JP5550009B2 - Method for producing electrode composition for iontophoresis - Google Patents

Description

  The present invention relates to an electrode composition for iontophoresis, an electrode for iontophoresis, and a method for producing an electrode for iontophoresis. According to the present invention, a large amount of medicine can be absorbed from the skin for a long time.

  As an administration method for absorbing a drug from the skin, for example, a patch preparation containing a local anesthetic in an adhesive layer and administered from the skin or mucous membrane has been developed (Patent Document 1). In this method, an adhesive patch preparation in which a local anesthetic is carried on the skin is applied, and the local anesthetic is percutaneously penetrated subcutaneously, so that anesthesia can be performed without pain such as injection. However, in this method, the effect of local anesthesia cannot be obtained unless the patch preparation is applied for a relatively long time.

  On the other hand, a method of increasing percutaneous absorption of a local anesthetic or the like by an iontophoresis method (iontophoresis: a method in which an ionized drug or the like is put into a body tissue by an electric current) is known (Patent Document 2) Actually, electrodes for transdermal introduction of local anesthetics are marketed by Iome and Veteris in the United States. In this iontophoresis, a drug-holding layer carrying an anesthetic is affixed to the skin, and the anesthetic can be permeated subcutaneously by applying a voltage. It is possible to quickly penetrate the anesthetic under the skin.

However, the drug holding layer described in Patent Document 2 uses a porous material such as a nonwoven fabric or a nylon membrane, and the drug holding layer using these porous materials does not have a sufficient amount of drug.
Further, when a nonwoven fabric or nylon membrane is used as the drug holding layer, it is necessary to fix the nonwoven fabric or nylon membrane with a seal or a bandage. In this case, since the drug holding layer itself has no adhesiveness, even if it is fixed with a seal or the like, the adhesion between the skin and the drug holding layer is low, and the penetration efficiency of the drug into the skin is reduced.
Furthermore, in the conventional method, since direct current is used for iontophoresis, the temperature of the electrode rises when energized, so that it cannot be energized for a long time, and the drug can sufficiently penetrate into the skin and mucous membrane. There was something I couldn't do.

JP 2004-143052 A JP-A-9-201420

An object of the present invention is to provide an electrode composition for iontophoresis, which has high adhesion to the skin, can carry a large amount of drug, and can release the carried drug sufficiently under the skin, and iontophoresis An electrode and a method for producing an iontophoresis electrode are provided.
As a result of intensive studies to solve the above problems, the present inventors have incorporated a polyanionic water-soluble polysaccharide into an iontophoresis electrode composition, thereby allowing a large amount of drug to be ionized. It was found that it can be supported on the electrode composition. In addition, the electrode composition for iontophoresis containing a polyanionic water-soluble polysaccharide can be brought into close contact with the skin or mucous membrane. Therefore, the iontophoresis electrode can be applied to the skin without being fixed by a seal or the like. Can be affixed. Furthermore, since the electrode has excellent adhesion to the skin or mucous membrane, a large amount of drug can be efficiently penetrated into the skin. Furthermore, by combining the electrode and an alternating current, iontophoresis can be continued for a long time without lowering the penetration efficiency of the drug.
The present invention is based on such knowledge.

  Accordingly, an object of the present invention is to provide an electrode composition for iontophoresis that has high adhesion to the skin, supports a large amount of drug, and can sufficiently release the supported drug subcutaneously. It is to provide.

The present invention relates to an iontophoresis electrode composition comprising a polyanionic water-soluble polysaccharide.
In a preferred embodiment of the electrode composition for iontophoresis according to the present invention, a cationic agent is further included. In a preferred embodiment of the electrode composition for iontophoresis according to the present invention, the polyanionic water-soluble polysaccharide is an alginate, particularly sodium alginate, potassium alginate, or ammonium alginate. In a preferred embodiment of the iontophoresis electrode composition according to the present invention, the iontophoresis electrode composition is freeze-dried. Furthermore, in the preferable aspect of the electrode composition for iontophoresis by this invention, it is an object for alternating current.
The present invention also relates to an iontophoresis electrode comprising the iontophoresis electrode composition and a conductor.
Furthermore, the present invention also relates to an ion electricity introduction method characterized in that an alternating current is passed through the iontophoresis electrode.

