JPH0549702A - Iontophoresis device - Google Patents

Abstract

PURPOSE:To prevent the generation of the disease such as erythema and bulla by selecting the positive and negative polarity applied on a pair of electrodes which are set on a living body epidermis, keeping an interval, and gradually varying the electric current on the start of electric conduction and in the polarity selection. CONSTITUTION:Introduction electrodes 1 and 2 consisting of metal electrodes 11 and 21 made of platinum, etc., and aqueous medium layers 12 and 22 and a selecting means 5 are connected through lead wires 3 and 4, and a timer means 7 and an electric power source 6 are connected with the selecting means 5. The timer means 7 controls the timing for selecting the electric current of the electrodes 1 and 2 to positive and negative in a prescribed frequency according to the necessity so that pH of the aqueous medium layers 12 and 22 on the electrodes 1 and 2 is within 3-9. On the basis of the control of the timer 7, the selecting means 5 selects the positive and negative through the control so that the change in speed by the increase and reduction of electric current in selection is reduced. This control is carried out also on the start of electric condition.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an improved iontophoresis device.

More specifically, the present invention relates to a drug to be absorbed into a living body through the outer skin in both the aqueous medium connecting the pair of electrodes applied to the outer skin with a space and the outer surface of the living body. In order to keep the pH of the aqueous medium at 3 to 9 as necessary, the current is gradually increased or decreased when the polarity (positive / negative) of the current supplied to the electrodes is switched. The present invention relates to an iontophoresis device.

[0003]

2. Description of the Related Art Iontophoresis
Is also called ion permeation method and is defined as introducing an ionic or water-soluble drug into the living body through the outer skin of the body by an electric current for therapeutic purposes.

[0004] Biological integument is a living tissue that constitutes the interface between the living body and the outside world, and indicates skin, oral mucosa, etc., and is most commonly skin.

The actual mode of iontophoresis is 190
Many devices have been devised and improved since the early 0's (Praveen Yyle, “Drug Delivery Device”)
s ", 1988, Marcel Dekker Inc., P. 421-
455). However, it is basically composed of a power source, a pair of electrodes connected to the power source, and a conductive medium left between the electrodes and the outer skin of the living body.

As electrodes, ordinary platinum, carbon, silver /
A silver chloride electrode or the like is used. Further, as the conductive medium to be installed between the electrode and the outer skin, usually karaya gum,
Natural resin polysaccharides such as tragacanth gum and sansangum or partially saponified polyvinyl alcohol, polyvinyl formal, polyvinyl methyl ether and its copolymers, polyvinyl resins such as polyvinylpyrrolidone and polyvinyl methacrylate, polyacrylic acid and its sodium salt, polyacrylamide and its portion Hydrolyzate, partially saponified polyacrylic acid ester, acrylic resin such as poly (acrylic acid-acrylamide), and other hydrophilic natural or synthetic resins are treated with water and / or alcohols such as ethylene glycol and glycerin. It is provided as a soft film or sheet-like gel which is softened and plasticized and has self-shape retention and skin adhesiveness. Water and / or ethylene glycol, glycerin, etc. on conductive gel or water absorbent paper etc., cloth such as gauze, textiles such as absorbent cotton, sponge or porous material such as synthetic resin continuous foam or water absorbent resin, etc. Those impregnated with alcohols are used.
Among these, an aqueous medium containing water is usually used.

[0007]

In iontophoresis, an ionic drug is usually administered in vivo. When the drug is positively charged, the positively charged drug is contained in the conductive medium placed between the positive (positive) pole and the in vivo skin, and the repulsion between the positive and negative electrons causes the drug to be produced from the conductive medium. Administer to the body. On the other hand, when the drug is negatively charged, a negatively charged drug is contained in a conductive medium placed between the negative (negative) electrode and the in vivo skin, and the repulsion between the negative electricity causes the drug to be a conductive medium. To be administered in vivo. In this case, it is usual to install the drug on the opposite side between the conductive medium containing no drug and the outer skin.

The ionic drug has a counter ion, but the counter ion does not usually have a pharmacological effect such as Na ion and Cl ion. Therefore, the polarity of the ionic drug is pharmacological. It means the polarity of the part having an effect. In any case, a closed circuit is formed with a power source-positive (positive) electrode-conductive medium-living body skin-living body-living body skin-conducting medium-negative (negative) electrode- (power source), and a current flows. The electric current causes the drug to be absorbed into the living body from the drug-containing conductive medium.

