KR20010033208A - Regulator with artificial load to maintain regulated delivery - Google Patents

Abstract

An electron transport device with a drug delivery control device adapts to variable skin resistance values to deliver the drug at an appropriate drug dosage time rate. The electron transport device adapts to skin resistance that decreases over time when the electron transport device is used, and to different skin resistances at different skin surface locations. The drug delivery control device includes a voltage booster, a series connectable artificial impedance and a feedback sensor, all of which are connected to a controller. The device outputs a load voltage through two electrodes. The controller monitors the output of the feedback sensor to determine skin resistance, load current, or load voltage. Based on the monitored value, the load voltage through the electrodes is controlled so that the target drug dosing rate is maintained even if the initial skin resistance drops during the period in which the electron transport device is used. Artificial impedance is selectively controlled to prevent overdose when the skin resistance drops above a certain resistance value, such as a load voltage greater than the supply voltage resulting in overdose.

Description

REGULATOR WITH ARTIFICIAL LOAD TO MAINTAIN REGULATED DELIVERY}

As used herein, the term "electrotransport" generally refers to the transfer of an agent (eg a drug) through a membrane, such as the skin, mucous membranes, or nails, the transfer of electrical potential Application is at least partially induced or promoted. For example, beneficial therapeutic agents can be introduced into the body circulation of an animal (eg a human) by electron transport transfer through the skin.

The electron transport process is useful for dosing across the skin of drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate and many other drugs. Perhaps the most common use of electron transport is in diagnosing cystitis by transferring pilocarpine salts into ions. Pilocarpine promotes the production of sweat. The salinity of sweat is then collected and analyzed to detect the presence of the disease.

Currently known electron transport devices use two or more electrodes positioned in direct contact with a portion of the animal's body (eg skin). The first electrode, called an active or donor electrode, transports a therapeutic agent (eg a drug or prodrug) into the body by electron transport. A second electrode, called a counter or return electrode, forms an electrical circuit with the first electrode through the animal's body. A source of electrical energy, such as a battery, supplies electrical current into the body through the electrodes. For example, if the therapeutic agent transferred into the body is positively charged (eg, cation), the anode will be the active electrode and the cathode will act as the counter electrode to form the circuit. If the transferred therapeutic agent is negatively charged (eg anion), the cathode will be the donor electrode and the anode will be the counter electrode.

Instead, both the positive and negative electrodes can be used to transport drugs with opposite electrical charges into the body. In this situation, both electrodes are considered donor and counter electrodes. For example, the anode can act as a "counter" electrode of the cathode while simultaneously transporting the cation's therapeutic agent. Similarly, the negative electrode can act as a "counter" electrode of the positive electrode while simultaneously transporting a negative ion therapeutic agent into the body.

Electromigration, a widely used electron transport process (also called iontophoresis), induces the transport of electrically induced charged ions. Another form of electron transport, electroosmosis, involves the flow of a liquid solvent from a donor reservoir, which includes an agent that is transported under the influence of an applied electric field.

Another form of electron transport process, electroporation, involves the formation of pores that are present temporarily in biological membranes by the application of high voltage pulses. In part, the therapeutic agent may be transported through the skin by passive diffusion due to the difference in concentration between the concentration of the drug in the donor reservoir of the electron transport device and the concentration of the drug in the tissue of the patient's body. In any given electron transport process, one or more of these processes may occur simultaneously in a given range. Thus, the term "electron transport" as used herein should be interpreted in its broadest sense as rational, so that it is, for example, electrically derived from one or more therapeutic agents, whether charged, uncharged or a mixture of both. Or improved transportation. In addition, the load current and the current flowing through the skin are defined as the current flowing between the two electrodes.

Electron transport devices generally require an agent or a reservoir or source of a precursor of such an agent, and they are transported into the body by electron transport. Examples of such reservoirs or sources of preferably ionized or ionizable agents are pouches described in Jacobsen, US Pat. No. 4,250,878 or preformed gel bodies described in US Pat. No. 4,383,529 in Webster. It includes. Such reservoirs are electrically connected to the anode or cathode of the electron transport device, providing a fixed or renewable source of one or more predetermined treatment items.

Recently, a number of US patents have been patented in the field of electron transport, indicating continued interest in this type of drug delivery. For example, US Pat. No. 3,991,755 to Vernon et al., US Pat. No. 4,141,359 to Jacobsen et al., US Pat. No. 4,398,545 to Wilson; US Pat. No. 4,250,878 to Jacobsen; US Pat. No. 5,207,752 to Sorenson et al., Lattin et al. U. S. Patent No. 5,213, 568, and Flower U. S. Patent No. 5,498, 235 disclose electron transport devices and applications thereof.

More recently, electron transport transfer devices have become very small, especially with the development of miniaturized electrical circuits (eg integrated circuits) and stronger and lighter batteries (eg lithium batteries). The emergence of inexpensive, miniaturized electronic circuits and compact, high energy batteries has made the entire device inconspicuous and small enough to be worn in the patient's skin and clothing. This makes the patient completely mobile and allows the electron transport device to perform all normal activities during the period of active drug delivery.

However, conventional electron transport devices have drawbacks that limit their wide application. One such limitation is the difficulty in controlling the amount of drug delivered. Accurate transfer is difficult due to the fact that the electrical resistance of the patient's body surface (eg skin) is not constant during electron transfer transfer. Since the voltage (V) required to drive a particular level of electrical current (I) through the patient's skin is proportional to the resistance (R) of the skin (e.g., according to Ohm's law where V = IR _SKIN ), The required voltage of is not constant during electron transport transfer. For example, when the electron transport medication is started, the patient's initial skin resistance is relatively high, requiring the power supply to generate a relatively high voltage to carry a predetermined level of electron transport current. However, after a few minutes (eg 1 to 30 minutes after the current is applied through the skin) the skin resistance is lowered so that the voltage required to transfer a particular electrical current level is required at the beginning of the electron transport transfer. Much lower than the voltage.

Another difficult problem with the adjustment of the electron transport device is that although the skin of the entire body is basically similar in structure, there are many local changes in thickness, mechanical strength, softness and most importantly skin resistance.

Prior art dermal through electron transport transfer devices supply a set voltage to any skin surface regardless of the resistance of the skin. In addition, in some of the prior art of some transdermal electron transport transfer devices, the voltage multiplier of the power source and / or the voltage boost circuit is selected high enough to overcome the high skin resistance at the start of operation. However, once the operation reaches a steady state, due to the accompanying drop in skin resistance, the prior art device has an excessive operating voltage. Thus, by supplying a higher voltage than needed, this prior art device allows the administration of more drug than necessary once the skin resistance falls from its initial high level.

Therefore, in the improved electron transport apparatus and method, it is possible to maintain the drug delivery rate of the target value even when the skin resistance falls from its initial value, so that it is required to transfer the drug delivery rate of the target value to different areas of the skin having different resistances. .

BACKGROUND OF THE INVENTION The present invention generally relates to an electrotransport device for transporting an agent (eg a drug) that is beneficial to a patient through the skin or mucous membranes. More particularly, the present invention relates to a portable or patient wearable electron transport transfer device having a voltage booster and an artificial load to maintain controlled transfer of beneficial agents.

1 is a perspective view of an electron transport drug delivery device of the present invention.

2 is an exploded view of the electron transport apparatus of the present invention.

3 is a graph showing the decrease over time of skin resistance of a patient.

4 is a graph of a predetermined current-time profile of the load current supplied by the electron transport apparatus of the present invention. This graph is an example of a current-time profile.

5 is a graph of the time of the load voltage of the electron transport apparatus of the present invention.

6 is a schematic block diagram of a drug delivery regulator of the present invention.

7 is a schematic logic diagram of the drug delivery regulator of the present invention.

8 is a timing diagram of the operation of the circuit of FIG.

9 is a schematic logic diagram of another drug delivery regulator of the present invention.

10 is a timing diagram of the operation of the circuit of FIG.

11 is a perspective view of an electron transport drug delivery device including a detachable drug unit.

12 is an exploded view of the electron transport apparatus of FIG. 11.

13 is a schematic logic diagram of another drug delivery regulator of the present invention.

