JPH10192420A - Device for iontophoresis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a device for iontophoresis involving less dispersion in the medicine dosage. SOLUTION: An iontophoretic device is composed of a pair of electrode means 3a and 3b installed on the exodermis of vital organism and an electric circuit part 4 equipped at least with a power supply means and a current changeover means, wherein the electrode means 3a and 3b have electrodes 1a and 1b and aqueous media 2a and 2b which connect the electrodes with the exodermis of vital organism electrically, and the aqueous medium 2a or 2b of at least either electrode means 3a or 3b contains medicine to be dosed into the vital organism through the exodermis, and the power supply means feeds a constant current to between the two electrodes while the current changeover means changes over the current direction alternately.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an apparatus for iontophoresis.

[0002]

2. Description of the Related Art Iontophoresis
Is a method of introducing an ionic or water-soluble drug into a living body through an integument of a living body by an electric current for the purpose of treatment. Here, the living body skin is a living tissue constituting an interface between a living body and the outside world, and indicates skin, oral mucosa, and the like, and is most commonly skin.

[0003] The history of iontophoresis is 190 years old.
It has been known since the early 0's and it has been clarified that many drugs can be administered to living bodies by iontophoresis (Praveen Tyle, ed.
vices, 1988. Marcel Dekker, Inc., 421-445
Page ”). In recent years, iontophoresis has been vigorous due to the fact that the skin has been attracting attention as a systemic administration site of drugs, and the miniaturization of devices such as current supply and control has progressed with advances in electronics. Has been studied. In particular, it is regarded as promising as a method for administering a peptide / protein drug that has been newly discovered or has become possible to be mass-produced due to the development of biotechnology.

[0004] The actual mode of iontophoresis is as follows.
Many devices have been devised and improved since the early 900's and are diverse (Praveen Tyle's “Drug Delivery De
vices ", supra). However, it is basically composed of a power source, a pair of electrodes connected to the power source, and an aqueous medium disposed between the electrode and the living body skin.

[0005]

In the conventional iontophoresis, when electricity is passed through the outer skin of a living body, polarization occurs in the living body. As a result, damage (irritative redness, etc.) occurs in the living body, and the drug is transported. It has been widely accepted that the effective current required for the treatment decreases and that the drug cannot be effectively introduced into the living body.

On the other hand, a method of applying a current as a high-frequency pulse wave, and in addition to this, a short circuit is provided,
A method of positively discharging (depolarizing) before the end of a unit pulse (JP-A-60-156475 and JP-A-60-188176)
), And periodically interrupts the direct current flowing through the living body from one electrode to the other electrode, and simultaneously applies a short-duration current pulse through the living body from the other electrode to the other electrode at a predetermined time interval in the reverse direction. Flowing method (Japanese Patent Laid-Open No. 622-2)
6789) has been devised.

However, in the above-mentioned method using a high frequency, although the apparent current value becomes large, most of the current flows through the condenser part of the living body, so that the current does not become an effective current for the penetration of the drug, and the current efficiency is reduced. It must be said that these methods are extremely low (see T.Ba
gnietski et al J. Control.Release, 11 (1990) 113-122
reference).

On the other hand, living skin is equivalent to a circuit in which a resistor and a capacitor are connected in parallel, and has an impedance peculiar to the living skin. In the following, the value is high. Further, this impedance has a large individual difference and changes with time.
Therefore, there is a problem that the amount of the drug to be administered varies due to a large variation in the impedance of the living skin.

In the conventional simple DC energizing method and the aforementioned depolarizing pulse energizing method, since the pH fluctuation of the electrode and the aqueous medium is large at the time of energization, the energization is switched equally between positive and negative to suppress the pH fluctuation. Method (Japanese Unexamined Patent Publication No.
70) has been proposed, but even with this method, there is a problem that the dose of the drug is not stable.

[0010] It is an object of the present invention to solve the above-mentioned problems and to provide an apparatus for iontophoresis with less variation in drug dose.

[0011]

The iontophoresis device according to the present invention has the following features. (1) At least a pair of electrode means, a power supply means, and a current switching means arranged on a living body skin, the electrode means having an electrode and an aqueous medium, and the aqueous medium electrically connecting the electrode and the living body skin The aqueous medium of at least one of the electrode means contains a drug to be administered into a living body through the outer skin of the living body, and the power supply means is capable of applying a constant current between both electrodes. An apparatus for iontophoresis, wherein the means can alternately switch the direction of the constant current.

