JPH1176428A - Iontophoresis device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To effectively perform absorption of a medicine for a long time by providing a plurality of positive/negative electrodes, which are impregnated with the medicine, and the opposed electrode containing no medicine and successively applying current to the plurality of medicine containing electrodes by means of a treatment condition setting means, by which a treatment time, a rest time, the number of switching times and the like are set, in usage. SOLUTION: An iontophoresis device 1 is provided with a switching means 2 for a power source and a treatment condition setting means 3, by which a treatment time, a rest time, and the number of switching times are set. In the iontophoresis device 1, which is also provided with a power source means 4 such as a direct current constant current electric source like an electrode small-sized battery and a direct current pulse generator and a current regulating means 5, electric current can be applied to an electrode 6, which is provided with an aqueous medium layer, and to plurality of medicine containing electrodes 7. A plurality of medicine containing electrodes 7, which are impregnated with a medicine to be absorbed in the organism, are controlled so as to carry out excitation in order. On an arrangement face of each of the electrodes 6, 7, an insulating substance 8 is arranged, and a low electrically conductive substance such as silicone rubber and natural rubber, which is sticky to a skin, is layered on it.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an apparatus for iontophoresis, and more particularly to an apparatus for iontophoresis capable of efficiently introducing a drug into a living body through the skin by repeatedly administering a small amount of the drug. .

[0002]

2. Description of the Related Art Iontophoresis, also called ion permeation, is a method of introducing an ionic or water-soluble drug through a skin into a living body by electric current for therapeutic purposes. In recent years, skin and mucous membranes have attracted attention as a systemic administration site of a drug, and studies to absorb the drug into a living body by iontophoresis have been energetically conducted.

[0003]

[0002] Iontophoresis is known as a method that can control drug absorption (for example, P. Lelawongs et al., Int. J. Pharmaceut., 6
1: 179 (1990)). On the other hand, it has been proposed that long-term energization should be avoided in terms of stimulation. As a response, to suppress the pH change that causes skin irritation,
A method of alternately switching the positive and negative of the applied voltage between the electrodes has been devised (Japanese Patent Laid-Open No. 4-224770). In addition, a method has been devised in which an Ag / AgCl electrode that suppresses a change in pH is used, and furthermore, the electrode is regenerated by switching between positive and negative, thereby enabling long-time energization while reducing stimulation (WO94 / 28967WO95). / 00200, WO95 / 09032). In these inventions, the effect of increasing the absorption rate and absorption amount of the drug is also shown. A therapeutic device for introducing a drug composed of positive and negative ions by switching the polarity has also been disclosed (JP-A-62-159661, Japanese Patent Publication No. 3-2662).
2). However, when switching is performed twice or more, the same drug storage layer is energized a plurality of times, so that the first and second times are performed.
The drug concentration in the drug storage layer after the first time differs. In general, the drug absorption rate is affected by the drug concentration. Therefore, in the above-described method, the drug absorption rates are different in the first and second iontophoresis treatments, and it is difficult to control the absorption amount. Therefore, other solutions are needed to control long-term drug absorption.

[0004]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the absorption rate of the drug was maximized at a relatively early stage of the iontophoresis treatment. It became clear that it became lower. Therefore, in order to efficiently absorb a drug for a long period of time, it has been found that it is preferable to frequently administer a small dose rather than simply performing iontophoresis treatment with a high dose. Therefore, as a device capable of continuously and efficiently absorbing a drug into a living body, two or more drug storage layers are provided, and only one iontophoresis treatment is performed on one drug storage layer. The present invention has been achieved by adopting a configuration in which energization is sequentially switched to the storage layer.

That is, the present invention provides a plurality of positive or negative electrodes containing a drug, one counter electrode containing no drug, and processing condition setting means for setting a processing time, a pause time, and / or the number of times of switching. The present invention provides an iontophoresis device for frequently administering a small amount of a drug, characterized in that when used, a plurality of drug-containing electrodes are sequentially energized by the processing condition setting means.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the device of the present invention, a single short-time iontophoresis is performed to monitor the blood concentration or the duration of pharmacological action, thereby simulating frequent administration. , Dosage, treatment time, and number of switchings can be determined. Further, the apparatus may be provided with a function capable of setting the iontophoresis processing time, the number of times of switching, and the like, so that the above-described simulation result is automatically performed by one switch operation. In addition,
If a relatively long pharmacological action is exhibited by one energization, the drug may be intermittently administered with a certain pause during switching.

