JP2002508228A - Regulator with artificial load to maintain regulated dosing - Google Patents

Abstract

(57) [Summary] The present invention relates to an electric transport device provided with a drug administration device that administers a drug at an appropriate administration rate over a long period of time in response to a fluctuating skin resistance value. The electrotransport device accommodates a reduction in skin resistance during use of the device and different skin resistance at different skin surface locations. Some dosing devices include a voltage intensifier, an artificial impedance connectable in series, and a feedback sensor, all connected to a controller. This device outputs a load voltage between two electrodes. The controller monitors the output of the feedback sensor and measures either skin resistance or load current or voltage. Based on the audited value, the load voltage between the electrodes is controlled so that the target drug administration rate is maintained even if the initial skin resistance decreases over time when the electrotransport device is used. The artificial impedance is selectively controlled to prevent the skin resistance from dropping below a predetermined resistance and overloading a load voltage greater than the supply voltage.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates generally to an electrotransport device for administering an active ingredient (eg, a drug) to a patient transdermally or through a mucosa. More particularly, the present invention relates to an electrotransport device that is portable, ie, portable with a patient, that includes a voltage intensifier and an artificial load for maintaining a regulated dose of the active agent.

BACKGROUND OF THE INVENTION [0002] "Electric delivery," as used herein, generally refers to the administration of a drug (eg, a drug) through the epidermis, such as the skin, mucous membranes, nails, etc., where the administration is at least partially controlled. That are triggered or assisted by applying electrical pressure to the For example, beneficial therapeutic agents may be delivered to animals (by electrotransport through the skin).
For example, it is introduced into the human body circulation.

The electrotransport method has been found to be useful in the transdermal administration of drugs including lidocaine hydrochloride, hydrocrotisone, fluoride, penicillin, dexamethasone sodium phosphate, and many others. ing. Perhaps the most common use of electrotransport is the diagnosis of cystic fibrosis by administration of pilocarpine salts by iontophoresis. Pilocarpine stimulates sweating. The sweat is then collected and its chloride content is analyzed to verify the presence of the disease.

[0004] Known electrotransport devices use at least two electrodes that adhere to a portion of the animal's body (eg, skin). A first electrode, called the active electrode, or donor electrode, administers a therapeutic agent (eg, a drug or prodrug) into the body by electrotransport. A second electrode, called a counter or return electrode, closes the electrical circuit of the first electrode that has passed through the body of the animal. A source of electrical energy, such as a battery, supplies current through the electrodes. For example, if the therapeutic agent to be administered into the body is positively charged (ie, cation), the anode becomes the active electrode and the cathode becomes the counter electrode that completes the circuit. If the therapeutic agent to be administered is negatively charged (ie, an anion), the cathode becomes the donor electrode and the anode becomes the counter electrode.

[0005] Both the anode and the cathode can alternatively be used to administer a charged agent to the opposite electrode into the body. In this state, both electrodes become the donor electrode and the counter electrode. For example, the anode can serve as a cathode "counter" electrode while delivering a cationic therapeutic agent. Similarly, the cathode can act as an anode "counter" electrode while delivering the anionic therapeutic agent.

[0006] A widely used electrotransport method, ion transfer (also referred to as iontophoresis), involves electrically induced transport of charged ions. Another form of electrotransport, ion transfer, relates to the flow of a liquid solvent from a donor reservoir, which contains the drug to be administered under the influence of an applied electric field.

[0007] Yet another form of electrotransport involves the application of high voltage pulses to form instantaneous pores in a biofilm. A portion of the therapeutic agent can be administered through the skin by passive diffusion due to the difference in concentration between the agent concentration in the donor reservoir of the electrotransport device and the concentration in the body tissue of the patient. Regardless of the electrotransport method, one or more of these methods will occur to some extent simultaneously. Accordingly, the term "electrotransport" as used herein should be interpreted in its broadest sense, e.g., at least one therapeutic agent that is charged or uncharged, or a mixture thereof. , Electrically induced, or electrically enhanced transport. Furthermore, the terms load current and current flow through the skin are defined as the current flowing between the two electrodes.

[0008] An electrotransport device, generally a reservoir or source of the drug or its precursor, is required, and the drug or its precursor is administered to the body by electrotransport. Examples of such reservoirs or sources of drug, preferably ionized or capable of being ionized, are described in US Pat. No. 4,250,87 to Jacobson.
No. 8 and the preformed gel body described in Webstad U.S. Pat. No. 4,383,529. Such a reservoir is electrically connected to the anode or cathode of the electrotransport device and provides a fixed or replaceable source of one or more desired therapeutic agents.

Recently, a number of US patents have been issued in the field of electrotransport, indicating continued interest in such forms of drug administration. For example, U.S. Pat. No. 3,991,755 to Vernon et al. And U.S. Pat. No. 4,141,359 to Jacobson et al.
U.S. Pat. No. 4,398,545 to Wilson; U.S. Pat. No. 4,250,878 to Jacobson; U.S. Pat. No. 5,207,752 to Sorenson et al.
U.S. Pat. No. 5,213,568 to Latin et al. And U.S. Pat. No. 5,498,235 to Flower disclose examples of electrotransport devices and some applications thereof.

[0010] More recently, electrotransport devices have been miniaturized, particularly with the development of microelectronic circuits (eg, integrated circuits) and more powerful lightweight batteries (eg, lithium batteries). The advent of inexpensive miniature electrical circuits and miniature high-energy batteries means that the entire device can be manufactured to be inconspicuously portable on clothing and on the patient's skin. This allows the patient to be kept fully ambulatory and to perform all normal actions even while the electric transport device is actually performing a drug administration operation.

However, the prior art electrotransport devices have disadvantages that limit the widespread application of this useful device. One of the limitations is the difficulty in adjusting the amount of drug administered. Precise administration is complicated by the fact that the electrical resistance of the patient's body surface (eg, skin) is not constant upon administration by electrical delivery.
The voltage (V) required to drive a specific level of current (I) through the patient's skin
Is proportional to the resistance (R) of the skin (ie, according to Ohm's law, V = I × R of the skin), the voltage required for power delivery will not be constant during administration by electrotransport. For example, when electrotransport drug administration begins, the patient's initial skin resistance is relatively high, and the power supply to supply a predetermined level of electrotransport current requires the generation of a relatively high voltage. However, after a few minutes (ie, about 1 to 30 minutes after applying the current through the skin), the resistance of the skin drops and the voltage required to deliver a given level of current is It is much lower than the voltage at the start of dosing.

[0012] Other complications related to the adjustment of the electric delivery device are that, although the skin of the whole body is basically similar, its thickness, mechanical strength, softness, and more importantly The point is that there are many regional variations in skin resistance.

[0013] Prior art transdermal electrotransport administration devices provide an indistinguishable set voltage to any skin surface, independent of the skin resistance. Moreover, in other prior art transdermal electrotransport administration devices, the voltage of the power supply and / or the boost factor of the voltage boost circuit is selected to be high enough to overcome the high skin resistance seen at the start of operation. Have been. However, when the operation reaches a stable state, the prior art device supplies an excessive working voltage due to a reduction in skin resistance. Thus, by providing a higher voltage than required, these prior art devices administered an overdose of drug after the skin resistance had dropped from the initially high level.

[0014] As described above, even when the skin resistance falls below the initial value, the target drug administration rate can be maintained, and the target drug administration rate can be maintained even for different areas of skin exhibiting different resistances. There is a need for an improved electrotransport device capable of providing dosing at the same time.

DISCLOSURE OF THE INVENTION One embodiment according to the present invention is an electric transport device provided with a drug administration device, which is used for a long period of time in response to a changing skin resistance value, in particular, an electric transport device. The present invention relates to an electrotransport device capable of administering an appropriate dose while there is a reduction in skin resistance during use and for different resistances at different skin surface locations.

[0016] In another embodiment, the drug administration device includes a voltage intensifier, a serially connectable artificial impedance, and a feedback sensor, all of which are connected to the controller. This device outputs a load voltage between two electrodes. The controller monitors the output of the feedback sensor to measure (a) skin resistance, (b) load current, or (c) load voltage, and initially responds to the period during which the electric transport device is used. The load voltage between the electrodes is controlled based on the monitored value so that the target drug administration rate is maintained even when the skin resistance of the battery decreases. The artificial impedance is created and applied to avoid overdosing when the skin resistance falls below the battery voltage of the device.

DETAILED DESCRIPTION OF THE INVENTION FIG.
2 and FIGS. 11 and 12.

