor” reservoir and contains the therapeutic agent to be delivered (e.g. a drug) and the other reservoir typically contains a biocompatible electrolyte.

The push button switch 12, the electronic circuit on the board unit 18 and the battery 32 are adhesively “sealed” between the upper housing 16 and the lower housing 20. The upper housing 16 is preferably made of rubber or some other elastomeric material. The lower housing 20 is preferably made of a plastic or elastomeric material (e.g. Polyethylene), which can be simply poured to form the recesses 25, 25 'and easily cut to form the openings 23, 23'. The assembled device 10 'is preferably water-resistant (ie, splash-proof) and most preferably water-tight. The system has a low profile that adapts easily to the body and thus allows freedom of movement at and around the carrying point. The reservoirs 26, 28 are located on the skin contact side of the device 10 'and are spaced from one another sufficiently to prevent accidental electrical shorting during normal handling and use.

The device 10 ′ adheres to the body surface (e.g. the skin) of the patient with the aid of the circumferential adhesive pad, which has an upper side 34 and a body contact side 36. The adhesive side 36 has adhesive properties which ensure that the device 10 'remains in place during the normal activities of the user on the body and still permits reasonable removal after the predetermined wearing time (e.g. 24 hours). The adhesive top 34 sticks to the lower housing 20 and holds the electrodes and medicament reservoirs within the housing recesses 25, 25 ′ and the lower housing 20 to the upper housing 16.

The push button switch 12 is conveniently located on top of the device 10 'and is easy to operate through clothing. To activate the device for dispensing the drug, the push-button switch 12 is preferably activated within a short period of time, e.g. B. three seconds, twice, whereby the likelihood of inadvertent activation of the device 10 'is minimized.

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After the initial initiation of drug delivery, the patient's skin resistance is typically relatively high, whereas after a period of time the skin resistance drops significantly. Fig. 3 graphically shows this property and that the drop in skin resistance R leads to a stable amount essentially asymptotically. At a delivery rate of 0.1 mA / cm²The stable amount is typically on the order of 20 to 30 kO / cm², while the initial value of the skin resistance is several times greater.

In known electrotransport delivery devices, the voltage of the energy supply and / or the gain multiple of the voltage amplifier circuit was selected to be sufficiently large to overcome the high skin resistance present at the start of operation. However, once the operation had reached the stable value with the accompanying drop in skin resistance, the known devices had an excessive operating voltage.

In certain known devices, the applied voltage required to deliver a given current in the stable operating range was half or less of the voltage required to deliver the same level of current at the beginning of the electrotransport delivery. As a result, these known devices have not been very inexpensive because of the voltage wasted in the voltage booster circuit after the skin resistance has dropped from its initial high level.

4 shows a block diagram of an electrotransport voltage amplifier circuit 100 having an adjustable gain factor that is adjusted in accordance with the measured therapeutic current load level in accordance with the present invention. This enables better utilization of the batteries and leads to considerable size and cost savings compared to the prior art described above. The circuit 100 has an energy source in the form of a battery 102 and a voltage-controlled electrical node 104, which is connected to an electrode unit 108. The electrode unit 108 is attached to a body region 110 of a living being in a conventional manner, such as by means of adhesives, tapes, straps or the like. The body surface of the living being is shown schematically as a variable load resistance R._v shown to indicate the typical change in the load resistance of the skin when an electrical current I is applied.

An electrode unit 112 is attached in the same way to another body region 110 of the living being and connected to a series-connected measuring resistor 114. The electrodes 108, 112, the body surface 110 and the measuring resistor 114 form a current I | leading current path. The electrode units 108, 112 are equivalent to the electrode / reservoir combinations 22, 26 and 24, 28 shown in FIG. At least one of the electrode assemblies 108, 112 contains a therapeutic agent (e.g., a salt drug) in a form (e.g., an aqueous solution) suitable for electrotransport delivery to the body 110 of the living being.

An energy storage inductor 118 is connected between the battery 102 and the anode of a rectifier diode 120. The cathode of diode 120 is connected to voltage controlled electrical node 104. A filter capacitor 122 is connected between node 104 and ground.

A controlled switch 124 with a control input 126 is connected with one connection 128 to the node of the anode of the diode 120 and the inductance and with the other connection 130 to ground. The control input 126 can alternatively open or close the switch 124, as a result of which a low-resistance connection is created between the terminals 128 and 130 and as a result of which the inductance 118 is or is not connected to ground by a low-resistance path. The switch 124 can be an electronic switching device such as a bipolar or FET transistor.