The present invention relates to a method of immersing a conductive material, which is connected to a positive electrode and capable of forming an oxide passive film, in a solution containing a polyanionic water-soluble polysaccharide, and electrolyzing the conductive material. The present invention relates to a method for producing an iontophoresis electrode, which includes a step of depositing a polysaccharide.
The present invention also provides: (a) a conductor that can form an oxide passive film connected to the positive electrode, is immersed in a solution containing a polyanionic water-soluble polysaccharide, and electrolyzed; A method for producing an electrode for iontophoresis, comprising: a step of depositing a polyanionic water-soluble polysaccharide on a conductive layer; and (b) a step of crosslinking the polyanionic water-soluble polysaccharide deposited on the conductor using a metal ion. .
Furthermore, the present invention provides (a) a conductor capable of forming an oxide passivation film connected to a positive electrode, immersed in a solution containing a polyanionic water-soluble polysaccharide, and electrolyzed, A step of depositing a polyanionic water-soluble polysaccharide on the body, (b) a step of crosslinking the polyanionic water-soluble polysaccharide deposited on the conductor using a metal ion, and (c) the polyanionic water-soluble polysaccharide. A step of binding a cationic drug to
The manufacturing method of the electrode for iontophoresis containing this.

In a preferred embodiment of the method for producing an iontophoresis electrode of the present invention, the conductor is aluminum, aluminum alloy, chromium, chromium alloy, titanium, titanium alloy, iron, iron alloy, zirconium, zirconium alloy, niobium, A metal selected from the group consisting of niobium alloy, tantalum, and tantalum alloy.
In another preferred embodiment of the method for producing an iontophoresis electrode of the present invention, the polyanionic water-soluble polysaccharide is an alginate, in particular, sodium alginate, potassium alginate, or ammonium alginate.

According to the iontophoresis electrode of the present invention, a large amount of drug can be carried on the electrode. Furthermore, the electrode composition for iontophoresis of the electrode contains a polyanionic water-soluble polysaccharide, so that the electrode can be in close contact with the skin or mucous membrane, and the drug can be efficiently transferred subcutaneously. it can. Therefore, the electrode of the present invention is effective for anesthesia in a short time without causing pain by releasing the cationic anesthetic.
Furthermore, by combining the iontophoresis electrode of the present invention with an alternating current, the polarization action between the skin and the electrode can be suppressed. That is, in the conventional method using a direct current, electrode polarization is formed between the skin and the electrode as the energization time becomes longer. Therefore, the penetration efficiency of the drug is lowered. Further, if energization is performed for a long time in such a situation, the temperature of the electrode rises, and the electrode melts and may cause burns. However, according to the combination of the iontophoresis electrode and the alternating current of the present invention, electrode polarization formation hardly occurs, and energization is possible for a long time.
The electrode for iontophoresis produced by the method for producing an electrode for iontophoresis of the present invention has excellent adhesion between the conductor and the gel of the polyanionic water-soluble polysaccharide, and allows the drug to permeate by iontophoresis. In this case, the gel of the polyanionic water-soluble polysaccharide is not detached from the conductor.