(2) The switching frequency of the applied constant current is in the range of 1 KHz to 30 KHz, and the energization time in one direction within one cycle of energization is 55% of one cycle.
%. The apparatus for iontophoresis according to the above (1), wherein the direction of the current is switched so as to be in the range of% to 95%.

[0013]

In the device of the present invention, unlike the conventional iontophoresis device, a constant current is always applied between both electrodes by using a constant current power supply, and the direction of the applied current is alternated. Has been switched to. Therefore, regardless of the impedance of the target living body, the value of the current applied between the electrodes can be kept constant, and the dose of the drug can be stabilized.

[0014]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The apparatus of the present invention will be described below in detail with reference to the drawings. FIG. 1 is a view showing an example of an apparatus for iontophoresis according to the present invention, which comprises a pair of electrode means (3 a, 3 b) and an electric circuit section 4.
The electrode means is shown in a sectional view. In the example shown in the figure, a pair of electrode means (3a, 3b) comprises a sheet-like electrode (1a, 1b) and a sheet-like aqueous medium (2a, 2b).
b) and one of the aqueous mediums 2a
Contains drugs. The electrodes (1a, 1b) and the electric circuit section 4 are electrically connected by conductive lines.
The electric circuit section 4 has a current switching means (not shown) and a power supply means (not shown) for outputting a DC constant current. The current switching means generates a timer pulse wave voltage and reverses the polarity of both electrodes (1a, 1b) at predetermined time intervals to alternately switch the direction of the current. The electric circuit section 4 is further provided with a switch (not shown) for turning on / off the power supply means, an abnormality detection means (not shown) for ensuring safety, and a power supply stopping means (not shown). I have.

FIG. 2 is a block diagram of the electric circuit section of the apparatus of the present invention, and shows the electric circuit section 4 of the apparatus of the present invention shown in FIG. 1 in further detail. The same parts as those in FIG. 1 are denoted by the same reference numerals, and description thereof will be omitted. In the example shown in FIG. 1, the electric circuit section 4 includes a current switching unit and a power supply unit 6 as shown in FIG. 1, and the current switching unit includes a timer unit 7, an inverter 8 for inverting a timer output signal, and an inverter 8. Switching element (9
1, 92, 93, 94). Power supply means 6
The DC constant current output in the electrodes passes through the switching elements (91, 92, 93, 94) and passes through the electrodes (3a, 3a).
b) applied during. At this time, a pulse voltage generated by the timer means 7 is applied to the gate of the switching element, and the switching element (91, 92, 93, 94) applies a direction of the current flowing between the electrodes (3a, 3b) at regular intervals. Switch.

FIG. 3 is a diagram showing a current waveform and a voltage waveform between the electrodes in FIG. 2. FIG. 3 (a) shows a current waveform, and FIG. 3 (b) shows a voltage waveform. As shown in FIG. 3A, between the two electrodes, the current is supplied for T1 time from one direction, and then the current is supplied for T2 time from the opposite direction. The value of the current flowing between the two electrodes is always kept at a constant value (I). Also, as shown in FIG. 3B, the voltage fluctuates according to a change in load resistance, that is, a change in impedance of a living body.

The pair of electrode means used in the present invention may be any one that can be arranged on the outer skin of the living body and is composed of an electrode and an aqueous medium. Specifically, a material formed by laminating a sheet-like electrode and a sheet-like aqueous medium is preferable.

As the electrode, a platinum, carbon, silver / silver chloride electrode or the like can be used. Specifically, a copper foil having a surface plated with silver, a film having a surface coated with a conductive carbon paint, or the like can be used.

Examples of the aqueous medium include natural resin polysaccharides such as karaya gum, tragacanth gum, and sansan gum, partially saponified polyvinyl alcohol, polyvinyl formal, polyvinyl methyl ether and copolymers thereof, vinyl resins such as polyvinyl pyrrolidone, polyvinyl methacrylate, and polyacrylic acid. And various kinds of hydrophilic natural or synthetic resins such as acrylic resins such as sodium salts thereof, polyacrylamides and partial hydrolysates thereof, partially saponified polyacrylates, and poly (acrylic acid-acrylamide). Or ethylene glycol, soft plasticizing with alcohols such as glycerin and self-shaping,
A conductive gel in the form of a flexible sheet having skin adhesion can be used. In addition to conductive gel, water and / or ethylene may be added to paper such as water supply paper, cloth such as gauze, fiber such as absorbent cotton, synthetic resin continuous foam, sponge or porous material such as water absorbent resin, and the like. Those impregnated with alcohols such as glycol and glycerin can also be used. Among these, an aqueous medium containing water is usually used.