The apparatus of the present invention will be described below in detail with reference to the drawings as necessary. FIG. 1 schematically shows a specific example of the iontophoresis device of the present invention.
It is. In the figure, 1 is an iontophoresis device, 2 is a switch means for turning on / off the power, and 3 is a processing condition setting means for setting a predetermined processing time, a pause time, and the number of times of switching. The present means may be any means as long as each set value can be input externally and the drug-containing electrodes are sequentially energized in accordance with the input conditions. The conditions are not particularly limited. For example, the processing time is 1 minute to 24 hours, the pause time is 0 to 12 hours, and the number of times of switching is 1 to 10 times. 4
Denotes a power supply means such as a DC constant current power supply such as a small power supply battery or a DC pulse generator, and further includes a current limiting resistance means for ensuring safety for preventing an overcurrent.
Reference numeral 5 denotes a current adjusting means. 6 and 7 indicate electrodes,
7 contains a drug to be absorbed into the living body.
In this specification, an electrode containing a drug may be referred to as a drug storage layer. The electrodes 6 and 7 also include an aqueous medium layer. For example, an aqueous medium layer is laminated on electrodes of platinum, silver / silver chloride, titanium, nickel, stainless steel, carbon, and the like. The aqueous medium referred to in the present invention is an electrically conductive medium containing water or an aqueous solution, and may be any medium as long as it can be used as an electrode. For example, a sponge or a porous material such as absorbent cotton, gauze, a synthetic resin continuous foam or an absorbent resin or the like is arranged in advance, and a drug solution is impregnated at the time of use, or a natural resin polysaccharide such as karaya gum, tragacanth gum or polyvinyl alcohol, or polyvinyl alcohol Formal, polyvinyl methyl ether and copolymers thereof, vinyl resins such as polyvinyl pyrrolidone and polyvinyl methacrylate, polyacrylic acid and its sodium salt, polyacrylamide and its partial hydrolyzate, polyacrylate partially saponified, poly (acrylic acid- Various natural or synthetic resins having hydrophilicity, such as acrylic resins such as acrylamide) are gelled or solidified, or are softly plasticized with water and / or alcohols such as ethylene glycol and glycerin. And a flexible film or sheet-like gel having self-retaining property and skin-adhesive property and containing a drug in advance. If necessary, an isotonic agent, a preservative, a buffer, a stabilizer, and a pH adjuster can be used in the aqueous medium layer. As tonicity agents, sodium chloride, glycerin, etc., as preservatives, p-hydroxybenzoates, benzalkonium chloride, chlorobutanol, etc., as buffering agents, acetic acid, sodium acetate, citric acid Sodium hydrogen citrate, sodium dihydrogen citrate, sodium citrate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, boric acid, borax, etc. are stable As the agent, sodium edetate, etc., pH
Sodium hydroxide, hydrochloric acid, and the like are used as adjusting agents. In addition, a semipermeable membrane, a release controlling membrane, or the like, or a pressure-sensitive adhesive layer may be laminated between the electrode, the aqueous medium layer, and the skin contact surface according to the purpose.

Reference numeral 8 denotes an insulating material, and a material having an adhesive property to the skin may be laminated. As the adhesive substance, a substance having low conductivity is preferable. For example, a rubber adhesive such as silicone rubber, natural rubber, isoprene-based rubber, isobutylene-based rubber, and diene-based rubber is used.