It is a schematic diagram showing the administration of the drug to the skin by the iontophoresis method using the iontophoresis electrode of the present invention. It is a figure explaining administration to the skin of a cationic medicine by application of current of polyanionic water-soluble polysaccharide and cationic medicine. It is a photograph of the electrode composition for iontophoresis using 1% sodium alginate. It is a photograph of the electrode composition for iontophoresis using 1% sodium alginate and aluminum. It is a photograph of the electrode composition for iontophoresis containing lidocaine. It is a schematic diagram of an experimental system for measuring an electrode composition for iontophoresis of a cationic drug. It is the graph which showed the difference in discharge | release of lidocaine from the electrode composition for iontophoresis when a voltage is applied and when a voltage is not applied. It is a schematic diagram (A) of the cell made from polystyrene used for the manufacturing method of the electrode for iontophoresis of this invention. (B) shows the size of the conductor (electrode) used. At a current density of 3.0mA / cm ^2, 60 seconds (A), 120 seconds (B), 300 seconds (C), or 600 seconds (D) is a photograph showing the appearance of the aluminum electrode was energized. It is the figure which showed the FT-IR spectrum of the aluminum electrode surface dried after supplying with current density 0.5mA / cm < ² > for 60 seconds, 120 seconds, 300 seconds, or 600 seconds. It is the graph which showed the change of the alginic acid deposition amount to the aluminum electrode by the energization time and the increase in current density. It is a SEM photograph of the cross section of the aluminum electrode energized for 60 seconds, 120 seconds, 300 seconds, or 600 seconds at a current density of 0.5 mA / cm ² .

[1] Iontophoresis electrode composition and iontophoresis electrode using the same The iontophoresis electrode composition of the present invention may contain a polyanionic water-soluble polysaccharide. The polyanionic water-soluble polysaccharide is not particularly limited as long as it is a water-soluble polysaccharide capable of holding a cationic drug by electrostatic interaction. For example, alginate, gellan, gellan gum, Xanthan chitosan and carrageenan can be mentioned, and alginates are particularly preferable. Examples of the alginate include sodium alginate, potassium alginate, and ammonium alginate, and sodium alginate is particularly preferable. Among polyanionic water-soluble polysaccharides, alginate can be cross-linked with a metal ion such as calcium and gelled. By cross-linking, the alginate dissolves even when the temperature of the electrode increases due to energization. There is nothing. On the other hand, examples of the crosslinking agent used in the base material that must be crosslinked and gelled using a crosslinking agent other than metal ions include glutaraldehyde and bismaleimide. Many have skin irritation and toxicity. Therefore, alginate is preferable as a polyanionic water-soluble polysaccharide from the viewpoint of gelation by metal ions.

  The electrode composition for iontophoresis can be used for iontophoresis as a gel composition that gels and retains a cationic drug. Gelation can be performed by a conventional method. For example, in the case of sodium alginate, it can be gelled by adding calcium chloride to an aqueous solution of sodium alginate. The gelled iontophoresis electrode composition contains a polyanionic water-soluble polysaccharide as a base material and a solvent. Examples of the solvent include ketones such as acetone or ethyl methyl ketone, alcohols such as ethanol or methanol, water, or a mixture thereof, and water is particularly preferable.

The content of the polyanionic water-soluble polysaccharide in the gel composition is preferably 0.1 to 10% by weight, more preferably 0.1 to 3% by weight. If it is less than 0.1% by weight, the adhesion of the electrode composition for iontophoresis to the skin may be deteriorated, and if it exceeds 10% by weight, the followability to the skin may be deteriorated.
Further, in the dry weight obtained by drying the gel composition, the content of the polyanionic water-soluble polysaccharide excluding the cationic drug is preferably 50 to 100% by weight, and more preferably 80 to 100% by weight.

  The electrode composition for iontophoresis can contain a cationic agent by electrostatic interaction with a polyanionic water-soluble polysaccharide. The cationic drug is a drug that can be cationized, and is not particularly limited as long as it is a drug that can be contained in the iontophoresis electrode composition in a cationized state. Examples include morphine, buprenorphine, isosorbite nitrate, propranolol, procaine, lidocaine, fentanyl, scopolamine, pilocarpine, vasopressin, desmopressin, scopolamine, histamine, insulin, dexamethasone, hydrocortisone, gentamicin, or estrogen.

  The content of the cationic drug in the gel composition can be selected appropriately depending on the type of drug, the disease in which the drug is used, the age of the patient, symptoms, etc., but preferably 0.01 to 90 It can be used in the range of wt%, more preferably 0.01 to 10 wt%.

  The cationic drug can be retained in the iontophoresis electrode composition by mixing and gelling the composition before gelation, or after the gelling, the cationic drug is added. It is also possible to immerse the gelled composition in the solution containing it.

