An electrotransport delivery device with voltage boosting circuit

(54) NAME Electron transport device with voltage boosting circuit intended for drug administration (56) PUBLICATIONS QUOTED: - - (57) SUMMARY:

Electrotransport device (10) for administering therapeutic agents comprising an adjustable voltage gain multiple regulator (100, 200) to amplify the voltage from a voltage source (102, 202) to a working voltage (V_w) having a value just sufficient to provide the desired therapeutic current level (I I) through the electrodes (108, 112), at least one of which contains the therapeutic agent to be administered.

1OO

<img file="SE520344C2_D0001.tif" />

The numbers in brackets indicate international identification code, INID code. Letters in clamps indicate international document code.

520 344

Summary

Electrotransport device (10) for administering therapeutic agents comprising an adjustable voltage gain multiple regulator (100, 200) to amplify the voltage from a voltage source (102, 202) to a working voltage (V_w) having a value just sufficient to provide the desired therapeutic current level (I I) through the electrodes (108, 112), at least one of which contains the therapeutic agent to be administered.

520 344

The invention relates to an electrotransport device for transdermal or transmucosal administration of a useful agent (e.g., a drug) to a patient. In particular, the invention relates to a portable or patient-carried electrotransport delivery device which has an improved power supply.

The term "electrotransport" used as follows generally refers to the administration of an agent (e.g., a drug) through a membrane, such as skin, mucosa, or nails, which administration is induced or facilitated by the application of an electrical potential. For example, a drug may be introduced into the circulatory system of an animal (e.g., a human) by electrotransport administration through the skin.

Electrotransport methods have been found to be useful in transdermal administration of drugs which include lidocaine, hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, and many other drugs. Perhaps the most common use of electrotransport in the diagnosis of cystic fibrosis by administering pilocarpine salts is ionophoretic. Pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of a disease.

Hitherto known electrotransport devices use at least two electrodes arranged in immediate contact with a part of the body (e.g., the skin). A first electrode, designated the active electrode or donor electrode, delivers the therapeutic agent (e.g., a drug or prodrug) into the body through electrotransport. The second electrode, called the counter or conduction electrode, forms an electrical circuit with the first electrode through the patient's body. A source of electrical energy, such as a battery, supplies electrical power to the body through

520 344 electrodes. For example, if the therapeutic agent to be administered to the body is positively charged (i.e., a cation), the anode will be the active electrode and the cathode will serve as the counter electrode to close the circuit. If the therapeutic agent to be administered is negatively charged (i.e., an anion), the cathode will be the sensor electrode and the anode will be the counter electrode.

Alternatively, both the anode and cathode can be used to administer drugs with opposite electrical charge into the body. In this case, both electrodes are sensor and counter electrodes. For example, the anode may be simultaneously applied to a cationic therapeutic agent and act as a "counter electrode" to the cathode. In the same way, the cathode can simultaneously be applied to an anionic therapeutic agent into the body and act as a "counter electrode" to the anode.

A widely used electrotransport method, electromigration (also referred to as iontophoresis), involves the electrically induced transport of charged ions. Another type of electrotransport, electroosmosis, comprises the flow of a liquid solvent from the donor reservoir, liquid containing the agent to be supplied, under the influence of the applied electric field. Still another type of electrotransport method, electroporation, involves the formation of temporarily existing poles in a biological membrane by applying high voltage pulses. A therapeutic agent may be partially applied to the skin by passive diffusion through the concentration difference between the concentration of the drug in the donor reservoir and the electrotransport device and the concentration of the drug in the tissues of the patient's body. In all electrotransport processes, more than one of these processes can occur to a certain extent simultaneously. Thus, the term "electrotransport" as used hereinafter should be given the widest possible meaning so as to include the electrically induced or enhanced transport of at least one therapeutic agent, whether charged, uncharged, or a mixture thereof.

520 344

The terms "drug" and "therapeutic agent" are used interchangeably and are intended to have their broadest meaning, namely, which therapeutically active substance is added to a living organism to produce a desirable, usually useful, effect. This includes therapeutic agents in all major therapeutic areas including, but not limited to: anti-infection agents such as antibiotics and antivirals; painkillers which include fentanyl, sufentanil, buprenorph and painkillers; anesthetic; appetite suppressants, anti-arthritis; agents for asthma, such as terbutaline; remedies for epilepsy; antidepressants; antidiabetic agents; antidiarrherala; antihistamines; anti-inflammatory agents; headache remedies; antidote agents such as scopolamine and ondansetron; remedies for nausea; antineoplastics; agents against Parkinson's; pruritus; antipsychotics; antipyretic agents, including gastrointestinal and urinary tract; anticholinergics; sympathomimetrics; xanthine derivative; cardiovascular agents which include calcium channel blockers such as nifedipine; beta-blockers, such as dobutamine and ritodrine; antiarrhythmics; antihypertensive agents such as atenolol; ACE inhibitors such as ranitidine; diuretics; vasodilators, which include common, coronary peripheral, and brain agents; stimulants for the central nervous system; cough agents and antidotes; anti-mucosal swelling; diagnostic agents; jormones, such as parathyroid hormone; muscle relaxants; parasympatolytikum; parasympatomimetikum; prostaglandins; proteins; peptides; psychologically stimulating agents; various types of sedatives.

