JPH04224770A - Apparatus for iontophoresis - Google Patents

Abstract

PURPOSE:To provide an apparatus to resolve a limited absorption rate and absorption level of medicine and extreme change in pH of aqueous media contacting a vital integument in iontophoresis. CONSTITUTION:In an apparatus for iontophoresis which has a pair of electrode means 1 and 2 to be applied to a vital integument at an interval, the pair of the electrode means 1 and 2 both include aqueous media 12 and 22 to keep electrodes in electric contact with the surface of the vital integument while a medicine is contained in the aqueous media to cause absorption into an organism through the vital integument. A voltage adjusting means 4 is included to switch positive and negative positions of a voltage to be applied between both the electrodes alternately.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to an improved apparatus for iontophoresis.

[0002] More specifically, the present invention discloses a drug to be absorbed into a living body through the living skin, into an aqueous medium connecting a pair of electrodes applied at intervals to the living skin and an aqueous medium connecting the living skin. It relates to an iontophoresis device in which the polarity (positive/negative) of the voltage supplied to the electrodes is appropriately switched in order to maintain the pH of the aqueous medium at 3 to 9 as necessary.

0003

[Prior art] Iontophoresis
Oresis) is also called iontophoresis and is defined as the introduction of ionic or water-soluble drugs into a living body through the outer skin of the living body using an electric current for therapeutic purposes.

[0004] The integument of a living body is a living tissue that constitutes the interface between the living body and the outside world, and includes the skin, oral mucous membrane, etc., and is most commonly the skin.

[0005] The history of ionphoresis dates back to 1900.
It has been known since the early 1990s that many drugs can be administered to living organisms by iontophoresis (Dru
g Delivery Devices” 1988, Marcel Dekker, Inc. Published p421~
(See page 454).

[0006] In recent years, iontophoresis has received attention due to the fact that the skin has attracted attention as a site for systemic administration of drugs, and advances in electronics have led to miniaturization of devices for supplying and controlling current. It has been extensively researched and is seen as a promising method for administering peptide and protein drugs, which have been newly discovered or made mass-producible through the development of biotechnology.

[0007] The actual aspects of iontophoresis are 19
Since the early 2000s, many innovations and improvements have been made to the device, and it is diverse (see “Dru
g Delivery Devices, supra). However, it basically consists of a power source, a pair of electrodes connected to it, and a conductive medium placed between the electrodes and the skin of the living body.

[0008] Also, as an electrode, ordinary platinum, carbon,
A silver/silver chloride electrode or the like is used. In addition, the conductive medium placed between the electrode and the body skin is usually a natural resin polysaccharide such as karaya gum, tragacanth gum, or sunsan gum, or partially saponified polyvinyl alcohol, polyvinyl formal, polyvinyl methyl ether and its copolymer, or polyvinylpyrrolidone. , vinyl resins such as polyvinyl methacrylate, polyacrylic acid and its sodium salt, polyacrylamide and its partially hydrolyzed products, partially saponified polyacrylic esters, poly(acrylic acid-
Various hydrophilic natural or synthetic resins such as acrylic resins such as acrylamide) are softened and plasticized with water and/or alcohols such as ethylene glycol and glycerin to produce flexible films that have self-shape retention and skin adhesion. Supplied as a gel sheet. Water and/or ethylene glycol, glycerin, etc. may be applied to conductive gel or water-filling paper, etc., gauze, etc., absorbent cotton, etc., to sponges or porous materials, etc. A material impregnated with alcohol is used. Among these, an aqueous medium containing water is usually used.

[0009]

Problems to be Solved by the Invention In iontophoresis, an ionic drug is usually administered into a living body. When the drug is positively charged, the positively charged drug is contained in a conductive medium placed between the positive (anode) electrode and the outer skin of the body, and the repulsion between the positive charges makes the drug conductive. Administer in vivo from a vehicle. On the other hand, if the drug is negatively charged, the negatively charged drug is contained in a conductive medium placed between the negative (cathode) electrode and the outer skin of the body, and the drug is absorbed by the repulsion between the negative electricity. Administer in vivo through a conductive medium. At this time, the counter electrode is usually placed between the conductive medium containing no drug and the outer skin of the living body.

[0010] Although ionic drugs have counter ions, counter ions usually have no pharmacological effects, such as Na ions and Cl ions, so the polarity of the ionic drugs mentioned above does not mean pharmacological effects. It means the polarity of the part that has the effect. In either case, power source - positive (anode) electrode - conductive medium -
Biological skin - Living body - Biological skin - Conductive medium - Negative (cathode) electrode -
(power source) and a closed circuit is formed to flow a current, and this current causes the drug to be absorbed into the living body from the drug-containing conductive medium.