FIG. 1 shows a perspective view of an electrotransport administration device 10 with an optional operating switch in the form of a push button 12 and an optional light emitting diode (LED) 14 that is turned on while the device 10 is operating. Have.

FIG. 2 is an exploded view of the second device 10 of the present invention. The device 10 of FIG. 2 differs from the device 10 of FIG. 2 includes an upper housing 16, a circuit board 18, a lower housing 20, an anode electrode 22, and a cathode electrode 2.
4. An anode reservoir 26, a cathode reservoir 28, and a skin-compatible adhesive layer 30. The upper housing 16 has side collars 15 that help hold the device 10 of FIG. 2 on the patient's skin. The upper housing 16 can be formed of an elastic body that can be injection-molded (for example, ethylene vinyl acetate). Upper housing 16 can also be formed from rubber or other elastic material. Printed circuit board 18 includes integrated circuit 19 coupled to a separate element 40 and battery 32. The circuit board 18 is attached to the housing 16 by screws (not shown in FIG. 2) penetrating the openings 13a and 13b.
Is heated / welded to thermally fix the substrate. The lower housing 20 is attached to the upper housing 20 with an adhesive layer 30, and the upper surface 34 of the adhesive layer 30 is bonded to both the lower housing 20 and the upper housing 16 including the lower surface of the collar 15.

The button-type battery 32 is shown (only the portion) on the lower surface of the circuit board 18. Other types of batteries may be used as the power source for the device 10. Apparatus 10
Generally comprises a battery 32, electronic circuits 19, 40, electrodes 22, 24, and drug / chemical product reservoirs 26, 28, all of which are integrated as one unit. The output side (not shown in FIG. 2) of the circuit board 18 is provided by conductive adhesive pieces 42, 42 'through openings 23, 23' in recesses 25, 25 'formed in the lower housing 20. It is electrically connected to the electrodes 24 and 22. On the other hand, the electrodes 22, 24 are in direct mechanical and electrical contact with the upper surfaces 44 ', 44 of the drug reservoirs 26, 28. The bottom surfaces 46, 46 of the drug reservoirs 26, 28
Through the openings 29 ', 29 of the patient.

The lower housing 20 can be formed of a plastic or elastic plate (eg, polyethylene), and can easily form notches in the recesses 25 and 25 ′ and the openings 23 and 23 ′. . The assembled device 10 is preferably water resistant (i.e., splash proof) and most preferably waterproof. The system is thin so that it easily conforms to the body, so that the attachment and its surroundings are deformable. Reservoirs 26, 28 are located on the skin contact side of device 10 and are sufficiently isolated to prevent inadvertent electrical shorts during normal handling and use.

Any drug can be used as long as it is at least partially ionized. The terms "drug" and "drug" are used interchangeably and are intended to be interpreted in the broadest possible sense. That is, a therapeutically active substance that is administered to living tissue and produces the desired, usually beneficial, effect. For example, the terms “drug” and “drug” are therapeutic compounds and molecules belonging to all therapeutic areas, including anti-infectives (such as antibiotics and antivirals),
Analgesics (such as fentanyl, sufentanil, buprenorphine and sedatives), anesthetics, antiarthritics, antiasthmatics (such as terbutaline), anticonvulsants, antidepressants, antidiabetic drugs, antidiarrheal drugs, antihistamines , Anti-inflammatory drugs, anti-migraine drugs, motion sickness preparations (scopolamine, ondansetron, etc.), anti-neoplastic drugs, anti-parkinsonism drugs, burn drugs, antipsychotic drugs, antipyretics, antispasmodics (gastrointestinal and urinary ), Anticholinergics, sympathomimetics, xanthine and its derivatives, cardiovascular preparations (calcium channel blockers such as nifedipine), beta agonists (dobutamine, ritodrine, etc.), beta blockers, Arrhythmics, antihypertensives (such as atenolol), ACE inhibitors (such as lisinopril), diuretics, vasodilators (general, tubular arteries, Stimulants, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones (such as thyroid hormones), hypnotics, immunosuppressants, muscle relaxants, sympathomimetic, These include, but are not limited to, parasympathetic agents, prostaglandins, proteins, peptides, neurostimulants, sedatives and tranquilizers.

The electrotransport device according to the present invention comprises baclofen, beclomethasone, betamethasone, buspirone, cromolyn sodium, diltiazem, doxazosin, droperidol, encainide, fentanyl, hydrocortisone, indomethacin, ketoprofen, lidocaine, methotrexate, metoclopramide, miconazole, miconazole And / or medicaments, including nicardipine, piroxicam, prazosin, scopolamine, sufentanil, terbutaline, testosterone, tetracaine and verapamil.

The electrotransport device according to the present invention can administer peptides, polypeptides, proteins and other macromolecules. These molecules are known in the prior art to be difficult to administer transdermally or through mucous membranes due to their size. For example, such molecules have a molecular weight between 300 and 40,000 daltons, and include LHRH and its analogs (such as buserelin, goserelin, gonadorelin, naphrelin, leuprolide), GHRH, GHRF, insulin, insulinotropin, heparin. , Calcitonin, octreotide, endorphin,
TRH, NT-36 or N-[[(s) -4-oxy-2-azetidinyl] carbonyl] L-histidyl-L-prolinamide], lipresin, pituitary hormones (HGH, HMG, HGG, desmopressin acetate, etc.), Folsil, luteoid, a-ANF, growth factor releasing factor (GFRF), b-MSH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor, asparaginase,
Bleomycin sulfate, chymopapain, cholecystokinin, serosal gonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, hirulog, hyaluronidase, interferon, interleukin-2, menotropins (ulforolitropin ( FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator,
Urokinase, vasopressin, desmopressin, ACTH analog, ANP, AN
P clearance inhibitor, angiotensin II antagonist, antidiuretic hormone agonist, bradykinin antagonist, CD4, seldase, CSF, enkephalin, FAB
Residue, IgE peptide inhibitor, IGF-1, neurotropin factor, colony inducing factor, thyroid hormone and agonist, thyroid hormone antagonist, prostaglandin antagonist, pentigetide, protein C, protein S, renin inhibitor, thymosin -Alpha-1-anti-trypsin (recombinant), TGF-beta, and the like, but are not limited thereto.

The device 10 can optionally have properties that allow the patient to control the dose delivered by electrical transport. Depressing the pushbutton switch 12 causes the electronics of the circuit board 18 to pass a predetermined DC current through the electrodes / reservoirs 22, 26 and 24, 28 at a predetermined length of dosing interval. The push button switch 12 is conveniently located on the top of the device 10 and is easily activated through clothing. Pressing the push button switch 12 twice within a short period of time, such as three seconds, can be used to operate the device for administration of the drug, thereby minimizing the possibility of inadvertent operation of the device 10. I have to. The device may communicate a visual and / or audible confirmation of a set of drug administration intervals to the patient by illuminating the LED 14 and / or by audio signals, for example from a buzzer. The drug is administered by electrical delivery for a predetermined period of time through the patient's skin, such as an arm.

The anode electrode 22 can be made of silver, and the cathode electrode 24 can be made of silver chloride. Both reservoirs 26, 28 can be constructed from a polymeric hydrogen material. Electrodes 22, 24 and reservoirs 26, 28 are connected to lower housing 28.
In the recesses 25 ′, 25.

The device 10 includes a top surface 34 and a body contact side 36 on a patient's body surface (eg, skin).
And the peripheral adhesive layer 30 having the following. Adhesive side 36 has adhesive properties such that device 10 can be held in place during normal user activity and can be removed normally after a predetermined wear period (eg, 24 hours). . The upper bonding surface 34 is bonded to the lower housing 20 and the lower housing 2
0 remains adhered to the upper housing 16.

The reservoirs 26 and 28 generally comprise a gel matrix in which at least one of the reservoirs 26 and 28 has a uniformly dispersed drug solution. A drug having a concentration of about 1 × 10 ⁻⁴ M to 1.0 M can be used, and the drug concentration is preferably in the lower portion of the width. The compatible polymer of the gel matrix can be essentially any nonionic synthetic and / or natural polymer material. When the active agent has a polarity and / or is capable of ionizing, a polarity is implemented to increase the solubility of the components. Optionally, the gel matrix is water swellable. Examples of compatible synthetic polymers include poly (acrylamide)
, Poly (2-hydroxyethyl acrylate), poly (2-hydroxypropyl acrylate), poly (N-vinyl-2-pyrrolidone), poly (n-methylolacrylamide), poly (diacetoneacrylamide), poly (2 -Hydroxylethyl methacrylate), poly (vinyl alcohol) and poly (allyl alcohol). Hydroxyl functional condensation polymers (ie, polyesters, polycarbonates, polyurethanes) are also examples of compatible polar synthetic polymers. Examples of naturally occurring polar generating polymers (or derivatives thereof) suitable for use as gel substrates include cellulose ether, methyl cellulose ether, cellulose and cellulose hydroxide, methyl cellulose and methyl cellulose hydroxide, guar and Rubber materials such as locust, karaya, and gelatin, and derivatives thereof. Polymers containing ions can also be used as the substrate as long as the available counterion is a drug ion or other ion charged to the opposite polarity to the active drug.