The power supply means may be any as long as it can supply a constant current between the electrodes, and includes a DC constant current power supply. A DC constant-current power supply is a power supply that has a very large internal impedance (ideally infinite) and can supply a constant current to it regardless of the load. Also changes. Specifically, there are a simple constant current circuit using the constant current characteristics of a transistor, a high-precision constant current circuit using an OP amplifier, and the like.

The current switching means of the device of the present invention is not particularly limited as long as it alternately switches the direction of the current applied between the two electrodes from the power supply. Specifically, the current switching means alternately switches the direction of the current by switching the switching element by applying a timer pulse wave voltage for which the energization time is set as shown in FIG. 2 to the gate of the switching element. Are preferred. It is preferable to use an FET or a transistor as the switching element. High speed switching is not possible with relay contacts, which is not suitable.

The switching frequency of the current direction in the present invention (when one cycle from the start of energization in one direction to the start of energization in the next direction is defined as one cycle)
When the frequency is increased, it is necessary to set in consideration that the energy loss required for switching increases and the output power of the circuit as viewed from the battery decreases. Therefore, in the present invention, it is preferable to set the switching frequency of the current direction in the range of 1 KHz to 30 KHz in view of such points and in consideration of economy.

In the present invention, it is preferable to switch the direction of the current so that the energization time in one direction within one cycle of the energization is 55% to 95% of one cycle.
That is, in the example of FIG. 3, one cycle is defined as T1 + T2,
1 is 55% to 95% of T1 + T2, or T
2 is preferably set to be 55% to 95% of T1 + T2. If it is 50%, it is the same as when a simple alternating current is applied, and it is not preferable because the ions cannot be moved in a specific direction only by vibrating. 100%
Then, it becomes the same as a simple DC constant current.

The timer means generates a timer pulse wave voltage, and the direction of the current is switched at every set time by applying the timer pulse wave voltage to the gate of the switching element. The inverter inverts the waveform of the timer pulse voltage. The switching element switches the direction of current by applying a timer pulse voltage to its gate, and a normally-off type p / n-type FET (field effect transistor) or a transistor can be used.

FIG. 4 is a circuit diagram of the electric circuit section 4 shown in FIG. 2, and shows current switching means and power supply means. The electric circuit section 4 includes a charge pump type voltage doubling circuit 81, a timer circuit 82, an inverter circuit 83, a simple constant current circuit 84, switching elements (91, 92, 93,
94).

As shown in FIG. 1, the apparatus of the present invention may be provided with a switch for turning on / off the power supply means, an abnormality detection means for ensuring safety, a power supply stop means, and the like, as necessary. good.

Drugs which are desired to be introduced into a living body by the device of the present invention include those which have a problem in the introduction into a living body by ordinary methods, for example, those which have no administration method other than injection, oral, nasal, transdermal, etc. Administered via routes such as the lungs but with low bioavailability, percutaneous administration is desirable but difficult to introduce with conventional ointments, creams, sprays, etc., timing of administration,
Those for which it is desired to freely control the time, dose, and the like are listed.

The above-mentioned drugs include many peptide and protein drugs. Specific examples include insulin, calcitonin, vasopressin, LH-RHTR
H, ACTH, ANF, CCK, β-endorphin,
Enkephalin, glucagon, MIF, MSH, PT
H, somatostatin, interferon and the like. These peptidic drugs are electrically neutral at each isoelectric point, but are positively charged if the pH is lower than the isoelectric point, and negatively charged if the pH is higher than the isoelectric point. It is suitable for use in an apparatus. Whether a positive or negative charge is provided depends on the pH of the aqueous medium to be contained.