When an electric current flows between the electrode and the aqueous medium, electrolysis of water occurs, and the following reaction (chemical reaction 1) occurs at both the positive and negative electrodes.
) progresses.

0012

embedded image As a result, hydrogen ions (H+) are generated on the positive electrode side, and hydroxide ions (OH−) are generated on the negative electrode side. These ions are more mobile than other ions and can quickly move away from the electrode, through the aqueous medium, and into the patient's integument, such as the skin, causing the pH to become significantly higher or significantly higher as the energization time increases. A low area forms near the skin.

[0013] The pH of the skin surface layer is usually 4.5 to 6.5.
Although it is said to be weakly acidic, it is known that the pH that causes irreversible damage to the skin is pH<3 or pH>9 (A.C. Allenby et al.
, Br. J. Dermatul. (1969), 81
, Supplement, 4, 31).

When applying iontophoresis to living organisms, depending on the salt concentration in the aqueous medium, the type of salt, etc., the pH of the aqueous medium can easily rise or fall to an extreme range of pH<3 or pH>9. sell.

[0015] This aqueous medium having an extreme pH range is the cause of skin burns, redness, and other disorders. Conventionally, several methods have been devised to overcome this skin damage that is difficult to avoid with iontophoresis using an aqueous medium. (1) Time limit for applying ionphoresis The pH should be within the range (pH 3 to 9) that does not cause irreversible damage to the skin.
In order to suppress H, it is sufficient to limit the time during which iontophoresis is applied to the skin. However, since the rate of change in pH varies depending on the amount of current, and the amount of current varies greatly depending on the drug, skin condition, etc., it is actually extremely difficult to set an appropriate time limit. Also, since time is limited, there is a limit to the amount of absorption. (2) Use of buffer solution It is easy to think of using a buffer solution to suppress changes in pH, but ions at high concentrations in buffer solutions are generally small and have good mobility (for example, phosphate ions). , sodium ions, etc.) compete with drug ions to be introduced into the living body (skin), resulting in a decrease in the absorption rate and amount of the drug. (3) Method using a flowing electrode (Japanese Patent Application Laid-Open No. 1-97474
) According to this method, the aqueous solution containing the drug is introduced and expelled without being able to withstand the drug content, so H+ or OH- generated during iontophoresis is constantly removed. However, in this method, it is necessary to keep the drug-containing aqueous solution flowing, which requires complicated equipment and is not easy.

[0016]Therefore, there is a need for a simple and effective method for maintaining the pH of an aqueous medium in contact with the integument (skin) of a living body in an appropriate range (pH=3 to 9).

On the other hand, in conventional iontophoresis, when electricity is passed through the outer skin of a living body, polarization occurs in the living body, which results in damage to the living body (irritative redness, etc.), and also reduces the effectiveness necessary for drug transport. It is also widely accepted that the current decreases and drugs cannot be effectively introduced into the body. To deal with this, there is a method of applying current as a high-frequency pulse wave, and a method of actively discharging (depolarizing) by providing a short circuit in addition to a high-frequency pulse wave before the end of the unit pulse (Japanese Patent Application Laid-Open No. 1988-60). -15647
5, 60-188176, etc.), or by periodically interrupting the positive direct current flowing through the living body from one electrode to the other, and simultaneously applying short-duration current pulses from the other electrode to one electrode through the living body. Method of flowing in the opposite direction at predetermined time intervals (Japanese Patent Application Laid-Open No. 62-26789)
etc. have been devised. However, although the apparent current value increases with high frequency, most of the current flows through the capacitors of the living body, so it is not effective for drug penetration, and these methods are said to be extremely low in terms of current efficiency. I have no choice but to (see T. Bagnietski for details)
et al J. Control. Release
, 11 (1990) 113-122).

Therefore, the drawbacks of conventional iontophoresis are: (1) the absorption rate and amount of the drug are low; and (2) the pH of the aqueous medium that comes into contact with the outer skin of the living body fluctuates extremely.
It is hoped that this point will be resolved.

[0019]

[Means for Solving the Problems] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have found that each aqueous medium connects a pair of electrodes applied at intervals to the skin of a living body and the skin surface. By containing the drug to be introduced through the outer skin and appropriately switching the polarity (positive/negative) of the voltage supplied to the electrodes, extreme fluctuations in the pH of the aqueous medium can be prevented and continuous By allowing the drug to be absorbed into the body and further depolarizing the skin, the absorption rate of the drug into the body can be increased.
We have discovered an iontophoresis device that can also increase the amount of absorption, and have arrived at the present invention.