One embodiment of the present invention provides a suitable drug dosage time rate adapted to varying skin resistance values, in particular the reduction of skin resistance when a electrotransport device is used and the different skin resistance according to different skin surface locations. An electron transport device having a drug transport control device for transporting.

In another embodiment, the drug delivery control device includes a voltage booster, a series connected artificial impedance, and a feedback sensor, all of which are connected to a controller. The device outputs a load voltage across both electrodes. The controller monitors the output of the feedback sensor to determine (a) skin resistance, (b) load current or (c) load voltage and control the load voltage across the electrodes based on the monitored value and thus the drug of the target value. Dosage rates are maintained even when the initial skin resistance drops over the period of use of the electron transport device. Artificial impedance is made to prevent overdose when skin resistance drops below the battery voltage of the device.

Embodiments of electron transport drug delivery devices including the electron transport drug regulator of the present invention are shown in FIGS. 1-2 and 11-12.

1 is a perspective view of an electron transport transport apparatus 10 having an optional active switch 12 in the form of a push button switch and an optional light emitting diode (LED) 14 that is turned on when the apparatus 10 is in operation. .

2 is an exploded view of a second device 10 of the present invention. The device 10 of FIG. 2 differs in the location of the LED 10 and the device 10 of FIG. 1. The device 10 of FIG. 2 includes an upper housing 16, a circuit board assembly 18, a lower housing 20, a positive electrode 22, a negative electrode 24, an anode reservoir 26, a cathode reservoir 28. And a skin adhesion part 30. The upper housing 16 has side wings 15 to assist in supporting the device 10 of FIG. 2 being on the skin of the patient. The upper housing 16 may be made of an injection moldable elastomer (eg ethylene vinyl acetate). The printed circuit board assembly 18 includes an integrated circuit 19 that is coupled with a separating element 40 and a battery 32. The circuit board assembly 18 is attached to the housing 16 by posts (not shown in FIG. 2) passing through the openings 13a and 13b, the ends of the posts supporting the circuit board assembly 18. It is heated and dissolved to heat attach to the housing 16. The lower housing 20 is attached to the upper housing 16 by an adhesive portion 30, and the upper surface 34 of the adhesive portion 30 includes the upper housing including the lower housing 20 and the bottom surfaces of the wings 15. (16) adhered to both.

What is (partly) visible on the bottom of the circuit board assembly 18 is the button cell battery 32. Other types of batteries may also be used for the power device 10. The device 10 generally consists of a battery 32, an electronic circuit 19, 40, electrodes 22, 24 and drug / chemical reservoirs 26, 28, all of which are integrated into a unitary unit. Are integrated. The outputs of the circuit board assembly 18 (not shown in FIG. 2) are the depressions 25 formed by the electrically conductive adhesive strips 42, 42 ′ in the lower housing 20. , Electrical contact with the electrodes 24 and 22 through the openings 23, 23 ′ of 25 ′. Next, the electrodes 22 and 24 are in direct mechanical and electrical contact with the tops 44, 44 ′ of the drug reservoirs 26 and 28. Bottom surfaces 46 ′, 46 of the drug reservoirs 26, 28 contact the patient's skin through the openings 29 ′, 29 of the adhesive 30.

The lower housing 20 is made of a plastic or elastomeric sheet material (e.g. polyethylene) so that it can be easily molded to be cut to form depressions 25, 25 'and to form openings 23, 23'. Can be. The assembled device 10 is preferably water resistant (eg splash proof) and more preferably waterproof. The system has a low profile that easily adapts to the body, thus ensuring freedom of movement or rotation in the wear portion. The reservoirs 26 and 28 are located at the skin contact of the device 10 and well apart to prevent accidental electrical shorts during normal adjustment and use.

Any agent can be used as long as it is at least partially ionized. The terms "drug" and "agent" are used interchangeably and are intended to have the broadest reasonable interpretation. That is, any therapeutically active substance that is transferred to living organisms and produces a desirable, usually beneficial effect. For example, the terms "drug" and "agent" include anti-infective drugs (such as antibiotics, antiviral agents), analgesics, anesthetics, anti-arthritis drugs (such as fentanyl, sufentanil, buprenol and analgesic combinations), Antispasmodics (such as furbutalin), antispasmodics, antidepressants, antidiabetic medications, antidiabetics, antihistamines, anti-inflammatory drugs, antimigraine drugs, antisickness agents (such as scopolamine and ondansetron), antitumor agents, antiparkinsonian medications, antipruritic drugs, Antipsychotics, antipyretic drugs, antispasmodics (including gastrointestinal tract and urination), anticholinergic agents, sympathetic neurostimulants, xanthine and derivatives thereof, cardiovascular agents (including calcium hair blockers such as nifedipine), such as dobutamine and lithodrin ) Beta agents, beta blockers, antiarrhythmics, antihypertensives (such as atenolol), ACE inhibitors (such as lisinopril), diuretics, vasodilators (including systemic, coronary, peripheral and cerebral), central nervous system stimulants , Cough and persimmon Preparations, nasal decongestants, diagnostics, hormones (such as parathyroid hormone), hypnotics, immunosuppressants, muscle relaxants, parasympathetic agents, parasympathetic neurostimulants, prostaglandins, proteins, peptides, neurostimulants, sedatives and neurostabilizers Includes therapeutic compounds and molecules from all therapeutic categories, including but not limited to.

Electron transport device of the present invention is a bacrophene, beclomethasone, betamethasone, buspyrone, chromoline sodium, diltiazem, doxazosin, dropperidol, encanide, fentanyl, hydrocortisone, indomethacin, ketopro Drugs including pens, lidocaine, methotrexate, metoclopramide, myconazole, midazolam, nicardipine, pyroxicam, prazosin, scopolamine, sufentanil, tubutalin, testosterone, tetracaine and verapamil And agents can be transferred.

The electron transport device of the present invention also transports peptides, polypeptides, proteins and other polymers. It is known in the prior art that such molecules are difficult to transport through the skin or mucous membranes due to their size. For example, such molecules may have molecular weights in the range of 300-40,000 Daltons, such as LHRH and drugs (such as buserelin, goserelin, gonadorelin, naprelin and leuprolide), GHRH, GHRF, insulin, insulin Pin, heparin, calcitonin, octreotide, endorphin, TRH, NT-36 or N-[[(s) -4-oxo-2-azetidinyl] carbonyl] L-histidyl-L-prolineamide], Ripressin, Pituitary Hormone (like HGH, HMG, HCG, Desmopressin Acetate), Polysiluteoid, Alpha-ANF, Growth Factor Release Factor (GFRF), Beta-MSH, Somatostatin, Bradykinin, Somatot Tropine, platelet-induced growth factor, asparaginase, bleomycin sulfate, chymopapine, cholecystokinin, floric gonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), Glucagon, Hirulog, Hyaluronidase, Interferon, Interleukin-2, ( Menotropin, Oxytocin, Streptokinase, Tissue polominogen activator, Eurokinase, Vasopressin, Desmopressin, ACTH analogue, ANP, ANP antiseptic, Angiotensin II antagonist) Antidiuretic hormone, antidiuretic hormone antagonist, bradykinin antagonist, CD4, seredase, CSF, enkephalin, FAB, IgE peptide inhibitor, IGF-1, neurotropic factor, colony stimulating factor, parathyroid hormone and drugs, parathyroid hormone antagonist , Prostaglandin antagonists, pentagetide, protein C, protein S, renin inhibitors, thymosin alpha-1 antitrypsin and TGF-beta.

Device 10 optionally allows the patient to self-administer the medication by electronic transport. When the push button switch 12 is pressed, the electronic circuit on the circuit board assembly 18 transfers a predetermined DC current to the electrodes / stores 22, 26 and 24, 28 at a transfer interval having a predetermined period. The push button switch 12 is conveniently located on the top of the device 10 and is easily operated through the clothing. Two clicks of the push butt switch 12 within a short time interval (eg 3 seconds) can be used to drive the device for the delivery of the drug, thus minimizing the possibility of inadvertent drive of the device 10. do. Device 10 may send confirmation of the onset of visual and / or auditory drug delivery interval by LED 14, which may be a lit and / or audible sound signal (eg, a “beeper”. ") to be. The drug is transported through the patient's skin (eg arms) by electron transport over a predetermined transport interval.