Electrotransport is also useful in the controlled administration of peptides, polypeptides, proteins and other macromolecules. These macromolecular substances usually have a molecular weight of at least 300 Daltons, and in particular they have a molecular weight of 300-40000 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: insulin; insulotropin; calcitonin; octreotide; endorphin; TRH; NT-36 (chemical name is N = [[[s) -4-oxo-2520 344]

azetidinyl] carbonyl] -L-histidyl-L-prolinamide); liprecin; growth hormones such as HGH, HMG and desmopressin acetate; follikelluteoider; aANF; growth factors such as growth factor triggering factor (GFRF or GHRH); bMSH; somatostatin; bradykinin; somatotropin; platelet-derived growth factor; asparaginase; chymopapain; cholecystokinin; chorinic gonadotropin; corticotropin (ACTH); erythropoietin; epoprostenol (inhibitor against platelet aggregates); gjukagon; HCG; hirulog; hyaluronas; interferon; interleukins, menotropins (urofollitropin) (FSH) and LH); oxitokin; streptokinase; plasminogen activator for tissue; vasopressin; desmopressin; ACTH analogues; ANP; ANP releasing inhibitors; angiotensin II antagonists; antidiuretic hormone antagonists; antagonists against bradykinin: CD-4; ceredase; CSFs; enkephaliner; FAB fragments; IgE peptide suppressors; IGF-1; neurotropic factors; colony stimulating factors; parathyroid hormone and antagonists; antagonists to parathyroid hormone; antagonists to prostaglandin; pentigtide: protein C; protein S, renin inhibitors; thymosin alpha-1; thrombolytics; TNF, vaccines; analog vasopressin antagonists; alpha-1 anti-trypsin (recombinant); and TGF-beta.

Electrotransport devices usually require a reservoir or source of the agent, or a precursor of such agent, to be administered to the body by electrotransport. Examples of such reservoirs or sources of preferably ionized or ionizable agents include a bag described in US-A-4 250 878 or a preformed gel body described in US-A-4 383 529. Such reservoirs are electrically connected to the anode or cathode of an electrotransport device to provide a constant or reusable source for one or more desired therapeutic agents.

Recently, a number of US patents have been issued in the field of electrotransport, showing an ongoing interest in this area of ​​drug administration. For example, US-3,991,755, US-A-4,141,359, US-A-4,398,545 and US-A-4,250,878 show examples of electrotransport devices and some applications thereof.

More recently, electrotransport administration devices have become much smaller, especially in connection with the development of miniaturized electrical circuits (e.g.

520 344 ex integrated circuits) and more powerful lightweight batteries (eg lithium batteries). The advent of inexpensive miniaturized electronic circuits and compact high-energy batteries has provided whole devices that can be made small enough to be easily worn on the patient's skin, under the clothing. This allows the patient to be fully mobile and able to do all normal activities, even during periods when the electrotransport device is actively administering drugs.

Nevertheless, some limitations remain, which reduce further use of this valuable technology. One such limitation is the size and cost of an electrotransport administration device. Specifically, the batteries needed for electrotransport devices make a significant contribution to the overall size and weight, as well as the cost, of these smaller patient-based electrotransport delivery devices. A reduction in the number and / or cost of these batteries would allow the electrotransport of drug delivery devices to be made smaller and at a lower cost.

One method of reducing the number of batteries needed for power in an electrotransport device is to use a voltage amplifier circuit.

Amplifier circuits are well known in the electrical field. Conventional amplifier circuits have a setting (e.g., 3.0 volts) and amplify it by a predetermined multiple (e.g., x2) to give a "amplified" output voltage (e.g., 6.0v = 3.0vx 2). Voltage amplifier circuits have been used in transdermal electrotransport delivery devices. See US-A-5 254 081 (see column 2, lines 34-39).

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

520 344

The problem of reducing the cost of a voltage source in an electrotransport delivery device is compounded by the fact that the electrical resistance in the patient's body surface (e.g., skin) is not constant during electrotransport administration. Since the voltage (V) necessary to drive a particular level of electrical current (i) through the patient's skin is proportional to the resistance (R) in the skin (ie according to Ohm's law, where V = iRhud), the voltage requirements of the voltage source are not constantly during electrotransport administration. For example, when electrotransport administration is initiated, the patient's original skin resistance is relatively high, which means that the voltage source must provide relatively high voltage to supply a predetermined level of electrotransport current. However, after several minutes (ie, after about 1 to 30 minutes of current supplied through the skin), the skin's resistance decreases, so that the voltage requirement needed to apply a particular level of electrical current becomes significantly less than the voltage needed at the beginning of the electrotransport administration. See, for example, US-A-5,374,242, which describes the varying skin resistance and the use of 2 or more batteries connected either in parallel or in series to cope with the varying skin resistance.

Although conventional voltage amplifier circuits can provide the output voltage necessary for the high initial skin resistance, they reduce the efficiency of the device and require more battery voltage during periods when the skin resistance is lower than the initial state, resulting in lower efficiency and increased battery size and cost.

US-A-4,141,359, which is referred to, discloses a direct-to-direct current converter having a converter that inductively couples periodic variations of current in a primary coil to pulses in a secondary coil with a fixed voltage multiple of the primary voltage source. These pulses of secondary current from the coil are passed through the skin with therapeutic electrodes. The average or direct current value of the secondary current is controlled by a fault voltage and feedback circuit so that the average value of the secondary current is kept constant. A disadvantage with Jacobsens

520 344 circuit is that the peak value of the fixed and multiplied voltage is directly above the electrode. The peak voltage is unnecessary for those cases where the skin resistance is low, and results in unnecessarily high current pulses of therapeutic current and possible adverse effects on the skin.

US-A-5,426,387 discloses a device comprising a switching mode power source equipped with an electronic switching means, which in closing controls the applied power to a coil discharged when the electronic switching means is reopened, to a capacitor having connections at which the output voltage from the device occurs. The apparatus comprises a clocked digital counter and a microcontroller for successfully charging the counter with a predetermined sequence of numbers which serves as a band for the count performed by the counter, the counter cyclically controlling the closure of the electronic switching means for a predetermined time interval so that the output voltage of follows a predetermined waveform, which corresponds to the number sequence. A disadvantage of the device of US-A-5,426,387 is that it requires a relatively expensive, complex and physically large microcontroller / counting device to provide a certain level of therapeutic current. As a result, the device may not be suitable for certain applications in which a small, lightweight and inexpensive electrotransport delivery device is desirable or necessary.

It is an object of the invention to provide a device operating with improved efficiency of an electrotransport means supply device having a voltage amplifier circuit.