The electrode composition for iontophoresis of the present invention contains additives other than polyanionic water-soluble polysaccharides within a range that does not impair the adhesion to the skin or mucous membrane as an electrode, the amount of drug carried, and the electrical conductivity. It is possible. Examples of such additives include pH adjusters such as acids, bases, and buffers, preservatives such as methyl paraoxybenzoate or benzalkonium chloride, antioxidants such as sodium sulfite and L-ascorbic acid, Mention may be made of electrical antioxidants, surfactants such as Tween 80, and oxidants such as quinone or nitric acid. Such additives are appropriately selected in order to adjust the pH and prevent the growth of bacteria and molds according to the type of polyanionic water-soluble polysaccharide used, the type of cationic drug, or a combination thereof. However, those that do not easily form electrode polarization are preferable, and those that do not compete with the ions of the drug to be penetrated are preferable in order not to impair the penetration of the drug. That is, ions that dissociate and compete with the ions of the cationic drug are not preferable because they may prevent the drug from penetrating into the skin.
Therefore, the electrode composition for iontophoresis of the present invention preferably does not contain an additive that dissociates ions that compete with ions of a substantially cationic drug. Here, “substantially free of additives that dissociate ions competing with ions of a cationic drug” does not cause excessive electrode polarization and is energized for a long time (preferably 30 minutes or more, more preferably 1 It means that an additive competing with the ion of the cationic drug may be included to such an extent that it does not interfere with the time).

  The electrode composition for iontophoresis of the present invention can be used as an electrode for iontophoresis in combination with a conductor. The conductor is not limited as long as it can be energized, but a metal is preferable, and examples thereof include Al, Pt, Au, Ag-AgCl, stainless alloy, and Ti, and in particular, Ag. -AgCl or Pt is preferred. Since the electrode composition for iontophoresis of the present invention contains a polyanionic water-soluble polysaccharide, it is excellent in adhesion to a conductor, particularly a metal. The metal can be brought into close contact with the surface of the electrode composition for iontophoresis to form an electrode, but can also be inserted into the composition when the electrode composition for iontophoresis is gelled. is there.

The gel thickness of the electrode composition for iontophoresis that constitutes the electrode for iontophoresis is not particularly limited as long as it is a thickness that can be applied to the skin as an electrode. It is 05 mm to 5 cm, more preferably 0.1 mm to 1 cm, and most preferably 0.2 mm to 5 mm. In addition, the shape of the contact surface to be applied to the skin or mucous membrane may be appropriately determined according to the area of the skin that absorbs the drug, and is not particularly limited, but may be a circle, an ellipse, a square, a rectangle, or the like Can be mentioned. Yet, the cross-sectional area of the contact surface is also in accordance with the area of skin to absorb the drug, but can be appropriately determined, preferably 0.5cm ² ~150cm ^2, more preferably ^{1 cm} 2 to 50 cm ² is there.

The electrode composition for iontophoresis can be lyophilized. Freeze drying can be performed by a conventional method using a freeze dryer. Freeze drying enables long-term storage and facilitates transportation. Freeze-drying can be carried out with either an iontophoresis electrode composition containing a cationic drug or an iontophoresis electrode composition containing no cationic drug, but when returned to a gel In addition, since it can be used without penetrating the drug, it is preferable to freeze-dry the iontophoresis electrode composition containing the cationic drug.
In the case of an electrode composition for iontophoresis containing a cationic drug, water can be supplied to the freeze-dried composition, returned to a gel-like composition, and used as it is as an electrode for iontophoresis. In the case of an electrode composition for iontophoresis that does not contain a cationic drug, water is supplied to the freeze-dried composition, returned to a gel-like composition, and then gelled into a solution containing the cationic drug. By immersing the chemical composition, the cationic drug can be retained and used as an electrode for iontophoresis.
Further, for example, when applying to the mucous membrane in which water such as saliva exists in the oral cavity, it can be applied directly to the oral cavity without supplying water. That is, the iontophoresis electrode composition absorbs moisture such as saliva to form a gel, and can be used as an iontophoresis electrode.