A control circuit 132 with its control output 134 is connected to the switch control input 126. The control circuit 132 has a feedback input 133 for controlling the control output 126 and a switch input 136.

The operation of the adjustable voltage booster circuit 100 is explained with reference to FIG. 5. After switching on the circuit 100, e.g. B. by means of the push button switch 12 shown in Fig. 1, the control circuit 132 first connects the input 136 to ground. This enables the measuring resistor 114 to carry current h from the load 110.

The control circuit 132 is designed to then switch the control output 134,

AT 408 616 B so that the switch 124 connects one end of the inductance 118 to ground during the period T1. During the time T1, the current I | coming from the battery 102 increases through the inductance to the maximum value l_P. at.

At the end of the time T1, the control circuit 132 changes the output 134 to the switch input 126 again, whereby the switch 124 is opened for a time period T2. During T2, the current I, does not flow through the inductance to ground, but rather through the diode in the electrical node 104. The filter capacitor 122 creates a low-impedance path for the instantaneous current I |, which then drops to zero during the time T2 as soon as the voltage at the electrical node 104 is increased by the charge on the capacitor 122

During the time T1, the inductance 118 stores energy by being charged with the current I,. During the duration T2, the inductance emits energy to the filter capacitor 122 through the diode 120. The inductor 118 thereby transfers energy from the battery 102 to the capacitor 122 with low losses determined only by the diode drop and the negligible series resistance of the inductor 118, the battery 102 and the electrical connections. Thus the energy source for the current is l | not battery 102 directly, but rather either capacitor 122 (ie during time T1) or the combination of capacitor 122 and inductor 118 (ie during time T2).

The control circuit 132 is designed to repeat the T1-T2 cycle indefinitely or to switch it off as described below. The voltage V_w At node 104, depending on the values ​​of time periods T1 and T2, the battery voltage is amplified to an adjustable multiple. The gain multiple can thus be adjusted by adjusting the values ​​T1 and T2.

The dotted lines in FIG. 5 indicate missing or delayed pulses which are controlled by the control circuit 132. They can occur when pulses are not necessary to replace charge retained by capacitor 122, e.g. B. when the desired therapeutic current li is relatively low. The dotted lines in Fig. 5 indicate that gain control can be by pulse width modulation (PWM), pulse frequency modulation (PFM), pulse jumps, or a combination thereof.

The adjustable working voltage V_w causes the current l | through the body 110 of the living being, through the measuring resistor 114, the switch input 136 and to ground.

The feedback input 133 detects the voltage at the measuring resistor 114 caused by the current h. The control circuit 132 is designed to respond to the feedback input 133 in order to increase the working voltage V._w by setting the time periods T1 and T2. This is done by comparing the voltage measured at input 133 with a set reference voltage in control circuit 132. If the voltage measured at input 133 is less than the reference voltage, control circuit 132 opens and closes switch 124 at a high frequency, up to V_w is amplified to the appropriate level. In general, the longer switch 124 is closed (ie, the longer T1), the greater the voltage developed across inductor 118 and the greater the gain factor. The battery voltage can therefore be boosted because of the inductance 118. The voltage developed across the inductance 118 is equal to the inductance value (L) multiplied by the speed of the current flowing through the inductance:

V_ind = L (dl, / dt).

Thus, a higher voltage comes from the inductance 118 (which is partly due to the inductance value of the inductance 118 and partly due to the speed of the current flowing through the inductance 118, which is controlled by the values ​​of T1 and T2) at a lower current, since the power into inductance 118 must be equal to the power from the inductance.

The control circuit 132 is also designed in such a way that, in combination with the values ​​of the inductance 118, the value of the load resistor 110 and the capacitance of the capacitor 122, the periods T1, T2, depending on the voltage at the feedback input 133, are such that the filter capacitor 122 the voltage V_w smooths and adjusts and thus creates a current I of a predetermined, essentially constant amount (direct current).