That is, the present invention is an iontophoresis device having a pair of electrode means applied to the outer skin of a living body at a distance, and in both of the pair of electrode means, the electrode and the outer skin surface of the living body are connected to each other. an aqueous medium for electrically connecting the organ, and a drug to be absorbed into the living body through the outer skin of the living body is contained in the aqueous medium;
The present invention also relates to an iontophoresis device comprising voltage adjusting means for alternately switching between positive and negative voltages applied between both electrodes.

[0021] According to the present invention, the voltage adjusting means adjusts the pH of the aqueous solution in the aqueous medium in both electrode means to 3 to 3.
Includes an iontophoresis device to maintain the temperature at 9.

The present invention further provides an iontophoresis device in which the voltage applied between both electrodes is a DC/DC voltage, and the voltage applied between both electrodes has a frequency of 1 Hz to 5 KHz. Includes devices for iontophoresis where the DC pulse wave voltage is in the range of .

[0023] The present invention will be explained in detail below, using the drawings as necessary.

FIG. 1 schematically shows a specific example of the iontophoresis apparatus of the present invention. In the same figure,
Reference numerals 1 and 2 denote introduction electrodes A and B, in which metal electrodes 11 and 21 made of gold, aluminum, etc. are laminated with aqueous medium layers 12 and 22 containing a drug to be absorbed into the living body. 3 and 5 indicate lead wires. Note that these are schematically shown in cross-sectional views. Reference numeral 4 indicates an electric circuit section as a voltage adjustment means, and as necessary, power supply means such as a DC constant current power source such as a small battery or a DC pulse generator, a switch means for turning the power on and off, and a predetermined Equipped with voltage control means for generating DC DC voltage or DC pulse wave voltage and reversing the positive and negative sides of both electrodes at predetermined intervals, as well as current limiting resistance means for ensuring safety to prevent overcurrent. has been done. The aqueous medium referred to in the present invention may be any medium as long as it contains water or an aqueous solution, can conduct electricity, and can be used as an electrode.

FIG. 2 shows a more detailed example of the electric circuit section 4 in the iontophoresis apparatus of the present invention shown in FIG. That is, 6 in FIG. 2 is a power supply means, 7 is a timer means,
Reference numeral 8 designates a switching means that works in conjunction with the timer means 7 to alternately switch between positive and negative voltages applied to each of the introduction electrodes A and B at a predetermined period.

[0026] By switching the polarity (positive/negative) of the voltage supplied to the electrode, the pH of the aqueous medium in contact with the biological skin can be adjusted.
The reason for not allowing extreme changes in is understood as follows. That is, it is now assumed that one electrode A is connected to the positive (anode) pole and the other electrode B is connected to the negative (cathode) pole. On the positive side

[0027]

[Chemical formula 2] The reaction shown by formula (1) occurs, and the aqueous medium is O
It becomes acidic quickly due to the loss of H-. On the other hand, on the negative side

[0028]

[Chemical 3] A reaction shown by the formula (2) occurs, and the aqueous medium is H
It quickly becomes alkaline due to the loss of +. If this state continues, a rapid decrease in pH will be observed on the positive electrode side, and a rapid increase in pH will be observed on the negative electrode side. However, when the polarity of the applied voltage is switched, the reaction of equation (1) will occur on the positive electrode side. Instead, the reaction of formula (2) occurs, and on the negative electrode side, instead of the reaction of formula (2), the reaction of formula (1) occurs, and the pH of the aqueous medium moves in the opposite direction. . By repeating the polarity switching again, the pH of the aqueous medium can be maintained within a range that does not irritate the skin. In this way, it became possible to perform iontophoresis without drastically changing the pH of the aqueous medium.