  One embodiment of the ion electrophoretic method (iontophoresis) of the present invention will be described with reference to the schematic diagram of FIG. 1, but the ion electrophoretic method of the present invention is limited to the description and embodiment of FIG. It is not something. The iontophoresis electrode (11) of the present invention and an electrode not containing a drug, for example, a metal electrode (15) are connected to a power source (14). The iontophoresis electrode composition side of the iontophoresis electrode (11) is brought into contact with the skin or mucous membrane infiltrated with the drug, and the electrode not containing the drug is also brought into contact with the skin or the like. By applying an electric current to the metal (12) in this state, the cationic drug is released from the iontophoresis electrode composition (13) and absorbed from the skin. Specifically, as shown in FIG. 2, the polyanionic water-soluble polysaccharide and the cationic drug in the electrode composition for iontophoresis are bonded by electrostatic interaction, and an electric current is applied to this electrode. As a result, an electric field is formed, and the cationic drug is released from the polyanionic water-soluble polysaccharide. The detached cationic drug is released from the iontophoresis electrode composition and absorbed from the skin. In the electrode composition for iontophoresis according to the present invention, since the polyanionic water-soluble polysaccharide and the cationic drug are bonded by electrostatic interaction, it is possible to carry a large amount of the cationic drug. Become.

  In addition to the metal electrode, the electrode composition for iontophoresis of the present invention that does not contain a drug can also be used as the electrode that does not contain a drug. Alternatively, an electrode made of a conductive material such as an acrylic acid-acrylamide copolymer, an acrylamide polymer, agar, gelatin, Karaya gum, tragacanth gum, or polyvinyl alcohol can be used.

  In iontophoresis, the electrode is usually fixed to the skin with a seal or the like. The iontophoresis electrode (1) of the present invention and the electrode not containing a drug may be fixed to the skin with a seal or the like as in the prior art, but the iontophoresis electrode of the present invention has high adhesion. Therefore, it can be used without fixing with a seal or the like. That is, the electrode composition for iontophoresis of the present invention adheres to the skin and exhibits sticking ability to follow the movement of the skin even in a variable part such as a joint, and such a variable part is not fixed with a seal or the like. Can be used. In other words, since the iontophoresis electrode composition of the present invention carries a drug and has high adhesion to the skin or mucous membrane, it can also serve as an adhesive seal.

In the ion introduction method of the present invention, a direct current such as a continuous direct current or a pulsed direct current or an alternating current can be used as the current, but an alternating current is preferable because a long-time current can be applied.
The current density of the alternating current, preferably 1.0 mA / cm ² to about 0.01, and more preferably 0.5 mA / cm ² 0.1. The frequency is preferably 1 Hz to 100 kHz, more preferably 100 Hz to 10 kHz, and most preferably 500 Hz to 5 kHz. The energization is preferably bidirectional wave energization, and the duty cycle of the rectangular wave is preferably 50 to 95%, more preferably 60 to 95%, and even more preferably 60 to 90%.

  Mammals such as humans, monkeys, cows, horses, pigs, rats, or mice can be mentioned as the target animals for the iontophoresis method of the present invention. A cationic drug can be introduced into the body from the skin or mucous membrane (for example, oral mucosa) of these target animals by ion electrophoretic introduction.

[2] Method for Producing Iontophoresis Electrode The method for producing an iontophoresis electrode of the present invention is one preferred embodiment of the method for producing an iontophoresis electrode, and includes an iontophoresis electrode composition. It can be manufactured using the polyanionic water-soluble polysaccharide contained therein and a conductor capable of forming a passive film of oxide.
In the method for producing an iontophoresis electrode according to the present invention, a conductor connected to a positive electrode and capable of forming an oxide passive film is immersed in a solution containing a polyanionic water-soluble polysaccharide and electrolyzed. Thus, a step of depositing the polyanionic water-soluble polysaccharide on the conductor is included. The deposited polyanionic water-soluble polysaccharide is gelled by ionic bonds and hydrogen bonds.

