CA2217711C

CA2217711C - Electrotransport delivery with voltage boosting circuit

Info

Publication number: CA2217711C
Application number: CA002217711A
Authority: CA
Inventors: Thomas A. Riddle; Larry A. Mcnichols; John D. Badzinski
Original assignee: Alza Corp
Current assignee: Alza Corp
Priority date: 1995-06-02
Filing date: 1996-05-30
Publication date: 2009-05-19
Anticipated expiration: 2016-05-30
Also published as: KR19990014954A; DE19681422T1; CN1186449A; SE520344C2; CN1099300C; US6035234A; DE69624109T2; AU5963096A; DE69624109D1; US20050075623A1; KR100454667B1; ATE225200T1; JPH11511677A; US6842640B2; CA2217711A1; EP0830176B1; AT408616B; CH690818A5; DK0830176T3; SE9704478L

Abstract

An electrotransport device (10) for delivering therapeutic agents includes an adjustable voltage boost multiple controller (100, 200) for boosting the voltage from a power source (102, 202) to a working voltage V w having a value just sufficient to provide the desired therapeutic current level I1 through the electrodes (108, 112), at least one of which contains the therapeutic agent to be delivered. Therapeutic agents to be delivered according to the present invention include fentanyl and other agents.

Description

~ ELECTROTRANSPORT DELIVERY

This invention relates to an electrotransport device 6 for transdermally or transmucosally delivering a beneficial 7 agent, including fentanyl and other drugs to a patient.
8 More particularly, the invention relates to a portable or 9 patient-worn electrotransport delivery device having an improved power supply.

13 The term "electrotransport" as used herein refers generally to the 14 delivery of an agent (e.g., a drug) through a membrane, such as skin, ,s mucous membrane, or nails, which delivery is induced or aided by the 16 application of an electric potential. For example, a beneficial therapeutic 17 agent may be introduced into the systemic circulation of an animal ,a (e.g., a human) by electrotransport delivery through the skin.
19 The electrotransport process has been found to be useful in the transdemial administration of drugs including lidocaine hydrochioride, 21 hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, 22 and many other drugs. Perhaps the most common use of electrotransport 23 is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically.
24 The pilocarpine stimulates sweat production; the sweat is coliected and analyzed for its chloride content to detect the presence of the disease.
26 Presently known electrotransport devices use at least two electrodes, 27 positioned in intimate contact with some portion of the body (e.g., the skin).
28 A first electrode, called the active or donor eiectrode, delivers the therapeutic 29 agent (e.g.; a drug or a prodrug) into the body by electrotransport.

1 The second electrode, called the counter or return electrode, closes an 2 electrical circuit with the first electrode through the patient's body. A
source of 3 electrical energy, such as a battery, supplies electric current to the body 4 through the electrodes. For example, if the therapeutic agent to be delivered into the body is positively charged (i.e., a cation), the anode will be the active 6 electrode and the cathode will serve as the counter electrode to complete the 7 circuit. If the therapeutic agent to be delivered is negatively charged 8 (i.e., an anion), the cathode will be the donor electrode and the anode will be 9 the counter electrode.
Alternatively, both the anode and cathode may be used to deliver 11 drugs of opposite electrical charge into the body. In this situation, both 12 electrodes are considered donor and counter electrodes. For example, 13 the anode can simultaneously deliver a cationic therapeutic agent and 14 act as a "counter" electrode to the cathode. Similarly, the cathode can simultaneously deliver an anionic therapeutic agent into the body and 16 act as a"counter" electrode to the anode.
17 A widely used electrotransport process, electromigration (also called 18 iontophoresis), involves the electrically induced transport of charged ions.
19 Another type of electrotransport, electroosmosis, involves the flow of a liquid solvent from the donor reservoir, which liquid contains the agent to be 21 delivered, under the influence of the applied electric field. Still another type of 22 electrotransport process, electroporation, involves the formation of transiently 23 existing pores in a biological membrane by the application of high voltage 24 pulses. A therapeutic agent can in part be delivered through the skin by passive diffusion by reason of the concentration difference between the 26 concentration of drug in the donor reservoir of the electrotransport device 27 and the concentration of drug in the tissues of the patient's body. In any =
28 given electrotransport process, more than one of these processes may be 29 occurring simultaneously to a certain extent. Accordingly, the term "electrotransport", as used herein, should be given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one therapeutic agent, whether charged, uncharged, or a mixture thereof.

The terms "drug" and "therapeutic agent" are used interchangeably and are intended to have their broadest interpretation, namely any therapeutically active substance that is delivered to a living organism to produce a desired, usually beneficial, effect. This includes therapeutic agents in all the major therapeutic areas including, but not limited to: anti-infectives such as antibiotics and antiviral agents; analgesics, including fentanyl, fentanyl hydrochloride, sufentanil, buprenorphine, analgesic analogues and analgesic combinations; anesthetics;
anorexics; antiarthritics; antiasthmatic agents such as terbutaline; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antimotion sickness preparations such as scopolamine and ondansetron;
antinauseants; antineoplastics; antiparkinsonism drugs;
antipruritics; antipsychotics; antipyretics; antispasmodics, including gastrointestinal and urinary; anticholinergics;
sympathomimetrics; xanthine derivatives; cardiovascular preparations, including calcium channel blockers such as nifedipine; beta blockers; beta-agonists such as dobutamine and ritodrine; antiarrythmics; antihypertensives such as atenolol; ACE inhibitors such as ranitidine; diuretics;
vasodilators, including general, coronary, peripheral, and cerebral; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones such as parathyroid hormone; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; parasympathomimetrics;

3a prostaglandins; proteins; peptides; psychostimulants;
sedatives; and tranquilizers.

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 have a molecular weight of 300-40,000 Daltons.

1 Specific examples of peptides and proteins in this size range include, 2 without limitation, the following: LHRH; LHRH analogs such as buserelin, 3 gonadorelin, nafarelin and leuprolide: insulin; insulotropin; calcitonin;
4 octreotide; endorphin; TRH; NT-36 (chemical name is N = [[(s)-4-oxo-2-azetidinyl] carbonyl]-L-histidyl-L-prolinamide); liprecin; pituitary hormones 6 such as HGH, HMG and desmopressin acetate; follicle luteoids; aANF;

7 growth factors such as growth factor releasing factor (GFRF or GHRH);
8 bMSH; somatostatin; bradykinin; somatotropin; platelet-derived growth 9 factor; asparaginase; chymopapain; cholecystokinin; chorionic gonadotropin;
corticotropin (ACTH); erythropoietin; epoprostenol (platelet aggregation 11 inhibitor); glucagon; HCG; hirulog; hyaluronidase; interferon;
interieukins;
12 menotropins (urofollitropin (FSH) and LH); oxytocin; streptokinase; tissue 13 plasminogen activator: vasopressin; desmopressin; ACTH analogs; ANP;
14 ANP clearance inhibitors; angiotensin II antagonists: antidiuretic hormone agonists; antidiuretic hormone antagonists: bradykinin antagonists: CD-4;
16 ceredase; CSFs; enkephalins; FAB fragments; IgE peptide suppressors;
17 IGF-1; neurotrophic factors; colony stimulating factors: parathyroid hormone 18 and agonists; parathyroid hormone antagonists: prostagiandin antagonists;
19 pentigetide; protein C; protein S; renin inhibitors; thymosin alpha-1;
thrombolytics; TNF; vaccines; vasopressin antagonist analogs; alpha-1 21 anti-trypsin (recombinant); and TGF-beta.
22 Electrotransport devices generally require a reservoir or source of the 23 agent, or a precursor of such agent, that is to be delivered into the body by 24 electrotransport. Examples of such reservoirs or sources of, preferably ionized or ionizable, agents include a pouch as described in Jacobsen 26 US Patent 4,250,878, or a pre-formed gel body as disclosed in Webster 27 US Patent 4,383,529. Such reservoirs are electrically connected to the anode 28 or the cathode of an electrotransport device to provide a fixed or renewable 29 source of one or more desired therapeutic species.