However, due to the current flow in this manner, there are cases in which erythema, blisters, and other disorders occur on the outer skin of the living body. (1) Electrolysis occurs between the electrode and the aqueous medium, and the pH of the aqueous medium tends to be acidic on the positive electrode side and alkaline on the negative electrode side.
(2) It may be due to electric polarization in the outer skin of the living body.

[0010]

As a result of intensive studies to solve the above problems, the inventors of the present invention gradually increased and decreased the current when the polarity (positive / negative) of the current supplied to the electrodes was appropriately switched. It was found that an improved iontophoresis device that is less likely to cause skin damage can be obtained by carrying out the above method, and thus reached the present invention.

That is, the present invention is an iontophoresis device having a pair of electrode means applied to the outer skin of the living body at intervals, wherein the positive and negative currents applied between both electrodes are alternated. An iontophoresis device characterized in that it is provided with a switching means for switching to current, and a current adjusting means for gradually changing the current at the time of starting the energization of the current and switching between positive and negative polarities. is there.

According to the present invention, the current adjusting means is
An iontophoresis device that changes the current in the range of 0.1 to 0.6 mA / min is included. Furthermore, both of the pair of electrode means are provided with an aqueous medium for electrically connecting the in vivo skin and the electrode, and the aqueous medium contains a drug to be absorbed into the living body through the in vivo skin. A device for iontophoresis, which is characterized by being densified, is included.

The present invention includes an iontophoresis device in which the voltage adjusting means maintains the pH of the aqueous solution in the aqueous medium at both electrode means at 3 to 9.

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. In the figure,
Reference numerals 1 and 2 are introduction electrodes, and aqueous medium layers 12 and 22 each containing a drug to be absorbed by a living body are laminated on metal electrodes 11 and 21 such as platinum and aluminum.
Reference numerals 3 and 4 represent lead wires. 6 is a power supply means,
For example, it means a DC direct current power source that can be set to a current of 0.1 mA / cm ² . Reference numeral 7 is a timer means, and the aqueous medium layers 12 and 22 containing the drug in the electrodes 1 and 2
The positive / negative switching timing of the currents of both electrodes 1 and 2 is controlled at a predetermined frequency as needed so that the pH of the electrodes is within the range of 3 to 9, and more preferably within the range of 5 to 8. It is for doing. 5 is connected to the timer means 7 and has a function as a switching means for switching the positive and negative currents of both electrodes 1 and 2, and at the same time, for decreasing the speed of rising and falling of the current at the time of switching. It also has a function as a current adjusting means. In addition, it is preferable that 5 has a function of gradually increasing the current value not only when the positive / negative current is switched but also when the first energization is started.

As a characteristic of the present invention, any current adjusting means for gradually increasing / decreasing the current at the time of starting energization of the current and at the time of switching between positive and negative currents can be used as long as it achieves the intended function. May be

Specific examples thereof include automatic output adjusting means such as analog switches, programmable variable resistors, multipliers and integrators. A practically preferable one is a variable gain amplifier circuit using an analog switch.

Further, in this case, "gradually" cannot be unconditionally defined because it changes depending on the magnitude of the applied voltage, the impedance of the living body, the polarity switching time and the like.

However, it is usually desirable to use a DC direct current of 0.1 to 1.0 mA while switching the polarity at intervals of 5 to 30 minutes.
A speed of 0.6 mA / min is desirable.

The power supply means in the present invention may be any DC constant current power supply such as a small battery or a DC pulse generator as long as it can generate a current.

In the present invention, the voltage may be continuously applied during one period until the electric polarities of both electrodes 1 and 2 are switched, or intermittently if the electric polarities are the same. Good. That is, the current flowing through the closed circuit may be a DC direct current or a DC pulse.
The depolarization mechanism may also be activated at the end of the pulse.

The DC direct current referred to in the present invention is
A DC pulse wave voltage means a state in which one electrode is supplied with a substantially constant current for a predetermined time, and one electrode has a pulse shape with the same polarity (positive / negative) for a predetermined time. It means a state in which a current is applied.

Comparing the DC direct current and the DC pulse, the DC direct current is preferable from the viewpoints of drug transport efficiency and circuit simplicity. That is, when apparently the same current flows, the DC direct current most effectively permeates the drug through the outer skin. In addition, the circuit design is easier than the pulse design.
Therefore, it is a desirable aspect of the present invention to supply a direct current of a direct current to the electrodes and change the polarity as appropriate.

On the other hand, in the DC pulse, useless current is generated as the frequency increases. This phenomenon is continuous with the frequency, and it is difficult to determine the maximum allowable pulse frequency that can be used in the present invention, but it can be set to 5 KHz or less in consideration of economical efficiency. Therefore, for example, 5
It is also an aspect of the present invention to supply a DC pulse voltage of not more than KHz and not less than 1 Hz to the electrodes and appropriately change the polarity thereof.