The electrode unit 108 and 112 and thus the body 110 of the living being are not

AT 408 616 B exposed to high peak voltages as in the prior art, but rather experience the minimum voltage that is sufficient to maintain the target current h

The periods T1 and T2 are used by the control circuit 132 to amplify V_w to the minimum absolute value for a current l | adjusted to maintain a predetermined set point. If the resistance of the load 110 is too great to maintain the predetermined value of l | without exceeding V_w A voltage limiting device, such as a Zener diode 116 connected between the electrode units 108 and 112, limits the voltage at the load 110 to enable a safe level. A typical safe maximum limit value for V_w is about 24 V. Other values ​​of the limit voltage can be achieved by means of Zener diodes 116 with different breakdown voltages or by using other protective measures, as explained below.

As soon as the resistance of the load 110 decreases enough to cause the current I i to reach the predetermined desired level at the maximum safe voltage, the control circuit 132 responds to the feedback signal at the feedback input 133 and adjusts T1 and T2 to amplify V_w to a multiple that is sufficient to maintain the current at the predetermined level, regardless of further drops in resistance.

The working voltage V_w at the controlled electrical node 104 is thus amplified to a gain multiple of the battery voltage, which is used to maintain the current I | with the predetermined value is sufficient as long as the load voltage is lower than the limiting voltage set by the ZDiode 116.

The low loss transfer of energy from battery 102 to load and capacitor 122 maximizes the life of battery 102 for a given therapeutic lifestyle or extends the life of a therapeutic treatment for a given cost.

The predetermined current I i applied to the load can be constant or variable over time. In any case, the control circuit 132 is provided with means for setting a predetermined current-time profile to be applied. This can be done by means well known to those skilled in the art, such as a differential comparator having one input connected to measuring resistor 114 and the other input connected to a constant reference voltage or the other input connected to the output of a D / A converter which is fed from a clocked ROM is controlled with a predetermined pattern (not shown in Fig. 4).

The circuit 100 may also be provided with a protection circuit 138 which has a high and low impedance test function and an input 140 and which detects the voltage drop across the load 110 and compares the detected voltage drop signal with a preset lower limit. Circuit 138 also has an input 142 at which the current h applied to load 110 is sensed and compares the sensed current with a preset upper limit. Protection circuits with impedance testing and shutdown protection are well known to those skilled in the art, e.g. The protection circuits shown in Figure 1 of U.S. Patent 4,141,359 (Jacobson et al), incorporated herein by reference.

The protection circuit 138 monitors the resistance of the load 110 by means of the voltage input 140 and the current input 142 and switches off the voltage booster function of the circuit 100 if the resistance of the load 110 exceeds a predetermined upper limit or falls below a predetermined lower limit. Incorporation of protection and shutdown circuit 138 of the type described in U.S. Patent 4,141,359 into amplifier circuit 100 is well within the capabilities of those skilled in the electrical art.

For use, the electrode units 108 and 112 are attached to the skin surface 110 by conventional means and the therapeutic current is switched on by means of a switching device (not shown) such as the switch 12 shown in FIG. The control circuit 132 begins to control the switching on and off of the switch 124. During the switch-on times T1, repeated pulses of the inductance current I | alternately routed to ground and discharged into capacitor 122 during switch-off times T2. These pulses of the inductance current l | cause the voltage V_w is multiplied by the adjustable gain multiple by setting the switch-on and switch-off times T1, T2 until the signal to the feedback input 133 indicates that the load current I is being regulated.

Fig. 6 shows a further adjustable amplifier circuit 200 according to the invention, which has a

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Battery 202, an inductor 204, a diode 206, a voltage-controlled electrical node 207, a low-resistance filter capacitor 208 and electrode units 210, 212, which are attached by conventional means to spaced-apart locations on the body 213 of a living being. The body 213 of the living being is shown schematically as a variable load resistance R_v shown to illustrate the fact that the load resistance varies with time and current.

At least one of the electrode units 210, 212 contains a therapeutic agent in the form of a form suitable for electrotransport into the body 213 of the living being.

The circuit 200 has an N-channel field effect transistor (FET) switch 218 for switching over the inductance current I_H an inductance current measuring resistor 220 and a load current measuring resistor 214. The circuit also includes a highly efficient adjustable DC-DC boost controller 216. A preferred controller 216 is Maxim MAX773 from Maxim Integrated Products, Inc. of Sunnyvale, CA.