Positive electrode 22 may be made of silver, and negative electrode 24 may be made of silver chloride. Both reservoirs 26 and 28 may be made of a polymer hydrogel material. The electrodes 22, 24 and the reservoirs 26, 28 are retained in the depressions 25 ′, 25 of the lower housing 20.

The device 10 is secured to the patient's body surface (eg skin) by a peripheral adhesive 30 having an upper surface 34 and a body contact 36. The adhesive 36 has an adhesive feature that ensures that the device 10 remains on the body during normal activity of the user and allows proper removal after a predetermined (eg, 24 hour) wearing period. The upper adhesive portion 34 is fixed to the lower housing 20 and holds the lower housing 20 attached to the upper housing 16.

Reservoirs 26 and 28 generally consist of a gel matrix with a drug solution uniformly dispersed in one or more reservoirs 26 and 28. As low drug concentrations in the preferred range, drug concentrations in the range of approximately 1 × 10 ⁻⁴ M to 1.0 M or more may be used. Suitable polymers for the gel matrix essentially include any nonionic synthetic and / or naturally occurring polymeric materials. Ionization (polar) properties are performed when the active agent can be ionized and / or ionized to increase agent solubility. Optionally, the gel matrix will be water expandable. Examples of suitable synthetic polymers include poly (acrylamide), poly (2-hydroxyethyl acrylate), poly (2-hydroxypropyl acrylate), poly (N-vinyl-2-pyrrolidone), poly (n-methylolacrylamide), poly (diacetone acrylamide), poly (2-hydroxylethyl methacrylate), poly (vinyl alcohol) and poly (allyl alcohol), but are not limited thereto. Hydroxyl functional concentrated polymers (eg polyesters, polycarbonates, polyurethanes) are also examples of suitable ionic synthetic polymers. Naturally occurring (or derivatives) ionic polymers suitable for use as gel matrices include cellulose ethers such as guar, locust, karaya, xanthan, gelatin and derivatives thereof, methyl cellulose ethers, Illustrated by cellulose and hydroxylated cellulose, rubbers. Ionic polymers can also be used for the matrix provided to useful counter ions that become oppositely charged drug ions or other ions compared to the active agent.

Thus, the polypeptide analog of the present invention will be incorporated into a drug reservoir (eg the gel matrix described above) and administered to a patient using an electron transport drug delivery system. Incorporation of the drug solution may be performed by a variety of methods, for example by absorbing the solution into a reservoir matrix, by premixing the drug solution with the matrix material prior to hydrogel formation, and the like.

11-12 show yet another embodiment of the electron transport drug delivery device of the present invention. This embodiment includes a reusable electronic controller and a drug unit. The reusable controller in FIGS. 11-12 is usually designed to be integrated with a drug delivery regulator and used in conjunction with a drug unit for transferring drugs stored in the drug unit through the skin.

FIG. 11 is a perspective view of an electron transport device 320 having a reusable electronic controller 322 in the form of coupled and uncoupled to the drug-storage unit 324. The reusable electronic controller 322 is adapted for use with, for example, a plurality of drug units 324, similar and / or very different drug units 324 in series. On the other hand, the drug unit 324 typically has a more limited lifespan and is discarded after use, for example when the drug contained therein is transported or depleted. Thus, after a drug contained in drug unit 324 is depleted after a predetermined operating life (eg, 24 hours), drug unit 324 is separated from reusable electronic controller 322 and is of the same or different structure and / or Or a new drug unit 324 of the composition. The reusable electronic controller 322 is designed to be provided with one of a plurality of different predetermined electrical output values set when the controller is manufactured. Different electrical outputs of the reusable electronic controller 322 are designed to be used for different drug units 324.

For purposes of illustration, the reusable electronic controller 322 can be designed for use in at least two different drug units 324, both units being used in the same reusable controller 322 to continuously dispense the drug. Transfer for 12 hours. Two different drug units 324 contain the same drug in their respective donor reservoirs but each contains a different amount of drug. Drug unit 324 containing a greater amount of drug is a "high dose" drug unit used for higher DC current (eg, 2 mA) from reusable electronic controller 322. The drug unit 324 containing the smaller amount of drug is a “low dose” drug unit used for lower DC current (eg, 1 mA) from the reusable electronic controller 322. Thus, the reusable electronic controller 322 is designed to apply one of two different DC currents (eg, 1 mA or 2 mA) depending on the combination of the low dose or high dose drug unit 324.

The present invention sends a signal to the reusable electronic controller 322 regardless of which type of drug unit is coupled (e.g., high or low dos), and sets the output of the appropriate controller (e.g. Current output or low current output setting) to match the combined drug unit. In the apparatus shown in FIGS. 11 and 12, the drug unit 324 signals to the reusable electronic controller 322 by means of an optical signal, the optical signal being (eg, by snap connectors 326, 328). When coupled to the drug unit 324, it is automatically sent and read (eg, decrypted) by the reusable electronic controller 322. When reading the signal, the controller appropriately selects the correct electrical output and applies it to the combined drug unit 324.

12 shows an exploded view of both drug unit 324 and reusable electronic controller 322. The reusable electronic controller 322 consists of an upper housing 368 and a lower housing 350, both of which are typically formed of a molded plastic such as polypropylene. The upper housing 368 is coupled with the lower housing 350 by an adjacent splash proof and preferably a waterproof peripheral sealant. The seal can be made by adhering the housings together to ordinary connections using waterproof adhesives or the like, by heat sealing or ultrasonic welding of the connections between the housings 350, 368. The lower housing 350 has an opening 352 for receiving a battery 354. Battery contacts 364 and 366 are provided to make contact with respective poles of the battery 354. The removable cover 360 is turned into the opening 352 to maintain the position of the battery 354. The cover 360 has a slot 362 for inserting coins or a screw driver blade for turning the cover 360 so as to access (eg, replace) the battery 354. Remove it from (352). Reusable electronic controller 322 includes a battery, such as a button cell battery, for powering an electrical circuit (not shown) on circuit board 359. The circuit board 359 is formed in a conventional manner to control the electrical components (eg, the timing, frequency waveforms, etc.) of the electrical output (eg, voltage and / or current) of the reusable controller 322. The conductive traces are patterned to interconnect them. Conductive traces on the circuit board 359 are deposited by a conventional silk screen printing process or a conventional solder coated copper plate mask and etch process. The insulating substrate on the circuit board 359 can be made of standard FR-4 or the like. Although not critical to the present invention, the reusable electronic controller 322 may display a liquid crystal that can be displayed through the push button switch 374 and the window 358 (FIG. 12) that can be used for the start operation of the device 310. Display system information such as display 356 (FIG. 11), special type of drug unit 324 coupled to the controller, applied current level, dosing level, number of doses transferred, current elapsed time, battery capacity, etc. Include.

The lower housing 350 is provided with holes 375a and 375b holding the electrically conductive receptacles 330 and 332. The ends of the receptacles 330, 332 are located by the respective conductive fixtures 376a, 376b and are in electrical contact with the outputs of the electronic circuit on the circuit board 359.

The drug unit 324 is configured to be detachably coupled with the reusable electronic controller 322 to the top of the drug unit 324 adjacent and opposite the bottom of the reusable electronic controller 322. The upper drug unit 324 is provided with a male portion of the two snap connectors, the male portions being posts 326 and 328 extending upward from the drug unit 324. Receptacle 330 is positioned and sized to receive donor post 326, and receptacle 332 is positioned and sized to receive counter post 328. One snap connector pair, e.g., receptacle 332 and post 328, may provide another snap connector pair (e.g., to provide reusable electronic controller 322 with a polarity characteristic connection of drug unit 324. For example, it may be made larger than the receptacle 330 and the post 326. The receptacles 330, 332 and the posts 326, 328 are made of an electrically conductive material (eg, silver, brass, stainless steel, platinum, gold, nickel, beryllium-copper, etc.) or a silver coating, for example. Metal coating polymers). Donor post 326 is electrically connected with donor electrode 390, and donor electrode 390 is electrically connected to donor reservoir 401, which typically contains a solution (eg, a drug salt) of the transported therapeutic agent. Connected. Counter post 328 is electrically connected to counter electrode 388, and counter electrode 388 is electrically connected to counter reservoir 399, which typically contains a biologically suitable electrolyte (eg, buffered salts). do. Electrodes 388 and 390 are typically made of conductive materials, which may be silver (eg, silver foil or silver powder mounted on a polymer) positive electrode and silver chloride negative electrode. Repositories 399 and 401 typically comprise hydrogel matrices that hold drug or electrolyte solutions and, in use, are placed in contact with the body surface (eg, skin) of a patient (not shown). The electrodes 388, 390 and the reservoirs 399, 401 are isolated from each other by a foam member 396. The underside of foam member 396 (eg, in contact with the patient) may be coated with a skin contact adhesive to secure drug unit 324 to the body of the patient. A relief liner 402 covers the body contact surfaces of the two reservoirs 399 and 401 and the adhesive coated surface of the foam member 396 before the drug unit 324 is used. The relief liner 402 as one embodiment is a silicone coated polyester sheet. The relief liner 402 is removed when the device 320 is applied to the skin of a patient (not shown).