The aqueous medium referred to in the present invention may be any as long as it contains water or an aqueous solution and can be energized. Specific examples thereof include the above-mentioned electrically conductive medium containing water.

As a drug which is desired to be introduced into a living body by iontophoresis, a drug which has a problem of being introduced into a living body by a usual method, for example, there is no administration method other than injection, oral, nasal, transpulmonary, etc. , Which has low bioavailability, but which is difficult to introduce with conventional ointments, creams, sprays, etc., control of timing, time, dose etc. Some things that are desired to be done are listed.

As such drugs, many peptides
Examples include protein drugs. Specific examples include insulin, calcitonin, vasopressin, LH-RH, TR
H, ACTH, ANF, CCK, β-endorphin,
Enkephalin, glucagon, MIF, MSH, PT
H, somatostatin, interferon and the like. These peptidic drugs are electrically neutral at their respective isoelectric points, 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, and are subject to iontophoresis. Is suitable as Whether to have positive or negative charge depends on the pH of the aqueous medium to be contained.

It is known that a drug whose absorption is enhanced by iontophoresis is not limited to an ionic drug having a positive or negative charge, and may be electrically neutral or uncharged. It is estimated that such a phenomenon is based on electroosmosis (R. Burnette
et al, J. Pharm. Sci., 75, 738-743 (1986)).

Therefore, the above peptides do not necessarily have to be charged. As for the drugs targeted for iontophoresis other than peptide / protein drugs, most of them are ionic drugs.

Specific examples include analgesics (eg, morphine hydrochloride, hydromorphone hydrochloride, buprenorphine hydrochloride,
Bupranolol hydrochloride), local anesthetics (eg tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, lidocaine hydrochloride, oxyprocaine hydrochloride, diethylaminoethyl parabutylaminobenzoate hydrochloride, pupivacaine hydrochloride, mepivacaine hydrochloride), antihistamines (eg diphenhydramine hydrochloride) Carbinoxamine maleate, chlorpheniramine maleate, isopentidyl hydrochloride, clemizole hydrochloride), antibiotics (β-lactam antibiotics (eg, methicillin sodium, oxacillin sodium, cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride, hetacillin potassium), Penicillins such as carpenicillin sodium, cephalothin sodium, cefazolin sodium, cefapirine sodium, cefotidin sodium , Cefamethazole sodium, cefuroxysporin such as cefuroxysodium), oleandomycin phosphate, lincomycin hydrochloride, clindamycin hydrochloride and other macrolide antibiotics, fradiomycin sulfate and other aminoglycoside antibiotics, amber Chloramphenicol sodium salt, tetracycline hydrochloride, sodium fusidate), chemotherapeutic agents (eg, isoniazid sodium methanesulfonate, ethambutol hydrochloride), hypnotics / sedatives (eg, flurazepam hydrochloride), anti-inflammatory agents (eg, diclofenac sodium) , Sodium salicylate, benzydamine hydrochloride, ergotamine tartrate, dimethothiazine mesylate), depressants (eg, isoprenaline hydrochloride, betahistine mesylate), psychiatric agents (eg, chlorpromazine hydrochloride, imipu hydrochloride) Ramin, amitributyrin hydrochloride, mianserin hydrochloride, doxepin hydrochloride), agents for autonomic nerves (eg, distigmine bromide), antispasmodics (eg, atropine sulfate, butylscopolamine bromide, trospium chloride, pipetanate hydrochloride), anti-Parkinson agents (eg, hydrochloric acid) Piperiden), antiarrhythmic agent (eg, propranolol hydrochloride, bufetrol hydrochloride, indenolol hydrochloride, bucromol hydrochloride, timolol melenate), antihypertensive agent (eg, clonidine hydrochloride, petanidine sulfate, prazosin hydrochloride), coronary vasodilator (eg.) , Diltiazem hydrochloride, verapamil hydrochloride, trimetadisine hydrochloride), antitussive expectorant (eg, tylbutaline sulfate, chlorprenaline hydrochloride, bromhexine hydrochloride, turobutyrol hydrochloride, ketotifen fumarate), peptic ulcer treatment (eg, glycopyrronium bromide) , Adrenal g Mont agents (e.g., sodium phosphate, hydrocortisone, dextranase shark Chizon sodium, prednisolone sodium phosphate), antineoplastic agents (e.g., hydrochloric Repamizoru, sulfuric bleomycin, hydrochloric bleomycin), and the like.