1 Recently, a number of US Patents have issued in the electrotransport 2 field, indicating a continuing interest in this mode of drug delivery. For 3 example, Vernon et al US Patent 3,991,755, Jacobsen et al US Patent 4 4,141,359, Wilson US Patent 4,398,545, and Jacobsen US Patent 4,250,878 5 disclose examples of electrotransport devices and some applications thereof.

6 More recently, electrotransport delivery devices have become much 7 smaller, particularly with the development of miniaturized electrical circuits 8 (e.g., integrated circuits) and more powerful light weight batteries (e.g., lithium 9 batteries). The advent of inexpensive miniaturized electronic circuitry and compact, high-energy batteries has meant that the entire device can be 11 made small enough to be unobtrusively worn on the skin of the patient, 12 under clothing. This allows the patient to remain fully ambulatory and able to 13 perform all normal activities, even during periods when the electrotransport 14 device is actively delivering drug.
Nevertheless, some limitations still remain, restricting the wider 16 application of this valuable technique. One such limitation is the size and 17 cost of electrotransport delivery devices. In particular, the batteries needed to 18 power electrotransport devices comprise a significant contribution to the 19 overall size and weight, as well as the cost, of these smaller, patient-worn electrotransport delivery devices. A reduction in the number and/or cost of 21 these batteries would allow electrotransport drug delivery devices to be made 22 smaller and at lower cost.
23 One method of reducing the number--of batteries-us-ed t-o-power-an --24 electrotransport device is to use a voltage boosting circuit. Boosting circuits are well known in the electrical arts. Conventional boosting circuits take an 26 input voltage (e.g., 3.0 volts) and boost it by a predetermined multiple 27 (e.g., x2) to give a "boosted" output voltage (e.g., 6.0 v = 3.0 v x 2).
Voltage 28 boosting circuits have been used in transdermal electrotransport delivery 29 devices. See Maurer et al US Patent 5,254,081 (at column 2, lines 34-39).

1 These circuits allow an electrotransport device to deliver a 2 predetermined level of electric current with fewer batteries, or battery(ies) 3 of lower voltage, than would otherwise be needed without the use of a 4 boosting circuit. Thus, conventional boosting circuits help reduce the size and cost of an electrotransport delivery device by requiring fewer, and/or 6 lower voltage, batteries to power the device.
7 The problem of reducing the cost of the power supply for an 8 electrotransport delivery device is complicated by the fact that the electrical 9 resistance of the patient body surface (e.g., skin) is not constant during electrotransport delivery. Since the voltage (V) necessary to drive a particular 11 level of electric current (i) through the patient's skin is proportional to the 12 resistance (R) of the skin (i.e., according to Ohm's Law wherein V = i Rski,), 13 the voltage requirements of the power supply are not constant during 14 electrotransport delivery. For example, when electrotransport administration is begun, the patient's initial skin resistance is relatively high, requiring the 16 power supply to produce relatively high voltage to deliver a predetermined 17 level of electrotransport current. However, after several minutes (i.e., after 18 about I to 30 minutes of current being applied through the skin) the skin 19 resistance drops, such that the voltage requirement needed to deliver a particular level of electric current becomes significantly less than the voltage 21 required at the start of electrotransport delivery. See for example Haak et al 22 US Patent 5,374,242 which discloses the variable skin resistance and the 23 use of 2 or more batteries connected either in parallel or in series to 24 accommodate the changing skin resistance.
Although conventional voltage boosting circuits can supply the output 26 voltage necessary to accommodate the high initial skin resistance, they 27 reduce the efficiency of the apparatus and require more battery output 28 voltage during periods when the skin resistance is lower than the initial state, 29 resulting in lower efficiency and increased battery size and costs.

1 Jacobsen et ai 'US Patent 4,141,359 discloses a DC-DC converter 2 having a transformer to inductively couple periodic variations of current in a 3 primary coil to pulses of current in a secondary coil at a fixed voltage muftiple 4 of the primary pawer supply. These pulses of secondary coil current are conducted through the skin by therapeutic electrodes. The average, or DC
6 value of the secondary current is controlled by an error voltage and feed back 7 circuit such that the average value of the secondary current is held constant.
$ One disadvantage of the Jacobsen circuit is that the peak value of the fixed 9 and multiplied voltage appears directly across the electrodes. The peak voltage 9s unnecessary for conditions where the skin resistance is low, and 11 results in unnecessarily high current pulses of therapeutic current and possible 12 adverse effects on the skin.
13 Teiitaud et al U.S. Patent 5,426,387 discloses a device including a 14 switched-mode power supply equipped with an electronic switching member, the closing of which controls power supplied to an inductor which discharges, 16 when the electronic switching member re-opens, into a capacitor having 17 terminals at which the output voltage of the device appears. The device 18 includes a clocked digital counter and a microcontroller for successively i 9 loading the counter with a predetermined sequence of numbers which serve as a bound for the count performed by the counter, wherein the counter cyclically 21 controls the closing of the elecrranic switching member for a predetermined 22 time interval so that the output voltage of the device tracks a predetermined 23 waveform corresponding to the sequence of numbers. One disadvantage of 24 the Teilfaud device is that it requires a relatively costly, complex and physicaffy large microcontroffer/counter arrangement to provide a particular level of 26 therapeutic current. As a result, the Teillaud device may not be suitable for 27 certain applications in which a small, light-weight and inexpensive 28 electrotransport delivery device is desirable or required.

AMENDED SHEET

'67696-243 7a DESCRIPTION OF THE INVENTION

It is an aspect of the present invention to provide a method of operating with increased efficiency an electrotransport agent delivery device having a voltage boosting circuit.

It is another aspect of the present invention to provide a method of operating an electrotransport agent delivery device in which the power supply voltage is boosted to a level which is optimally suited to the conditions (e.g., skin resistance) of agent delivery.

According to another aspect of the present invention, there is provided an electrotransport delivery device, comprising: a first electrode adapted for placement in contact with an animal skin surface; a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode; a second electrode adapted for placement in contact with an animal skin surface; a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrodes; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

According to another aspect of the present invention, there is provided a control circuit for use with an electrotransport delivery device including first and second electrodes adapted for placement in contact with an animal skin surface, the control circuit comprising: a DC
supply node for receiving a DC power input; an inductor having first and second inductor contacts, the first '67696-243 7b inductor contact being coupled to said DC supply node; a diode having an anode coupled to the second inductor contact and a cathode coupled to said first electrode; a switch having a control input, said switch being positioned between the anode and a circuit ground; a filter capacitor coupled between the cathode and the circuit ground; a current sensing resistor coupled between said second electrode and the circuit ground; and a switch controller having a control output coupled to the control input of said switch and a sensor input coupled to a node between said second electrode and said current sensing resistor; wherein said switch controller toggles said switch to induce a working voltage at said first electrode, the induced working voltage driving an electrotransport current through the current sensing resistor; and wherein said switch controller compares a voltage arising at the sensor input with a reference voltage and boosts the working voltage to a value sufficient to make the voltage arising at the sensor input substantially equal to the reference voltage.

In another aspect of the present invention there is provided a method for operating an electrotransport agent delivery device having a voltage boosting circuit which boosts the power supply (e.g., battery) output voltage, in which boosting circuit the boost multiple is automatically controlled in response to the skin resistance of the patient. The device is adapted to deliver a therapeutic agent through an animal body surface (e.g., human skin) by electrotransport.

According to another aspect of the present invention, there is provided a method of regulating an output current of an electrotransport delivery device having a first electrode and a second electrode comprising:

7c coupling a voltage booster circuit to the first electrode to provide a load voltage to the first electrode; determining a load resistance between the first electrode and the second electrode; and controlling the voltage booster circuit to adjust the load voltage based on the load resistance such that at steady state a predetermined level of current is maintained across the first and second electrodes.