6 shows, in simplified form, the MAX773 controller 216 schematic which is sufficient for the purposes of the invention. A detailed schematic of the MAX773 control unit can be found in MAX773 data sheet 19-0201, Rev 0, 11, 93 available from the manufacturer. The control unit 216 is an integrated circuit with internal components connected by traces formed during the integrated circuit manufacturing process are. External pins are provided for connection to external components and are deposited and formed on an insulating substrate by conventional methods such as plating or depositing copper or other conductors. References to electrical connections in this specification are internal or external as shown in FIG. 6. Reference to components of the MAX773 control circuit is used to explain the function of circuit 216. In contrast to conventional pulse frequency converters (PFM), in which an error voltage of a voltage divider circuit is used to control the output voltage of the converter to a constant value, the control unit 216 is connected to a measuring resistor 214 in order to generate an error voltage for controlling the average load current I. . The MAX773 control unit also operates at high frequencies (up to 300 kHz), which enables the use of small external components.The control unit 216 has a voltage reference pin 256, a ground pin 258, a grounding switch input 260, a low level threshold value input 262, a feedback input 264, and a shutdown input 266 , a current measuring input 268 and a power line input 270.

The control unit 216 furthermore has a first comparator 230 with two inputs and one output 231, a second comparator 232 with two inputs and one output 233, a first reference voltage 242, a second reference voltage 244 (e.g. 1.5 V), a third comparator 246 with two inputs and one output 247, a PFM / PWM control circuit 240 with a switch control output 252 and a switch control output 254 and a second N-channel FET switch 250.

The operation of circuit 200 will now be explained with reference to FIGS. In the circuit 200, the control unit 216 is used in a novel manner in order to achieve a highly effective conversion of the energy from the battery 202 to an adjustable, increased voltage V_w to create at the voltage-controlled electrical node 207 and for the simultaneous control of the load current li.

According to FIG. 6, according to the invention, part of the load current I | fed back to the feedback input 264, to which a terminal of the measuring resistor 214 is also connected. The same connection of the resistor 214 is also connected to the electrode unit 212 for receiving the load current I | tied together. The other connection of the resistor 214 is connected to the input 260 of the control unit 216. The input 260 is internally connected to the drain of the N-channel switch 250. The source of switch 250 is connected to system ground. The gate of switch 250 is connected to output 247 of comparator 246. The inverting input of comparator 26 is connected to input pin 262 which is grounded. The non-inverting input of comparator 246 is connected to reference voltage 244, which is also connected to reference voltage pin 256.The comparator is controlled so that output 247 is always high is. The switch 250 is therefore controlled to connect the pin 260 to ground and to divert the load current h through the measuring resistor 214 to ground.

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The input 264 is connected to the inverting input of the comparator 232. The non-inverting input of the comparator 232 is connected to the reference voltage 244. The output 233 of the comparator 232 is connected to the PFM / PWM control circuit 240.

The output 231 of the comparator 230 is connected to the PFM / PWM control circuit 240. The inverting input of the comparator 230 is connected to the reference voltage 241. The non-inverting input of the comparator 230 is connected to the current measuring input. The input 268 is connected to a connection of the inductance current measuring resistor 220. The other connection of the resistor 220 is to ground. The ground pin 258 of the control unit 216 is also grounded.

An output of the PFM / PWM control circuit 240 is connected to the output 252. The input 270 is connected to one pole of the battery 202. The other pole of battery 202 is grounded. An output of the PFM / PWM control circuit 240 is connected to the output 254. Both outputs 252 and 254 are connected to the gate of the external N-channel switch 218. The drain of switch 218 is connected to the junction of one end of energy storage inductance 204 with the anode of a rectifier diode 206. The source of the switch 218 is connected to one terminal of the inductance current measuring resistor 220, which is connected to the current measuring input 268.

The other connection of the inductance 204 is connected to the power line input 270 and the pole of the battery 202. A filter capacitor 278 is connected between input 270 and ground. The filter capacitors 276 and 278 have low dynamic impedance at the pulse frequencies in question.

The cathode of the diode 206 is connected to an electrical node 207 which is also connected to a connection of a filter capacitor 208, the cathode of a Zener diode 280 and the electrode unit 210. The anode of Zener diode 280 and the other terminal of capacitor 208 are grounded. The node 207 completes the circuit 220, which the working voltage V_w amplified at node 207 to an adjustable multiple of the voltage of the energy source, ie the battery 202.