On the other hand, it can be understood as follows that by switching the polarity of the voltage supplied to the electrodes, the rate and amount of absorption of the drug into the living body increases. That is, according to the present invention, the drug is contained in both the aqueous medium that connects the outer skin surface and a pair of electrodes that are applied at intervals to the outer skin of the living body. Now, let us consider the case where the part of the drug that exhibits pharmacological activity is positively charged (that is, the drug is a positive ion). Assume that one of the pair of aqueous media is correctly connected to the negative electrode, and the other is connected to the negative electrode. At this time, positively charged pharmacologically active moieties, ie, drug ions, present in the aqueous medium connected to the positive electrode are introduced into the body through the body's outer skin by electrophoresis. At this time, the positively charged pharmacologically active moieties in the aqueous medium connected to the negative electrode, i.e. drug ions, are not introduced into the body through the biological envelope (if the pharmacologically active moiety of the drug is negatively charged ( i.e. the drug is a negative ion), a negatively charged pharmacologically active moiety is present in an aqueous medium connected to a negative electrode, i.e. a drug ion is introduced into the body through the biological envelope and is present in an aqueous medium connected to a positive electrode. It is easily understood that drug ions are difficult to introduce into living organisms). Now, let's consider the case where the polarities of both poles are switched. At this time, the repulsion of the polarity between the drug ion and the electrode disappears at the electrode (the positive electrode when the above-mentioned drug is a positive ion), where drug ions were introduced into the living body through the outer skin of the living body, and the drug While it becomes difficult for the ions to be introduced, polar repulsion occurs between the drug ions and the electrode at the electrode where it was previously difficult to introduce the drug (the negative electrode when the drug is a negative ion), and the drug ions are transferred into the living body through the outer skin of the living body. It will be introduced in That is, in this device, since the drug is contained in both aqueous media, even if the polarity of the electrode is switched, the drug will always be introduced into the living body from one of the aqueous media through the outer skin of the living body.

[0030] Furthermore, when electricity is passed through the outer skin of a living body, polarization occurs in the living body, resulting in damage to the living body (irritancy, redness, etc.).
It has already been mentioned that the effective current required to transport the drug decreases as this occurs, and both the absorption rate and amount of the drug into the living body decrease.However, according to the present invention, by switching the polarity of the electrode, The polarization that occurs in the living body is eliminated, and as a result, the effective current necessary for introducing the drug into the living body is secured, and the rate and amount of absorption into the living body are increased. It is extremely important for the drug contained in the medium to be continuously introduced into the body through the outer skin of the body in order to improve the absorbability of the drug.

[0031] Now, in the present invention, a drug to be introduced through the integument is contained in an aqueous medium connecting a pair of electrodes applied to the integument of a living body at intervals and the integument surface, and the pH of the aqueous medium is This is an iontophoresis device characterized by appropriately switching the polarity (positive or negative) of the voltage supplied to the electrodes in order to keep the voltage between 3 and 9. It is characterized by two points: it simultaneously switches the polarity and maintains the pH of the aqueous medium between 3 and 9. It is novel that both of a pair of aqueous media must contain a drug.

[0032] A pair of aqueous media may both contain the same drug, or may each contain different drugs. It is essential that the aqueous medium on either pole side always contains at least one kind of drug. For example, when there is only one type of drug, whether the drug is a positive ion or a negative ion, it is always introduced into the body from one side by switching the polarity. Even if there are two types of drugs and their charges are the same, if the drug's charge and the electrode polarity are the same by switching the polarity, one of the two types will be released from either side. Introduced into the body. Even when the charge of the drug and the polarity of the electrode are different, it can be introduced into the body by electroosmosis. When there are two types of drugs and their charges are different, when each charge matches the polarity of the electrode, each drug is introduced into the body from each pole due to electrical repulsion, and the charges and electrodes are different. When the polarities of the two electrodes are different from each other, each drug can be introduced into the living body from each electrode by electroosmosis.

[0033] If one of the aqueous media does not contain a drug, the drug will be introduced from the drug-containing aqueous medium side regardless of polarity switching, but the drug will be introduced from the drug-free aqueous medium side. Needless to say, no drugs were introduced. Therefore, in terms of drug introduction efficiency, it is clear that this invention is inferior to the present invention in which drugs are contained in both aqueous media.

Furthermore, the pH of the aqueous medium can be adjusted to 3 by changing the polarity.
Regarding the feature of maintaining the pH between 3 and 9, the idea of switching the polarity to maintain the pH within the range of 3 to 9 is new and has never been devised before. Tokukai Showa 6
2-139672 and Japanese Patent Application Laid-Open No. 62-159661 disclose a treatment device for positive and negative iontophoresis and a low frequency treatment device for introducing both positive and negative ions, which iontophores the entire drug consisting of positive and negative ions by switching the polarity. However, these cases differ from the present invention in that the drug is contained in one of the electrodes and the drug is not contained in the other electrode.

[0035] In this way, a drug is contained in both of a pair of aqueous media, and the polarity is switched to adjust the pH of both aqueous media.
It is completely novel to keep the value between 3 and 9, more preferably between 5 and 8, as it overcomes the drawbacks of conventional iontophoresis.

[0036] According to the present invention, the aqueous medium that connects a pair of electrodes applied to the integument of a living body at intervals and the integument surface both contain the drug to be introduced through the integument, and the aqueous medium pH of 3-9, preferably 5-9
The present invention includes an iontophoresis device characterized in that the polarity (positive/negative) of the voltage supplied to the electrodes is appropriately switched in order to maintain the polarity of the voltage.