Another object of the invention is to provide an apparatus operating with an electrotransport agent delivery device, in which the voltage of the voltage source is amplified to a level that is optimally suitable for the conditions (e.g., skin resistance) of the drug administration.

520 344

The invention relates to a drug delivery electrotransport device having a voltage amplifier circuit which amplifies the voltage source of the (battery) voltage, in which the amplifier circuit amplifier multiple is automatically controlled depending on the skin resistance of the patient. The device is adapted to administer a therapeutic agent through the surface of an animal body (e.g., human skin) by electrotransport.

The device has a voltage source (eg one or more batteries) with an output voltage. The output voltage of the voltage source is amplified by a voltage amplifier, which has an adjustable gain multiple to provide a working voltage. A body surface parameter, selected from the electrical resistance of the body surface, the voltage drop across the body surface and the current supplied through the body surface is sensed and the gain multiple is adjusted based on the sensed body surface parameter to provide an adjusted working voltage. By adjusting the gain multiple based on the sensed body parameter (e.g., skin resistance), the device supplies only the level of voltage needed to supply a predetermined level of electrotransport current, with no additional voltage consumed by the amplifier circuit. Thus, the method according to the invention relates to improved efficiency in the operation of an electrotransport delivery device.

The above and other features, aspects and advantages of the invention will become more apparent with the following description and drawings, in which:

Fig. 1 is a perspective view of an electrotransport device for administering drugs according to the invention;

Fig. 2 is an exploded view of an electrotransport device according to the invention;

Fig. 3 is a graph illustrating how the patient's skin resistance decreases with time:

520 Fig. 4 is a schematic diagram of an adjustable voltage amplifier circuit according to the invention;

Fig. 5 is a timing diagram using the circuit of Fig. 4;

Fig. 6 is a schematic diagram of another adjustable voltage amplifier circuit according to the invention;

Fig. 7 is a timing diagram of the use of the circuit of Fig. 6; and Fig. 8 is a schematic diagram of another adjustable voltage amplifier circuit according to the invention.

The electronic circuit of the invention can be used in substantially all electrotransport delivery devices, although the circuits have special use in these devices adapted to administer agents transdermally through electrotransport. Examples of electrotransport delivery devices which can be used with the circuits of the invention are shown in Figures 1 and 2. Referring to Figs. 1 is shown a perspective view of an electrotransport device 10 possibly having an actuator switch in the form of a push button switch 12 and an optional LED (LED) 14 which is turned on when the device 10 is used.

Fig. 2 is an exploded view of a second device 10 'according to the invention. The device 10 'in Figure 2 differs from the device 10 in Figure 1 in the placement of both LEDs 14'. LED 14 'is located adjacent pushbutton switch 12 on a single of device 10' in this embodiment of the invention. Device 10 'includes an upper housing 16, a circuit board 18, a lower housing 20, anode electrode 22, cathode electrode 24, anode reservoir 26, cathode reservoir 28, and skin compatible adhesive plate 30. The upper housing 16 has lateral wings 15 which help to hold the device 10 'against a patient's skin. The upper housing 16 is preferably comprised of an injection-moldable elastomer (e.g., ethylene vinyl acetate). The circuit board 18 includes one

520 344 P ”; Uy · &lt;ί;

An integrated circuit 19 connected to discrete components 40 and battery 32. The circuit board 18 is connected to the housing 16 via contacts (not shown in Fig. 2) passing through the openings 13a and 13b. The ends of the pins are heated / melted to heat seal the circuit board against the housing 16. The lower housing 20 is connected to the upper housing 16 through the adhesive plate 30, the upper surface 34 of the adhesive plate 30 is attached to both the lower housing 20 and the upper housing 16 comprising the bottom surfaces of the wings

15.

On the underside of the circuit board 18 is shown (partially) a button cell battery 32. Other types of batteries can also be used to supply device 10 '.

The device 10 'usually consists of battery 32, electronic circuits 19, 40, electrodes 22, 24 and drug / chemical reservoirs 26, 28, all of which are integrated into a self-supporting unit. The outputs (not shown in Fig. 2) of the circuit board make electrical contact with the electrodes 24 and 22 through the openings 23, 23 'of the recesses 25, 25' formed in the lower housing 20 by electrically conductive adhesive strips 42, 42 '. The electrodes 22 and 24, in turn, are in direct mechanical and electrical contact with the tops 44 ', 44 of the drug reservoirs 26 and 28. The bottom sides 46', 46 of the drug reservoirs 26, 28 come into contact with the patient's skin through the openings 29 ', 29 of the adhesive plate. 30 °.

After the push-button switch 12 is pressed, the electronic circuit on the circuit board supplies a predetermined direct current to the electrodes / reservoirs 22, 26 and 24, 28 for a predetermined length supply interval. Preferably, the device transmits to the user a visual and / or audible confirmation of the switching on of the drug supply by LED 14 'being lit and / or an audible beep from, for example, a "beeper". Medicines are thereby administered from one of the reservoirs 26, 28 and through the patient's skin by electrotransport.

The anode electrode 22 preferably comprises silver and the cathode electrode 24 preferably comprises silver chloride. Both reservoirs 26 and 28 preferably consist of

520 344 polymeric hydrogel materials. Electrodes 22, 24 and reservoirs 26, 28 are retained by the lower housing 20. One of reservoirs 26, 28 is "donor" reservoir and contains the therapeutic agent (e.g., a drug) to be administered and the other reservoir usually contains a biocompatible electrolyte.

The pushbutton switch 12, the electronic circuit on the circuit board, and the battery 32 are glued (sealed) between upper housing 16 and lower housing 20. Upper housing 16 preferably consists of rubber or other elastomeric material. Lower casing 20 preferably consists of a plastic or elastomeric sheet material (e.g. polyethylene) which can be molded easily to form indentations 25, 25 'and cut to form apertures 23, 23'. The assembled device 10 'is preferably water resistant (ie, splash proof) and is preferably waterproof. The system has a low profile that easily encloses the body, allowing permissive movement at and around the site where it is worn. The reservoirs 26, 28 are located on the contacting side which contacts the skin of the device 10 'and are sufficiently separated to prevent involuntary electrical short circuits in normal use.