Thus, post 326 and receptacle 330 include a snap connector that electrically connects the output 378a of the circuit on circuit board 359 to electrode 390 and reservoir 401. Similarly, post 328 and receptacle 332 include a snap connector that electrically connects the output 378b of the circuit on circuit board 359 to electrode 388 and reservoir 399. In addition to providing the electrical connections described above, the two snap connectors also provide a detachable (eg non-permanent) mechanical connection of the drug unit 324 to the reusable electronic controller 322. Thus, the electrically conductive snap connectors 326, 330 and 328, 332 are (i) a mechanical coupling of the drug unit 324 and the connector 322 (ii) a reusable electronic controller 322 and a drug unit ( 324 provides the function of electrical connection at the same time.

According to this embodiment of the present invention, the drug unit 324 properly sets the electrical output of the controller to a predetermined output value suitable for the specific drug unit 324 and stores the specific drug unit 324 and the specific drug therein. To do so, provide an optical signal to the reusable electronic controller 322. As clearly shown in FIGS. 11 and 12, the mating surface of the drug unit 324 has two surface regions 340, 342. Surface area 340 is shown as "white" to indicate high light reflectivity, while surface area 342 is shown as "black" to indicate low light reflectance. Regions 340 and 342 are provided directly on the backing layer 344 of the drug unit 324 (eg, by printing or painting) or generally on the backing layer 344 by a suitable adhesive. It may be provided on a thin piece of paper or mylar 343 that is mounted on it.

The reusable electronic controller 322 is mounted on the circuit board 359 and has a pair of light reflecting switches 334, 336 for projecting through the holes 337a, 337b of the lower housing 350. . The switches 334, 336 are towards and adjacent the drug unit 324. Reflective regions 340, 342 are located on drug unit 324 when reusable electronic controller 322 and drug unit 324 are coupled, so that regions 340, 342 are respectively reflective switches ( 336, 334 is located very close to.

Light reflecting switches 334 and 336 are arranged to shine light into the light reflecting regions 340 and 342, respectively. Reflective regions 340 and 342 are aligned such that illumination from switch 334 is independently reflected back to switch 334 by region 342. Similarly, illumination from switch 336 is independently reflected back to switch 336 by region 340. In one embodiment, the switches 334 and 336 have photo emitter shaped illumination sources 346a and 346b and matching phototransistor types, such as SFH901 or SRH902 from Siemens Optoelectronics Division, Cupertino, CA, respectively. Light sensing photodetectors 348a and 348b are provided, respectively. Phototransistors 348a and 348b are coupled in a circuit (described below) that generates signals responsive to injected light.

The switches 334, 336 are mounted by conventional means, such as through holes and solder connections on the circuit board 359 and respective traces (not shown).

Flexible support layer 344, which may be made of a material (eg, polyethylene sheet) that does not permeate the passage of liquid moisture, forms the top layer of drug unit 324. Holes 384a and 384b are provided through support layer 344, and through holes 382a and 382b are provided through strip 343 in aligned alignment. Conductive base rivets 326a and 328a are introduced through openings 384a and 384b and through holes 382a and 382b respectively, with support layers 344 interposed between posts 326 and 328. Make it fixed.

The electrodes 388 and 390 are made of an electrically conductive material such as carbon powder / fiber mounted on the polymer matrix, metal powder or metal foil mounted on the polymer matrix. Electrodes 388 and 390 are in contact with base rivets 326a and 328a. A conductive adhesive filled with carbon or silver particles is used to bind the electrodes 388 and 390 to the base rivets 326a and 328a. Electrodes 388 and 390 are in electrical contact with reservoirs 399 and 401, respectively. An insulating closed cell foam layer 396 has cavities 398 and 400 therein, the cavities each comprising reservoirs 399 and 401. Typically, one of the reservoirs 399, 401 is a donor reservoir containing a liquid solution of a therapeutic agent transported by electron transport, while the other contains a solution of a biologically suitable electrolyte (eg salt). It is a counter store. The matrix of the reservoirs 399, 401 can be a gel.

Transmission information about the drug unit 324, via the optical signal transmitted to the reusable electronic controller 322, is achieved by providing reflective regions 340, 342 with different reflectivity levels. For example, at the wavelength of illumination from the switches 334, 336, the region 340 can be standard white with a reflectivity of about 90%, while the region 342 has a reflectivity of about 10-15%. It may be a plane black having. Together with the two light reflecting surface regions, each region has one of two possible light reflectances, and the drug unit 324 comprises the following “reflective code”; (1) a first optical signal when both regions 340 and 342 have a small reflectivity; (2) a second optical signal when both regions 340 and 342 have high reflectivity; (3) a third optical signal when region 340 has a small reflectivity and region 342 has a high reflectivity; (4) Send four differently coded optical signals based on the fourth optical signal when region 340 has high reflectivity and region 342 has low reflectivity to reusable electronic controller 322. Regions 340 and 342 can also be coded by coloring with a color having an appropriate reflectivity.

An apparatus such as, for example, an electronic circuit for carrying out the method of controlling drug delivery of the present invention is installed in the electron transport drug delivery devices of the present invention described above. More specifically, electronic circuits fabricated on the circuit board assembly 18 of FIG. 2 or the circuit board 359 of FIG. 12 are provided to regulate drug delivery of the present invention. An electronic circuit is referred to as a regulator below.

The adjuster initiates drug delivery only when the delivery device is attached to the patient's skin surface and when the push button switch is specifically pressed such as for example a double click. As shown in the current (i) vs. time (t) graph of FIG. 4, while the regulator supplies an initial current i with a boosted voltage to overcome high initial skin resistance, start the step-up period T ₀ . During the step-rise period (T ₀ ), the regulator maintains the voltage present on the skin between the maximum value (24V) and the minimum value (0V) to reduce the sensory stimulation of the patient with the initial applied current. The voltage is supplied to a regulator between two electrodes, for example 22 and 24 of FIG. 2 or 388 and 390 of FIG. 12. After the step-rise period, the regulator maintains the elevated voltage at the transfer current id during the transfer period T _d . This provides a steady state operation of the device and provides a drug transfer rate along with the transfer current provided by the controlled variable voltage.

Although the initial skin surface resistance is relatively high, over time the skin resistance drops significantly. 3 is a graphical representation of the characteristic showing skin resistance (R) gradually decreasing to a steady state value. At a discharge rate of 0.1 ma / cm ² , this steady state value is typically between 20 and 30 kohm-cm ² , while the initial value of skin resistance is several times this.

When the skin resistance is significantly lowered, the anode voltage V _g drops below the battery voltage V _b . This causes excessive load current to flow through the skin even when the battery voltage is supplied without a boosted voltage, causing the regulator to initiate an over dose mode at time T1. This is illustrated in Figure 5 with the anode voltage (V _a) y axis and time (t) being the in the x-axis.

If the overdose mode lasts longer than the first maximum low load detection period, for example 10 seconds, an artificial impedance control enabler is connected in series with the skin surface. If the impedance value of the controller is high enough, it becomes possible to lower the current value supplied to the skin and also to control the load current by the voltage boosted by the regulator.

Furthermore, even after the connection of the artificial impedance, if the low load condition of the skin is longer than the second maximum low load detection period, for example 10 seconds, the regulator will cut off the voltage supplied to the electrodes.