[0037] Drugs that are desired to be introduced into the body by iontophoresis include drugs that have problems in being introduced into the body by normal methods, such as those for which there is no other method of administration other than injection, orally, nasally, or pulmonaryly. etc., but have low bioavailability; transdermal administration is desired but it is difficult to introduce with conventional ointments, creams, sprays, etc.; There are things that are desirable to control.

[0038] As such drugs, many peptides and
Examples include protein drugs. Specific examples include insulin, calcitonin, vasopressin, LH-RHTRH,
Examples include ACTH, ANF, CCK, β-endorphin, enkephalin, glucagon, MIF, MSH, PTH, somatostatin, and interferon. These peptide drugs are electrically neutral at their respective isoelectric points, but they become positively charged when the pH is lower than the isoelectric point, and negatively charged when the pH is higher than the isoelectric point, resulting in iontophoresis. Suitable as a target. Whether it is positively or negatively charged depends on the pH of the aqueous medium in which it is contained.

[0039] It is known that drugs whose absorption is enhanced by iontophoresis are not necessarily limited to ionic drugs with either a positive or negative charge, but may also be electrically neutral or uncharged drugs. . It is presumed that this phenomenon is based on electroosmosis (R, Bur
Nette et al, J. Pharm. Sci.
, 75, 738-743 (1986)).

[0040] Therefore, the above peptides do not necessarily need to be electrically charged. Other than peptide/protein drugs, there are many common ionic drugs that can be subjected to iontophoresis. Specific examples include analgesics (e.g., morphine hydrochloride, hydromorphone hydrochloride, buprenorphine hydrochloride, bupranolol hydrochloride), local anesthetics (e.g., tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, lidocaine hydrochloride, oxybrocaine hydrochloride, parahydrochloride). diethylaminoethyl butylaminobenzoate, pupivacaine hydrochloride, mepivacaine hydrochloride), antihistamines (
Examples: diphenhydramine hydrochloride, carbinoxamine maleate, chlorpheniramine maleate, isopentidyl hydrochloride, clemizole hydrochloride), antibiotics (β-lactam antibiotics (e.g., methicillin sodium, oxacillin sodium, cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride) , hetacillin potassium,
Penicillins such as carpenicillin sodium, cephalosporins such as cephalothin sodium, cefazolin sodium, cephapirin sodium, cefotidine sodium, cefametazole sodium, cefuroxy sodium), oleandomycin phosphate, lincomycin hydrochloride, Macrolide antibiotics such as clindamycin hydrochloride, aminoglycoside antibiotics such as fradiomycin sulfate, chloramphenicol sodium succinate, tetracycline hydrochloride, sodium fusidate)
, chemotherapeutic agents (e.g., isoniazide sodium methanesulfonate, ethambutol hydrochloride), hypnotic/sedative agents (e.g., flurazepam hydrochloride), analgesic anti-inflammatory agents (e.g., diclofenac sodium, sodium salicylate, benzydamine hydrochloride, ergotamine tartrate, dimethothiazine mesylate) , antidepressants (e.g., isoprenaline hydrochloride, betahistine mesylate), psychiatric agents (e.g., chlorpromazine hydrochloride, imipramine hydrochloride, amitributyline hydrochloride, mianserin hydrochloride, doxepin hydrochloride), agents for autonomic nerves (e.g., distigmine bromide), antispasmodics (e.g., atropine sulfate, butylscopolamine bromide, trospium chloride, pipetanate hydrochloride), antiparkinsonian drugs (e.g., piperidine hydrochloride), antiarrhythmic drugs (
e.g., propranolol hydrochloride, bufetrol hydrochloride, indenolol hydrochloride, bucromol hydrochloride, timolol maleate), antihypertensive agents (e.g., clonidine hydrochloride, petanidine sulfate, prazosin hydrochloride), coronary vasodilators (e.g., diltiazem hydrochloride, verapamil hydrochloride, trimetadicine hydrochloride), antitussive expectorants (e.g., tilbutaline sulfate, chlorprenaline hydrochloride, bromhexine hydrochloride, tubutyrol hydrochloride, ketotifen fumarate), peptic ulcer treatment agents (e.g., glycopyrronium bromide), adrenal hormones (e.g., Hydrocortisone sodium phosphate, dexamethison sodium, prednisolone sodium phosphate), anti-malignant tumor agents (eg, repamisole hydrochloride, pleomycin sulfate, pleomycin hydrochloride), etc.