The device 10 'adheres to the patient's body surface (e.g., the skin) through a peripheral adhesive plate 30 having an upper side 34 and a side 36 in contact with the skin. The adhesive side 36 has adhesive properties which ensure that the device 10 'remains in place on the body during normal use activity, but still allows removal after a predetermined (e.g., 24 hour) period. The upper adhesive side 34 adheres to the lower casing 20 and retains the electrodes and drug reservoirs within the casings 25, 25 'as well as retains it under the casing 24 to the top casing 16.

The pushbutton switch 12 is advantageously placed on the upper side of the device 10 'and is easily operated through the clothing. A double push of the push button switch within a short period of time, e.g., 3 seconds, is preferably used to activate the drug delivery device, thereby minimizing the likelihood of unintentional actuation of the device 10 '.

520 344

When the drug is first started, the skin's resistance to the patient is usually relatively high, while after a period of time, the skin's resistance drops significantly. Fig. 3 illustrates this property graphically, showing that the decrease of the skin's resistance R is essentially asymptotic to a steady state value. For a discharge rate of 0.1 mA / crrU, this steady state value is typically on the order of 20 to 30 kohm / cmL while the initial value of the skin's resistance is several or many times that.

In prior art electrotransport administration devices, the voltage source and / or amplification multiple of the voltage amplifier circuit was selected large enough to overcome the high skin resistance present at the start of use. However, when use has reached steady state, with consequent cases of skin resistance, devices of the prior art have excess working voltage. In some prior art devices, the applied voltage needed to supply a particular steady state current was used half or less of the voltage needed to provide the same current level at the start of electrotransport administration. Thus, these prior art devices were not cost effective since the voltage was discarded in the voltage amplifier circuit when the skin resistance has well fallen from its original high level.

Fig. 4 is a schematic diagram of a voltage amplifier electrotransport circuit 100 having an adjustable gain multiple controlled by a sensing therapeutic load current level in accordance with the invention. This provides more efficient use of batteries and results in significant size and cost savings when compared to the prior art just described. The circuit 100 comprises a voltage source in the form of a battery 102, and a voltage controlled electrical connection 104 electrically connected to an electrode device 108.

The electrode assembly 108 is attached to a region of an animal body 110 by conventional methods such as adhesives, cords, belts or the like. animal body^{520 344} PjU9 ΐ ^: is shown schematically as a variable load resistance, R_v to show the variation of load resistance typically in the skin when applying electric current I] therethrough.

An electrode device 112 is simultaneously connected to another part of the animal body 110. The electrode device 112 is connected to a series current sensing resistor 114. The electrodes 108, 112, the body surface 110 and the sensing resistor 114 form a load current path for conducting the load current, I |. The electrode devices 108, 112 are equal to the electrode / reservoir combinations 22, 26 and 24, 28 shown in Figure 2. At least one of the electrode devices 108, 112 contains a therapeutic agent (e.g., a drug salt) in a form (e.g., aqueous solution) suitable for electrotransport administration into the animal body 110.

A battery indicator 118 is connected between the battery 102 and the anode of the feedback diode 120. The cathode of the diode 120 is connected to voltage controlled electrical connection 104. A filter capacitor 122 is connected between the connection 104 and system ground.

A controlled switch 124 having a control value 126 has one end 128 connected to the connection of the anode in diode 120 and coil 118 and another end 130 connected to system ground. Alternatively, the control value 126 can open and close the switch 124 creating a low resistance connection between the ends 128 and 130 thereby connecting or disconnecting the coil 118 via a path with low resistance to system ground. Switch 124 may be an electronic switching device such as a bipolar or FET transistor.

A control circuit 132 has a control output 134 connected to switch control input 126. Control circuit 132 includes a feedback input 134 for controlling control output 126 and a switching input 136.

The use of the adjustable voltage amplifier circuit 100 can be explained with reference to Fig. 5. After starting the circuit 100, e.g.

520 344 pushbutton switch 12 shown in Fig. 1, control circuit 132 is first adapted to connect input 136 to system ground. This affects the sensing resistor 114 to start conducting load current, Ii from the load 110.

The control circuit 132 is arranged to switch on the control output 134 so that the switch 124 is connected to a single of the coil 118 to ground for a period of time T1. During the time T1, the coil current Ij, driven by the battery 102, increases to a maximum value IpV at the end of time T_1? For example, control circuit 132 is adapted to change output 134 to switch switching input 126 again, which opens switch 124 for a period of time T2. During T2, coil current I, will not flow to ground, but will be forced through diode 120 into electrical connection 104. Filter capacitor 122 provides a low impedance path for the temporary current Ij, which then sinks to zero during time, T2 when the voltage at the electrical node 104 is increased by charging the capacitor 122.

Meanwhile T1, the coil stores energy by charging with the current Ij. During the period T2, coil 118 discharges energy into filter capacitor 122 through diode 120. Coil 118 thereby transfers energy from battery 102 into low loss capacitor 122, limited only by diode drop in diode 120 and negligible series resistances in coil 118, battery 102 and the electrical connections. Thus, the voltage source for load current is I | not directly the battery 102 but rather either the capacitor 122 (ie, during the time T1) or a combination of the capacitor 122 and the coil 118 (ie, during the time T2).

The control circuit 132 is adapted to repeat the T1, T2 cycle indefinitely or when stopped as described below. Voltage V_w at the connection 104 is thereby increased to an adjustable multiple of the battery voltage 102 depending on the values ​​of the time periods T1 and T2. Thus, the gain multiple can be controlled by changing the values ​​T1 and T2.