The above adjustment method is shown with reference to FIG. 6, which is a schematic block diagram of one device embodiment performing this method. The regulator 50 includes a controller 53 connected to the battery 51. The controller 53 is also connected to two terminals of the voltage booster 55, the impedance connecting switch 77 and the regulating resistor 59. In this preferred embodiment, the artificial impedance (eg, resistor) 57 is connected in series between the negative electrode assembly 65 and the impedance connection switch 77. However, the artificial impedance 57 and the impedance connecting switch 77 can be connected in series between the voltage booster 55 and the positive electrode assembly 63. This structure is not shown in FIG.

The impedance connecting switch 77 connects the artificial impedance 57 in series only during the overdose mode between the electrode assembly 65 and the regulating resistor 59, otherwise the switch 77 is connected to the electrode assembly 65. Is directly connected to the resistor (59).

During the setup period, the controller 53 drives the voltage booster 55 to supply the boosted voltage through the two electrodes 63 and 65 attached to the skin surface 61. The boosted voltage is initially required because the skin surface 61 has a high resistance value, which hinders the flow of current between the electrodes 63 and 65.

During the setup period and the dosing period, load current flows from the electrode assembly 63 through the skin 61 to the electrode assembly 65, the regulating resistor 59 and the system ground port 73. The feedback input port 71 with a sufficiently high resistance prevents the load current from flowing into the port 71. The load current path causes the controller 53 to monitor the load current between the electrodes 63 and 65 using the voltage value sensed at the feedback input port 71. In other words, by using the resistance value of the previously known regulating resistor 59 and by using the voltage value of the feedback input port 71, the controller 53 is designed to determine the current flowing through the regulating resistor 59. The determined current is an exact approximation of the load current.

Using an approximate load current, the controller 53 adjusts the voltage booster 55 to supply sufficient voltage to maintain the dosing current. This is achieved by turning on voltage booster 55 and boosting the supply voltage when the feedback voltage falls below the target voltage, and by turning off voltage booster 55 when the feedback voltage is equal to or above the target voltage. do. When the voltage booster 55 is turned off, the voltage from the battery 51 is supplied without being boosted. The target voltage is equal to the voltage through the regulating resistor 59 when the load current is equal to the application current.

When the feedback voltage is higher than the preset voltage, the regulator enters overdose mode. The preset voltage can be set to accurately determine when the skin resistance becomes so low that the anode voltage cannot drop below the battery voltage. As an example, the preset voltage may be set to 10% of the target voltage.

After the first maximum low load detection period from the start of the overdose mode, the controller 53 using the impedance switch control 75 connects the impedance 57 in series between the electrode assembly 65 and the regulating resistor 59. To be. This step stops excess dosing current and causes the controller to adjust the load current using the voltage booster 55.

However, if the overdose mode is longer than the second maximum low load detection period, the controller 53 cuts off the voltage supplied from the electrode assembly 63 even after series connection of the artificial impedance 57.

As safety means a voltage limiter 79 is connected between the electrode assembly 63 and the terminal of the regulating resistor 59. If the voltage booster boosts the voltage more than, for example, a safety level of 25V, the voltage limiter stops further boosting of the voltage supplied to the electrode 63.

The apparatus described above with reference to FIG. 6 may be performed using ASICs or logic circuits. In addition, the embodiment shown in FIG. 6 is only one embodiment, and thus, the components, the controller 53, the voltage booster 55, the artificial impedance 57 and the regulating resistor 59 may be one integrated circuit or It can be done using separate integrated circuits. The functioning of each of the above components as software modules and programming them with a microprocessor can also be embodied in the present invention.

FIG. 7 is a schematic detailed view of the first embodiment described in FIG. 6. The regulator 100 is electrically connected to a power source 102 in the form of a battery and a voltage controlled electrical junction 104 connected to the electrode assembly 108. The electrode assembly 108 is attached to one area of the skin surface 110 by conventional devices such as adhesives, straps, belts or the like. The skin surface is schematically shown as a variable resistive load R _v , indicating a change in the typical load resistance of the skin when applying an electric current I _L flowing therethrough. The electrode assembly 112 is similarly attached to another area of the skin surface 110.

The electrode assembly 112 is connected in series to the regulating resistor 114. The electrodes 108 and 112, the skin surface 110 and the regulating resistor 114 form a load current path for conducting the load current I _L.

The voltage booster 141 includes an energy storage inductor 118 connected between the battery 102 and the anode of the rectifying diode 120. The cathode of diode 120 is connected to voltage controlled electrical junction 104. The voltage booster 141 includes a filter capacitor 122 connected with the junction 104 and the control switch 124 and has a control input 126. The control switch 124 has one terminal 128 connected to the junction of the anode of the diode 120 and the inductor 118 and another terminal 130 connected to the system ground. Control input 126 alternately opens and closes switch 124 to create a low resistance connection between terminals 128 and 130, thereby connecting inductor 118 to the system ground via a low resistance path, or Disconnect. The switch 124 may be an electronic switch device such as a bipolar or field effect transistor (FET).

The control circuit 132 has a control output 134 connected to the switch control input 126. The control circuit 132 includes a feedback output 133 for controlling the control output 134 and the ground input 136.

The regulator 100 is provided with a microcontroller 138. The microcontroller 138 is idle until a threshold voltage appears on the regulating resistor 114. This threshold voltage rises when the controller is attached to the patient and the variable skin resistance rises between the electrode assemblies 108 and 112. Microcontroller 138 uses an internal counter and a low current transfer time software routine, for example of 0.1 mA. This time period is programmable. After this time, the microcontroller 138 transfers a dose current of, for example, 0.5 mA during the second programmable time period. Microcontroller 138 delivers another dose current of, for example, 0.1 mA for a third programmable time period. The periods may vary from 0 seconds to a time determined by limitations of the microcontroller 138 memory or battery life.

In addition, the microcontroller 138 receives a feedback at the input 140 that senses the current I _L through the skin 110 by sensing the voltage drop of the regulating resistor 114, and the second voltage. Compare the drop to the preset limit. The microcontroller 138 also receives an input 142 that senses the voltage drop through the skin 110 and compares the sensed voltage with a preset maximum limit. The artificial impedance includes a controllable resistor 123, which is connected in series between the controllable switch 127 and the electrode assembly 112. The controllable switch 127 is controlled by the load control output 135 of the microcontroller 138.

If the feedback voltage sensed by the microcontroller 138 at the feedback input 140 is higher than the preset voltage limit longer than a predetermined time, the controllable switch 127 sends the controllable resistor 123 to the regulating resistor 114. Connect it. If a high feedback voltage condition is maintained after the connection controllable switch 127 is closed, the microcontroller shuts down the control circuit 132 and also stops the load current I _L. At other times, the load switch connects the electrode assembly 112 directly to the regulating resistor 114.

The microcontroller 138 monitors the resistance of the skin 110 by the voltage input 142 and the current input 140, and when the resistance of the skin 110 exceeds a predetermined upper limit in accordance with a stored program or a predetermined value. Shut down the voltage boosting function of regulator 100 when less than the lower limit. The above mentioned first maximum low load detection period and the second maximum low load detection period are measured by the microcontroller 138 in the same way as for example tracking the number of overflow interrupts of the timer.

Microcontroller 138 also monitors system status. The low battery signal from the control circuit 132 (not shown in FIG. 7) informs the microcontroller 138 of the low battery condition. The microcontroller 138 then illuminates the state of attention with an LED (light emitting diode, not shown in FIG. 7).

Typical operation of voltage boost circuit 141 connected to other circuits of regulator 100 can be understood with reference to FIG. For example, after initiation of the operation of the regulator 100 by the push button switch 12 shown in FIG. 1, the control circuit 132 first connects the input 136 to system ground. This makes it possible for the regulating resistor 114 to flow the conductive load current I _L from the load 110.

The control circuit 132 configures a toggle control output 134 such that the switch 124 connects one end of the inductor 118 to ground during the T1 period. During the T1 period, the inductor current I _i driven from the battery 102 is increased to the maximum value I _p . Here, T1 is part of the setup period.

At the end of the T1 period, the control circuit changes the output 134 back to the toggle switch input 126, leaving the switch 124 open for the T2 period. During the T2 period, the inductor current I _i will not flow to ground, but will be conducted through the diode 120 to the electrical junction 104. Filter capacitor 122 provides a low impedance path for the instantaneous current (I _i) and of current (I _i) will decline to a value of zero for the T2 period, the electrical junction 104, the voltage the capacitor 122 of the Boosted by change. Here, the T2 period is another part of the setup period.