[0041] In addition to the drug that is desired to be introduced into the body through the outer skin, many salts for adjusting the pH can be added to the aqueous medium. Adding a large amount of salts is not preferable from the viewpoint of drug transport efficiency because drug ions compete with these salts. However, it is sometimes added to ensure the driving force for introducing the drug.

[0042] In the present invention, the polarity (positive/negative) of the voltage supplied to the electrode can be appropriately switched in order to maintain the pH of the aqueous medium at 3 to 9, preferably 5 to 8. Since the change in pH varies depending on the pH of the aqueous medium at the start, the amount of current, the concentration of coexisting salts, etc., it cannot be defined unconditionally. It is necessary to apply current in one direction under given conditions, observe the change in pH, and then reverse the polarity at appropriate intervals. Normally, when flowing a direct current of 0.1 mA to 0.5 mA, the approximate time it takes for the pH of the aqueous medium 0.02 M citrate buffer to move by 1 is about 60 minutes. It will be. Such polarity switching is preferably carried out at a frequency of usually once every 1 to 120 minutes, particularly once every 5 to 60 minutes. Switching is usually activated by a switch mechanism in conjunction with a timer. This method is common and can utilize conventional mechanisms.

[0043] In the present invention, the voltage may be applied continuously during a section until the electric polarity is switched between the electrodes A and B, or it may be applied intermittently if the polarity is the same. good. That is, the current flowing through the closed circuit may be a DC straight current as shown in FIG. 3 or a DC pulse as shown in FIG. 4. Also, a depolarization mechanism may be activated at the end of the pulse.

[0044] In the present invention, the DC/DC voltage refers to a voltage in which a substantially constant voltage is applied to one electrode for a predetermined period of time, as illustrated in FIG. The wave voltage refers to a state in which a pulse voltage of the same polarity (positive/negative) is applied to one electrode for a predetermined period of time, as illustrated in FIG.

[0045] When DC flat current and DC pulse are compared, DC flat current is preferable from the two points of view of drug transport efficiency and circuit simplicity. That is, when apparently the same current flows, DC/DC most effectively penetrates the drug through the outer skin of the body. Also, the circuit design is easier compared to the pulse. Therefore, it is a desirable embodiment of the present invention to supply DC/DC voltage to the electrodes and change the polarity as appropriate.

On the other hand, with DC pulses, as the frequency increases, wasteful current is generated. This phenomenon is continuous with respect to frequency, and although it is difficult to determine the maximum allowable pulse frequency that can be used in the present invention, it can be set to 5 KHz or less in consideration of economical efficiency and the like. Therefore, it is one aspect of the present invention to supply a DC pulse voltage of, for example, 5 KHz or less to 1 Hz or more to the electrodes and change the polarity as appropriate.

In this way, according to the present invention, the aqueous medium connecting the pair of electrodes applied at intervals to the integument and the integument surface both contain the drug to be introduced through the integument, and the aqueous medium An iontophoresis device is provided which is characterized by appropriately switching the polarity (positive/negative) of the voltage supplied to the electrode in order to maintain the pH of the medium between 3 and 9, and the present invention provides a safe and effective iontophoresis device. The significance of Resis becoming a reality is great. Further, the device of the present invention is characterized in that the pH fluctuation of the aqueous medium at each electrode during operation is as small as within ±2, preferably ±1 or less.

[0048] The present invention will be specifically illustrated by Examples below, but the present invention is not limited thereto.

[0049]

Example 1 The iontophoresis apparatus of the present invention as shown in FIGS. 1 and 2 was used to administer calcitonin to hairless rats.

That is, as a DC constant current power source, Phor
Esor II PM700 type (manufactured by IOMED (Utah, USA)) was used as an electrode with an inner diameter of 20 mm and a thickness of 0.6 mm.
Two platinum plates with a diameter of 2 mm were used. A conductor was drawn from the platinum plate so that it could be connected to a power source. Salmon calcitonin (manufactured by Sigma) was used as calcitonin, dissolved in 7.8 μM citrate buffer, and then
Adjust the pH to approximately 5.0 with a 0.1M aqueous sodium hydroxide solution.
A solution adjusted to 5 was prepared. On the other hand, the above electrode was fixed with 1% agar gel on the closed side of a cylindrical plastic cell with an inner diameter of 29 mm and a height of 10 mm and closed on one side. The depth of the gel was approximately 4.5 mm. The conductor wires from the electrodes could be brought out to the outside through a small hole in the closed part and connected to a power source.

Two of the plastic cells thus produced were adhered to the abdomen of a hairless rat (Wistar strain, male, 7 weeks old) by applying adhesive to the edge of the opening. Inject the calcitonin solution from the outside through the small hole in each closed part into the space between the abdominal skin of the hairless rat and the agar inside the cell using a syringe barrel and a syringe needle,
The space was filled with calcitonin solution.