It should be noted that drugs whose absorption is enhanced by iontophoresis are not necessarily limited to ionic drugs having either a positive or negative charge, and may be electrically neutral or non-charged. ing. It has been estimated that such a phenomenon is based on electroosmosis (R.
Bumetle et al, J. Pharm. Sci., 75, 738-743 (1986)). Therefore, the above-mentioned peptides need not necessarily be charged.

[0030] Drugs other than the above-mentioned peptide / protein drugs which are the objects of the present invention include many common ionic drugs. Specific examples include analgesics (eg, morphine hydrochloride, hydromorphone hydrochloride, buprenorphine hydrochloride,
Bupranolol hydrochloride), local anesthetic (eg, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, lidocaine hydrochloride, oxyprocaine hydrochloride, diethylaminoethyl parabutylaminobenzoate hydrochloride, bupivacaine hydrochloride, mepivacaine hydrochloride), antihistamines (eg, diphenhydramine hydrochloride, Carbinoxamine maleate, chlorpheniramine maleate, isotipendyl hydrochloride, clemizole hydrochloride, antibiotics (β-lactam antibiotics (eg, methicillin sodium, oxacillin sodium, cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride, hetacillin potassium) , Penicillins such as carbenicillin sodium, cephalotin sodium, cefazolin sodium, cefapirin sodium, cefatidin sodium Cephalosporins such as cephamethazol sodium and cefuroxy sodium), macrolide antibiotics such as oleandomycin phosphate, lincomycin hydrochloride, clindamycin hydrochloride, aminoglycoside antibiotics such as fradiomycin sulfate, succinic acid Chloramphenicol sodium, tetracycline hydrochloride,
Sodium fusidate), chemotherapeutic agents (eg, sodium isoniazid methanesulfonate, ethambutol hydrochloride), hypnotics and sedatives (eg, flurazepam hydrochloride), analgesics and anti-inflammatory agents (eg, diclofenac sodium, sodium salicylate, benzidamine hydrochloride, ergotamine tartrate) , Dimethothiazine mesylate), analgesics (eg, isoprenaline hydrochloride, betahistine mesylate), agents for psychiatric nerves (eg, chlorpromazine hydrochloride, imipramine hydrochloride, amitriptyline hydrochloride, mianserin hydrochloride, doxepin hydrochloride), agents for autonomic nerves (eg, odor Distigmine), antispasmodics (eg, atropine sulfate, butylscopolamine bromide, trospium chloride, pipetanate hydrochloride), antiparkinson agents (eg, biperiden hydrochloride), arrhythmia drugs (eg, propranolol hydrochloride, bufetrol hydrochloride) Indenolol hydrochloride, bucmorol hydrochloride, timolol maleate), antihypertensives (eg, clonidine hydrochloride, betanidine sulfate, prazosin hydrochloride), coronary vasodilators (eg, diltiazem hydrochloride, verapamil hydrochloride, trimetadisine hydrochloride), antitussive expectorants (examples) , Terbutaline sulfate, chlorprenaline hydrochloride, bromhexine hydrochloride, tulobuterol hydrochloride, ketotifen fumarate),
Peptic ulcer treatment (eg, glycopyrronium bromide), corticosteroids (eg, hydrocortisone sodium phosphate, dexamethasone sodium, prednisolone sodium phosphate), antineoplastic agents (eg, levamisole hydrochloride,
Bleomycin sulfate, bleomycin hydrochloride) and the like.

In the aqueous medium, in addition to the drug to be introduced into the living body through the outer skin, many salts for adjusting the pH may be added. It is not preferable to add a large amount of salts from the viewpoint of drug transport efficiency because drug ions compete with these salts. However, it may be added to secure a noise for introducing the drug.

[0032]

EXAMPLES The present invention will be specifically described below with reference to examples. Example 1 Polyacrylic acid-based hydrophilic conductive gel (Nitogel AT-2 manufactured by Nitto Denko Corporation, length 33 mm × width 33 mm × thickness 1 m)
m, 1.3 g (for the composition, see JP-B-61-42564)
Then, 0.3 g of a 33% aqueous solution of lidocaine hydrochloride was added dropwise to uniformly infiltrate the solution, and a gel having a lidocaine hydrochloride concentration of 6% was prepared and attached to one Ag electrode. In addition, the same Nitogel AT-2 as described above is attached to the other Ag electrode without inserting a drug. The electrode means obtained in this manner were respectively attached to the back of the subject, and these were connected to the electric circuit section shown in FIG. 4 by conductive wires. Further, the set values of the constant current shown in FIG. 3 are as follows: I = 10 mA, T1 = 0.21 sec / 1000, T
2 = 0.09 sec / 1000, and electricity was supplied for 5 minutes. After energization, the electrode was peeled from the back of the hand, and the anesthetic effect was examined with a cotton needle. As a result, pain was significantly reduced at the administration site on the positive electrode side impregnated with the drug.