520 344

Dotted lines in Fig. 5 show lost or delayed pulses controlled by the control circuit 132. This may occur when the pulses do not necessarily replace charge coming from capacitor 122, for example when the therapeutic current I_swhat is needed is relatively low. The dotted line in Fig. 5 shows that the amplifier multiple control means may be a pulse width modulation (PVM), pulse frequency modulation (PFM), pulse skipping, or a combination thereof .

The adjustable working voltage V_w causing the charge current I; to flow through the animal's body load 110, through the sensing resistor 114 and into the switching input 136 to ground.

The feedback input 133 senses the voltage across the sensing resistor 114 caused by the load current I). The control circuit 132 is adapted to respond to the feedback input 132 to amplify the operating voltage V_w by regulating the time periods, T1 and T2. This is accomplished by comparing the voltage sensed at input 133 to a set reference voltage within the control circuit 132. If the voltage sensed at input 133 is less than the reference voltage, the control circuit 132 opens and closes switch 124 at a high frequency until V_w raised to the appropriate level. Usually, the longer the switch 124 is closed (i.e., the longer the T1), the greater the voltage developed in the coil 118 and the greater the gain multiple. The battery voltage 132 can be amplified by the coil 118. The voltage developed in the coil 118 equals the inductance value (L) multiplied by a rate at which current flows through the coil:

V_ind = L (dI_in/ Dt).

Thus, from the coil 118, a high voltage (whereby the voltage is determined to a portion of the inductance value of the coil 118 and to a portion of the current flow rate through the coil 118 controlled by the values ​​T1 and T2) at a lower current when the power enters the coil 118 must be equal to the power output from coil 118.

520 344

The control circuit 132 is optionally adjusted so that in combination with the values ​​from coil 118, the values ​​of load resistance 110 and capacitance value are arranged in capacitor 122, time periods T1, T2 to correspond to the voltage at feedback input 133 so that filter capacitor 122 softens and regulates voltage V_w to give a charging current, Ij of a substantially constant direct current of predetermined value.

The electrode devices 108 and 112, and thus the animal body 110, are not exposed to high peak voltages as in prior art, but instead sense only a minimum voltage value sufficient to drive the desired load current Ij.

The time periods T1 and T2 are controlled by the control circuit 132 to increase V_w to a minimum absolute value to give the charge current I | to maintain a desired predetermined value. If the resistance of the load 110 is too high to give a predetermined value of Ii to be obtained without having V_w exceeding a safety level, limiting the voltage limiting device, such as a zener diode 116 connected across electrode means 108 and 112 voltage applied to load 110. A typical safety maximum limiting value for V_w is about 24 volts. Other values ​​of voltage limitation can be obtained by zener diodes 116 having different cutting voltages, or by using other protective measures described below.

Once the resistance of the load 110 decreases enough to allow the load current I | to reach the desired predetermined level at maximum safety voltage, the control circuit 132 will respond to feedback in the feedback input 133 and will adjust T1 and T2 to increase V_w to a multiple just enough to maintain current at a predetermined level regardless of further reduction of resistance.

The working voltage V_w thus, at the controlled electrical connection 104 is amplified to a gain multiple of the battery voltage 102 just enough to

520 344 maintain the load current h at a predetermined value as long as the load voltage is less than the limiting voltage set by the zener diode 116.

The low loss of energy transfer from the battery 102 to the load 110 and the capacitor 122 maximizes the useful life of the battery 102 at a given battery capacity. This allows smaller batteries to be used for a particular therapeutic range or extends the life of the therapeutic treatment for a certain cost. .

The predetermined current Ij applied over the load 110 may be constant or vary with time. In any case, the control circuit 132 is provided with means for establishing a predetermined current time profile to be applied. This can be accomplished by means well known in the art, such as a differential comparator having an input connected to a sensing resistor 114, a constant reference voltage connected to the second input, or having the second input connected to the output of a D / A converter which is powered of a clocked ROM, which has a preprogrammed pattern (not shown in Fig. 4).

The circuit 100 can also be provided with a protective circuit 138. The protective circuit 138 has high impedance and low impedance controlling functions and includes an input 140 which detects the voltage drop across the load 110 and compares the detected voltage drop with a predetermined minimum limit therefor. Circuit 138 also includes an input 142 which senses current I] applied through load 110 and compares the sensed current to a predetermined maximum value therefor. Protection circuits that provide impedance control and impact protection are well known in the art. See, for example, the protective circuits shown in Fig. 1 according to US-A-4 141 359 to which reference is made.

The protection circuit 138 monitors the resistance of the load 110 through voltage input 140 and current input 142 and shuts down the voltage gain function of the circuit 100 when the resistance of the load 110 exceeds a predetermined upper limit or goes below a predetermined lower limit. Enclosures of the protection and disconnection circuit^{520 344 :} HJ 'h · 1 / -:

138 of the type described in US-A-4,141,359 into the amplifier circuit 100 is adjacent to a person skilled in the electrical field.

In use, the electrode devices 108 and 112 are attached to the skin surface 110 by conventional means and the therapeutic current initiated by a switching means (not shown) such as switch 12 shown in Fig. 1. Control circuit 132 begins to check and disconnect switch 124. Repeating pulses of coil current f is alternately charged during the on-time periods, T1 through switch 124 to ground and discharged during the off-time periods on shutdown, T2 into capacitor 122. These pulses of coil current f give the voltage V_w to be multiplied by an adjustable gain multiple by controlling and times T1, T2 until the signal being fed back to input 133 indicates that the charging current f is in control.

Fig. 6 shows another adjustable amplifying circuit 200 according to the invention. Circuit 200 includes a battery 202 a coil 204 a diode 206, a voltage controlled electrical connection 207, a low resistance filter capacitor 208, electrode means 210,

212, which is connected by conventional means to isolated areas of the animal body

213th The animal body 213 is schematically represented as a variable load resistance R_v to emphasize the fact that the resistance of the load 213 varies with time and current.