During the T1 period, the inductor 118 stores energy by being charged by the current. During the T2 period, the inductor 118 discharges energy through the diode 120 to the filter capacitor 122. Thus, the inductor 118 transfers energy from the battery 102 to the capacitor 122 only by the voltage drop across the diode 120 and by the negligible series resistance of the inductor 118, battery 102 and electrical connections. Transmit with limited low loss. Thus, the direct energy source of the load current I _L is not the battery 102, but the capacitor 122 (eg, during the T1 period) or the combination of the capacitor 122 and the inductor 118 (eg, During the T2 cycle).

The control circuit 132 repeats the T1, T2 cycles indefinitely or stops as described below. The voltage V _W at the junction 104 is thus stepped up to a multiple of the adjustable battery 102 voltage depending on the values of the periods T1 and T2. Thus the voltage boost can be adjusted by adjusting the T1 and T2 values.

The dotted lines in FIG. 8 represent missing or delayed pulses as being controlled by the control circuit 132. These may occur when the pulses need to replace the depleted charge from the capacitor 122, for example when the required treatment current I _L is relatively low. The dotted lines in FIG. 8 indicate that voltage boost control can be achieved by pulse width modulation (PWM), pulse frequency modulation (PFM), pulse skipping, or a combination thereof.

The adjustable operating voltage V _W causes the load current I _L to flow through the skin surface 110, regulating resistor 114 to the system ground at the switch input 136.

The feedback input 133 senses the voltage through the regulating resistor 114 caused by the load current I _L. The control circuit 132 is responsive to the feedback input 133 and load resistor 123 by boosting V _W by adjusting the time periods T1 and T2 or by controlling the loading switch 127. To adjust the operating voltage. This is accomplished by comparing the voltage sensed at the input 133 with a set reference voltage in the control circuit 132, for example a target voltage.

If the voltage sensed at the input 133 is lower than the first reference voltage, the control circuit 132 opens and closes the switch 124 at high frequency until V _W is stepped up to an appropriate level. In general, the longer the switch 124 is closed (e.g., the longer the Tl period), the greater the voltage boosted in the inductor 118, and the greater the voltage boost. The battery 102 voltage can be boosted by the inductor 118. The voltage V _ind boosted by the inductor 118 is equal to the rate of change of the current flowing through the inductor multiplied by the inductance value L:

V _ind = L * (dI / dt) expression. One

Thus, the inductor 118 at a high voltage low current (partly determined by the inductance value of the inductor 118, partly by the rate of change of the current flow through the inductor 118, and controlled by the T1 and T2 values). ) Is because the power going into the inductor 118 is equal to the power coming out of the inductor 118.

Thus, electrode assemblies 108 and 112 and skin surface 110 are not exposed to high peak voltages, but instead experience a constant value that is only the lowest value sufficient to drive the desired load current I _L.

The time period (T1 and T2) and is boosted by the minimum absolute value to provide the load current (I _L), a I _L is controlled by the control circuit 132, to maintain a predetermined desired value. If the resistance value of the skin surface 110 is so large that a predetermined value of I _L cannot be obtained without having a stable level exceeding V _W , such as a zener diode 116 connected through the electrode assemblies 108 and 112. The voltage limiting device limits the voltage applied to the skin 110. Typical stable maximum limit of V _W is about 24 V. Other values of the limit voltage can be achieved by means of zener diodes with different breakdown voltages or by using other practices described in detail below.

Once the resistance of the skin surface 110 causes the load current I _L to reach a desired predetermined level of maximum safety voltage, the control circuit 132 will respond to the feedback at the feedback input 133, T1 and T2 will be adjusted to boost V _W to a multiple that is sufficient to keep the current at a predetermined level. In addition, if the skin resistance value is so low that the load voltage drops below the battery voltage, the controllable resistor 123 is connected to enable the controller to adjust the load voltage using the voltage booster 141.

Thus, the operating voltage V _W at the controlled electrical junction 104 is sufficient to maintain the load current I _L at a predetermined value as long as the load voltage is lower than the limit voltage set by the zener diode 116. 102) The voltage is boosted by multiple boosting of the voltage.

Small loss of energy transfer from the battery 102 to the skin 110 and the capacitor 122 maximizes the useful life of the battery 102 at a given battery capacity. This allows the use of smaller batteries in a given treatment regime and allows for longer life of treatment treatment at a given cost.

The predetermined current applied through the skin 110 is constant or changes over time according to the current-time profile. In any case, the control circuit 132 establishes a predetermined current-time profile that is applied. This may include one input connected to the regulating resistor 114 and the other input connected to the output of the DA converter driven by a clocked ROM having a constant reference voltage connected to the other input or having a pre-programmed pattern. Can be achieved by known techniques, such as having a differential comparator.

In addition, in the control circuit 132, the inductor 118 value, the load resistance value 110 through the skin, the capacitance value of the capacitor 122, the time periods T1 and T2 and the load resistor 123 are inputted with feedback. Aligned in response to the voltage at 133, the filter capacitor 122 flexibly adjusts the voltage V _W to provide the load current I _L , which is an essential constant (DC) current of a predetermined value.

13 is a schematic diagram of an alternative drug delivery control circuit 400. The regulator 400 is similar to the drug delivery regulator circuit 100 described above with reference to FIG. 7, and the reference numerals for the elements are similar. In the regulator circuit 100 of FIG. 7, the microcontroller 138 senses a decrease in skin resistance between the electrodes 108 and 112. When the skin resistance approaches the first predetermined minimum resistance, the switch 127 is driven to couple the resistor 123 in series with the electrode 112 and the resistor 114. As such, the resistance between node 102 and input 136 of control circuit 132 is increased. It will be appreciated that this combined resistance can be reduced to be lower than the first predetermined minimum resistance value. For example, the skin resistance can be reduced to substantially 0 Ω. The regulator circuit 100 is shut off when experiencing this state. An alternative embodiment of the drug delivery regulator 400 (FIG. 13) compensates for reduced skin resistance lower than the first predetermined minimum resistance value.

The drug delivery regulator circuit 400 includes a battery 102, a voltage boosting circuit 141, electrodes 108 and 112, a microcontroller 138 and a control circuit 132. The regulator circuit also includes a variable resistor 402 and a resistor control circuit 404. As one embodiment, the variable resistor can be a field effect transistor (FET) with channel resistance, and the resistor adjustment circuit 404 can be an op-amp coupled to the gate electrode of the FET. Referring back to FIG. 7, in the regulator 100, the capacitor 122 forms an RC circuit in combination with the series resistors defined through the skin 110 and the resistor 114.

If the skin resistance becomes too low, the voltage at node 104 drops below the battery voltage, and resistor 123 is coupled in series with skin resistance and resistor 114 to efficiently increase the resistance of the RC circuit. If the skin resistance continues to drop, node 104 may again fall below the battery voltage. To alleviate this potential problem, regulator 400 includes a variable resistor 402.

In operation, when a current flows through the skin during the T1 and T2 periods, a voltage drop is provided through the resistor 114. Effectively, the resistance distribution circuit is provided by skin resistance, variable resistor 402 and resistor 114. Thus, the skin resistance and the resistance value through the variable resistor 402 determine the voltage at node 408. Amplifier 404 receives an input voltage from microcontroller 138 via output node 135. When the voltage at node 408 exceeds the voltage provided to node 135, the amplifier adjusts the control voltage provided to variable resistor 402. In one embodiment where the variable resistor 402 is a field effect transistor, the amplifier 404 reduces the gate voltage and the resistance through the source and drain of the transistor is increased. Those skilled in the art will appreciate that the proper choice of FETs allows the regulator to provide a constant current between the electrodes 108 and 112 even when the skin resistance is zero. The regulators of FIGS. 7, 9 and 13 include a variable resistor circuit 101. This circuit causes the regulator to change the resistance path through the electrodes. Each embodiment causes control circuits 132 and 138 to control the series resistance. 7 and 9 include different resistance paths, while the embodiment of FIG. 13 includes a variable resistor circuit. The variable resistor circuit 101 is shown in FIG. 7 as having either a low resistance path (substantially 0 Ω) or a resistor 123 coupled in series to a load resistor. 9 shows both a low resistance path (via switch 274) and a resistor 272 connected in parallel to form a low resistance path. Thus, one of ordinary skill in the art, having the benefit of the present invention, will understand other ways of performing the variable resistor circuit.