Thus, the polypeptide analogs of the present invention can be contained in a drug reservoir, eg, a gel matrix, as described above, and optionally administered to a patient using the electrotransport drug delivery system illustrated above. Is administered. The mixing of the drug solution can be performed by various methods. That is, it can be performed by allowing the reservoir substrate to absorb the solution, mixing the drug solution with the substrate material before the hydrogel is formed, and the like.

FIGS. 11 and 12 show another embodiment of the drug delivery device according to the present invention. This embodiment includes a reusable electronic controller and a medicine unit. The reusable controller of FIGS. 11 and 12 typically contains a medication administration regulator and is designed to be used with a medication unit to transdermally administer medication stored in the medication unit. I have.

FIG. 11 is a perspective view of an electric transport device 320 having a reusable electric controller 322. The electronic controller 322 is detachably formed in the medicine storage unit 324. The reusable electronic controller 322 is configured to be reusable, ie, for use with a plurality of drug units 324, for example, several similar and / or very different drug units 324. . On the other hand, the medicine unit 32
No. 4 typically has a more limited lifespan and is configured to be disposed of after use, ie, after the drug contained therein has been administered or removed.
As described above, after the medicine stored in the medicine unit 324 is consumed after the elapse of a predetermined use life (for example, 24 hours), the medicine unit 324 is detached from the reusable electronic controller 322, It is replaced with a new drug unit 324 of the same or different structure and / or composition. The reusable electronic controller 322
Designed to provide one of a plurality of different predetermined electrical outputs, the output of which can be set when the controller is manufactured. Reusable electronic controller 32
The two different electronic outputs are designed to be used for different drug units 324.

For display purposes, the reusable electronic controller 322 can be designed for use with at least two different drug units 324, both units having the same reusable electronic control Formed to be used with the
Administer the drug continuously over 2 hours or more. The two different drug units 324 store the same drug in their respective donor reservoirs, but differ in the amount of drug stored. The medication unit 324 containing more medication is a "multi-dose" medication unit, configured from the reusable electronic controller 322 to be used at a higher DC current (eg, 2 mA). The drug unit 324 containing less drug is a "low dose" drug unit, and the reusable electronic controller 3
From 22, it is configured to be used at a lower DC current (eg, 1 mA). Thus, the reusable electronic controller 322 may be configured to provide one of two different DC currents (ie, 1 mA or 2 mA) depending on whether the attached medication unit 324 is multi-dose or low-dose. It is designed to provide.

In the present invention, either type of drug unit (eg, a multi-dose or a low-dose drug unit) is attached to the reusable electronic controller 322 and the attached drug unit is attached to the reusable electronic controller 322. A signal is generated to properly set the output of the matching controller (ie, to set a high or low current output). In the device shown in FIGS. 11 and 12, the drug unit 324 sends a signal to the reusable electronic controller 324 by an optical signal,
4 is automatically sent when it is attached to electronic controller 324 (ie, by snap-on connectors 326, 328) and read into electronic controller 324 (see FIG. 4).
That is, it is decoded). By reading the signal, the controller properly selects the correct electrical output that is compatible with the installed drug unit 324.

In FIG. 12, there is shown a medicine unit 324 and a reusable electronic controller 3.
22 shows an exploded view of both. The reusable electronic controller 322 comprises an upper housing 368 and a lower housing 350, both of which are typically made of a molded resin such as polypropylene. The upper housing 368 is attached to the lower housing 350 by a water-resistant, preferably waterproof, peripheral seal. The sealing can be performed by heat-sealing or ultrasonic welding of the joint between the two housings 350 and 368, and bonding the common joint using a waterproof adhesive or the like. Opening 352 for receiving battery 354 is provided in lower housing 350. Battery contacts 364, 366 are provided for making electrical contact with both poles of the battery 354. A removable cover 360 is screwed into the opening 352 to hold the battery 354 in place.
The cover 360 has a groove 362 into which a coin or a driver tooth is inserted so that the cover 360 can be rotated to be removed from the opening 352 so that the battery 354 can be taken in and out (ie, replaced). The reusable electronic controller 322 includes a battery 354, for example, a button-type battery, and supplies power to electronic circuitry (not shown) on the circuit board 359. The circuit board 359 is formed in a conventional manner and interconnects electrical elements that control the magnitude, timing, frequency, waveform, etc. of the electrical output (eg, voltage and / or current) of the reusable electronic controller 322. Including patterned conductive paths. The conductive paths on the circuit board 359 can be formed by a conventional silk-screen printing method or a conventional solder-coated copper plate and etching method. The insulating substrate of the circuit board 359 can be made of ordinary FR-4 or the like. Although not critical to the invention, the reusable electronic controller 322 includes a pushbutton switch 374 that can be used to initiate operation of the device 310.
And window 358 (see FIG. 12) for the particular type of drug unit 324 attached to the controller and system information such as applied current, dose level, number of doses, elapsed time of current application, and battery strength. Liquid crystal display 3 that can be displayed through
56 (see FIG. 11).

The lower housing 350 is provided with holes 375 a and 375 b for holding the conductive outlets 330 and 332. The outlets 330 and 332 are connected to the respective holes 35.
7a, 375b extend into the lower housing 350. Outlet 330,
The terminals of 332 are fixed in place and each conductive grip fastener 376a
, 376b make an electrical connection to the output of the electronic circuit on circuit board 359.

The medication unit 324 is removably mounted on the reusable electronic controller 322 such that the top of the medication unit 324 is adjacent to the reusable electronic controller 322 and faces the back thereof. The top of the medication unit 324 is provided with two male snap-on connectors, which are indicated by posts 326, 328 extending upwardly from the medication unit 324. Outlet 330 is formed at a position and size at which donor post 326 fits, and outlet 332 is formed at a position and size at which counter post 328 fits. For example, one snap connector pair of outlet 332 and post 328 may be replaced with another snap connector pair (ie, , Outlet 330 and post 326). The outlets 330 and 332 and the posts 326 and 328 are made of a conductive material (for example, a metal such as silver, tin, stainless steel, platinum, gold, nickel, or beryllium copper, or a metal such as silver-coated ABS or the like). Coating polymer). Donor post 326 is electrically connected to donor electrode 390, which in turn is electrically connected to donor reservoir 401, which typically contains a solution of the therapeutic agent to be administered (eg, a drug salt). You. Counter post 3
28 is electrically connected to a counter electrode 388, and the counter electrode 390 is
Typically, it is electrically connected to a counter reservoir 399 containing a solution of a biocompatible electrolyte (eg, saline treated with a buffer). The electrodes 388, 390 are typically made of a conductive material and may be a silver (eg, silver foil or polymer with silver powder added) anode electrode or a silver chloride cathode electrode. Storage 399,
401 typically includes a hydrogen substrate that holds a drug or electrolyte solution, and is configured to allow contact with the body surface (ie, skin) of a patient (not shown) during use. Electrodes 388, 390 and reservoirs 399, 401 are separated by a forming element 396. The bottom (ie, patient contacting) surface of the molding element 396 can be coated with a skin contact adhesive to hold the drug unit 324 to the patient's body. Before the drug unit 324 is used, the removal liner 402 covers the body contacting surfaces of the two reservoirs 399 and 401 and the adhesive application surface of the molding element 396. In one embodiment, the removal liner 402 is a silicone-coated polyester sheet. The removal liner 402 is removed before the device 320 is applied to the skin of the patient (not shown).

Thus, the post 326 and the outlet 330 form a snap connector and electrically connect the output 378 a of the circuit of the circuit board 359 to the electrode 390 and the reservoir 402. Similarly, the post 328 and the outlet 332 form a snap connector, and the circuit output side 378b of the circuit board 359 is connected to the electrode 388 and the reservoir 39.
9 electrically. In addition to providing the electrical connection described above, the two snap-on connectors provide a reusable electronic controller 322 for the medication unit 324.
Provide a separable (ie, non-permanent) mechanical connection to the Thus, the conductive snap connectors 326, 330 and 328, 332 are (i)
And (ii) electrically connecting the electrical output of the reusable electronic controller 322 to the drug unit 324.