At least one of the electrode members 210, 212 contains a therapeutic agent in a suitable form for electrotransport administration into the animal body 213.

Circuit 200 includes an N-channel field effect transistor (FET) switch 218, to switch the coil current I_;, a resistor 220 sensing the current in the coil and a resistor 214 sensing the current of the load. The circuit also includes a high-efficiency, adjustable direct-current DC step up regulator 216. A preferred controller 216 is Maxim MAX773 manufactured by Maxim Integrated Products, Inc. of Sunnyvale, CA.

520 344

Fig. 6 shows a simplified diagram of MAX773 controller 216 sufficient for the purposes of the invention. A more detailed diagram of the MAX773 controller can be seen in MAX773 data sheet 19-0201; Rev 0; 11; 93, as the manufacturer's phase. The controller 216 is an integrated circuit having internal components connected by conductive grooves formed during the manufacturing process of the integrated circuit. External pins are used to provide electrical connection to external components through conventional circuitry, such as plated or deposited copper or other conductors deposited and formed on insulating substrates. Reference to electrical connection in the description herein is understood as internal or external as shown in Fig. 6. Reference to the components of the MAX773 regulator circuit are illustrative of the purposes of describing the function of the circuit 216. Unlike traditional pulse frequency converters (PFMs) which use fault voltage from the voltage conductor circuit to control the output voltage of the converter at a constant value, controller 216 is connected to use the sensing resistor 214 to generate an error voltage to control the average load current I |. The MAX773 controller also operates at high frequencies (up to 300 kHz) which allows the use of small external components. The controller 216 includes a reference voltage terminal 256, a ground terminal 258, a ground switching input 260, a low-level threshold input 262, a feedback input 264, a downlink input 266, a current sensing input 268, and a power supply bus input 270.

The controller 216 also includes a first two input comparator 230 having an output 231, a second two input comparator 232 having an output 233, a first reference voltage 242, a second (e.g., 1.5 volts) reference voltage 244, a third two input comparator 246 having an output. 247, a PFM / PWM driver 240 having a switching control output 252 and a switching control output 254, and a second N-channel FET switch 250.

Use of the circuit 200 can be understood with reference to Figs. 6 and 7. The circuit 200 uses the controller 216 in a new way to provide a high efficiency transmission of

520 344 PhUh ^:· L · energy from the battery 202 to an adjustable elevated voltage V_w at a controlled electrical connection point 207 and at the same time the load current fr

Referring to Fig. 6 of the invention, a portion of the load current Ii is fed back to the input 264. One end of the sensing resistor 214 is connected to the feedback input 264. This same end of the resistor 214 is also connected to the electrode means 212 to receive the load current Ij. The other end of the resistor 214 is connected to the input 260 of the controller 216. The input 260 connects internally to the drain of the N-channel transistor switch 250. The source of the transistor switch 250 is connected to system ground. The gate of transistor switch 250 is connected to the output 247 of the comparator 246. The inverting input of the comparator 246 is connected to the input terminal 262. The input terminal 262 is connected to system ground. The non-inverting input of comparator 246 is connected to a reference voltage 244. Reference voltage 244 also connects to reference voltage terminal 256. Comparator 246 is operated so that output 247 is always high. Therefore, the transistor switch 250 will be driven to conduct the connection 260 to ground, which lowers the load current I_t to ground through the sensing resistor 214.

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

The output 231 of the comparator 230 is connected to the PFM / PWM driver circuit 240. The inverting input of the comparator 230 is connected to the reference voltage 242: The non-inverting input of the comparator 230 is connected to the current sensing input 268. Input 268 is connected to one of the coil current sensors 220. the end of resistor 220 is connected to system ground. The ground pin 258 in the controller 216 is also connected to system ground.

An output of PFM / PWM driver 240 is connected to output 252. Input 270 is connected to one end of battery 202. The other end of battery 202 is connected to system ground.

520 344 p / UMAt

An output of PFM / PWM driver 240 connects output 254. Outputs 252 and 254 are both connected to the gate of external N-channel transistor switch 218. Drain of transistor switch 218 is connected to a switching point on one end of the energy storage coil 204 and the anode of rectifier diode 206. The source of transistor switch 218 is connected to one end of the coil current sense resistor 220, which is connected to the current sense input 268.

The other end of coil 204 is connected to power bus input 270 and the other end to battery 202. A filter capacitor 276 is connected between input 270 and ground. A filter capacitor 278 is connected between the voltage terminal 256 and ground. The filter capacitors 276 and 278 have low dynamic impedance at the pulse frequencies of interest.

The cathode of diode 206 is connected to an electrical connection 207. The connection point 207 is also connected to one end of filter capacitor 208, the cathode of a zener diode 280 and the electrode means 210. The anode of the zener diode 280 and the other end of capacitor 208 are connected to ground. The connection point 207 closes circuit 200 which amplifies the operating voltage V_w at the connection point 207 through an adjustable multiple of the voltage of the voltage source, i.e., battery 202.

The zener diode 280 provides an opportunity to limit voltage peaks across the electrode means 210 and 212 and thus the maximum voltage exerted on the animal body load 213.

Referring to Figures 6 and 7, the operation of the adjustable voltage gain multiple circuit 200 is explained. When voltage is applied by the battery 202 to the input 240 and the input signal 266 is of the correct logic level, the controller 216 begins to operate. When the input 262 is kept low and the non-inverting input of the comparator 247 is at, for example, 1.5 volts from the reference voltage 244, the output of the comparator 246 will be high. With a high voltage on the gate of transistor switch 250 and input 260 will be driven to ground through the drain

520 344 in transistor switch 250. This allows resistor 214 to receive load current I] from electrode means 212.

As with traditional PFM converters, the transistor switch is not turned on until the voltage comparator 232 senses that the output current is out of control. However, unlike traditional PFM converters, the MAX773 uses the combination of peak coil current limiting resistor 220, reference voltage 242 and comparator 230 together with maximum switch on time and minimum switch-off time generated by PFM / PWM drive circuit 240; there is no oscillator. The typical maximum switch-on time, T2 is 16 microseconds. The typical minimum switch-off time, T2, is 2.3 microseconds.