FIG. 9 shows a variation of an embodiment of the regulator for the invention described in FIG. 7. The regulator 200 includes a battery 202, an inductor 204, a diode 206, a voltage control circuit junction 207, a low resistance filter capacitor 208 and electrode assemblies 210, 212, which are conventional Is attached to the separated area of the skin surface 213 by means of. Skin surface 213 is represented as variable load resistance R _V to emphasize the fact that the resistance of skin 213 changes with time and current. At least one of the electrode assemblies 210, 212 includes a therapeutic agent in a form suitable for electron transport transfer to the skin surface 213.

The regulator 200 includes an N-channel field effect transistor (FET) switch 218 for the switching inductor current I _i , the inductor current sense resistor 220 and the regulation resistor 214. This circuit also includes a high efficiency adjustable DC-DC step-up controller 216.

Adjustable DC-DC step-up controller 216 can be a Maxim MAX773 controller manufactured by Maxim Integrated Products, Inc. of Sunnyvale, CA. 9 also shows a simplified schematic diagram of a MAX773 controller suitable for the purposes of the present invention. A more detailed schematic of the MAX773 controller can be found in the MAX773 data sheet 19-0201; Rev 0; 11; Can be found at 93. A simplified block diagram of the MAX773 data sheet information is shown in FIG. The MAX773 controller 216 includes a reference voltage pin 256, a ground pin 258, a feedback input 264, a shutdown input 266, a current sense input 268 and a power bus input 270.

The MAX773 controller 216 also includes a first two-input comparator 230 with an output 231, a second two-input comparator 232 with an output 233, a first reference voltage 242, a second reference. 2 (eg, 1.5 V) reference voltage 244, a PFM / PWM drive circuit 240 having a switch control output 252, and a switch control output 254.

In addition, the regulator 200 includes a boost monitor comparator 273, an excess voltage monitor comparator 275, a controllable switch 274, a controllable resistor 272 and a cutoff switch 276. The microcontroller (not shown in FIG. 9) also includes a regulator 200. The boost monitor signal 277, the excess voltage monitor signal 279, the feedback signal 265 and a pair of reference voltages (not shown in FIG. 9) are connected as inputs to the microcontroller. Next, the microcontroller controls the controllable switch 274, the cutoff switch 276 and the shutdown signal 271.

Microcontroller of the present invention is Chandler, AZ. Microchip Technology, Inc. It may be a PIC16C620-SSOP microcontroller manufactured by. This microcontroller is described in more detail in pages 2-203 to 2-212 of the PIC 16/17 Microcontroller Data Book, May 1995, which is provided herein by reference. Typical operation of the regulator 200 can be understood with reference to FIGS. 9-10. The circuit 200 provides a high efficiency conversion of energy from the battery 202 to the adjustable stepped voltage V _W at the voltage controlled electrical junction 207 using the MAX773 controller 216, while Control the load current I _L.

Unlike conventional pulse frequency (PFM) converters, which use the error voltage from the voltage divider circuit to control the output voltage of the converter to a constant value, the MAX773 controller 216 is connected to the regulating resistor 214 to provide an average load current (I Generates an error voltage controlling _L ). The MAX773 controller 216 also operates at high frequencies (above 300kHz) to allow the use of small external components.

Referring to FIG. 9, according to the present invention, a portion of the load current I _L is fed back to the feedback input 264. Electrode assemblies 210 and 212 are attached to skin resistance 213, indicated as a variable resistance load. The MAX773 controller 216 is an integrated circuit with internal elements connected by conductive traces formed during the integrated circuit fabrication process. External fins are provided for electrical connection of external elements by conventional printed circuit forms such as plated or deposited copper or other conductors deposited and formed on insulating substrates. The internal or external of what is shown in FIG. 9 is understood with reference to the electrical connections described herein. A description of the functionality of the circuit 216 is understood with reference to the elements of the MAX773 controller 216 circuit.

One terminal of the regulating resistor 214 is connected to a feedback input 264. The same terminal of this regulating resistor 214 is also connected to the electrode assembly 212 to receive the load current I _L. The other terminal of the regulating resistor 214 is connected to the system ground. Input 264 is connected to the inverting input of comparator 232. The non-inverting input of comparator 232 is connected to reference voltage 244. The output 233 of the comparator 232 is connected to the PFM / PWM drive circuit 240.

The output 231 of the comparator 230 is connected to the PFM / PWM drive circuit 240. The inverting input of comparator 230 is connected to reference voltage 242. The non-inverting input of comparator 230 is connected to current sense input 268. Input 268 is connected to one terminal of inductor current sense resistor 220. The other terminal of resistor 220 is connected to the system ground. Ground pin 258 of the MAX773 controller 216 is also connected to system ground.

One output of the PFM / PWM drive circuit 240 is connected to the output 252. Input 270 is connected to one terminal of battery 202. The other terminal of battery 202 is connected to system ground. The other output of the PFM / PWM drive circuit 240 is connected to the output 254. Outputs 252 and 254 are both connected to the gate of an external N-channel switch 218. The drain of the switch 218 is connected to one end of the energy storage inductor 204 and the connecting connection of the anode of the rectifying diode 206. The source of the switch 218 is an inductor current sense resistor connected to the current sense input 268. It is connected to one terminal of 220.

The other terminal of the inductor 204 is connected to the power bus input 270 and the terminal of the battery 202. Filter capacitor 276 is connected between input 270 and system ground. Filter capacitor 278 is connected between voltage pin 256 and system ground. Filter capacitors 276 and 278 have a low operating impedance at the pulse frequencies of interest.

The anode of the diode 206 is connected to the electrical junction 207. The junction 207 is also connected to one terminal of the filter capacitor 208, the cathode of the zener diode 280 and the electrode assembly 210. The positive terminal of the zener diode 280 and the other terminal of the capacitor 208 are connected to ground. The junction 207 completes a circuit 200 that boosts the operating voltage V _W at the junction 207 by, for example, an adjustable multiple of a power supply voltage, such as the battery 202. Zener diode 280 limits the peak voltage through electrode assemblies 210 and 212, thus limiting the maximum voltage experienced in skin 213.

With reference to FIGS. 9 and 10, the typical operation of the regulator 200 can be understood. When power is applied by the battery 202 to the power bus 262 via the power input 270 and the shutdown input signal 271 is at the correct logic level, the MAX773 controller 216 and the microprocessor begin operation.

Like a traditional PFM converter, switch 218 is not turned on until voltage comparator 232 detects that the output current is out of regulation. However, unlike traditional PFM converters, the MAX773 controller 216 has a peak inductor current with maximum switch on-time and minimum switch off-time generated by the PFM / PWM drive circuit 240. It uses a combination of limit sense resistor 220, reference voltage 242 and comparator 230, with no oscillator. Typical maximum switch on time (T1) is 16ms. Typical minimum switch off time (T2) is 2.3 s.

Once off, the minimum offtime keeps switch 218 off for time T2. After this minimum time, the switch 218 either (1) remains off if the output current (I _L ) is in regulation, or (2) turns on again if the output current (I _L ) is not adjusted. Becomes one of

When the switch 218 is off, the inductor current I _i flows from the diode 206 to the capacitor 208 at the junction 207 and fills the predetermined charge exited by the skin 213. This method of switching the charging current I _{L provides} an adjustable step-up multiple of the battery 202 voltage to the operating voltage V _W at the junction 207, which supplies the desired constant current I _L. It can be seen that it is enough. The peak voltage carried by the inductor 204 is required to overcome the diode drop of the diode 206 and the operating voltage V _W , thus minimizing energy loss from the battery 202.

The MAX773 controller 216 circuit allows the circuit 200 to operate in continuous-conduction mode (CCM) while maintaining high efficiency of overload. When the power switch 218 is turned on, the switch either (1) the maximum on time turns off the switch (typically 16 s) or (2) the inductor current I _i is the inductor current limiting resistor 220, the reference voltage It remains on until the peak current limit I _p set by 242 and comparator 230 is reached. The on time in this case will be shorter than the maximum on time (T1). Limiting the peak inductor current to a predetermined maximum value I _p prevents saturation of the inductor 204 and enables the use of small inductor values and hence small devices.