According to this embodiment of the present invention, the medication unit 324 determines the electrical output of the controller with a predetermined pre-determined value appropriate for the particular medication unit 324 and the particular medication contained therein. An optical signal is sent to the reusable electronic controller 322 so that it can be set correctly to the output set. As is evident from FIGS. 11 and 12, the interface of the drug unit 324 has two surface areas 340, 342. Surface area 340 is shown as "white" with high light reflection, and surface area 342 is shown as "black" with low light reflection. Both regions 340, 342 may be provided directly on the back layer 344 of the drug unit 324 (eg, by printing or painting), or alternatively, by applying a thin piece of paper or mylar to the back layer 344 with a suitable adhesive. Is also good.

The reusable electronic controller 322 includes a pair of light reflection switches 334 and 336 mounted on a circuit board 359, and the holes 337 a and 33 in the lower housing 350.
7b. Switches 334 and 336 are adjacent to drug unit 324. The reflective areas 340, 342 are positioned on the drug unit 324 adjacent to the reflective switches 336, 334, respectively, when the reusable electronic controller 322 and the drug unit 324 are coupled.

The light reflection switches 334, 336 are adjusted to illuminate the light reflection areas 340, 342, respectively. The reflective areas 340, 342 are adjusted so that illumination from the switch 334 is independently reflected at the area 342 and returned to the switch 334. Similarly, illumination from switch 336 is independently reflected at region 340 and
It is adjusted to return to 36. In one embodiment, switches 334, 336
Illuminated light sources in the form of photoemitters 346a, 346b, respectively, and matched photodetectors are phototransistors 348a, such as SFH901 or SFH902, available from Siemens Optoelectronics Headquarters, Cupertino, California. 348b. The phototransistors 348a and 348b are connected to a circuit (described later) and emit a signal in response to an incident light beam.

The switches 334 and 336 are mounted on each wiring (not shown) on the circuit board 359 by a conventional means such as soldering holes.

A flexible back layer 344 made of a material that is impermeable to the passage of liquids (eg, a polyethylene sheet) forms the top layer of the drug unit 324.
Holes 384a and 384b passing through the back layer 344 are provided, and holes 382a and 382b passing through the band 343 are provided at adjusted positions. Conductive base rivets 326a, 328a are provided with holes 384a, 384b, and holes 382a, 382a, 384a, respectively.
Extending through 82b and coupled to posts 326, 328, secures back layer 344 in-between.

The electrodes 388, 390 are formed of a conductive material such as a carbon powder / fiber filled polymer matrix, a metal powder filled polymer matrix, or a metal foil. Electrodes 388, 3
90 contacts the base rivets 326a, 328a. Electrodes 388, 3
To bond 90 to base rivets 326a, 328a, a carbon-filled or silver-particle-filled conductive adhesive is used. Electrodes 388, 390 are in electrical contact with reservoirs 399, 401, respectively. The insulative closed cell molding layer 396 has cavities 398, 400, which contain reservoirs 399, 401, respectively. Typically, one of the reservoirs 399, 401 is a donor reservoir containing a solution of the therapeutic agent to be administered by electrotransport, and the other contains a solution of a biocompatible electrolyte (eg, saline). Including a counter reservoir. Substrates for reservoirs 399, 401 are:
It can be a gel.

Pharmaceutical unit 32 transmitted by optical signal to reusable electronic controller 322
Information about 4 is obtained by giving the reflection areas 340, 342 different levels of reflectivity. For example, at the wavelength of the light emitted from the switches 334, 336, the region 340 is a normal white having a reflectivity of about 90%, and the region 342 is about 15%.
Matte black with a% reflectance. By having two light-reflecting surface areas, each area having any one of the two light-reflecting possibilities, the drug unit 324 has four differently coded based on the "reflectance codes" shown below. The transmitted signal can be sent to a reusable electronic controller 322. That is, (1) a first optical signal having a low reflectance in both regions, (2) a second optical signal having a high reflectance in both regions, (3) a region 340 having a low reflectance, and a region 342 having a low reflectance. There are four optical signals, a third optical signal having a high reflectance, and (4) a fourth optical signal having a high reflectance in the region 340 and a low reflectance in the region 342. Regions 340 and 342 are
The coding can be done by simply applying a paint having the appropriate reflectivity. The regions 340, 342 can also be coded by printing or by applying an adhesive tape having appropriate reflectivity.

An apparatus, such as an electronic circuit, for performing the method for adjusting a drug administration according to the present invention is mounted in the above-described electric carrier drug administration apparatus according to the present invention. More specifically, an electronic circuit configured on circuit board 18 of FIG. 2 or circuit board 359 of FIG. 12 is implemented to regulate the administration of the drug of the present invention. The electronic circuit is hereinafter referred to as a regulator.

The regulator initiates the administration of the medicament only when the administration device is attached to the patient's skin and the push-button switch is operated at a specific interval, for example a double click. Here, in the relationship between current (i) and time (t) in FIG. 4, the regulator starts from the setup period T ₀ , during which time the regulator was augmented to overcome the initial high skin resistance. The initial current (i) is supplied in voltage. During the set-up period T _0, regulator, since the current applied initially to suppress Koyo by transparently to the patient, the maximum voltage seen on the skin (2
4 V) to a minimum (0 V). The voltage is applied by the regulator, for example, between the two electrodes 22 and 24 in FIG. 2 or 388 and 390 in FIG. After the set-up period, the controller controls the boost voltage to maintain the dosing current (id) during the dosing period (T _d ). This provides a stable state of the device and maintains the drug dosing rate by the dosing current with controlled fluctuating voltage.

Even though the initial skin surface resistance is relatively high, after some time the skin resistance is visibly reduced. FIG. 3 is a graph of this characteristic, and shows that the decrease in the skin resistance R almost approaches a stable value. For a dose rate of 0.1 ma / cm ² , this stable value is usually on the order of 20 to 30 kohm-cm ² , and the initial value of skin resistance is several times or more.

When the skin resistance is sufficiently reduced, the anode voltage (V _a ) can be reduced to the battery voltage (V _b ) or less. This causes the regulator to enter the overdosage mode during time T1, during which time excessive load current will flow through the skin even if the battery voltage does not apply the boost voltage. This situation is shown in FIG. 5, where the anode voltage Va is shown on the y-axis and the time (t) is shown on the x-axis.

Further, if the overdosage mode lasts longer than the first maximum low load detection period, eg, 10 seconds, a control enabler, eg, an artificial impedance, is connected in series with the skin surface. Is done. If the impedance of the control enabler is large enough, the current applied to the skin will be reduced and the controller will be able to control the load current with the boost voltage.

Further, if the low load condition of the skin continues for longer than the second maximum low load detection period, for example, 10 seconds, after the connection of the artificial impedance, the regulator is applied to the electrode. Cut off the applied voltage.

The above-described adjustment method is shown in FIG. 6, which shows a schematic block diagram of an embodiment of one device for implementing the method. The regulator 50 includes the battery 5
1 includes a controller 53 connected to it. The controller 53 further includes a voltage intensifier 55,
It is connected to two terminals of the impedance connection switch 77 and the adjustment register 59. In the illustrated embodiment, the artificial impedance 57 (eg,
The resistor is connected in series between the cathode electrode 65 and the impedance connection switch 77. However, the artificial impedance 57 and the impedance connection switch 77 can be connected in series between the voltage intensifier 55 and the anode electrode 63. This structure is not shown in FIG.

The impedance connection switch 77 connects the artificial impedance 57 in series between the electrode 65 and the adjustment register 59 only during the overdose mode, otherwise the switch 77 directly registers the electrode 65. Connect to 59.

During the set-up time, the controller 53 activates the voltage booster 55 to supply an increased voltage between the two electrodes 63, 65 applied to the skin surface 61. The boosted voltage is required because the skin 61 initially has a high resistance to suppress the current between the electrodes 63 and 65.

During the set-up and administration periods, the load current flows from the electrode 63 through the skin 61 to the electrode 65, the adjustment register 59, and the system ground port 73. The feedback input port 71 having a sufficiently high resistance prevents the load current from flowing into the port 71. The load current path allows the controller 53 to monitor the load current between the electrodes 63 and 65 by using the voltage value detected at the feedback input port 71. In other words, by using the known resistance value of the adjustment register 59 and by using the voltage value at the feedback input port 71, the controller 53 measures the current flowing through the adjustment register 59. Designed for The measured current is a nearly accurate load current.