The pair of aqueous media may contain the same drug in both, or may contain different drugs in each. It is essential that at least one of the drugs is contained in the aqueous medium on either side of the poles. For example, in the case of one kind of drug, regardless of whether the existing drug is a positive ion or a negative ion, it is always introduced into the living body from either side by switching the polarity. There are two types of drugs,
Further, even when the charges are the same, when the charge of the drug and the polarity of the electrode are the same by switching the polarities, either one of the two kinds is introduced into the living body from either side. Even when the charge of the drug and the polarity of the electrode are different, it can be introduced into the living body by electroosmosis. When there are two types of drugs and their charges are different, when each charge and the polarity of the electrode match, each drug is introduced into the living body from each pole by electrical repulsion, and the charge and the electrode When the polarities are different from each other, each drug can be introduced into the living body from each electrode by electroosmosis.

In addition to the drug to be introduced into the living body through these outer coats, many salts for adjusting pH can be added to the aqueous medium. Addition of a large amount of salts is not preferable from the viewpoint of drug transport efficiency because drug ions compete with these salts. However, it may be added to ensure the driving force for introducing the drug.

In the present invention, the polarity (positive / negative) of the voltage supplied to the electrodes can be appropriately switched in order to keep the pH of the aqueous medium at 3 to 9, preferably 5 to 8, and in this case, "appropriately". Since the pH changes depending on the pH of the aqueous medium at the start, the amount of current, the coexisting salt concentration, etc., it cannot be unconditionally defined. It is necessary to apply electricity in one direction under given conditions, observe the change in pH, and then reverse the positive and negative at appropriate intervals. Usually, when a direct current of 0.1 to 0.5 mA is applied, the pH of 0.02 M citrate buffer, which is an aqueous medium, is
It would be a rough guideline that the time required to move 1 is about 60 minutes. It is preferable that the switching of the polarity is performed once every 1 to 120 minutes, especially 5 to 60 minutes. Switching is normally operated by a switch mechanism linked with a timer. This method is general and ordinary mechanisms can be used. Hereinafter, the present invention will be specifically illustrated by examples, but the present invention is not limited thereto.

[0034]

Example 1 In order to investigate the influence of the iontophoresis device of the present invention on the skin during energization, the iontophoresis device of the present invention as shown in FIG. 1 was applied to hairless rats.

That is, ADVANTES is used as a DC power source.
TR 6145 and platinum plate (5 x 5 m
m ^2, thickness 0.6 mm) incorporating cells (1.1cmφ ×
1.0 cm) was used. This cell was placed on the abdomen of a hairless rat anesthetized with urethane at two locations with a distance of 1 cm between
Each cell was filled with saline.

The platinum plate of the cell and the power source are connected to each other, and a maximum of 0.
The electric current was applied at 1 mA / cm ² , the polarity was gradually switched at a speed of 0.1 mA / min every 20 minutes, and the skin condition after a certain period of time was evaluated according to the criteria for erythema and blisters shown in Table 1. In addition, as a control example 1, when a current of 0.1 mA / cm ² was applied without switching the polarity, as a control example 2, 0.1 mA / cm ² was applied.
The same evaluation as in Example 1 was performed for each case in which the polarity was instantaneously switched at 20 cm / cm ² and electricity was applied. The results are shown in Table 2.

[0037]

[Table 1]

[0038]

[Table 2]

[0039]

Example 2 The effect on human skin when the iontophoresis device of the present invention was applied to human skin was examined.

That is, ADVANTE is used as the DC power source.
STR6145 was used, and a cup (3 cmφ × 0.5 cm) equipped with a platinum plate was used as an electrode. The cups were attached to the human forearm at two places with a distance of 1 cm, and each cup was filled with physiological saline.

Connect the platinum plate of the cup and the power supply to
Energize at a current of mA / cm ² and gradually switch the polarity at a rate of 0.2 mA / min every 5 minutes to change the skin condition after a certain time.
As in Example 1, evaluation was made according to the criteria shown in Table 1.

In Comparative Example 3, the current was applied at 0.1 mA / cm ² without switching the polarity, and as Comparative Example 4, the instantaneous polarity was switched every 5 minutes and the current was applied. The skin condition was evaluated.

Further, regarding Example 2 and Comparative Example 4,
The presence or absence of skin irritation during polarity switching was examined. The respective results are shown in Tables 3 and 4.

[0044]

[Table 3]

[0045]

[Table 4]

[0046]

Example 3 To examine the skin permeability of a drug by the device of the present invention, i.
An in vitro permeation experiment was performed.