According to still another aspect of the present invention, there is provided a transdermal electrotransport delivery container comprising a therapeutic agent contained within a gel suitable for transdermal electrotransport of the therapeutic agent to a subject, the container comprising: a first electrode adapted for placement in contact with a first skin surface of the subject; a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode; a second electrode adapted for placement in contact with a second skin surface of the subject; a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

According to yet another aspect of the present invention, there is provided a transdermal delivery system for delivering fentanyl or a pharmaceutically acceptable salt thereof to a patient, the system comprising: a first electrode adapted for placement in contact with a first skin surface of the patient; a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode; a second electrode adapted for placement in 7d contact with a second skin surface of the patient; a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

According to a further aspect of the present invention, there is provided a transdermal delivery system for delivering an analgesic for the treatment of pain, wherein the analgesic is transdermally delivered to a patient, the transdermal delivery system comprising: a first electrode adapted for placement in contact with a first skin surface of the patient; a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode; a second electrode adapted for placement in contact with a second skin surface of the patient; a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

According to yet a further aspect of the present invention, there is provided a transdermal electrotransport delivery container for delivering fentanyl or a pharmaceutically acceptable salt thereof to a patient, the container comprising: a first electrode adapted for placement in contact with a first animal skin surface; a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode; a second 7e electrode adapted for placement in contact with a second animal skin surface; a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

According to another aspect of the invention, there is provided a transdermal patch comprising a drug and an electrotransport delivery device of the invention for administering the drug to a human. Examples of drugs suitable for electrotransport delivery are known in the art.
Examples include analgesics (eg. fentanyl or an analog, ester or pharmaceutically acceptable salt thereof, including the hydrochloride salt; and sufentanil or a pharmaceutically acceptable salt thereof), opioids, insulin or an insulin mimic, insulinotropin, proteins, peptides and polypeptides.

While the invention is not limited to any particular drug or therapeutic agent, the invention has particular utility in the delivery of analgesics. One particularly suitable analgesic is fentanyl, preferably a hydrochloride or citrate salt dispersed in a hydrogel formulation for use in the electrotransport delivery device as described herein. A short-acting transdermal fentanyl analogue would also be suitable. A soft fentanyl analogue has been described in the art. Remifentanyl (Ultiva) is marketed by Glaxo Wellcome as an ultrashort acting opioid for intravenous analgesia in anaesthetic cocktails. Due to its high degree of efficiency against extreme pain, a safe soft analog of fentanyl could be used in cases of pain 7f management that are not presently suitable for the current opioid therapy.

1 The device has a source of electrical power (e.g., one or more batteries) with 2 an output voltage. The power source output voltage is boosted with a voltage 3 booster having an adjustable boost multiple to provide a working voltage.
4 A body surface parameter selected from the electrical resistance of the body surface, the voltage drop across the body surface and/or the current applied 6 through the body surface is sensed and the boost multiple is adjusted based 7 upon the sensed body surface parameter to achieve an adjusted working 8 voltage. By adjusting the boost multiple based upon the sensed body 9 parameter (e.g., skin resistance), the device applies only that level of voltage which is needed to deliver a predetermined level of electrotransport current, 11 without excess voltage being consumed by the boost circuit. Thus, the 12 method of the present invention provides increased efficiency in the operation 13 of an electrotransport delivery device.

BRIEF DESCRIPTION OF THE DRAWINGS

17 The above and other features, aspects, and advantages of the present 18 invention will become apparent from the following written description and 19 drawings, in which:
Fig. 1 is a perspective view of an electrotransport drug delivery device 21 of this invention;
22 Fig. 2 is an exploded view of an electrotransport device of this 23 invention;
24 Fig. 3 is a graph illustrating the decline of patient skin resistance with time;
26 Fig. 4 is a schematic diagram of an adjustable voltage boosting circuit 27 of this invention;
28 Fig. 5 is a timing diagram of the operation of the circuit of Fig. 4;
29 Fig. 6 is a schematic diagram of another adjustable voltage boosting circuit of this invention;

1 Fig. 7 is a timing diagram of the operation of the circuit of Fig. 6; and 2 Fig. 8 is a schematic diagram of another adjustable voltage boosting 3 circuit of this invention.

s MODES FOR CARRYING OUT THE INVENTION

7 The electronic circuit of the present invention can be used in 8 substantially any electrotransport delivery device although the circuitry has 9 particular utility in those devices adapted to deliver agents transdermally by electrotransport. Examples of electrotransport delivery devices which can be 11 used with the circuitry of the present invention are illustrated in Figs. 1 and 2.
12 With reference to Fig. 1, there is shown a perspective view of an 13 electrotransport device 10 having an optional activation switch in the form of a 14 push button switch 12 and an optional light emitting diode (LED) 14 which turns on when the device 10 is in operation.
16 Fig. 2 is an exploded view of a second device 10' of this invention.
17 The device 10' of Fig. 2 differs from device 10 of Fig. 1 in the location of LED
18 14'. LED 14' is located adjacent button switch 12 on one end of device 10' in 19 this embodiment of the invention. Device 10' comprises an upper housing 16, a circuit board assembly 18, a lower housing 20, anode electrode 22, cathode 21 electrode 24, anode reservoir 26, cathode reservoir 28 and skin-compatible 22 adhesive 30. Upper housing 16 has lateral wings 15 which assist in holding 23 device 10' on a patient's skin. Upper housing 16 is preferably composed of 24 an injection moldable elastomer (e.g., ethylene vinyl acetate). Printed circuit board assembly 18 comprises an integrated circuit 19 coupled to discrete 26 components 40 and battery 32. Circuit board assembly 18 is attached to 27 housing 16 by posts (not shown in Fig. 2) passing through openings 13a and 28 13b. The ends of the posts are heated/melted in order to heat stake the 29 circuit board assembly 18 to the housing 16. Lower housing 20 is attached to 1 the upper housing 16 by means of adhesive 30, the upper surface 34 of 2 adhesive 30 being adhered to both lower housing 20 and upper housing 16 3 including the bottom surfaces of wings 15.
4 Shown (partially) on the underside of circuit board assembly 18 is a 5 button cell battery 32. Other types of batteries may also be employed to 6 power device 10'.
7 The device 10' is generally comprised of battery 32, electronic 8 circuitry 19,40, electrodes 22,24, and drug/chemical reservoirs 26,28, all of 9 which are integrated into a self-contained unit. The outputs (not shown in 10 Fig. 2) of the circuit board assembly 18 make electrical contact with the 11 electrodes 24 and 22 through openings 23,23' in the depressions 25,25' 12 formed in lower housing 20, by means of electrically conductive adhesive 13 strips 42,42'. Electrodes 22 and 24, in turn, are in direct mechanical and 14 electrical contact with the top sides 44,44 of drug reservoirs 26 and 28.
The bottom sides 46',46 of drug reservoirs 26,28 contact the patient's skin 16 through the openings 29',29 in adhesive 30.
17 Upon depression of push button switch 12, the electronic circuitry on 18 circuit board assembly 18 delivers a predetermined DC current to the 19 electrodes/reservoirs 22,26 and 24,28 for a delivery interval of predetermined length. Preferably, the device transmits to the user a visual and/or audible 21 confirmation of the onset of the drug delivery by means of LED 14' becoming 22 lit and/or an audible sound signal from, e.g., a"beeper". Drug is thereby 23 delivered from one of reservoirs 26,28 and through the patient's skin by 24 electrotransport.
Anodic electrode 22 is preferably comprised of silver and cathodic 26 electrode 24 is preferably comprised of silver chloride. Both reservoirs 27 26 and 28 are preferably comprised of polymer hydrogel materials.
28 Electrodes 22,24 and reservoirs 26,28 are retained by lower housing 20.

1 One of reservoirs 26,28 is the "donor" reservoir and contains the therapeutic 2 agent (e.g., a drug) to be delivered and the other reservoir typically contains a 3 biocompatible electrolyte.
4 The push button switch 12, the electronic circuitry on circuit board assembly 18 and the battery 32 are adhesively "sealed" between upper 6 housing 16 and lower housing 20. Upper Housing 16 is preferably composed 7 of rubber or other elastomeric material. Lower housing 20 is preferabiy 8 composed of a plastic or elastomeric sheet material (e.g., polyethylene) 9 which can be easily molded to form depressions 25,25' and cut to form openings 23,23'. The assembled device 10' is preferably water resistant 11 (i.e.; splash proof) and is most preferably waterproof. The system has a 12 low profile that easily conforms to the body thereby allowing freedom of 13 movement at, and around, the wearing site. The reservoirs 26,28 are located 14 on the skin-contacting side of the device 10' and are sufficiently separated to prevent accidental electrical shorting during normal handling and use.
16 The device 10' adheres to the patient's body surface (e.g., skin) by 17 means of a peripheral adhesive 30 which has upper side 34 and body-18 contacting side 36. The adhesive side 36 has adhesive properties which 19 assures that the device 10' remains in place on the body during normal user activity, and yet permits reasonable removal after the predetermined 21 (e.g., 24-hour) wear period. Upper adhesive side 34 adheres to lower 22 housing 20 and retains the electrodes and drug reservoirs within housing 23 depression 25, 25' as well as retains lower housing 20 attached to upper 24 housing 16.
The push button switch 12 is conveniently located on the top side 26 of device 10' and is easily actuated through clothing. A double press of 27 the push button switch 12 within a short time period, e.g., three seconds, 28 is preferably used to activate the device for delivery of drug, thereby 29 minimizing the likelihood of inadvertent actuation of the device 10'.