Using the measured load current, controller 53 adjusts voltage amplifier 55 to provide a voltage sufficient to maintain the dosing current. This means that when the feedback voltage drops below the target voltage, the supply voltage is boosted by turning on the voltage booster, and when the feedback voltage rises above or equal to the target voltage, the voltage booster is turned off. This is done by turning it off. When the voltage booster 55 is turned off, the voltage from the battery 51 is supplied without being boosted. When the load current and the administration current are equal, the target voltage is
9 can be set to equal the current through.

When the feedback voltage is higher than a preset voltage, the regulator enters an overdose mode. The preset voltage may be set to accurately identify when the anode voltage has dropped below the battery voltage due to the low skin resistance. For example, the preset voltage can be set at 10% above the target voltage.

After the first maximum low load detection period from the start of the overdose mode, the controller 53 uses the impedance switch control 75 to change the impedance 57 to the electrode 65.
And the adjustment register 59 are connected in series. In this step, the overdose current is stopped and the controller can adjust the load current using the voltage intensifier 55.

However, even after the artificial impedance 57 is connected in series, if the overdose mode continues beyond the second maximum low load detection period, the controller 53 sets the The voltage supplied to 63 is cut off.

A voltage limiter 79 is connected between the electrode 63 and the adjustment register 59 as a safety device. If the voltage intensifier exceeds a safety level of, for example, 25V, the voltage limiter limits further boosting of the voltage supplied to the electrode 63.

The device described above with reference to FIG. 6 can be implemented by using an ASIC or a logic circuit. Further, the embodiment shown in FIG. 6 is just one embodiment, and thus the elements of the controller 53, the voltage booster 55, the artificial impedance 57, and the adjustment register 59 are one integrated circuit, Alternatively, it can be implemented using some integrated circuits. It is also an embodiment of the present invention that the function of each element described above is implemented as a software module and is programmed in the microprocessor.

FIG. 7 shows a detailed wiring diagram of one embodiment shown in FIG. Adjuster 1
00 is electrically connected to a power source in the form of a battery 102 and to a voltage controlled electrical junction 104 connected to an electrode 108. The electrode 108 is connected to one area of the skin surface 110 in a conventional manner, such as by gluing, a string, a belt or the like. The skin surface is shown schematically as variable resistance load R _v, it represents the normal variation of the load resistance at a current I _L to the skin. Electrode 112 is likewise connected to skin surface 1
Attached to 10 other areas.

The electrode 112 is connected in series with the regulator register 114. Electrodes 108, 11
2, the skin surface 110 and adjustment register 114, forms a path of the load current flowing the load current I _L.

The voltage intensifier 141 includes an energy storage inductor connected between the battery 102 and the anode of the rectifier diode 120.
ctor) 118. The cathode of the diode 120 is connected to the voltage-controlled electrical junction 104. The voltage intensifier 141 further includes a junction 104
, And a controlled switch 124 having a control input 126. Controlled switch 124 has one terminal 128 connected to the junction of the anode of diode 120 and inductor 118, and another terminal 130 connected to system ground. Control input 126 alternatively forms a low resistance connection between terminals 128 and 130, thereby connecting or disconnecting inductor 118 to system ground through a low resistance path. An open / close switch 124 can also be used. Switch 124 may be an electronic switch 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 input 133 for controlling a control output 134 and a ground input 136.

The regulator 100 is provided with a microcontroller 138. Micro controller 13
8 is dormant until a threshold voltage is found in the adjustment register 114. This threshold voltage occurs when the controller is attached to the patient and a varying skin resistance is seen between electrodes 108 and 112. The microcontroller 138
An internal counter and software routine are used to determine the time of the low current supply, for example, 0.1 mA. This time can be programmed. After this time has elapsed, the microcontroller 138 will deliver a dosing current of, for example, 0.5 mA during a second programmable time. The microcontroller 138 is, for example, 0.1 mA
Another dosing current can be applied for a third programmable time. The time can vary from 0 seconds to the memory limit of the microcontroller 138, or to battery life.

In addition, the microcontroller 138 receives feedback at the input 140 that senses the current I _L through the skin 110 by sensing the voltage drop in the Compare with preset voltage drop limit. The microcontroller 138 also receives an input 142 that senses a voltage drop across the skin 110 and compares the detected voltage drop with a preset maximum limit of the voltage drop. Artificial impedance is controlled by switch 1
It includes a controllable resistor 123 connected in series between 27 and electrode 112. The controllable switch 127 is controlled by the load control output 135 of the microcontroller 138.

When the microcontroller 138 detects that the feedback voltage detected at the feedback input 140 is higher than the preset voltage limit for more than a predetermined amount of time, the controllable switch 127 activates the controllable switch 127. The register 123 is connected to the adjustment register 114. State of the high feedback voltage, when continued even after the controllable switch 127 connected is closed, microcontroller blocks the control circuit 132, further stops the load current I _L. At other times, the load switch connects the electrode 112 directly to the adjustment register 114.

The microcontroller 138 monitors the resistance of the skin 110 via the voltage input 142 and the current input 140, and when the resistance of the skin 110 exceeds a predetermined upper limit according to a stored program, or When the voltage falls below the lower limit, the voltage boosting function of the regulator 100 is shut off. The first maximum low load detection period and the second maximum low load detection period described above are measured by the microcontroller 138, for example, by tracking the number of overflow interruptions of a timer.

[0069] Microcontroller 138 also monitors system events. Control circuit 13
2 (not shown in FIG. 7) informs microcontroller 138 of a low battery condition. The microcontroller 138 can thereby use the LED (
A light emitting diode (not shown in FIG. 7) flashes to call attention.

The normal operation of the voltage amplifying circuit 141 with respect to the relationship between the regulator 100 and other circuits is as follows:
This can be understood with reference to FIG. For example, after operating the push button switch 12 shown in FIG.
36 is connected to system ground. Thus, adjustment register 114, it is possible to conduct the start of the load 110 load current I _L.

The control circuit 132 locks the control output 134 and the switch 124
Is connected to ground for a time T1. This time T
During one, the inductor current Ii generated by the battery 102 increases to a maximum value _Ip . Here, T1 is a part of the setup time.

At the end of the T1 time, the control circuit is configured to change the output 134 and re-lock the switch input 126, thereby opening the switch 124 for a time T2. During T2, inductor current Ii is forced to flow through diode 120 to electrical junction 104 without flowing toward ground.
The filter capacitor 122 provides a low impedance path for the instantaneous current I _j , but then rises to zero during time T2 because the charge on the capacitor 122 causes the voltage at the electrical junction 104 to rise. descend. Where T
2 is another part of the setup period.

During time T 1, inductor 118 is charged with current and stores energy. During time T2, inductor 118 releases energy through diode 120 to filter capacitor 122. The inductor 118 is thereby connected to the diode 1
With only a small drop due to a voltage drop across the inductor 20 and a series of negligible resistances at the inductor 118, the battery 102, and the electrical junction, energy can be stored in the battery 1
02 to the capacitor 122. Thus, the energy source for load current I _L, rather than from direct battery 102, a capacitor 122 (i.e., time T
1) or from a combination of capacitor 122 and inductor 118 (ie, during time T2).

The control circuit 132 is formed so as to repeat the cycle of T1 and T2 indefinitely or until the cycle is stopped as described later. Thereby, the junction 1
The voltage V _{W at} 04 is increased to an adjustable magnification of the voltage of the battery 102 according to the time values of T1 and T2. This voltage boost can be adjusted by adjusting the values of T1 and T2.

A broken line in FIG. 8 indicates a missing or delayed pulse controlled by the control circuit 132. This occurs when a pulse is not needed to restore the depleted charge from capacitor 122, such as when the required treatment current I _L is relatively low. The dashed line in FIG. 8 indicates that the voltage boosting control uses pulse width adjustment (PWM),
This is due to pulse frequency adjustment (PFM), missing pulses, or a combination thereof.

[0076] The adjustable working voltage V _W is the load current I _L passes through the skin surface 110,
It passes through the adjustment register 114 and flows to the system ground at the switch input 136.

The feedback input 133 senses the voltage applied to the adjustment register 114 by the load current I _L. The control circuit 132 responds to the feedback input 133,
Or enhance V _W by adjusting the T1 and T2 times, or by either connecting the load register 123 by controlling the load switch 127, and is formed so as to adjust the working voltage. This reduces the voltage sensed at input 133 to
For example, this is performed by comparing with a reference voltage in the control circuit 132 such as the target voltage.