Once turned off, the minimal off-time keeps transistor switch 218 off during time T2. After this minimum time, either the transistor switch (1) stops at the output current I; is in control, or (2) is turned on again if the output current I | is impossible to regulate.

When transistor switch 218 is off, coil current f flows through diode 206 into capacitor 208 at connection point 207, which replenishes all charge withdrawn by load 213. It may be found that this method of coupling load current Ij provides an adjustable increase multiple of battery 202 a working voltage V_w at the junction point 207, just enough to supply the desired constant current h. The peak voltage provided by coil 204 will be exactly that needed to overcome the diode drop in diode 206 and operating voltage V, thus minimizing the energy loss from battery 202.

Regulator circuit 216 allows circuit 200 to operate in continuous conductive state (CCM) while maintaining high efficiency with heavy loads. When switch 218 is turned on, it stops until either (1) the maximum on time turns off (typically 16 microseconds later) or (2) when the coil current Ij reaches the peak current limit I_p set by the coil current limiting resistor 220,

520 344 reference voltage 242 and comparator 230.1 in this case the on-time will be the maximum on-time, T1. Limiting peak current through the coil to a predetermined maximum I_p avoids saturating coil 204 and allows the use of smaller values ​​on the coil, thus smaller components.

If the mean load current Ij is below the desired value set by V_REf of reference voltage 244 and resistance value R_s of sensing resistor 214 through the connection

Vref^&gt; Ii · R_s then PFRM / PWM driver 240 will automatically adjust on-time T1 and off-time T2 and alternately turn switch 218 on and off until load current I₍ is in control.

Operation of the adjustable gain multiple circuit can be initiated by connecting the shutdown input 266 to a logic high level through switching means, such as switch 12 shown in Fig. 1. When the shutdown input 266 is high, the MAX773 circuit will enter a shutdown position. In this mode, the internal auxiliary circuit is turned off (including the reference), the switch 250 assumes a high impedance state and the operating voltage V_w falls to a diode drop below battery voltage 202 (due to the direct current path through coil 204 from battery 202 to electrode means 210). The current supplied from the battery 202 is equal to V_w/ Ij. However, no current mode is available with the high impedance state of switch 250 and load current I | is zero.

In alternative embodiments of the invention, the current I₍ be programmed to follow a predetermined profile by programming the value of the charge current sensing resistor 214. 214 value can be programmed by switching the optional resistor in parallel or in series with the load current Ij. Such switch control means are well known in the art.

520 344

Fig. 8 shows a schematic diagram of an electrotransport device 300 having an alternative voltage amplifier circuit. Device 300, unlike devices 10 and 10 'shown in Figures 1 and 2, has a reusable controller 302 which is adapted to be separately coupled to a number of disposable, preferably dispensable drug units 304 one at a time in succession. The dispensing unit for drug 304 is connected to an animal (e.g. human) body surface, such as the skin 306 shown schematically in Fig. 8 as a resistor having a variable load resistance R 1. Unit 304 has a plurality of electrodes (i.e., anode electrode 308 and cathode electrode 310), at least one of which contains a therapeutic agent to be applied to skin 306 by electrotransport. The drug unit 304 and the controller 302 may be mechanically and electrically coupled to one another by a pair of metal snap connections 336, 338. Thus, electrotransport load current is applied to the₍ through the drug unit 304 and the patient's body via the conductive snap connections 336, 338.

The controller 302 comprises two circuit parts; a voltage amplifying circuit 312 for amplifying a supply voltage V + provided by the voltage source (e.g., a battery) 318 to a working voltage V_w and a low loading voltage lowering circuit 314. When the voltage V_w at load resistance R 1 is high, ie when V_w is greater than V + minus diode voltage, V_d (the case along with the series diode 315), the voltage amplifier circuit 312 supplies voltage to the load 306 through coil 320 and diode 315 which are described in more detail.

When the load resistance Ri drops to a low value, such that [(Ii · R,) + V_ref] &lt;(V₊- V_d), shifts the control of the load current I | to the current lowering circuit 314 which allows the controller 302 to operate with lower skin resistance (RJ with improved efficiency compared to the circuits described in Figures 4 and 6).

520 344

Work on the voltage amplifier circuit 312 in cooperation with the current lowering circuit 314 can be explained in combination with the use of an exemplary PFM / PWM controller 322. A representative example of such a controller 322 is MAX771 available from Maxim Integrated Products, Inc. of Sunnyvale, CA, although other PFM / PWM switching controllers available in the technology can also be used.

The voltage source 318 is usually a battery having a plus and a minus connection. The plus terminal, V + is connected to a voltage input pin 323 on the circuit 322 at one end of the coil 320. The negative terminal on the battery 318 is connected to system ground.

The second connection of coil 320 is connected to the connection line on the anode of diode 315 and drain 324 of an N-channel transistor switch 326.

The source of switch 326 is connected to one end of a peak current sensing resistor 328. The other end of resistor 328 is connected to system ground. The gate in switch 326 is connected to a switch control output 330 in circuit 322.

A sensing input 332 in circuit 322 is also connected to the switching point between source in transistor switch 326 and an end of resistor 328 which senses peak current.

The cathode of diode 315 is connected to one end of a filter capacitor 334. The other end of capacitor 334 is connected to system ground. The coupling point of capacitor 334 and diode cathode 315 is connected by a snap connection 336 to the anode electrode 308 in contact with the patient's skin 306. The cathode electrode 310 is also in contact with the patient's skin 306 and is connected to a snap connection 338.

520 344

Snap connection 338 is connected to the drain of a second N-channel transistor 340 which has a gate and a source. The transistor 340 drain and source are connected in series which form part of the current lowering circuit 314 which receives load current Ij. The source of transistor 340 is connected to one end of the first load current source resistor 314 which has a resistance value R2. The other end of resistor 342 is connected to a second load current source resistor 344 which has a resistance value R₃. The other end of the resistor 344 is connected to system ground.