That is, using the permeation apparatus using the three layers of cells made of the acrylic plate 30 shown in FIG. 2, the excised skins 33, 3 of the hairless rat are used between the cells AB and between the cells BC.
4 was placed so that the epidermis side of the skin faces each cell A, C side and the back side of the skin faces the cell B side. Reference numerals 31 and 32 indicate electrodes. Further, each cell A, C was treated with 10 mg / ml dexamethasone sodium phosphate, and cell B was 0.045%.
Each was filled with aqueous NaCl solution. The electrode on the side of cell A is the positive electrode, the electrode on the side of cell B is the negative electrode, and the power supply (ADVANT
EST R6145).

Electric current was applied at 0.1 mA / cm ² for 4 hours at a rate of 0.1 mA / min every 20 minutes while gradually switching the polarity.

After a certain period of time, 50 μl of the sample was sampled from the cell B and the concentration of dexamethasone sodium phosphate was measured by HPLC.

Further, as a control example 5, electricity was applied at 0.1 mA / cm ² for 4 hours without switching the polarity, and the concentration of dexamethasone sodium phosphate was measured in the same manner as in Example 3. Further, as a control example 6, electricity was applied for 4 hours while instantaneously switching the polarity every 20 minutes at 0.1 mA / cm ² , and the concentration of dexamethasone sodium phosphate in cell B was measured in the same manner as in Example 3. The results are shown in Table 5. Tables 6 and 7 show the condition of the skin after the experiment and the pH changes of the aqueous solutions in cells A and C, respectively.

[0051]

[Table 5]

[0052]

[Table 6]

[0053]

[Table 7]

[0054]

Example 4 Hairless rats (male, 8 weeks old 230-260) were used to examine the skin permeability of the drug by the device of the present invention.
An in vivo permeation experiment was performed using g).

That is, ADVANTES is used as a DC power source.
An acrylic cell (1.1 cmφ) in which TR 6145 was incorporated with a platinum plate (5 × 5 mm ² , thickness 0.6 mm) as an electrode.
× 1.0 cm) was used. This cell was placed on the abdomen of a hairless rat anesthetized with urethane at two locations with a distance of 1 cm. Each cell was filled with 10 mg / ml aqueous solution of sodium benzoate containing 370 KBq / ml of sodium benzoate labeled with 14C.

The platinum plate of the cell was connected to a power source, and
The current was applied at A / cm ² for 4 hours at a rate of 0.1 mA / min every 20 minutes while gradually switching the polarity. After a certain period of time, 200 μl of blood was collected from the jugular vein of the rat, and the sodium benzoate concentration in plasma was measured by a liquid scintillation counter (Beckman LS-3801).

Further, as a control example 7, electricity was applied at 0.1 mA / cm ² for 4 hours without switching the polarity, and the blood sodium benzoate concentration was measured as in the case of Example 4. The results are shown in Fig. 3.

[0058]

According to the present invention, it is possible to provide an improved iontophoresis device which prevents the occurrence of disorders such as blisters on the skin during treatment. In particular, the device of the present invention in which the drug is present in both electrode means is excellent in that it can prevent extreme fluctuations in the pH of the aqueous medium, ensure good absorption of the drug in the living body, and suppress damage to the skin. The effect is obtained.

[Brief description of drawings]

FIG. 1 is a schematic illustration of an iontophoresis device of the present invention.

FIG. 2 is a schematic cross-sectional view of a permeation cell device for examining skin permeability by iontophoresis.

FIG. 3 shows an example of changes over time in the concentration of sodium benzoate in blood in an evaluation system using hairless rats in vivo.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiki Suzuki 4-3-2 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (4)

[Claims] 1. An iontophoresis device having a pair of electrode means applied to the outer skin of a living body at intervals, for alternately switching positive and negative of a current applied between both electrodes. The iontophoresis device characterized in that it is provided with a switching means for controlling the current, and a current adjusting means for gradually changing the current at the time of starting the energization of the current and switching between positive and negative polarities. 2. The current adjusting means is 0.1 to 0.6 mA.
2. The current is changed within the range of 1 / min.
Iontophoresis device. 3. Both of the pair of electrode means are provided with an aqueous medium for electrically connecting the in vivo skin and the electrodes, and the aqueous medium is intended to be absorbed into the living body through the in vivo skin. The device for iontophoresis according to claim 1, wherein the device contains a drug. 4. The apparatus for iontophoresis according to claim 3, wherein said switching means is adapted to maintain the pH of the aqueous solution in the aqueous medium in both electrode means at 3 to 9.