If the voltage sensed at input 133 is lower than the first reference voltage, control circuit 132 will quickly open and close switch 124 until V _W is increased to a reasonable level. Generally, the longer the switch 124 is closed (ie, T
The longer the 1), the higher the voltage produced at inductor 118 and the higher the voltage boost. Battery 102 voltage is boosted via inductor 118. The voltage (Vind) generated by the inductor 118 is equal to the inductance value (L) multiplied by the charge rate of the current flowing through the inductor. Vind = L * (dI / dt) Equation 1

Thus, since the power entering the inductor 118 must be equal to the power exiting the inductor 118, a higher voltage (partially 1
The inductance value of 18 determines, in part, the rate of charge of the current passing through the inductor 118 controlled by the values of T1 and T2) but at a lower current.

The electrodes 108 and 112, ie, the skin surface 110, are therefore not subjected to a high peak voltage, but only to a minimum constant voltage for flowing the desired load current I _L.

The times T 1 and T 2 are adjusted by the control circuit 132 so that V _W is increased to the minimum value required to maintain the load current I _L at a predetermined desired value. For V _W to achieve a predetermined value of I _L without exceeding the safe level, when the resistance of the skin surface 110 is too high, for example, a voltage limiting such Zener diode 116 connected between the electrodes 108 and 112 The device limits the voltage on the skin 110. Safety minimum value of the typical V _W is approximately 24 volts. Other limit voltage values can be achieved by Zener diodes 116 having different breakdown voltages or other protection measures as described below.

[0082] When the resistance of the skin surface 110, the maximum safety to the load current I _L in the voltage becomes a level defined Me desired pre, skin resistance 110 is decreased, the control circuit 1
32, in response to the feedback in the feedback input 133, the current is adjusted T1 and T 2 to enhance V _W magnification only enough is maintained at a predetermined level. Further, if the load voltage drops too low below the battery voltage, a controllable register 123 is connected in series and the controller
1 can be used to adjust the load voltage.

[0083] Thus, sufficient as long as a low load voltage than the set limit voltage by the Zener diode 116, the working voltage V _W of controlled electrical junction 104, to maintain the load current I _L The battery 102 is boosted up to the voltage boost factor.

The low-loss transfer of energy from battery 102 to skin 110 and capacitor 122 maximizes the useful life of battery 102 of a given capacity. This may require a smaller battery for a given therapy, or extend the duration of the therapy procedure for a given cost.

The predetermined current applied through the skin 110 can be constant or can vary over time according to a current-time curve. In each case, control circuit 132 defines the current-time curve to be applied. This includes one input, known in the art, for example, connected to a regulated register,
A differential comparator having a constant reference voltage connected to another input, or a ROM with a clock having a pre-programmed pattern (not shown in FIG. 6)
Can be implemented by known means, such as a differential comparator having another input connected to the output of a DA converter driven by.

The control circuit 132 further adjusts the value of the load resistance through the skin 110, the capacitance value of the capacitor 122, the time of T 1, T 2, and the load register 123 by the combination with the value of the inductor 118. is the filter capacitor 122 in response to the voltage at the feedback input 133 is adjusted to stabilize the voltage V _W, so as to provide the load current I _L as a constant (DC) current of predetermined et values It is formed.

FIG. 13 is a schematic diagram of an alternative medication delivery regulator circuit 400. The regulator 400 is similar to the drug administration regulator circuit 100 described with reference to FIG. 7, and like elements are numbered the same. In the regulator circuit 100 of FIG. 7, the microcontroller 138 detects a decrease in skin resistance between the electrodes 108 and 112. When the skin resistance reaches a first predetermined minimum resistance, a switch 127 is activated,
A resistor 123 is connected in series with the electrode 112 and the resistor 114. In this way, the resistance between node 102 of control circuit 132 and input 136 is increased. It will be appreciated that the combined resistance can be even lower than the first predetermined minimum resistance. For example, skin resistance can be reduced to almost 0 ohms. An alternative embodiment of the drug administration regulator 400 (FIG. 13) compensates for skin resistance that has dropped below the first predetermined minimum resistance.

The medication administration regulator circuit 400 includes the battery 102, the voltage boost circuit 141, the power supplies 108, 112, the microcontroller 138, and the control circuit 132. The regulator circuit also includes a variable register 402 and a register control circuit 404. In one embodiment, the variable register is a field effect transistor (FET) having a channel resistance, and the register control circuit 404 is an operational amplifier (op-amp) connected to a gate electrode of the FET. it can. Again, the adjuster 10
0, the capacitor 122 is connected to the skin 110 as described with reference to FIG.
, And a series of resistors determined by the resistor 114 to form an RC circuit. If the skin resistance drops too much and the voltage at node 104 drops below the battery voltage,
Is connected in series with the skin resistance and the resistor 114 to effectively increase the resistance of the RC circuit. If skin resistance continues to drop, node 104 may fall back below battery voltage. To alleviate this problem, the adjuster 400 has a variable resistor 402.

In operation, a voltage drop is applied across resistor 114 between times T 1 and T 2 when current is flowing through the skin. In effect, the skin resistance, variable register 402 and register 114 provide a register divider circuit. Accordingly, the skin resistance and the value of the resistance of variable resistor 402 determine the voltage at node 408. Optional amplifier 404 receives an input voltage from microcontroller 138 via output node 135. When the voltage at node 408 exceeds the voltage at node 135, the optional amplifier adjusts the control voltage provided to variable register 402. In one embodiment, where the variable resistor 402 is a field effect transistor, the operational amplifier 404 reduces the gate voltage such that the resistance between the transistor source and the drain increases. As will be appreciated by those skilled in the art, by selecting an appropriate FET, the regulator can supply a constant current between the electrodes 108 and 112 even when skin resistance goes to zero. . The adjusters shown in FIGS. 7, 9, and 13 include a variable resistance circuit 101. This circuit allows the regulator to change the resistance path through the electrodes. Each embodiment allows the control circuits 132, 138 to control a series of resistors. 7 and 9, different resistance paths are included, and in the embodiment of FIG. 13, a variable resistance circuit is included. The variable resistance circuit 101 shown in FIG. 7 has a low resistance path (almost 0 ohm) or a resistor 12 connected in series with a load resistance.
3 is provided. FIG. 9 shows a variable resistance circuit 101 having both a low resistance path (through switch 274) and a resistor 272 connected in parallel to form a low resistance path. Thus, those skilled in the art having the benefit of this disclosure will appreciate different ways to implement a variable resistance circuit.

FIG. 9 shows another embodiment of the regulator according to the present invention shown in FIG. The regulator circuit 200 includes a battery 202, an inductor 204, a diode 206, a voltage-controlled electrical junction 207, a low-resistance filter capacitor 208, and a conventional attachment to a remote area of the skin surface 213. Electrodes 210 and 212 that are provided. Skin surface 213 is shown as a variable load resistance R _V to emphasize that the resistance varies with time and current. At least one of the electrodes 210, 212 includes a therapeutic agent in a form that can be administered to the skin 213 by electrotransport.

The regulator 200 includes an N-channel field effect transistor (EFT) switch 218 for switching the inductor current Ii, an inductor current sensing register 220,
And an adjustment register 214. The circuit also has a highly efficient and adjustable DC-
DC setup controller 216 is included.

The tunable DC-DC setup controller 216 is a MySim M made by Maxim Integrated Products, Inc. of Sunnyvale, CA.
AX773. FIG. 9 further shows a simplified MAX773 controller, which is sufficient for the purposes of the present invention. For further details on the MAX773 controller, see MAX773 Datasheet 19-0201: Rev.
0; 11; 93, which are hereby incorporated by reference. A simplified block diagram of the MAX773 data sheet is shown in FIG. The MAX773 controller 216 includes a reference voltage pin 256, a ground pin 258, a feedback input 264, a cutoff input 266, a current sensing input 268, and a power bus input 270.

The MAX773 controller 216 further includes a first two-input comparator 230 having an output 231, a second two-input comparator 232 having an output 233, a first reference voltage 242, and a second (eg, (1.5 volts) 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 has an increase monitoring comparator 273, an overvoltage monitoring comparator 275, a controllable switch 274, a controllable register 272, and a cutoff switch 276. A microcontroller (not shown in FIG. 9) is also
0 is included. The boost monitor signal 277, the overvoltage monitor signal 279, the feedback signal 265, and a pair of reference signals (not shown in FIG. 9) are connected as inputs of the microcontroller. Conversely, the microcontroller controls the controllable switch 274
, The cutoff switch 276 and the cutoff signal 271.