1 Upon first initiating agent delivery, the skin resistance of the patient 2 is typically relatively high, whereas after a period of time, the skin resistance 3 drops appreciably. Fig. 3 illustrates this characteristic graphically, showing 4 that the decline of skin resistance R is substantially asymptotic to a steady state value. For a discharge rate of 0.1 mA/cm2, this steady state value is 6 typically on the order of 20 to 30 kohm-cm2, while the initial value of skin 7 resistance is several or many times as much.
8 In prior art electrotransport delivery devices, the voltage of the power 9 supply and/or the boost multiple of the voltage boosting circuit, was/were chosen large enough to overcome the high skin resistance present at the start 11 of operation. However, once operation had reached steady state, with the 12 attendant drop in skin resistance, the prior art devices had excess working 13 voltage. In certain prior art devices, the applied voltage needed to deliver a 14 particular current at steady state operation was one half or less of the voltage required to deliver that same level of current at the start of electrotransport 16 delivery. Accordingly, these prior art devices were not very cost effective 17 because of the voltage wasted in the voltage boosting circuit once the skin 18 resistance dropped from its initial high level.
19 Fig. 4 illustrates a schematic diagram of a voltage boosting electrotransport circuit 100 with an adjustable boost multiple that is adjusted 21 according to the sensed therapeutic load current level in accordance with the 22 present invention. This permits more efficient use of batteries and results 23 in significant size and cost savings when compared to the just-described 24 prior art. The circuit 100 inciudes a power source in the form of a battery 102, and a voltage controlled electrical junction 104 electrically connected to an 26 electrode assembly 108. The electrode assembly 108 is attached to one 27 region of an animal body 110 by conventional means such as adhesive, 28 straps, belts or the like. The animal body surface is shown schematically 29 as a variable resistance load, Rv, to indicate the variation of load resistance typical of the skin when applying electric current li therethrough.

1 An electrode assembly 112 is similarly attached to another region of 2 the animal body 110. The electrode assembly 112 is connected to a series 3 current sensing resistor 114. The electrodes 108, 112, the body surface 110 4 and sense resistor 114 form a load current path for conducting the load current, I,. The electrode assemblies 108, 112 are equivalent to the 6 electrode/reservoir combinations 22, 26 and 24, 28 shown in Fig. 2.
7 At least one of the electrode assemblies 108, 112 contains a therapeutic 8 agent (e.g., a drug salt) in a form (e.g., an aqueous solution) suitable for 9 electrotransport delivery into the animal body 110.
An energy storage inductor 118 is connected between battery 102 and 11 the anode of rectifying diode 120. The cathode of diode 120 is connected to 12 the voltage controlled electrical junction 104. A filter capacitor 122 is 13 connected between the junction 104 and system ground.
14 A controlled switch 124, having a control input 126, has one terminal 128 connected to the junction of the anode of diode 120 and the inductor 118 16 and another terminal 130 connected to system ground. The control input 126 17 can alternately open and close the switch 124 creating a low resistance 18 connection between the terminals 128 and 130 thereby connecting or 19 disconnecting the inductor 118 through a low resistance path to system ground. The switch 124 may be an electronic switch device such as a bipolar 21 or FET transistor.
22 A control circuit 132 has a control output 134 connected to switch 23 control input 126. The control circuit 132 includes a feedback input 133 for 24 controlling the control output 126 and a switch input 136.
The operation of the adjustable voltage boost circuit 100 can be 26 understood with reference to Fig. 5. After initiation of the circuit 100, 27 for example, by means of a push button switch 12 illustrated in Fig. 1, 28 the control circuit 132 is adapted to first connect the input 136 to system 29 ground. This enables the sense resistor 114 to begin conducting load current, I1, from the load 110.

1 The control circuit 132 is configured to then toggle the control output 2 134 so that the switch 124 connects the one end of the inductor 118 to 3 ground for a period of time T1. During the time T1, the inductor current Ii, 4 driven by the battery 102, increases to a maximum value, IP.
At the end of time T1, the control circuit 132 is adapted to change 6 output 134 to toggle switch input 126 again which opens the switch 124 for a 7 time period, T2. During T2, the inductor current, I;, will not flow toward 8 ground, but is forced to conduct through the diode 120 into the electrical 9 junction 104. The filter capacitor 122 provides a low impedance path for the instantaneous current, I;, which then decays toward zero during the time, 11 T2, as the voltage at electrical junction 104 is boosted by the charging of the 12 capacitor 122.
13 During the time Tl, the inductor 118 stores energy by charging with the 14 current, I. During the period T2, the inductor 118 discharges energy into the filter capacitor 122 through the diode 120. The inductor 118 thereby 16 transfers energy from the battery 102 into the capacitor 122 with low loss, 17 limited only by the diode 120 drop and the negligible series resistance of the 18 inductor 118, battery 102 and the electrical connections. Thus, the energy 19 source for load current Ii is not directly the battery 102 but rather either the capacitor 122 (i.e., during time T1) or a combination of the capacitor 122 and 21 inductor 118 (i.e., during time T2).
22 The control circuit 132 is adapted to repeat the T1, T2 cycle indefinitely 23 or when stopped as described below. The voltage, VW, at the junction 104 is 24 thereby boosted to a adjustable multiple of the battery 102 voltage depending on the values of the time periods T1 and T2. The boost multiple thus can be 26 adjusted by adjusting the values of T1 and T2.
27 Dotted lines in Fig. 5 indicate missing or delayed pulses as controlled 28 by the control circuit 132. This may occur when pulses are not necessary to 29 replace charge depleted from the capacitor 122, for example, when the therapeutic current, Ii, demanded is relatively low. The dotted lines in Fig.

1 indicate that the boost multiple control means may be by pulse width 2 modulation (PWM), pulse frequency modulation (PFM), pulse skipping, 3 or some combination thereof.
4 The adjustable working voltage, VW, causes the load current, I,, to flow 5 through the animal body load 110, through the sense resistor 114 and into the 6 switch input 136, to ground.
7 The feedback input 133 senses the voltage across the sense resistor 8 114 caused by the load current, li. The control circuit 132 is adapted to 9 respond to the feedback input 133 to boost the working voltage, VW, by 10 adjusting the time periods, T1 and T2. This is accomplished by comparing 11 the voltage sensed at input 133 with a set reference voltage within control 12 circuit 132. If the voltage sensed at input 133 is less than the reference 13 voltage, then control circuit 132 opens and closes switch 124 at a high 14 frequency until VW is boosted to the appropriate level. In general, the longer 15 switch 124 is closed (i.e., the longer is T1), the greater the voltage which is 16 developed in inductor 118 and the greater the boost multiple. The battery 17 102 voltage can be boosted by reason of the inductor 118. The voltage 18 developed in the inductor 118 is equal to the inductance value (L) multiplied 19 by the rate at which current flows through the inductor:

21 Vind = L (dli/dt).
22 Thus, out of inductor 118 comes a higher voltage (which voltage is 23 determined in part by the inductance value of inductor 118 and in part by the 24 rate of current flow through inductor 118 which is controlled by the values of T1 and T2) at a lower current since the power into inductor 118 must equal 26 the power out of inductor 118.
27 The control circuit 132 is additionally adapted such that, in combination 28 with the values of the inductor 118, the value of the load resistance 110 and 29 the capacitance value of the capacitor 122, the time periods, TI, T2, are arranged in response to the voltage at the feedback input 133 such that filter 1 capacitor 122 smooths and adjusts the voltage VHõ to provide a load current, 2 Ii, of an essentially constant (DC) current of predetermined value.
3 The electrode assemblies 108 and 112, and thus the animal body 110, 4 are not exposed to high peak voltages as in the prior art, but instead experience only the minimum, voltage value sufficient to drive the desired 6 load current li.
7 The time periods T1 and T2 are adjusted by the control circuit 132 to 8 boost Võ, to the minimum absolute value to provide the load current li to 9 maintain a desired predetermined value. If the resistance of the load 110 is too high to allow the predetermined value of I, to be attained without having 11 V,, exceed a safe level, a voltage limiting device, such as a zener diode 12 connected across the electrode assemblies 108 and 112, limits the voltage 13 applied to load 110. A typical safe maximum limiting value for V, is about 14 24 volts. Other values of limiting voltage can be achieved by zener diodes 116 having different breakdown voltages, or by using other protection means 16 as described further below.
17 Once the resistance of the load 110 decreases sufficiently to allow the 18 load current, I,, to reach the desired predetermined level at the maximum safe 19 voltage, the control circuit 132 will respond to the feedback at feedback input 133 and will adjust T1 and T2 to boost V, to a multiple just sufficient to 21 maintain the current at the predetermined level independent of further 22 resistance decreases.
23 The working voltage, VW, at the controlled electrical junction 104 is 24 thus boosted to a boost multiple of the battery 102 voltage just sufficient to maintain the load current, I1, at the predetermined value as long as the load 26 voltage is less than the limiting voltage set by the zener diode 116.
27 The low loss transfer of energy from the battery 102 to the load 110 28 and capacitor 122 maximizes the useful life of the battery 102, for a given 29 battery capacity. This allows smaller batteries to be used for a given CA 02217711 1997-10-07. ,` f._J~V/J J t=

1 therapeutic regimen, or extends the lifetime of therapeutic treatment at a given 2 cost.
3 The predetermined current )t applied across load 110 may be constant or 4 varying with time. In either event, the control circuit 132 is provided with means for establishing a predetermined current-time profile to be applied.
This 6 may be accomplished by means well known in the art, such as a differential 7 comparator having one input connected to the sense resistor 114, a constant 8 reference voltage connected to the other input, or having the other input 9 connected to the output of a D to A converter driven by a clocked ROM having a pre-programmed pat:ern (not shown in Fig. 4).
11 The circuit 100 may also be provided with a protection circuit 138. The 12 protection circuit 138 has high impedance and low impedance checking 13 functions and inciudes an input 140 which senses the voltage drop across load 14 1 10 and compares the sensed voltage drop against a preset minimum limit therefor, Circuit 138 also includes an input 142 which senses the current ~
16 applied through load 110 and compares the sensed current against a preset 17 maximum limit therefor. ProteGtion circuits offering impedance checking and 18 shut ctown protection are well known in the art. See, for example the '19 protection circuits shown in Fig. 1 of Jacobsen et al US Patent 4,141,359.
The protection circuit 138 monitors the resistance of the load 110 by 21 the voltage input 140 and the current input 142 and shuts down the voltage 22 boosting function of the circuit 100 when the resistance of the load 110 23 exceeds a predetermined upper limit or decreases below a predetermined lower 24 limit. Incorporation of the protection and shutdown circuit 138, of the type cfescribe in US Patent 4,141,359, into the booster circuit 100 is within the 26 capability of a person having ordinary skill in the electrical arts.

Ak-IEND-FD SHi:EC

1 In use, the electrode assemblies 108 and 112 are attached to the 2 skin surface 110 by conventional means, and the therapeutic current is 3 initiated, by a switch means (not shown) such as switch 12 shown in Fig. 1.
4 The control circuit 132 begins controlling the on and off switching of switch 124. Repetitive pulses of inductor current, I;, are alternately 6 charged during the on time periods, T1, through the switch 124 to ground 7 and discharged during the off time periods, T2 into the capacitor 122.
8 These pulses of inductor current Ii cause the voltage, V,, to be multiplied by 9 an adjustable boost multiple by adjusting the on and off times T1, T2 until the signal to feedback input 133 indicates the load current I, is in regulation.
11 Fig. 6 shows another adjustable boost circuit 200 in accordance 12 with this invention. The circuit 200 includes a battery 202, an inductor 204, 13 a diode 206, a voltage controlled electrical junction 207, a low resistance filter 14 capacitor 208, and electrode assemblies 210, 212 which are attached by conventional means to spaced apart regions of animal body 213. The animal 16 body 213 is represented schematically as a variable load resistance Rõ to 17 emphasize the fact that the resistance of the load 213 does vary with time 18 and current.
19 At least one of the electrode assemblies 210, 212 contains a therapeutic agent in a form suitable for electrotransport delivery into the 21 animal body 213.
22 The circuit 200 includes an N-channel field effect transistor (FET) 23 switch 218, for switching inductor current I;, an inductor current sense 24 resistor 220, and a load current sense resistor 214. The circuit also includes a high efficiency, adjustable DC-DC step up controller 216. A preferred 26 controller 216 is the Maxim MAX773 made by Maxim Integrated Products, 27 Inc. of Sunnyvale, CA.
28 Fig. 6 shows a simplified schematic of the MAX773 controller 216 29 which is sufficient for purposes of the present invention. A more detailed schematic of the MAX773 controller can be found in the MAX773 data 1 sheet 19-0201;Rev 0; 11;93, which is available from the manufacturer.
2 The controller 216 is an integrated circuit having internal components 3 connected by conductive traces formed during the integrated circuit 4 manufacturing process. External pins are provided for electrical connection to external components by conventional printed circuit means such as plated or 6 deposited copper or other conductors deposited and formed on insulating 7 substrates. Reference to electrical connections in the description herein are 8 understood to be internal or external as shown in Fig. 6. References to the 9 components of the MAX773 controller circuit are illustrative for the purposes of describing the function of circuit 216. Unlike traditional pulse frequency 11 (PFM) converters, which use an error voltage from a voltage divider circuit to 12 control the output voltage of the converter to a constant value, controller 13 is connected to use the sense resistor 214 to generate an error voltage to 14 control the average load current I,. The MAX773 controller also operates with high frequencies, (up to 300 kHz) allowing the use of small external 16 components. The controller 216 includes a reference voltage pin 256, a 17 ground pin 258, a grounding switch input 260, a low level threshold input 262, 18 a feed back input 264, a shut down input 266, a current sense input 268, and 19 a power bus input 270.
Controller 216 also includes a first two-input comparator 230 having an 21 output 231, a second two-input comparator 232 having an output 233, a first 22 reference voltage 242, a second (e.g., 1.5 volt) reference voltage 244, a third 23 two-input comparator 246 having an output 247, a PFM/PWM driver circuit 24 240 having a switch control output 252 and a switch control output 254, and a second N-channel FET switch 250.
26 Operation of the circuit 200 can be understood by reference to 27 Figs. 6 and 7. The circuit 200 uses the controller 216 in a novel way to 28 provide a high efficiency conversion of energy from the battery 202 into an 29 adjustably boosted voltage V, at the voltage controlled electrical junction and simultaneously controlling the load current I,.

1 With reference to Fig. 6, in accordance with this invention, a portion of 2 the load current I, is fed back to the feed back input 264. One terminal of 3 sense resistor 214 is connected to the feed back input 264. This same 4 terminal of resistor 214 is also connected to the electrode assembly 212 for 5 receiving the load current I. The other terminal of resistor 214 is connected 6 to the input 260 of controller 216. The input 260 internally connects to the 7 drain of the N-channel switch 250. The source of switch 250 connects to 8 system ground. The gate of switch 250 connects to the output 247 of 9 comparator 246. The inverting input of comparator 246 connects to the 10 input pin 262. The input pin 262 is connected to system ground. The non-11 inverting input of comparator 246 is connected to the reference voltage 244.
12 The reference voltage 244 also connects to the reference voltage pin 256.
13 The comparator 246 is driven such that output 247 is always high.
14 Switch 250 will therefore be driven to conduct the pin 260 to ground, 15 sinking the load current li to ground through the sense resistor 214.
16 The input 264 connects to the inverting input of comparator 232.
17 The non-inverting input of comparator 232 is connected to the reference 18 voltage 244. The output 233 of comparator 232 is connected to the 19 PFM/PWM driver circuit 240.