The average load current I _L is equal to the reference voltage 244 (V _ref ) value divided by the adjustment resistor 214 (R _S ) value.

I _L = V _ref / R _S expression. 2

If the average load current I _L is below the desired value set by the reference voltage 244 (V _ref ) value and the regulating resistor 214 (R _S ) value, the PFM / PWM drive circuit 240 automatically The on time T1 and off time T2 are adjusted, and instead the switch 218 is turned on and off until the load current I _L is at or above the desired value.

During normal operation, current flows from the boosted voltage at the electrode assembly 210 to the electrode assembly 212 through the variable skin resistance R _V , through the controllable switch 274 to the cutoff switch 276, and Finally, it flows to the adjusting resistor 214. Thus, in normal operation both switches 274 and 276 are closed and current flows through the controllable switch 274 bypassing the controllable resistor 272.

The current delivered through the electrode assemblies 210 and 212 is regulated by the MAX773 controller 216 to maintain the voltage through the regulating resistor 214 at, for example, 1.5V. For example, if the MAX773 controller 216 is maintained at 1.5V through the regulating resistor 214, the regulation current becomes (15/15000 = 0.1mA), for example at 1.5KW.

However, if the variable skin resistance (R _V ) between the electrodes 210 and 212 is sufficient for the voltage appearing at the feedback input 264 of the MAX773 controller 216 to rise above the reference voltage (eg 1.5V). When dropped, the MAX773 controller 216 does not provide a boosted voltage, so the current is not regulated and the total battery voltage (battery 202) minus the voltage drop of the diode 206 applied to the electrode assembly 210 Activate the boost monitoring comparator 273. The regulator 200 is then in overdose mode. If the overdose mode lasts longer than the preset period, for example the first maximum low load sensing period measured by the microcontroller, the microcontroller turns off the controllable switch 274. The current then flows through the additional impedance of controllable resistor 272. This additional (or artificial) load added in series to the variable skin resistance ensures a regulated current from the electrode 210 to the electrode 212 even when the skin resistance drops to 0W. However, if the overdose condition lasts longer than another preset period, for example a second maximum load sensing period measured by the microcontroller, the microcontroller opens the cutoff switch 176 to draw the load current I _L. Cut off.

As an alternative embodiment of the invention, the current I _L can be programmed to follow a certain profile by programming the load current value through the regulating resistor 214. The regulating resistor 214 value can be programmed by switching additional resistors in parallel or in series with the load current I _L.

Although the present invention has been described in particular in terms of embodiments, including the best mode realized by the inventors in carrying out the invention, various changes will be possible and therefore various alternative embodiments will be derived without departing from the scope of the invention. will be. Eventually the scope of the invention will be determined only by the appended claims.

For example, the electron transport controller in the present invention may also be detachable. In addition, the functions performed in the embodiments by the circuits (shown in FIGS. 7 and 9) may be generally performed by software programmable in a digital environment.

Claims (25)

A voltage booster circuit connected to a first electrode to supply a load voltage to the first electrode; A control circuit coupled to the voltage booster circuit to adjust the load voltage in response to a load resistance between the first and second electrodes; And A variable resistance circuit connected in series with said load resistor, And the variable resistance circuit is connected to the control circuit to regulate the current through the load resistance. The method of claim 1, The variable resistance circuit, A first current path having a first resistance; A second current path having a second resistance greater than the first resistance; And And a switch circuit connected to said first and second current paths, said switch circuit selectively connecting one of said first or second resistors in series with said load resistor in response to said control circuit. Through agent feed regulator. The method of claim 2, And wherein said second current path is determined by a resistor having said first resistance connected in parallel to a switch of said switch circuit to provide said second resistance. The method of claim 1, The voltage booster circuit, An inductor circuit connected to a power supply; And A capacitor coupled to the inductor circuit, The control circuit controls the inductor circuit to generate a peak current, and selectively connects the inductor circuit to the capacitor to discharge the peak current and charge the capacitor to the load voltage. Feed regulator. The method of claim 1, The variable resistance circuit, A voltage control resistor circuit coupled in series with the load resistor; And And a resistor control circuit coupled to the voltage control resistor circuit for varying the resistance of the voltage control resistor circuit. The method of claim 5, And said voltage control resistor circuit is a field effect transistor. The method of claim 6, And the resistor control circuit is an operational amplifier connected to the gate electrode of the field effect transistor. In an electron transport skin transmissive transfer regulator for transferring a beneficial agent through the skin surface of an animal by supplying load voltage and load current through the first electrode assembly and the second electrode assembly using an electrical power source, Controller; A voltage booster electrically connected to the controller, the electrical power source and the first electrode assembly; A controllable device electrically connected to the second electrode assembly; A controllable switch connected to the controller and controlled by the controller, the controllable switch connectable to the second electrode assembly or the controllable device; And A sensor coupled to the controller and the controllable switch; And the controller determines the feedback value from the sensor and the controller and adjusts the load voltage by using the voltage booster, the controllable device, the controllable switch and the feedback value. The method of claim 8, The controller adjusts the load voltage such that the load current follows a predetermined current-time profile. The method of claim 8, The controllable switch connects the second electrode assembly to the sensor such that a closed electrical circuit is established with the controller via the voltage booster from the electrical power source, and the two electrode assemblies and the sensor are configured to control the control. Regulator, characterized in that connected without a possible. The method of claim 8, And the controller determines from the feedback value at least one of the load voltage, the load current and electrical resistance of the skin surface of the animal. The method of claim 8, And the controller boosts the load voltage using the voltage booster if the feedback value is lower than a target value. The method of claim 8, The controllable switch is configured to connect the controllable device in series between the second electrode assembly and the sensor if the feedback value is higher than the predetermined value for longer than a first predetermined period. The method of claim 13, And the controller shuts off a load voltage if the feedback value is higher than the predetermined value even after the controllable is connected in series longer than a second predetermined period. The method of claim 8, And a voltage limiter coupled between the first electrode assembly and the sensor to limit the load voltage to the predetermined value. The method of claim 8, And the sensor comprises a resistor. The method of claim 8, And said controllable device is artificial impedance. The method of claim 8, The voltage booster, An inductor connected to the electrical power source; And An inductor switch coupled to and controlled by the inductor and capacitor, The controller controls the inductor switch to connect the inductor to the electrical power supply, thereby charging the inductor to peak instantaneous current and connecting the capacitor to the inductor to discharge the current of the inductor to the capacitor. Regulator. A method of adjusting an electron transport system for transporting beneficial agents through the skin surface of an animal by supplying load voltage and load current through the first electrode assembly and the second electrode assembly using an electrical power source, the method comprising: Generating the load voltage; Boosting the load voltage; Calculating a feedback value from the sensor; And Controlling the controllable switch based on the feedback value. The method of claim 19, And said generated load voltage follows a predetermined current-time profile. The method of claim 19, Determining the load voltage, the load current, or the electrical resistance of the animal skin surface from the feedback value. The method of claim 21, And when the feedback value is lower than a target value, boosting the load voltage. In the method of coordinating agent transfer using an electronic transport system, Generating a first load voltage; Applying the first load voltage to a first electrode to provide a first load current through a load resistance between the first and second electrodes; Determining the load resistance; Generating a second load voltage in response to the determined load resistance; And Applying the second load voltage to the first electrode to provide a second load current through the load resistor. In the method of coordinating agent transfer using an electronic transport system, Generating a first load voltage; Applying the first load voltage to a first electrode to provide a first load current through a load resistance between the first and second electrodes; Determining the load resistance; Adjusting a resistor circuit connected in series with the load resistance in response to the determined load resistance. Controller; An inductor coupled to the controller, an electrical power source and a first electrode assembly, the inductor connected to the electrical power source; A voltage booster having an inductor switch coupled to the inductor and capacitor and coupled to and controlled by the controller; A controllable impedance coupled to a second electrode assembly and providing first or second impedance paths in series with the first and second electrode assemblies in response to the controller; And And a voltage limiter coupled to the first electrode assembly to limit the load voltage to a predetermined maximum value.