The device of the present invention is effective for administering a drug exhibiting a drug effect in a time-dependent manner, but can be used without particular limitation as long as the drug is desired to be continuously absorbed. . Examples of drugs that can be used in the device of the present invention include human growth hormone, gonadotropin, insulin, glucagon, calcitonin, elcatonin, luteinizing hormone releasing hormone (LHRH), oxytocin,
Thyroid stimulating hormone (TRH), calcitonin gene-related factor, vasopressin, lipressin, L-sparaginase, buserelin, glucagon-like peptide, angiotensin II antagonist, anthriopeptins,
Bradykinin, tissue plasminogen activator,
Cholecystokinin, Delta sleep inducing peptide, β-endorphin, melanocyte inhibitor I, melanocyte stimulating hormone, neuropeptide Y, nerve growth factor, gastrin antagonist, neurotensin, pancreatic enzyme, somatostatin, octreotide, motilin, brucine, colony stimulating factor , Cyclosporine, enkephalin, interferon, muramyl dipeptide, thymopoietin, tumor necrosis factor, epidermal cell growth factor, insulin-like factors I and II, interleukin-2, nerve growth factor, platelet-derived growth factor, transforming growth factor, cartilage Derived growth factor, colony stimulating factor, endothelial cell stimulating factor,
Erythropoietin, eye-derived growth factor, fibroblast-derived growth factor, fibroblast growth factor, glial cell growth factor, osteosarcoma-derived growth factor, thymosin and other peptides and proteins or those modified or minimized, Local anesthetics such as lidocaine hydrochloride, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, oxyprocaine hydrochloride, pupivacaine hydrochloride, mepivacaine hydrochloride, vincristine, mitomycin, doxorubicin, adriamycin, cisplatin, carboplatin, etoposide, procarbazine hydrochloride, tamoxifen citrate, fluorouracil , UFT, Tegafur, Carmofur, Methotrexate, Carbocon, Bleomycin hydrochloride, Pepromycin sulfate, Epirubicin hydrochloride, Pilal hydrochloride Cardiovascular functions such as anti-neoplastic agents such as syn, neocarzinostatin, lentinan, picibanil, schizophyllan, vincristine sulfate, nicametarate citrate, alprostadil, argatroban, citicoline, nizophenone fumarate, D-mannitol, nicorandil, diltiazem hydrochloride, etc. Gout treatments such as benzbromarone, allopurinol, colchicine, etc., agents for hyperlipidemia such as simvastatin, nicomol, pravastatin sodium, diphenhydramine hydrochloride, promethazine hydrochloride, chlorpheniramine maleate, mequitazine, clemastine fumarate, etc. Antihistamines, oxatomide,
Sodium cromoglycate, ketotifen fumarate, azelastine hydrochloride, amlexanox, terfenadine,
Emedastine fumarate, Tranist, Codeine phosphate,
Anti-allergic agents such as dihydrocodeine phosphate, epradinone hydrochloride, tipepidine hibenzate or antitussive expectorants, morphine hydrochloride, hydromorphine hydrochloride, buprenorphine hydrochloride, pentazocine, analgesics such as fentanyl, fentanyl citrate, nalbuphine hydrochloride, pentazocine lactate, flunitrazepam, Hypnotic sedatives or anxiolytics such as midazolam, secobarbital sodium, amobarbital sodium, phenytoin sodium, inotropic agents such as dopamine hydrochloride, dobutamine hydrochloride, amrinone, calcium antagonists such as nifedipine, nicardipine, diltiazem, verapamil, benidipine, clonidine hydrochloride , Betanidine sulfate, benazepril hydrochloride, cilazapril, captopril, celiprolol hydrochloride, tilisolol hydrochloride, terazosin hydrochloride, hydrochloric acid Antihypertensive agents such as nazocin and carvedilol, cortisone, hydrocortisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, paramethasone, estradiol, progesterone, norgestrel, levonorgestrel, norethindrone, medroxyprogesterone acetate, testosterone and esters thereof. Steroids, nitro compounds such as nitroglycerin, isosorbide dinitrate, nitroprusside, etc., atenolol, nadolol, sotalol, practol, pindolol, acebutolol, metoprolol, timolol, triprolol, oxprenolol, labetalol, bupranolol, alprenolol, propranolol Β-
Bronchodilators such as receptor blockers, theophylline, pyrbuterol hydrochloride, terbutaline sulfate, hexoprenaline sulfate, salbutamol sulfate, tulobuterol hydrochloride, procaterol hydrochloride, mabuterol hydrochloride, formoterol fumarate, aspirin, phenylbutazone, ibuprofen, naproxen, flurubiine Profen, flurbiprofen axetil, ketoprofen, alclofenac, diclofenac, fenbufen, mefenamic acid, flufenamic acid, methiazinic acid, proglametacin, benzidamine, mepilizole, tinolidine, bufexamac, o-hydroxyhippuric acid, p -Hydroxybenzoic acid, salicylic acid, piroxicam, biphenylacetic acid, indomethacin, loxoprofen sodium, tenidap, tenoxicam, etc. Symptomatic agent, difenidol hydrochloride,
Antihypertensive agents such as thiethylperazine maleate and betahistine mesylate, anticholinergic agents such as scopolamine and atropine, cisapride, domperidone, trimebutine maleate, metoclopramide, itopride hydrochloride and other digestive motor function regulators, chlorpromazine hydrochloride, etizolam, Psychiatric agents such as amitriptyline hydrochloride, clocapramine hydrochloride, haloperidol, mosapramine hydrochloride, perphenazine, cloxacillin sodium, benzylpenicillin potassium, ticarcillin sodium, ampicillin sodium, piperacillin sodium, cefoxitilin sodium, cefodidim sodium, Cefotaxime sodium, cefotetan, cefoperazone sodium,
Cefsulodin sodium, ceftazine, cefmetazole sodium, cefpirome sulfate, gentamicin sulfate, sisomicin sulfate, dibecaine sulfate, netilmicin sulfate, amikacin sulfate, ribostamycin sulfate, micronomycin sulfate, astromycin sulfate, lincomycin antibiotics Examples include substances, risurmycin preparations, josamycin preparations, chloramphenicol preparations, antibiotics such as tetracycline antibiotics, and nicotine used in transdermal absorption preparations.