20 The output 231 of comparator 230 is connected to the PFM/PWM

21 driver circuit 240. The inverting input of comparator 230 is connected to the 22 reference voltage 242. The non-inverting input of comparator 230 connects 23 to the current sense input 268. Input 268 is connected to one terminal of 24 inductor current sense resistor 220. The other terminal of resistor 220 connects to system ground. The ground pin 258 of the controller 216 is 26 also connected to system ground.
27 One output of the PFM/PWM driver circuit 240 connects to the 28 output 252. The input 270 is connected to one terminal of the battery 202.
29 The other terminal of the battery 202 is connected to system ground.
One output of the PFM/PWM driver circuit 240 connects output 254.

1 The outputs 252 and 254 are both connected to the gate of the external 2 N-channel switch 218. The drain of the switch 218 is connected to a joint 3 connection of one end of the energy storage inductor 204 and the anode of 4 rectifying diode 206. The source of the switch 218 is connected to the one terminal of the inductor current sense resistor 220 which is connected to the 6 current sense input 268.
7 The other terminal of the inductor 204 is connected to the power 8 bus input 270 and to the terminal of the battery 202. A filter capacitor 276 is 9 connected between the input 270 and ground. A filter capacitor 278 is connected between the voltage pin 256 and ground. The filter capacitors 276 11 and 278 have low dynamic impedance at the pulse frequencies of interest.
12 The cathode of diode 206 is connected to an electrical junction 207.
13 The junction 207 is also connected to one terminal of a filter capacitor 208, 14 the cathode of a zener diode 280 and the electrode assembly 210.
The anode of the zener diode 280 and the other terminal of capacitor 208 16 are connected to ground. The junction 207 completes the circuit 200 which 17 boosts the working voltage, VW, at the junction 207 by an adjustable multiple 18 of the voltage of the power source, i.e., battery 202.
19 The zener diode 280 provides a means to limit the peak voltage across the electrode assemblies 210 and 212 and thus the maximum voltage 21 experienced by the animal body load 213.
22 With reference to Figs. 6 and 7, the operation of the adjustable voltage 23 boost multiple circuit 200 can be understood. When power is applied by the 24 battery 202 to input 270 and the input signal 266 is of the correct logic level, the controller 216 begins operating. Since input 262 is held low, 26 and the non-inverting input of comparator 247 is at, e.g., 1.5 volts, 27 from reference voltage 244, the output of the comparator 246 will be high.
28 With a high voltage on the gate of the switch 250 the input 260 will be driven 29 to ground by the drain of switch 250. This enables the resistor 214 to receive load current li from the electrode assembly 212.

1 As with traditional PFM converters, the switch 218 is not turned on until 2 the voltage comparator 232 senses the output current is out of regulation.
3 However, unlike traditional PFM converters, the MAX773 uses the 4 combination of the peak inductor current limit sense resistor 220, reference voltage 242 and comparator 230 along with the maximum switch on-time 6 and minimum switch off-time generated by the PFM/PWM driver circuit 240;
7 there is no oscillator. The typical maximum switch on-time, T1, is 16 micro 8 seconds. The typical minimum switch off-time, T2, is 2.3 micro seconds.
s Once off, the minimum off-time holds the switch 218 off for time T2.
After this minimum time, the switch 218 either (1) stays off if the output 11 current li is in regulation, or (2) turns on again if the output current li is out 12 of regulation.
13 While the switch 218 is off, the inductor current li flows through the 14 diode 206 into the capacitor 208 at junction 207, replenishing any charge drawn off by the load 213. It can be seen that this method of switching the 16 charging current Ii provides an adjustable boost multiple of the battery 17 voltage to a working voltage V, at the junction 207, just sufficient to supply 18 the desired constant current I,. The peak voltage delivered by the inductor 19 204, will be just that required to overcome the diode drop of the diode 206 and the working voltage VW and thus minimizes energy loss from the 21 battery 202.
22 The controller 216 circuitry allows the circuit 200 to operate in 23 continuous-conduction mode (CCM) while maintaining high efficiency with 24 heavy loads. When the power switch 218 is turned on, it stays on until either (1) the maximum on-time turns it off (typically 16 microseconds later), or (2) 26 the inductor current I; reaches the peak current limit IP set by the inductor 27 current limit resistor 220, the reference voltage 242 and comparator 230.
28 In this event, the on time will be less than the maximum on time, T1.
Limiting 1 the peak inductor current, to a predetermined maximum, Ip, avoids saturating 2 the inductor 204 and allows the use of smaller inductor values, thus smaller 3 components.
4 If the average load current I, is below the desired value as set by the value V,ef of reference voltage 244 and the resistance value Rs of sense 6 resistor 214 through the relation 7 Vref > lt = Rs 8 then the PFM/PWM driver circuit 240 will automatically adjust the on time T1 9 and the off time T2 and alternately turn the switch 218 on and off until the load current li is in regulation.
11 Operation of the adjustable boost multiple circuit 200 may be initiated 12 by connecting the shut down input 266 to a logic high level by switch means, 13 such as switch 12 shown in Fig. 1. When shut down input 266 is high, the 14 MAX773 circuit enters a shut down mode. In this mode the internal biasing circuitry is turned off (including the reference), switch 250 enters a high 16 impedance state and the working voltage V,N falls to a diode drop below the 17 battery 202 voltage (due to the DC path through the inductor 204 from the 18 battery 202 to the electrode assembly 210). The supply current from the 19 battery 202 becomes equal to VW/ I,. However, no current path is available with the high impedance state of switch 250 and the load current I, is zero.
21 In alternate embodiments of this invention, the current li may be 22 programmed to follow a predetermined profile by programming the value of 23 the load current sense resistor 214. The resistor 214 value may be 24 programmed by switching additional resistors in parallel or series with the load current I,. Such switching control means are well known in the art.
26 Fig. 8 shows a schematic diagram of an electrotransport device 300 27 having an alternative voltage boosting circuit. The device 300, unlike devices 28 10 and 10' shown in Figs. 1 and 2, has a reusable controller 302 which is 29 adapted to be separably coupled to a plurality of single-use, preferably disposable, drug units 304, one at a time in succession. The disposable 1 drug unit 304 is attached to an animal (e.g., human) body surface, such as 2 the skin 306, which is schematically illustrated in Fig. 8 as a resistor having 3 a variable load resistance R1. Drug Unit 304 has a pair of electrodes 4 (i.e., an anodic electrode 308 and a cathodic electrode 310), at least one of which contains a therapeutic agent to be delivered through the skin 306 6 by electrotransport. The drug unit 304 and the controller 302 may be 7 mechanically and electrically coupled by a pair of metal snap 8 connectors 336,338. Thus, electrotransport load current II is supplied 9 to the drug unit 304 and the patient's body via the conductive snap connectors 336,338.
11 The controller 302 includes two circuit portions; a voltage boosting 12 circuit 312 for boosting a supply voltage V+ provided by the power source 13 (e.g., a battery) 318, to a working voltage, V,,,, and a low load voltage current 14 sinking circuit 314. When the voltage, VW, at the load resistance R1 is high, that is, when Vw is greater than V+, minus diode voltage, Vd, (dropped across 16 series diode 315), the voltage boost circuit 312 provides power to the load 17 306 through inductor 320 and diode 315 as described in more detail 18 hereinafter.
19 When the load resistance R1 decreases to a low value, such that [(II = R1 ) i' Vref] < (V+ - Vd), 21 the control of load current II shifts to the current sinking circuit 314 which 22 allows the controller 302 to operate at lower skin resistance (R1) with 23 improved efficiency compared to the circuits described in Figs 4 and 6.
24 Operation of the voltage boosting 312 circuit in cooperation with the current sinking circuit 314 can be explained in combination with the use of an 26 exemplary PFM/PWM controller 322. A representative example of such a 27 controller 322 is the MAX771 available from Maxim Integrated Products, Inc.
28 of Sunnyvale, CA although other PFM/PWM switching controllers available in 29 the art, can also be used.