Example 2 [Testing Apparatus] In the following Examples and Comparative Examples, a permeation test apparatus ("A" manufactured by Vangard International, Inc. NJ) shown in FIG. 5 was used.
The effect was measured in an in vitro experiment using utomatic Flow Thru Diffusion Cell Apparatus "). Note that FIG.
Is used as shown in FIG. In addition, test cell 5
The test cell 52 has an inner diameter of 6 mm.
Is joined to the main body 53 by screws.

[Test Target] A mini pig (Yucatan micropig, 5 months old, female, obtained from Nippon Charles River Co., stored at -80 ° C.) was placed on the skin 50 to be tested.
After thawing at room temperature, the fat layer was removed, and the dermis layer was sliced to adjust the skin thickness to 1.2 mm.

[Test Conditions] After setting the skin 50 between the test cell 52 and the main body 53, a 10% aqueous solution of lidocaine hydrochloride 54 was injected into the cell 52, and the Pt electrode 56a was arranged. Also, the permeate 5 flowing at the bottom of the test device 51
For No. 8, 0.9% NaCl physiological saline was used, and the flow rate was set to 2.4 cc / hour. Also, a Pt electrode 56b was arranged in the permeate. Next, at the constant current set values shown in FIG. 3, I = 1.7 mA, T1 = 0.26 sec / 1000,
T2 = 0.07 sec / 1000, average current 1 mA / cm ²
, And the power was supplied for 20 minutes. The average current was obtained from the following equation. (Equation) Average current = (T1−T2) / (T1 + T2) × I Further, the permeate discharged from the test apparatus 51 was sampled every hour, and the permeation amount of the drug solution was measured by HPLC. FIG. 6 shows the result.

Comparative Example 1 A test was performed in the same manner as in Example 2 except that a known constant-voltage power supply was used instead of the electric circuit unit 57 in FIG. FIG. 7 shows the results.

Comparative Example 2 A test was performed in the same manner as in Example 2 except that no current was applied. FIG. 8 shows the results.

[0038]

According to the device of the present invention, since the current efficiency is high and the variation of the current is small, the drug can be effectively introduced into the living body. Therefore, it is not necessary to set a voltage, and it is possible to suppress an obstacle to a living body such as irritating redness.

[Brief description of the drawings]

FIG. 1 is a diagram showing an example of an apparatus for iontophoresis of the present invention.

FIG. 2 is a block diagram showing an electric circuit unit of the device of the present invention.

FIG. 3 is a diagram showing a current waveform and a voltage waveform between electrodes of the device of the present invention.

FIG. 4 is a circuit diagram of an electric circuit unit of the device of the present invention.

FIG. 5 is a sectional view showing a transmission test apparatus.

FIG. 6 is a graph showing the results of Example 2.

FIG. 7 is a graph showing the results of Comparative Example 1.

FIG. 8 is a graph showing the results of Comparative Example 2.

[Explanation of symbols]

 1a electrode 1b electrode 2a aqueous medium 2b aqueous medium 3a electrode means 3b electrode means 4 electric circuit

Claims (2)

[Claims] 1. A pair of electrode means disposed on a living body skin,
At least a power supply means and a current switching means, the electrode means has an electrode and an aqueous medium, and the aqueous medium is for electrically connecting the electrode and the living body skin, and is connected to the aqueous medium of at least one of the electrode means. Contains a drug to be administered into a living body through a living skin, the power supply means can apply a constant current between both electrodes, and the current switching means can alternately switch the direction of the constant current. An apparatus for iontophoresis, wherein: 2. The switching frequency of the applied constant current is in the range of 1 KHz to 30 KHz, and the energization time in one direction within one cycle of energization is 55% to 9% of one cycle.
2. The apparatus for iontophoresis according to claim 1, wherein the direction of the current is switched so as to be 5%.