The Zener diode 280 forms a means for limiting the peak voltage at the electrode units 210 and 212 and thus the maximum voltage at the load 213 of the body of the living being.

The operation of the circuit 200 for the adjustable gain factor will now be explained with reference to FIGS. When power is supplied from the battery 202 to the input 270 and the input signal 266 is at the correct logic level, the control unit 216 begins to operate. Since the input 262 is held low and the non-inverting input 247 of the comparator is set to e.g. B. 1.5 volts of the reference voltage 244, the output of the comparator 246 is high. With a high voltage on the gate of switch 250, input 260 is driven to ground by the drain of switch 250. This enables the supply of the load current I | from the electrode unit 212 to the resistor 214.

As with conventional PFM converters, switch 218 is not turned on until voltage comparator 232 detects that the output current is out of regulation. However, unlike conventional PFM converters, the MAX773 uses the combination of the measuring resistor 220 for inductance current peak limitation, the reference voltage 242 and the comparator 230 together with the maximum switch-on time and minimum switch-off time generated by the PFM / PWM control circuit; there is no oscillator. The typical maximum switch-on time T1 is 16 ps, the typical minimum switch-off time T2 is 2.3 ps.

Once turned off, the minimum turn-off time keeps switch 218 turned off for time T2. After this minimum time (1), the switch 218 either remains switched off if the output current l | is in regulation, (2) or the switch 218 is switched on again if the output current h is out of regulation.

While switch 218 is open, inductor current h at node 207 flows through diode 206 to capacitor 208, replenishing the charge that has been drawn from load 213. It can be seen that this switching method of the charging current h has an adjustable gain multiple for the battery voltage and a working voltage V at node 207_w creates, which is just enough for the constant target current f. The peak voltage emitted by the inductor 204 is precisely that which is necessary to overcome the diode drop at the diode 206 and the

AT 408 616 B

Working voltage V_w is required, and thus minimizes energy losses from the battery 202.

The control unit 216 enables the circuit 200 to be operated in a continuous-conduction mode (CCM) while maintaining a high degree of efficiency under heavy loads. If the energy switch 218 is switched on, it remains switched on until (1) either it switches off the maximum switch-on time (typically 16 ps later) or (2) the inductance current I, the peak limit current I_P. which is set with the inductance peak current limiting resistor 220, the reference voltage 241 and the comparator 230. In this case, the switch-on time is less than the maximum switch-on time T1. By limiting the peak inductance current to a predetermined maximum l_P. the saturation of the inductance 204 is avoided and the use of smaller inductance values ​​and thus smaller components is made possible.

#

If the mean load current h is less than the setpoint value, which corresponds to the value V_ref the reference voltage 244 and the resistance value R._s of the measuring resistor 214 by means of the equation

V_ref = l | . Rs is set, the PFM / PWM control circuit 240 automatically sets the switch-on time T1 and the switch-off time T2 and switches the switch 218 on and off alternately until the load current L is in regulation.

The operation of the adjustable gain multiplier circuit 200 can be initiated by connecting the shutdown input 266 to a high logic level by means of a switching device such as the switch 12 shown in FIG. Once shutdown input 266 is high, the MAX773 circuit effects a shutdown mode in which the internal bias circuit (including the reference) is turned off, switch 250 is in a high impedance state, and the operating voltage is V._w falls on a diode drop below the battery voltage (because of the DC path from battery 220 through inductor 204 to electrode assembly 210). The supply current of the battery 202 becomes V_w/ I |. However, in the high impedance state of switch 250, there is no current path and the load current h is zero.

In an alternative embodiment of the invention, the current h can be programmed to follow a predetermined course by programming the value of the load current measuring resistor 214. The value of resistor 214 can be programmed to load current L by connecting additional resistors in parallel or in series. Such switching control devices are known to those skilled in the art.

8 shows a schematic circuit diagram of an electrotransport device 300 with an alternative voltage amplifier circuit. In contrast to the devices 10 and 10 'shown in FIGS. 1 and 2, the device 300 has a reusable control unit 302 which is designed for the separate connection of a plurality of preferably disposable single-use medicament units 304, one at a time at a time. The disposable drug unit 304 is attached to the body surface of a living being (e.g., a human), such as the skin 306, which is shown schematically in FIG. 8 as a resistor with a variable load resistance value Rt. The drug unit 304 has a pair of electrodes (ie, anode 308 and a cathode 310), at least one of which contains a therapeutic agent to be electrotransported through the skin 306. The drug unit 304 and the control unit 302 can be mechanically and electrically connected to one another by a pair of metal snap-in connectors 336, 338.