1 The power source 318 is typically a battery having a plus and minus 2 terminal. The plus terminal, V+, is connected to power input pin 323 on the 3 circuit 322 and to one terminal of the inductor 320. The minus terminal of the 4 battery 318 is connected to system ground.
5 The other terminal of the inductor 320 is connected to the junction of 6 the anode of the diode 315 and the drain 324 of an n-channel switch 326.
7 The source of switch 326 is connected to one terminal of a peak 8 current sense resistor 328. The other terminal of the resistor 328 is 9 connected to system ground. The gate of switch 326 is connected to a switch 10 control output 330 of circuit 322.
11 A sense input 332 of circuit 322 is also connected to the junction 12 between the source of switch 326 and one terminal of peak current 13 sense resistor 328.
14 The cathode of diode 315 is connected to one terminal of a filter 15 capacitor 334. The other terminal of capacitor 334 connects to system 16 ground. The junction of capacitor 334 and diode 315 cathode are connected 17 through snap connector 336 to the anodic electrode 308 in contact with the 18 patient's skin 306. Cathodic electrode 310 is also in contact with the patient's 19 skin 306 and is connected to snap connector 338.
20 Snap connector 338 is connected to the drain of a second n-channel 21 transistor 340 having a gate and source. The transistor 340 drain and source 22 are connected in series forming part of the current sinking circuit 314 which 23 receives the load current 11. The source of transistor 340 connects to one 24 terminal of a first load current source resistor 342 having a resistance value 25 R2. The other terminal of the resistor 342 is joined to a second load current 26 source resistor 344 having a resistance value R3. The other terminal of the 27 resistor 344 is connected to system ground.

1 The junction of the resistor 342 and resistor 344 are joined to the 2 inverting input of a high impedance, two-input differential op-amp 346, 3 having a high voltage gain, Av. The output of the op-amp 346 connects 4 to the gate of the transistor 340. The non-inverting input of the op-amp 346 connects to a reference voltage output 348 (Vref) of the circuit 322.
6 The junction of the transistor 340 source and the one terminal of 7 resistor 342 connect to a feedback input 350 (FB) of the circuit 322 to provide 8 control of the load current li through the patient.
9 Operation of the circuit 302 can be considered in two regimes: (i) when skin resistance R, is high, and (ii) when skin resistance R, is low. Operation 11 in regime (i) is as follows. When the skin resistance R, is high, such that 12 [(1I - R1 ) + Vref] > (V+ - Ud), 13 the current li is controlled by the circuit 322. There is feedback of the voltage 14 at the one terminal of the load current sense resistor 342 connected to the input 350. The circuit 322 compares the voltage at the input 350 to the 16 voltage at the Vref input 348 and adjusts the switching rate and pulse width of 17 the output 330 to alternately charge inductor 320 with current li, and 18 discharge into capacitor 334 through diode 315 until the feedback voltage at 19 input 350 (given by load current li times the sum of (R2+R3), i.e., the sum of the resistance values of feedback resistors 342 and 344) is equal to the Vret 21 voltage 348.
22 The value of resistors 342 and 344, the gain Av of the op-amp 346, 23 and the value of Vref at output 348 are selected such that, at the desired load 24 current li, the difference between the voltage Vref at output 348 and the feedback voltage at the junction of resistor 342 and resistor 344 to the 26 inverting input of the op-amp 346 will cause the output of op-amp 346 to drive 27 the gate of transistor switch 340 sufficiently so that it is full on.

'WO 96/38199 PCTIUS96/08258 1 A portion of the feedback voltage across resistors 342, 344 is fed back 2 to the inverting input of the op-amp 346. The ratio of the resistance values 3 R2 : (R2+R3) and the gain Av of the op-amp 346 is selected such that the 4 output of op-amp 346 drives the transistor switch 340 into a low impedance state so that it presents essentially no resistance relative to resistor 344.

6 Therefore, when the average value of li is too low, that is, when li times 7 (R3 + R2) is lower than Vref 348, the feedback input 350, in combination with 8 the peak current sense resistor 328 causes the switch output 330 to toggle at s a rate and pulse width sufficient to charge and discharge the inductor 320 with current II such that the average current li through the skin 306 will be in 11 regulation, without saturating the inductor 320.

12 The circuit 322 acts to limit li to a peak current such that inductor 320 13 will not saturate by sensing the peak voltage across resistor 328 and limiting 14 the on pulse width of the transistor 326.
Operation in regime (ii) on the other hand is controlled by the current 16 sinking circuit 314, as follows. As the patient's skin resistance R1 tends 17 toward a low value, such that 18 [(II - R1)+Vref] < (V+-Ud)+

19 the load current li will not be limited by the skin resistance R1 and will tend to increase.

21 In the limit, as R, approaches zero, li will increase, limited only by the 22 voltage V+ divided by the series resistance of resistors 342, 344 and the 23 resistance of the transistor 340.

24 An increase in Ii will drive the voltage at the source of the transistor 340 positive until the feedback input 350 causes the boost circuit to begin to 26 lose control over the load current li, as the circuit 322 will not have to toggle 27 the switch 326 to maintain load current li.

1 In the circuit of Fig. 8, the resistor 342 and 344 are selected so that the 2 ratio of R3 : (R2+R3) is sufficiently close to one, ie, the resistance value R2 is 3 much less than the resistance value R3 (eg, R2 = 3 ohms;

4 R3 = 1.5 k-ohms).. In regime (ii), as Ii increases and the voltage across resistor R3 rises, the voltage difference at the inputs to the op-amp 346 6 decrease enough to cause the output of the 7 op-amp 346 to lower the voltage at the gate of transistor 340.
8 Transistor 340 then comes out of saturation and begins to present a 9 varying impedance in series with R2 and R3. The transistor impedance will vary, being controlled by the op-amp 346 and the inputs, Vref and the portion 11 of the negative feedback voltage (ie, the feedback voltage to op-amp 346 12 which feedback voltage is equal to the load current times resistance value R3, 13 ie, Ii = R3). The variation of the additional impedance provided by transistor 14 340 prevents the tendency for Ii to continue to increase.

The gain Av of op-amp 346 and the ratio R3 : (R2+R3) are selected 16 such that the difference between the current Ii in regime (i) and regime (ii) 17 are sufficiently close. An op-amp with a gain greater than 1000 and resistor 18 R2 of 3 ohms, resistor R3 of 1.5 k-ohms will differ by much less than 5%.

19 Previously, this situation was overcome with additional control logic (i.e., a microprocessor), resistors and switches. The logic would detect a 21 "below supply voltage" situation and switch in a resistor in series with the 22 load 306, forcing the boost circuit 312 back on to reestablish current control.
23 The addition of a microprocessor and other components add cost and 24 additional current drain to operate, reducing efficiency. It is also less efficient to run the boost circuit 312 continuously, if it is not needed. This becomes 26 even more an issue when the supply voltage is larger.

1 The current sinking circuit 314 in combination with the boost circuit 312 2 provides a simple, low cost, electrically efficient and effective means for 3 controlling the therapeutic current li to a reasonable constant value over a 4 very wide range of skin resistance R, .

The additional impedance presented by the transistor 340 in regime (ii) 6 could be provided by other active devices, such as a p-channel transistor or a 7 pnp or npn bipolar transistor, or the like. Current sensing could be provided 8 by a Hall effect sensor or other magnetic sensing devices such as a switched 9 current sampling transformer. Suitable feedback amplification could also be provided by discrete transistors and resistor, capacitor circuit assembled into 11 a differential amplifier, which is well within the capability of those skilled in 12 the art.
13 Although this invention has been described with some particularity in 14 respect to embodiments thereof which, taken together, comprise the best mode known to the inventors for carrying out their invention, many changes could be 16 made, and many alternative embodiments could thus be derived without 17 departing from the scope of the invention. Consequently, the scope of the 18 invention is to be determined only from the following claims.