Next, one of the conductive wires coming out of these two cells (electrode and calcitonin-containing aqueous medium) was connected to the positive terminal of a DC constant current power supply, and the other to the negative terminal of a DC constant current power supply, and a current of 50 μA was applied. did. As shown in Figure 3, 20
Table 1 shows the pH changes in both aqueous media when electricity was applied for 2 hours by replacing the positive and negative electrodes every minute (pH is pH. mV
METER CL-70CHEMICAL INST
(measured using a product manufactured by RUMENT). In addition, Table 2 shows the changes in blood Ca concentration values of hairless rats during and after energization. Color method Calcium measurement test solution (quantified using Yatron Co., Ltd.).

At the same time, as a control example 1, calcitonin solution was injected into only one side of the cell, and that cell was connected to the positive terminal of the power supply, and 7.8 μM citrate buffer was injected into the other cell.
．． A solution whose pH was adjusted to about 5.5 with 1M sodium hydroxide solution was injected, connected to the negative terminal of a power source, and a current of 50 μA was applied for 2 hours without switching the polarity. Table 1 shows the pH changes in the bipolar aqueous medium in Control Example 1, and Table 2 shows the changes in blood Ca concentration values of hairless rats during and after energization. At the same time, as a control example 2, calcitonin solution was injected into both cells as in Example 1, and as in Example 1, one was connected to the positive terminal of a DC constant current power supply and the other to the negative terminal of the same power supply. A current of 50 μA was applied for 2 hours without switching the polarity. Table 1 shows the pH change of the bipolar aqueous medium in Control Example 2, and Table 2 shows the change in blood Ca concentration of hairless rats during and after energization.

Table 3 shows the results of observing the condition of the skin of the hairless rats that were in contact with the aqueous medium after the cells were removed after energization in Example 1, Comparative Example 1, and Comparative Example 2.

From the results of Tables 1 to 3, in the case of Example 1,
Calcitonin is absorbed most transdermally, and the pH of the aqueous medium
It can be seen that there is little change in the skin, and there is little irritation to the skin.

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

[Table 3]

[0059]

Example 2 The iontophoresis apparatus of the present invention as shown in FIGS. 1 and 2 was used to administer insulin to hairless rats.

That is, as a DC constant current power source, Phor
Esor IIPM 700 type (manufactured by IOMED (Utah, USA)) was used as an electrode with an inner diameter of 20 mm and a thickness of 0.
Two 6 mm platinum plates were used. A conductor was drawn from the platinum plate so that it could be connected to a power source. Using porcine insulin (manufactured by Hoechst) as insulin,
50U/m in 0.02M citrate buffer at pH 4.0
A solution dissolved at a concentration of 1 was used.

[0061] The method of manufacturing the cell attached to the hairless rat and the method of adhering the cell to the abdomen of the hairless rat were the same as in Example 1. Also, the hairless rat is Wistar, male, 7
Week-old ones were used. The insulin solution was injected from the outside through a small hole in the closed part of each cell into the space between the abdominal skin of the hairless rat and the agar inside the cell using a syringe barrel and needle, and the space was filled with the insulin solution.

Next, one of the conductive wires coming out of these two cells (electrode and insulin-containing aqueous medium) was connected to the positive terminal of a DC constant current power supply, and the other to the negative terminal of a DC constant current power supply, and a current of 50 μA was applied. did. As shown in FIG. 3, Table 4 shows the change in pH of the aqueous medium when the positive and negative electrodes were replaced every 20 minutes and electricity was applied for 2 hours (the pH measurement method was the same as in Example 1). Table 5 shows the changes in the blood sugar levels of the hairless rats during and after energization (the blood sugar levels were quantified using Glucose FA Test Wako manufactured by Wako Pure Chemical Industries, Ltd.).

At the same time, as a control example 3, insulin solution was injected into only one side of the cell, and that cell was connected to the positive terminal of the power source.
A 0.02 M citrate buffer solution with a pH of 4.0 was injected into the other cell, which was connected to the negative terminal of a power source, and a current of 50 μA was applied for 2 hours without switching the polarity. Table 4 shows the pH change of the bipolar aqueous medium in Control Example 3, and Table 5 shows the change in blood sugar level of the hairless rats during and after energization. At the same time, as a control example 4, insulin solution was injected into both cells as in Example 2, and as in Example 2, one was connected to the positive terminal of a constant current power supply and the other to the negative terminal of the same power supply. A current of 50 μA was applied for 2 hours without switching the polarity. Table 4 shows the pH change of the bipolar aqueous medium in Control Example 4, and Table 5 shows the change in blood sugar level of the hairless rats during and after energization.