The connection to resistor 342 and resistor 344 is coupled at the inverting input with a high impedance, two input differential op amplifiers 346 having a high voltage gain, A_v. The output of the operational amplifiers 346 is connected to the gate of the transistor 340. The non-inverting input of the op amp 346 is connected to a reference voltage output 48 (V_ref) in circuit 322.

The connection line from transistor 340 source and one end of resistor 342 is connected to a feedback input 340 (FB) in circuit 322 to control load current I | through the patient.

The use of circuit 302 can be divided into two regions; (i) when the skin's resistance R 1 is high and (ii) when the skin's resistance R 1 is low. Work in the field (i) is as follows. When the skin resistance Ri is high, so that [(I, · Ri) + V_ref]&gt; (V₊- V_d), current f is controlled through circuit 322. There is feedback if voltage at one end of load current sensing resistor 342 is connected to input 350. Circuit 322 compares voltage at input 350 to voltage at V_REf input 348 and adjust the switching speed and pulse width of output signal 330 for alternating charging coil 320 with current Ij, and discharging into capacitor 334 through diode 315 until the feedback voltage at input 350 (given by

520 344 load current in I times the sum of (R₂ + R3), ie the sum of the resistance values ​​of the feedback resistors 342 and 344) is equal to V_REf voltage 348.

The values ​​of resistors 342 and 344, the gain A_v in the op amp 346 and the value of V_REf at output 348 is selected such that at the desired load current Ii, the difference between V_ref at the output 348 and the feedback voltage at the coupling of resistor 342 and resistor 344 to the inverting input of op-amp 346 causes the output of op-amp 346 to drive the gate of transistor switch 340 sufficiently to be full.

Part of the feedback voltage across resistors 342, 344 is fed back to the inverting input of op amp 346. The ratio of resistance values ​​R₂: (R₂ + R3) and gain A_v in the op amp 346 is selected so that the output of op amp 346 drives the transistor switch 340 into a low impedance state so that it exhibits essentially no resistance relative to resistor 344.

Therefore when the mean value of Ii is too low, ie when I, times (R₂ + R₃) is lower than V_REf 348 senses feedback input 350 in combination with peak current sensing resistor 328 forces switch output 330 to switch at a speed and pulse width sufficient to charge and discharge capacitor 320 with current Ij, so that mean current Ii through the skin 306 will be controlled, without saturating coil 320 .

Circuit 322 acts as limiting 1; to a peak current so that the coil 320 does not saturate by sensing the peak voltage across resistor 328 and limiting the pulse width of transistor 326.

Work in the area (ii), on the other hand, is controlled by the current lowering circuit 314 which follows. As the patient's skin resistance Ri goes to a low value, so that [(I. · Ri) + V_ref] &lt;(V₊ - V_d), ^{520 344} However, the load current I 1 will not be limited by the resistance R 1 of the skin and will tend to increase.

At the limit when Rj goes to zero, Ij will increase, and is limited only by the voltage V + divided by the series resistance of resistors 342, 344 and the resistance of transistor 340.

An increase in I | will drive the voltage at the source of transistor 340 positive until feedback input 350 causes the increase circuit to start losing control of load current I | then circuit 322 will not switch switch 326 to maintain load current I₍.

In the circuit of Fig. 8, resistors 342 and 344 are selected such that the ratio of R₃ : (R2 + R3) is close enough to each other, ie the resistance value R2 is much smaller than the resistance value R₃ (e.g., R2 = 3 ohms; R₃ = 1.5 k-ohms) ... In the range (ii) when I | increases and the voltage across the resistor R₃ increases, the voltage difference at the inputs of the op amp 346 decreases enough to cause the output of op amp 346 to reduce the voltage on the gate of transistor 340.

The transistor 340 then becomes unsaturated and begins to show a varying impedance in series with R₂ and R₃. The transistor impedance will vary, which is controlled by the op amp 346 and the inputs, V_REf and the portion of the negative feedback voltage (i.e., the feedback voltage to op-amp 346 with feedback voltage equal to the load current times the resistance value R₃, i.e. Ij · R₃). The variation of any impedance given by transistor 340 prevents the tendency of I | to continue to increase.

The reinforcement A_v in the op amp 346 and the ratio R₃ : (R₂ + R₃) is chosen so that the difference between the current I | in region (i) and region (ii) are sufficiently close to each other. An op amp with amplification greater than 1000 and a resistor R2 of 3 ohms, resistor R₃ 1.5 k-ohms will separate much less than 5%. Earlier

520 344 this situation was overcome with extra control logic (ie microprocessor) resistors and switches. The logic would result in an "under supply voltage" situation and switch in a resistor in series with the load 306 to bring the amplifier circuit 312 back to restore power control. The addition of a microprocessor and other components adds costs and extra power loss at work, reducing activity. It is also less efficient to run the amplifier circuit 312 continuously if not necessary. However, this becomes more of a case when the supply voltage is greater.

The current lowering circuit 314 in combination with the amplifier circuit 312 provides a simple inexpensive, electrically efficient and effective for controlling the therapeutic current L to a fairly constant value over a wide range of skin resistance R_b

The additional impedance provided by transistor 340 in area (ii) may be provided by other active devices, such as a p-channel transistor or a pnp or npn bipolar transistor or the like. Current sensing can be provided by a Hall power sensor or other magnetic sensing device such as a switched current test transformer. Appropriate feedback gain can also be provided by discrete transistors and resistors, capacitor circuits in a differential amplifier which is very well possible for a person in the field.

Although the invention has been shown by embodiments thereof, which together show the best embodiment of the invention as known to the applicant, numerous changes can be made and many alternative embodiments could be made without leaving the scope of the invention. Thus, the scope of the invention is disclosed only by the claims.

520 344