Claims

CLAIMS:

1. An electrotransport delivery device, comprising:

a first electrode adapted for placement in contact with an animal skin surface;

a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode;
a second electrode adapted for placement in contact with an animal skin surface;

a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrodes; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

2. The electrotransport delivery device of claim 1, wherein the voltage booster circuit comprises:

an inductor circuit coupled to a power supply; and a capacitor coupled to the inductor circuit, wherein the control circuit controls the inductor circuit to generate a peak current, and the control circuit selectively couples the inductor circuit to the capacitor to discharge the peak current and charge the capacitor to the load voltage.

3. The electrotransport delivery device of claim 2, further comprising a switch having a first terminal coupled to the inductor, a second terminal coupled to ground, and a control input coupled to the control circuit.

4. The electrotransport delivery device of claim 3, further comprising a feedback loop coupled between the control circuit and the current sensing resistor for controlling an output of the control circuit to the control input of the switch.

5. The electrotransport delivery device of claim 3 or 4, wherein the switch is a field effect transistor.

6. The electrotransport delivery device of any one of claims 1 to 5, further comprising a voltage limitor coupled to the control circuit and voltage booster circuit to limit the voltage provided to the first electrode to a predetermined range.

7. The electrotransport delivery device of any one of claims 1 to 6 for delivering a drug to a patient in need thereof.

8. The electrotransport delivery device of claim 7, wherein the drug is an analgesic.

9. The electrotransport delivery device of claim 7 or 8, wherein the drug is fentanyl or a pharmaceutically acceptable salt thereof.

10. The electrotransport delivery device of claim 9, wherein the drug is fentanyl hydrochloride.

11. The electrotransport delivery device of claim 7 or 8, wherein the drug is an analogue of fentanyl.

12. The electrotransport delivery device of claim 7 or 8, wherein the drug is sufentanil, or a pharmaceutically acceptable salt thereof.

13. The electrotransport delivery device of claim 7, wherein the drug is insulin.

14. The electrotransport delivery device of claim 7, wherein the drug is insulinotropin.

15. The electrotransport delivery device of claim 7, wherein the drug is a protein.

16. The electrotransport delivery device of claim 7, wherein the drug is a peptide.

17. The electrotransport delivery device of claim 7, wherein the drug is a polypeptide.

18. The electrotransport delivery device of any one of claims 7 to 17, wherein the patient is a human.

19. A method of regulating an output current of an electrotransport delivery device having a first electrode and a second electrode comprising:

coupling a voltage booster circuit to the first electrode to provide a load voltage to the first electrode;
determining a load resistance between the first electrode and the second electrode; and controlling the voltage booster circuit to adjust the load voltage based on the load resistance such that at steady state a predetermined level of current is maintained across the first and second electrodes.

20. The method of claim 19, wherein determining the load resistance comprises sensing a feedback value from a current sensing resistor coupled to the second electrode.

21. The method of claim 20, wherein controlling the voltage booster circuit to adjust the load voltage comprises determining a current passing through the current sensing resistor from the feedback value.

22. The method of claim 20 or 21, wherein the load voltage is boosted when the current passing through the current sensing resistor is lower than the predetermined level of current.

23. The method of any one of claims 19 to 22, wherein the generated load voltage follows a predetermined current-time profile.

24. A transdermal electrotransport delivery container comprising a therapeutic agent contained within a gel suitable for transdermal electrotransport of the therapeutic agent to a subject, the container comprising:

a first electrode adapted for placement in contact with a first skin surface of the subject;

a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode;
a second electrode adapted for placement in contact with a second skin surface of the subject;

a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

25. The transdermal electrotransport delivery container of claim 24, wherein the voltage booster circuit comprises:

an inductor circuit coupled to a power supply; and a capacitor coupled to the inductor circuit, wherein the control circuit controls the inductor circuit to generate a peak current, and the control circuit selectively couples the inductor circuit to the capacitor to discharge the peak current and charge the capacitor to the load voltage.

26. The transdermal electrotransport delivery container of claim 25, further comprising a switch having a first terminal coupled to the inductor, a second terminal coupled to ground, and a control input coupled to the control circuit.

27. The transdermal electrotransport delivery container of claim 26, further comprising a feedback loop coupled between the control circuit and the current sensing resistor for controlling an output of the control circuit to the control input of the switch.

28. The transdermal electrotransport delivery container of claim 26 or 27, wherein the switch is a field effect transistor.

29. The transdermal electrotransport delivery container of any one of claims 24 to 28, further comprising a voltage limitor coupled to the control circuit and voltage booster circuit to limit the voltage provided to the first electrode to a predetermined range.

30. The transdermal electrotransport delivery container according to any one of claims 24 to 29, wherein the therapeutic agent is an analgesic.

31. The transdermal electrotransport delivery container of any one of claims 24 to 30, wherein the therapeutic agent is fentanyl or a pharmaceutically acceptable salt thereof.

32. The transdermal electrotransport delivery container of any one of claims 24 to 30, wherein the therapeutic agent is fentanyl hydrochloride.

33. The transdermal electrotransport delivery container of any one of claims 24 to 30, wherein the therapeutic agent is an analogue of fentanyl.

34. The transdermal electrotransport delivery container of any one of claims 24 to 33 for treating pain in the subject.

35. The transdermal electrotransport delivery container according to any one of claims 24 to 29, wherein the therapeutic agent is a peptide.

36. The transdermal electrotransport delivery container according to any one of claims 24 to 29, wherein the therapeutic agent is a polypeptide.

37. The transdermal electrotransport delivery container according to any one of claims 24 to 30, wherein the therapeutic agent is sufentanil or a pharmaceutically acceptable salt thereof.

38. The transdermal electrotransport delivery container according to any one of claims 24 to 29, wherein the therapeutic agent is insulin.

39. The transdermal electrotransport delivery container according to any one of claims 24 to 29, wherein the therapeutic agent is insulinotropin.

40. The transdermal electrotransport delivery container according to any one of claims 24 to 29, wherein the therapeutic agent is a protein.

41. A transdermal electrotransport delivery container for delivering fentanyl or a pharmaceutically acceptable salt thereof to a patient, the container comprising:

a first electrode adapted for placement in contact with a first animal skin surface;

a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode;
a second electrode adapted for placement in contact with a second animal skin surface;

a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

42. A transdermal delivery system for delivering fentanyl or a pharmaceutically acceptable salt thereof to a patient, the system comprising:

a first electrode adapted for placement in contact with a first skin surface of the patient;

a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode;
a second electrode adapted for placement in contact with a second skin surface of the patient;

a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

43. A transdermal delivery system for delivering an analgesic in the treatment of pain, wherein the analgesic is transdermally delivered to a patient, the transdermal delivery system comprising:

a first electrode adapted for placement in contact with a first skin surface of the patient;

a voltage booster circuit coupled to the first electrode to provide a load voltage to the first electrode;
a second electrode adapted for placement in contact with a second skin surface of the patient;

a current sensing resistor coupled in series to the second electrode to provide a selected current across the electrode; and a control circuit coupled to the voltage booster circuit and the current sensing resistor to adjust the load voltage to only a level sufficient to maintain a predetermined level of current across the electrodes at steady state.

44. A transdermal patch comprising an analgesic and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the analgesic to a human.

45. A transdermal patch comprising an opioid and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the opioid to a human.

46. A transdermal patch comprising fentanyl or an analog, ester or pharmaceutically acceptable salt thereof and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the fentanyl or the analogue, ester or salt thereof to a human.

47. A transdermal patch comprising fentanyl and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the fentanyl to a human.

48. A transdermal patch comprising fentanyl hydrochloride and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the fentanyl hydrochloride to a human.

49. A transdermal patch comprising sufentanil or a pharmaceutically acceptable salt thereof and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the sufentanil or the salt thereof to a human.

50. A transdermal patch comprising insulin and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the insulin to a human.

51. A transdermal patch comprising an insulin mimic and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the insulin mimic to a human.

52. A transdermal patch comprising insulinotropin and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the insulinotropin to a human.

53. A transdermal patch comprising a protein and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the protein to a human.

54. A transdermal patch comprising a polypeptide and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the polypeptide to a human.

55. A transdermal patch comprising a peptide and the electrotransport delivery device as defined in any one of claims 1 to 6 for delivery of the peptide to a human.