The microcontroller according to the present invention may be a PIC16C620-SSOP available from Microchip Technology, Chandler, AZ. This microcontroller is described in more detail in the PIC 16/17 Microcontroller Data Book, May 1995, pages 2-203 to 2-212, which is incorporated herein by reference. The normal operation of the adjuster 200 is shown in FIG.
10 and FIG. The circuit 200 has a MAX773
Battery 2 at voltage controlled electrical junction 207 using controller 216
Providing an energy conversion efficiencies as high as to adjustable enhanced voltage V _W 02, to control the load current I _L at the same time.

Unlike a conventional pulse frequency (PFM) converter that uses an error voltage from the voltage divider circuit to maintain a constant output voltage of the converter, the average load current I _A MAX773 controller 216 is connected to generate an error voltage that controls _L. MAX773 controller 216 also operates at high frequencies (up to 300 kHz), thereby allowing the use of small external components.

In FIG. 9, according to the present invention, a part of the load current I _L is fed back to the feedback input 264. Electrodes 210, 212 are applied to skin surface 213 and are indicated as variable resistance loads. MAX controller 216 is an integrated circuit,
It has internal components connected by conductive paths formed during the integrated circuit manufacturing process. Conventional printed circuits, such as plated or coated copper or conductors deposited and molded on an insulating substrate, provide external pins for electrical connection to external elements. . References to the electrical connections herein are understood both internally and externally from FIG. Reference to the MAX773 controller 216 circuit is provided for display purposes to describe the function of the circuit 216.

One terminal of the adjustment register 214 is connected to the feedback input 264. This same terminal of the control register 214 is also connected to the electrode 212 to receive load current I _L. The other terminal of the adjustment register 214 is connected to system ground. Input 264 is connected to the conversion input of comparator 232. The unconverted input of comparator 232 is connected to reference voltage 244. Comparator 23
2 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 conversion input of comparator 230 is connected to reference voltage 242. The unconverted input of comparator 230 is connected to current sense input 268. Input 268 is connected to one terminal of inductor current sense register 220. The other terminal of register 220 is connected to system ground. Ground pin 258 of 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 the battery 202 is connected to system ground. One output of the PFM / PWM drive circuit 240 is connected to the output 254. Outputs 252 and 254 are both external N
Connected to the gate of the channel switch 218; The drain of switch 218 is connected to the junction of one end of energy storage inductor 204 and the anode of rectifier diode 206. The power supply of switch 218 is connected to one terminal of inductor current sense register 220 connected to current sense input 268.

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

The cathode of diode 206 is connected to electrical junction 207. Joint 20
7 also has one terminal of the filter capacitor 208 and the Zener diode 2
80 and the electrode 210. The anode of zener diode 280 and the other terminal of capacitor 208 are connected to ground. Joint 20
7 completes the circuit 200 and increases the working voltage V _W at the junction 207 by the power source, ie, the voltage of the battery 202, by an adjustment factor. Zener diode 280
Limits the peak voltage across electrodes 210 and 212, and thus the maximum voltage at skin 213, respectively.

The normal operation of the adjuster 200 can be understood by referring to FIGS. 9 and 10. Power is supplied to the power bus 261 by the battery 202 via the power input 270, and if the cut-off input signal 271 is at the correct logic level, the MAX773 controller 216 and the microprocessor begin to operate.

As in a conventional PFM converter, switch 218 does not turn on until voltage comparator 232 senses that the output voltage has gone out of regulation. However, unlike a conventional PFM converter, the MAX773 controller 216 includes a peak inductor current limit sensing register 220, a reference voltage 242, and a comparator 23.
Use a combination of 0 and the maximum switch-on time and the minimum switch-off time produced by the PFM / PWM drive circuit 240, and no oscillator is provided. A typical maximum switch-on time T1 is 16 microseconds. A typical minimum switch off time T2 is 2.3 microseconds.

Once turned off, the minimum off-time keeps switch 218 off for time T2. After this minimum time, the switch 218 is (1) kept off if the output current _IL is within the adjustment range, or (2) turned on again if the output current _IL is outside the adjustment range, Works for either.

While the switch 218 is off, the inductor current I _i flowing through the diode 206 at the junction 207 to the capacitor 208 makes up for the charge consumed by the skin 213. How to switch the current I _L to the charge, the working voltage V _W of the joint 207, which provides an adjustable enhanced multiple of just an amount sufficient battery 202 voltage to supply the desired constant current I _L Is understood. Inductor 204
Peak voltage provided becomes only with an amount just required to overcome the diodes drop the working volts V _W diode 206 by, thereby, the battery 2
02 to minimize energy loss.

The MAX773 controller 216 circuit allows the circuit 200 to operate in continuous conduction mode (CCM) while maintaining high efficiency at high loads. Power switch 2
When 18 is turned on, (1) the maximum on-time elapses (typically 1
6 After microseconds), (2) inductor current I _i is, inductor current and limit register 220, the reference voltage 242 and comparator 230 and by the set peak current limit I
, the on state is maintained until either of the above is satisfied. In this state, the ON time is shorter than the maximum ON time T1. Limiting the peak inductor current to a predetermined maximum value Ip prevents the inductor 204 from saturating and allows smaller inductor values to be used, thereby allowing the use of smaller components. I do.

The average load current I _L is equal to a value obtained by dividing Vref of the reference voltage 244 by R _S of the adjustment register 214, and is represented by the following equation. _IL = Vref / _RS Equation 2

When the average load current I _L is lower than the desired value set by Vref of the reference voltage 244 and R _S of the adjustment register 214, the PFM / PWM drive circuit 240 automatically turns on the on-time T1. And off time T2, or alternatively,
Load current until the I _L is greater than or equal to a desired value, on the switch 218 to repeat the off.

During normal operation, current exits the boost voltage at electrode 210, passes through variable skin resistance R _V , to electrode 212, exits controllable switch 274, and goes to shut-off switch 276, Finally, the process reaches the adjustment register 214. Thus, in normal operation, both switches 274, 276 are closed and the current is controlled by switch 274.
To bypass the controllable register 272.

The current supplied through electrodes 210, 212 is regulated by MAX 773 to maintain the voltage through regulation register 214 at, for example, 1.5V. For example, M
The AX773 controller 216 sets the adjustment register 214 to, for example, 1.5 V at 1.5 KW.
, The adjusted current is (15/15000 = 0.1 mA).

However, the variable skin resistance RV between the electrodes 210 and 212 becomes too low and M
When the voltage at the feedback input 264 of the AX773 controller 216 rises above the reference voltage, for example, 1.5V, the MAX773 controller 216 does not supply an augmented voltage, and thus the current is not regulated, thereby applying to the electrode 210. Total battery voltage (battery 202) minus the voltage drop across diode 206
Activate the boost monitor comparator 273. Regulator 200 then enters an overdose mode. If the microcontroller determines that this overdose mode has lasted longer than a time, such as the first maximum low load detection period, the microcontroller shuts off the controllable switch 274. The current is then forced through the additional impedance of the controllable resistor 272. This additional (ie, artificial) load added in series with the variable skin resistance is such that the skin resistance is zero, for example.
Even when reduced to W, a regulated current from electrode 210 to electrode 212 is guaranteed. However, if the microcontroller determines that the overdose condition lasted for another predetermined period, for example, a second maximum load sensing period, the microcontroller opens the shut-off switch 176. , whereby you cut off the load current I _L.

In another embodiment of the present invention, the current I _L can be programmed to follow a predetermined curve by programming the value of the load current passing through the adjustment register 214. it can. The value of the adjustment register 214 can you to programmed by switching additional registers in parallel or series with the load current I _L.

Although the present invention has been described with reference to some specific examples of the embodiments of the present invention, when combined, the best mode for implementing the present invention as far as the inventor knows is provided. Nevertheless, many modifications and many alternative embodiments could be derived without departing from the scope of the present invention. Accordingly, the scope of the invention should be determined only by the following claims.

For example, in the present invention, the electric transport controller can also be disposable.
The functions executed by the circuit (see FIGS. 7 and 9) in the above embodiment are as follows.
Alternatively, it can be implemented by software in a digitally programmable element.

[Brief description of the drawings]

FIG. 1 is a perspective view of an electric carrier medicine administration device according to the present invention.

FIG. 2 is an exploded view of the electric transport device according to the present invention.

FIG. 3 is a graph showing how the skin resistance of a patient decreases with time.