Table 6 shows the results of observing the condition of the skin of the hairless rats that were in contact with the aqueous medium after the cells were removed after energization in Example 2, Comparative Example 3, and Comparative Example 4.

From the results in Tables 4 to 6, in the case of Example 2,
It can be seen that insulin is absorbed most transdermally, there is little change in the pH of the aqueous medium, and there is little irritation to the skin.

[0066]

[Table 4]

[0067]

[Table 5]

[0068]

[Table 6]

[0069]

[Example 3] A DC pulse generator (4KHz pulse wave: duty ratio = 50% was generated by an oscillator and amplified by an amplifier) was used as a power source, and a 4KH pulse was generated between the electrodes.
z, duty ratio = 50% DC pulse equivalent to 500μA
Calcitonin was administered to hairless rats using the iontophoresis device of the present invention under the same conditions as in Example 1 except for applying electricity.

As shown in FIG. 4, Table 7 shows the change in pH of the aqueous medium when the positive and negative electrodes were replaced every 20 minutes and current was applied for 2 hours. Further, Table 8 shows the changes in blood Ca concentration values of hairless rats during and after energization.

At the same time, as a control example 5, calcitonin solution was injected into only one side of the cell, and that cell was connected to the positive terminal of the power supply, and 7.8 μM citrate buffer was added to the other cell.
．． A solution whose pH had been adjusted to approximately 5.5 with 1M sodium hydroxide solution was injected, connected to the negative terminal of a power source, and a current of 500 μA was applied for 2 hours without switching the polarity. The pH change of the bipolar aqueous medium in the case of Control Example 5 is shown in Table 7, and
Table 8 shows the changes in blood Ca concentration values of hairless rats during and after energization. At the same time, as a control example 6, calcitonin solution was injected into both cells as in Example 3, and as in Example 3, one was connected to the positive terminal of a DC constant current power supply and the other to the negative terminal of the same power supply. A current of 500 μA was applied for 2 hours without switching the polarity. Table 7 shows the pH change of the bipolar aqueous medium in the case of Control Example 6, and the blood Ca of hairless rats during and after energization.
Table 8 shows the concentration changes.

Table 9 shows the results of observing the condition of the skin of the hairless rats that were in contact with the aqueous medium after the cells were removed after energization in Example 3, Comparative Example 5, and Comparative Example 6.

From the results in Tables 7 to 9, in the case of Example 7,
Calcitonin is absorbed most transdermally, and the pH of the aqueous medium
It can be seen that there is little change in the skin, and there is little irritation to the skin.

[0074]

[Table 7]

[0075]

[Table 8]

[0076]

[Table 9]

[0077]

Effects of the Invention According to the iontophoresis device of the present invention, it is possible to reduce the fluctuation range of the pH of the aqueous medium in contact with the surface of the skin of a living body, and to facilitate the elimination of polarization on the surface of the skin of a living body, thereby making it possible to improve the concentration of drugs in the body. can be efficiently absorbed.

[0078] In particular, when the voltage applied between both electrodes is a DC/DC voltage, it is advantageous in increasing the absorption efficiency of the drug into the living body.

[Brief explanation of the drawing]

FIG. 1 is a schematic illustration of the ionphoresis device of the present invention. A cross-sectional view of the electrode part.

FIG. 2 is a specific example of the electric circuit section 4 in the device of FIG. 1.

FIG. 3 shows the case of a direct current voltage among preferred embodiments of the direct current voltage applied to both electrodes in the iontophoresis device of the present invention.

FIG. 4 is a preferred embodiment of the DC voltage, similar to FIG. 3, in the case of a DC pulse wave voltage.

Claims (4)

[Claims] 1. An iontophoresis device having a pair of electrode means applied to the outer skin of a living body at a distance, the electrodes and the outer skin surface of the living body being electrically connected in both of the pair of electrode means. In addition, the drug to be absorbed into the body through the outer skin of the body is contained in the aqueous medium, and the voltage applied between both electrodes is positive and negative. An iontophoresis device characterized by comprising voltage adjustment means for alternately switching each voltage. 2. The iontophoresis apparatus according to claim 1, wherein the voltage adjusting means is for maintaining the pH of the aqueous solution in the aqueous medium in both electrode means at 3 to 9. 3. The iontophoresis apparatus according to claim 1, wherein the voltage applied between the two electrodes is a DC/DC voltage. 4. The iontophoresis device according to claim 1, wherein the voltage applied between both electrodes is a DC pulse wave voltage having a frequency in the range of 1 Hz to 5 KHz.