The control unit 302 has two circuit sections; a voltage amplifier circuit 312 for amplifying a supply voltage V + of an energy source (e.g. a battery) 318 to a working voltage V_w and a current limiting circuit 314 for low load voltage. When the voltage V_w at the load resistance R₁ is high, which is the case when V_w greater than V₊minus the negative diode voltage V._d (which is dropped across series diode 315) then voltage booster circuit 312 powers load 306 through inductor 320 and diode 315, as described in detail below.

If the load resistance Rt falls to a low value, so that [(Ii Ri) ⁺ V_ref] <(V₊ - V_d), then the control switches the load current h to the current limiting circuit 314, whereby the control unit 302 at lower skin resistance (R ^ with improved efficiency im

AT 408 616 B

Compared to the circuits described with reference to FIGS. 4 and 6 can be operated.

The operation of the voltage booster circuit 312 in conjunction with the current limiting circuit 314 will now be discussed in connection with the use of an exemplary PFM / PWM controller 322. A representative example of such a controller 33 is the MAX771 available from Maxim Integrated Products, Inc. of Sunnyvale, CA, although other PFM / PWM controllers available in the art can also be used.

The energy source 318 is typically a battery with a positive and a negative pole. The positive pole V + is connected to the input pin 323 of the circuit 322 and to one terminal of the inductance 320. The negative pole of battery 318 is connected to ground.

The other terminal of the inductance 320 is connected to the junction of the anode of the diode 315 with the drain 324 of an N-channel switch 326.

The source of switch 326 is connected to one terminal of a peak current measuring resistor 328. The other end of resistor 328 is grounded. The gate of switch 326 is connected to a switch control output 330 of circuit 322.

A measuring input 332 of the circuit 322 is also connected to the connection point between the source of the switch 326 and the one connection of the peak current measuring resistor 328.

The cathode of diode 315 is connected to one terminal of a filter capacitor 334, the other terminal of which is connected to ground. The junction of the capacitor 334 with the cathode of the diode 315 is connected by the snap connector 336 to the anode 308, which is in contact with the skin 306 of a patient. The cathode 310 is also in contact with the patient's skin 306 and is connected to the latching connector 338.

The latch connector 338 is connected to the drain of a second N-channel transistor 340 having a source and a source. The drain and source of the transistor 340 are connected in series and form part of the current limiting circuit 314 which controls the load current I | receives. The source of transistor 340 is connected to one terminal of a first load current source resistor 342 having a resistance of R₂ tied together. The other terminal of resistor 342 connects to a second load current source resistor 344 of resistance R₃ connected, the other connection to ground.

The junction of resistor 342 with resistor 344 is to the inverting input of a high-impedance differential operational amplifier 346 with two inputs and high voltage gain A._v connected. The output of operational amplifier 346 is connected to the gate of transistor 340. The non-inverting input of op amp 346 is connected to reference voltage output 348 (V_ref) of circuit 322.

The junction of the transistor 340 with the connection of the resistor 342 is connected to the feedback input 350 (FB) of the circuit 322 to create a control of the load current h through the patient.

The operation of circuit 302 can be viewed in two cases: (1) when the skin resistance R! is high and (2) when the skin resistance R- is low. The operational case (1) is as follows. When the skin resistance Rt is high, so

[(l | .R₁) + V_ref]> (V₊-V_d), then the current I i is controlled by circuit 322. The voltage at one connection of the load current measuring resistor 342 is fed back to the input 350. Circuit 322 compares the voltage at input 350 with the voltage at V._rerInput 348 and sets the switching speed and the pulse width of the output 330 to alternate the inductance 320 with the current I | to charge and to discharge through the diode 315 into the capacitor 334 until the feedback voltage at the input 350 (load current h times the sum of (R₂ + R₃), ie the sum of the resistance values ​​of the feedback resistors 342 and 344) equal to the voltage V_ref is.

The values ​​of resistors 342 and 344, gain A._v of op amp 346 and the value of V_r8f at the output 348 are selected such that at the load setpoint current h the difference between the voltage V._ref at output 348 and the feedback voltage at the junction of resistors 342 and 344 with the inverting input of operational amplifier 346 causes the output of operational amplifier 346 to drive the gate of transistor switch 340 to fully open.