FIG. 4 shows the current of the load current supplied by the electric transport device according to the present invention.
It is a graph which shows the example of a curve of time. This graph is an example of current-time.

FIG. 5 is a time line graph of the load voltage of the electric transport device according to the present invention.

FIG. 6 is a schematic block diagram of a medicine administration controller according to the present invention.

FIG. 7 is a schematic logic circuit diagram of a drug administration controller according to the present invention.

FIG. 8 is a timing graph of the operation of the circuit shown in FIG. 7;

FIG. 9 is a schematic logic circuit diagram of another drug administration controller according to the present invention.

10 is a timing graph of the operation of the circuit shown in FIG.

FIG. 11 is a perspective view of an electric carrier medicine administration device including a disposable medicine unit.

FIG. 12 is an exploded view of the electric transport device shown in FIG.

FIG. 13 is a schematic logic circuit diagram of another drug administration controller according to the present invention.

[Explanation of symbols]

10. 13. electric delivery dosing device; Light emitting diode, 16. Upper housing,
18. Circuit board, 19. Electronic circuit, 20. Lower housing, 22. Anode electrode, 24. Cathode electrode, 26. Anode reservoir, 28. Cathode storage, 32. Battery, 40. Electronic circuit, 50. Regulator, 51. Battery, 53. Controller, 55. Voltage intensifier, 57. Artificial impedance,
59. Adjustment register, 61. Skin surface, 63. Anode electrode, 65. Cathode electrode, 77. 79. impedance connection switch; Voltage limiter, 1
00. Regulator, 101. Variable resistor circuit, 102. Battery, 104. Electrical joint, 108. Electrode, 110. Skin surface, 112. Electrodes, 114. Adjustment register, 116. Zener diode, 118. An inductor, 120.
Rectifier diode, 122. Filter capacitor, 124. Switch, 1
26. Control inputs, 128, 130. Terminal, 132. Control circuit 133. Feedback input, 134. Control output, 135. Load control output, 136.
Switch input, 138. Microcontroller, 140. 141. feedback input (current); Voltage intensifier, 142. Feedback input (voltage), 20
0. Regulator circuit; 202. Battery, 204. An inductor, 206. Diode, 207. Electrical joints, 208. 213 Low resistance filter / capacitor
. Skin surface, 210, 212. Electrode, 214. Adjustment registers, 320. Electric carrier, 322. Electronic controller, 324. Drug unit, 350. Lower housing, 354. Battery, 359. Circuit board, 368. Upper housing, 388. Counter electrode, 390. A donor electrode, 399. Counter reservoir, 400. Drug administration regulator circuit, 401. Donor reservoir, 402. Variable registers, 404. 408. register control circuit; node.

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Claims (25)

[Claims] A voltage boosting circuit connected to a first electrode for providing a load voltage to the first electrode; and a voltage boosting circuit connected to the voltage boosting circuit and between the first electrode and the second electrode. A control circuit that adjusts the load voltage in response to the load resistance, and a variable resistance circuit that is connected in series with the load resistance, the variable resistance circuit being connected to the control circuit to adjust a current passing through the load resistance. A variable resistance circuit, and a transdermal drug delivery regulator comprising: 2. The variable resistance circuit, comprising: a first current path having a first resistance; a second current path having a second resistance larger than the first resistance; 2 in response to the control circuit.
2. The electrotransdermal transdermal drug delivery controller of claim 1, further comprising: a switch circuit that selects one of the first resistor and the second resistor and connects the resistor in series with the load resistor. 3. The second current path is formed by a resistor having the first resistor connected in parallel with a switch of the switch circuit to provide the second resistor. Electrotransport transdermal drug delivery regulator. 4. The voltage booster circuit includes an inductor circuit connected to a power supply, and a capacitor connected to the inductor circuit, wherein the control circuit controls the inductor circuit to generate a peak current. Wherein the control circuit selectively connects the inductor circuit to the capacitor to discharge the peak current and charge the capacitor to the load voltage. Electric delivery transdermal drug delivery regulator. 5. A variable resistance circuit, comprising: a voltage-controlled resistance circuit connected in series with the load resistance; and a variable-resistance circuit connected to the voltage-controlled resistance circuit, for changing a resistance of the voltage-controlled resistance circuit. The transdermal drug delivery regulator of claim 1, further comprising: a register control circuit configured to: 6. The electrotransdermal transdermal drug delivery controller of claim 5, wherein said voltage controlled resistor circuit is a field effect transistor. 7. The transdermal drug delivery regulator of claim 6, wherein said register control circuit is an operational amplifier connected to a gate electrode of said field effect transistor. 8. An electrotransport system for administering an active agent through the skin of an animal by using a power source and supplying a load voltage and a load current between a first electrode and a second electrode. A transdermal dosage controller, comprising: a controller; the controller; the power source; a voltage booster electrically connected to the first electrode; A control enabler connected to the controller, the control enabler switch being connectable to the second electrode or the control enabler, the control enabler being controlled by the controller. A switch, a sensor connected to the controller and the control enabler switch,
The controller measures a feedback value from the sensor, and the controller adjusts the load voltage using the voltage intensifier, the control enabler, the control enabler switch, and the feedback value. An adjuster comprising: a sensor; 9. The regulator of claim 8, wherein the controller adjusts the load voltage such that the load current flows along a predetermined current-time curve. 10. The control enabler switch connects the second electrode to the sensor and connects the voltage intensifier, the two electrodes, and the sensor without being connected to the control enabler. 9. The regulator of claim 8, wherein a closed electrical circuit is formed from the power source to the controller via. 11. The controller measures at least one of the load voltage, the load current, and the resistance of the animal skin surface from the feedback value.
The regulator of claim 8. 12. The regulator of claim 8, wherein the controller boosts the load voltage using the voltage booster when the feedback value is lower than a target value. 13. The control enabler switch, when the feedback value is higher than a predetermined value for a time longer than a first predetermined time,
Connecting the control enabler in series between the second electrode and the sensor;
The regulator of claim 8. 14. When the feedback value is higher than the predetermined value for longer than a second predetermined time, even after the control enabler is connected in series. 14. The regulator of claim 13, wherein a regulator shuts off the load voltage. 15. The apparatus according to claim 8, further comprising a voltage limiter connected between said first electrode and said sensor to limit said load voltage to a predetermined value.
Regulator. 16. The regulator of claim 8, wherein said sensor comprises a resistor. 17. The regulator of claim 8, wherein said control enabler is an artificial impedance. 18. The voltage booster comprises: an inductor connected to the power source; and an inductor switch connected to the inductor and a capacitor, wherein the controller controls the inductor switch. Connecting the inductor to the power source, thereby charging the inductor to a peak instantaneous current, and then connecting the capacitor to the inductor, and allowing the current in the inductor to pass through the capacitor. 9. The regulator of claim 8, including an inductor switch discharging into the inductor. 19. An electrotransport system for administering an active agent across an animal's skin by using a power source and supplying a load voltage and a load current between a first electrode and a second electrode. Generating the load voltage, increasing the load voltage, calculating a feedback value from a sensor, and controlling a control enabler switch based on the feedback value. Method. 20. The method according to claim 19, wherein the generated load voltage follows a predetermined current-time curve. 21. The method according to claim 19, further comprising measuring either the load voltage, the load current, or the electrical resistance of the animal surface from the feedback value. 22. The method according to claim 21, further comprising increasing the load voltage when the feedback value is lower than a target value. 23. A method for regulating drug delivery using an electrotransport system, comprising: generating a first load voltage; connecting the first load voltage to a first electrode; Providing a first load current through a load resistance between the first electrode and a second electrode; measuring the load resistance; generating a second load voltage in response to the measured load resistance; A second load voltage is connected to the first electrode and a second load voltage is connected to the second electrode through the load resistor.
Providing a load current. 24. A method of regulating drug delivery using an electrical delivery system, comprising: generating a first load voltage; connecting the first load voltage to a first electrode; Providing a first load current through a load resistance between the first electrode and the second electrode; measuring the load resistance; responsive to the measured load resistance, connected in series with the load resistance. Adjusting the register circuit. 25. A voltage booster connected to a controller, the controller, a power source, and a first electrode, the voltage booster connected to the power source, and the inductor and the capacitor. A voltage intensifier composed of a connected inductor switch, the inductor switch connected to the controller and controlled by the controller, and a controllable impedance connected to a second electrode. A controllable impedance providing a first or second impedance path in series with the first and second electrodes in response to the controller; a load voltage connected to the first electrode; And a voltage limiter that limits the voltage to a predetermined maximum value.