FIG. 2 (A) shows a more detailed example of the electric circuit section when the drug is introduced from the anode in the iontophoresis device of the present invention shown in FIG. is there. That is, 4 in FIG. 2 indicates a power supply means, 5 indicates a current adjusting means, and is linked to the processing condition setting means 3 so that the drug positive electrode 7,
7 ', 7 "indicate means for sequentially turning on and off the current. It is also possible to switch to manual operation.
Indicates a counter electrode.

FIG. 2 (B) shows a more detailed example of the electric circuit section when the drug is introduced from the cathode in the apparatus for iontophoresis of the present invention shown in FIG. . All have the same function except that the polarity in FIG. 2A is reversed, indicating that the polarity of the drug storage layer is not limited in the present invention. Also,
The present invention is not limited to the number of these electrodes, and any number of two or more drug storage layers can be arranged as long as the effective area is secured.

Examples of the present invention and experimental examples will be shown below, but the present invention is not limited thereto.

3A to 3F schematically show the skin mounting surface of an apparatus according to an embodiment of the present invention, and show a counter electrode 6, drug electrodes 7, 7 ', 7 ", 7". ', Insulator 8, 8', 8 ",
8 "". The insulators 8, 8 ', 8 ",
8 "'is disposed between the drug electrode and the counter electrode in order to electrically cut off the electrode and the counter electrode.

Experimental Example Preparation of a model rat for evaluating antidiuretic effect: A rat anesthetized with urethane was fixed on the back of an operating table, and hypotonic solution (saline: glucose solution: distilled water = 27: 3
6:37; 175 ± 5 mosm / kg) was continuously infused to 3.0 mL / h. Separately, urine was collected from the bladder every 15 minutes and urine volume was measured. After the urine volume was maintained at about 1 mL / 15 minutes, iontophoresis treatment was performed. In the iontophoresis treatment, two cylindrical silicone tubes are fixed to the abdomen of the depilated rat, an aqueous solution of the drug and physiological saline are injected, and an electric stimulator (SEM-3301, Nihon Kohden) and an isolator (SS -302J, Nihon Kohden).

Experiment of administration of vasopressin: 1 of vasopressin
1 mL of an aqueous solution of 0 μg / mL was injected into the anode side, and administered to the above-mentioned model rat for antidiuretic action evaluation by iontophoresis. The processing conditions were 0.1 mA (frequency 2000
(Hz, 50% duty ratio) for 8 hours, and then exchanged with a new 10 μg / mL aqueous solution of vasopressin for 1 hour, and further energized for 15 hours. (Small dose frequent administration). In this case, the processing condition settings include a processing time of 8 hours, a pause time of 0 hours, and one switching. Separately, 1 mL of a 20 μg / mL solution of vasopressin was administered to a model rat for antidiuretic effect evaluation by iontophoresis. As processing conditions, 0.1 mA
A current of (frequency 2000 Hz, conduction rate 50%) was supplied for 23 hours (single administration). These results are shown in FIG. As shown in FIG. 4, even when the dose of vasopressin and the total amount of electricity are the same, the urine volume reduction time due to the antidiuretic effect of desmopressin acetate is clearly longer in the case of small and frequent administration,
It lasted about 1.4 times.

[0015]

As described above, the present invention has an effect that the absorption of a drug can be sustained more efficiently than the conventional one at the same dose and the same amount of electricity.

[Brief description of the drawings]

FIG. 1 is a sectional view of an iontophoresis device of the present invention.

FIG. 2 is a schematic diagram showing an electric circuit of the iontophoresis device of the present invention. FIG. 2A shows a case where a drug is introduced from an anode, and FIG. 2B shows a case where a drug is introduced from a cathode.

FIG. 3 is a diagram schematically showing a skin mounting surface of an iontophoresis device for explaining an embodiment of the present invention, and FIGS. 3A to 3F show various mounting modes.

FIG. 4 is a graph showing the time course of rat urine volume over time in an experimental example, in which the pharmacological action of the device of the present invention is more sustained in a small number of frequent administrations than in a single administration of a conventional method in iontophoresis. It is a graph which shows that it is effective from a viewpoint. Solid circles indicate single doses, and open circles indicate frequent small doses.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Iontophoresis device 2 Switch means 3 Processing condition setting means 4 Power supply means 5 Current adjusting means 6 Counter electrode 7, 7 ', 7 ", 7"' Drug electrode 8, 8 ', 8 ", 8"' Insulator

Claims (1)

[Claims] 1. A method comprising: providing a plurality of positive or negative electrodes containing a drug, one counter electrode not containing a drug, and processing condition setting means for setting a processing time, a pause time and / or a number of times of switching. In this case, the apparatus for iontophoresis for frequently administering a small amount of a drug is characterized in that a plurality of drug-containing electrodes are sequentially energized by the processing condition setting means.