AT 408 616 B

A portion of the feedback voltage at the resistors 342, 344 is fed back to the inverting input of the operational amplifier 346. The ratio of the resistance values ​​R₂: (R2 + R3) and the gain A_v of operational amplifier 346 is selected such that the output of operational amplifier 346 switches transistor switch 340 to the low impedance state so that it exhibits essentially no resistance with respect to resistor 344.

If the mean of h is too small, i.e. if I, times (R₂ + R₃) less than V_ref is, therefore causes the feedback input 350 together with the peak current measuring resistor 328 that the switch output 330 toggles with a speed and a pulse width to the inductance 320 with the current I | to charge and discharge so that the mean current l | is regulated by skin 306 without saturating inductor 320.

Circuit 322 operates to limit i i to a peak current so that inductor 320 does not saturate by measuring the peak voltage across resistor 328 and limiting the turn-on pulse width of transistor 326.

On the other hand, the operation case (2) is controlled by the current diverting circuit 314 as follows. Since the skin resistance R₁ of the patient tends to a low value, so that l (l_l.R₁) + V_re,] <(V₊-V_(l), the load current becomes l | not limited by the skin resistance Ri and increase.

At the limit, as Ri approaches zero, h increases and is only of voltage V₊ divided by the series resistance of resistors 342, 344 and the resistance of transistor 340.

The increase in l | makes the voltage at the source of transistor 340 positive until feedback input 350 causes the amplifier circuit to take control of the load current I | begins to lose when the circuit 322 the switch 326 to maintain the load current I | does not have to switch.

In the circuit of FIG. 8, the resistors 342 and 344 are chosen such that the ratio of R₃: (R₂ + R₃) is sufficiently close to one, ie the resistance value R.₂ much smaller than the resistance value R.₃ is (e.g. R₂ = 3 Ω, R₃ = 1.5 kQ). In the operating case (2), when h increases and the voltage across the resistor R₃ increases, the voltage differential across the inputs of operational amplifier 346 drops enough to cause the output of operational amplifier 346 to decrease the voltage on the gate of transistor 340.

Transistor 340 then comes out of saturation and starts in series with R₂ and R₃ to show a variable impedance. The outputs from operational amplifier 346 and inputs V_ref as well as the portion of the negative feedback voltage (ie, the feedback voltage to operational amplifier 346 that is equal to the load current times the resistance R₃, ie I ,. R.₃ ist) controlled transistor impedance varies. This varying the additional impedance of transistor 340 prevents the slope of to increase further.

The reinforcement A_v of operational amplifier 346 and the ratio R₃: (R₂ + R₃) are chosen so that the difference between the current I, in operating case (1) and in operating case (2) is sufficiently narrow. An operational amplifier with a gain greater than 1000, a resistor R₂ of 3 Ω and a resistor R₃ of 1.5 kΩ differ by less than 5%. In the past, this situation was overcome with additional logic circuits (e.g. microprocessors), resistors and switches. The logic circuit sensed an "undersupply" condition and placed a resistor in series with load 306, resetting amplifier circuit 312 to resume current control. The addition of a microprocessor and other components increases the costs and leads to an increased power consumption for operation and to a lower degree of efficiency. It is also less efficient to operate the amplifier circuit 312 continuously if it is not necessary. This becomes an even bigger problem when the supply voltage is higher.

The current limiting circuit 314, in conjunction with the amplifier circuit 312, provides a simple, inexpensive, electrically efficient and effective means of controlling the therapeutic current I | with an acceptably constant amount over a wide range of skin resistance R_v

The additional impedance represented by transistor 340 in operating case (2) could also be represented by other active devices, such as a P-channel transistor or a bipolar pnp or npn transistor or the like. The current measurement could be through a hall effect sensor

AT 408 616 B or a magnetic measuring device, such as a switchable current sampling converter. A suitable feedback gain could also be achieved with discrete transistors, resistors and capacitors which are combined to form a differential amplifier, which is well within the capabilities of the person skilled in the art.

While the invention has been described in terms of particular embodiments which, taken together, represent the best mode known to the inventors for carrying out their invention, many changes could be made and thus many alternative embodiments derived without departing from the scope of the invention. Accordingly, the scope of the invention is to be determined solely by the following claims.