In the production method of the present invention, a conductor capable of forming a passive film made of an oxide is used as the conductor. There are conductors, particularly metals, which can form a thin passive film on the surface of the metal by an oxide in an oxidizing environment, and the formation of the passive film makes the metal corrosion resistant. It is applied and becomes difficult to corrode. By forming the passive film with an oxide, the bond with the polyanionic water-soluble polysaccharide can be strengthened.
Specific examples of the conductor can include aluminum, aluminum alloy, chromium, chromium alloy, titanium, titanium alloy, iron, iron alloy, zirconium, zirconium alloy, niobium, niobium alloy, tantalum, or tantalum alloy, In particular, aluminum or an aluminum alloy is preferable.

For example, in the case of aluminum or an aluminum alloy, a thin Al ₂ O ₃ film is formed on the surface of the metal as the passive film made of the oxide, thereby forming a passive film. In addition, a thin Cr ₂ O ₃ film is formed in the case of chromium or a chromium alloy, a thin TiO ₂ film is formed in the case of titanium or a titanium alloy, and a thin Fe ₂ O ₃ film is formed in the case of iron or an iron alloy. A film is formed on the surface of the metal.

  The aluminum alloy, chromium alloy, titanium alloy, iron alloy, niobium alloy, or tantalum alloy is not particularly limited as long as each metal contains 40% or more, but preferably 50%. More preferably, it is 70% or more, and most preferably 80% or more. Examples of the other metal mixed with each metal include copper, manganese, silicon, magnesium, zinc, nickel, molybdenum, aluminum, chromium, titanium, or iron, or a combination of two or more thereof. For example, as an aluminum alloy, an Al—Cu alloy, an Al—Mn alloy, an Al—Si alloy, an Al—Mg alloy, an Al—Mg—Si alloy, an Al—Zn—Mg alloy, or an Al— A Zn-Mg-Cu alloy can be mentioned. Moreover, stainless steel can be mentioned as an iron alloy.

On the other hand, noble metals such as platinum and silver are difficult to form a passive film made of oxides, as shown in Comparative Examples described later, so that polyanionic water-soluble polysaccharides can be firmly bonded to the surface. Therefore, it is not preferable as the conductor in the production method of the present invention. However, as the conductor in the iontophoresis electrode of the present invention, it is possible to use it in combination with the iontophoresis electrode composition by a usual method.

The size of the conductor is not particularly limited, and can be appropriately selected according to the use of the iontophoresis electrode produced by the production method of the present invention. Also, the thickness of the conductor is not particularly limited. For example, a conductor having a thickness of 0.001 mm to 1 mm can be used. When the iontophoresis electrode is used in close contact with the skin, Since the thing which can move along is preferable, the one where thickness is thinner is preferable, for example, 0.006-0.05 mm is preferable.

  In the production method of the present invention, the conductor is connected to the positive electrode and electrolyzed in a solution containing the polyanionic water-soluble polysaccharide, thereby depositing the polyanionic water-soluble polysaccharide on the conductor, Can be combined.

  The electrolytic cell (electrolytic cell) used for electrolysis can be appropriately selected and used according to the application. For example, electrolysis can be performed using an electrolytic cell made of polystyrene. A conductor for depositing the polyanionic water-soluble polysaccharide is connected to the positive electrode as an anode, and the cathode is connected to the cathode. The cathode conductor is not particularly limited as long as it can be electrolyzed. For example, a platinum electrode can be used. As the power source, those used for normal electrolysis can be appropriately selected and used. The amount of the electrolysis solution can also be adjusted according to the size of the conductor.

Since the electrolysis time for electrolysis increases, the amount of polyanionic water-soluble polysaccharide deposited increases, so that the electrolysis time can be appropriately adjusted in order to obtain the desired amount of deposition. For example, it is usually 10 seconds to 60 minutes, preferably 60 seconds to 10 minutes.
Moreover, since the deposition amount of the polyanionic water-soluble polysaccharide is increased by increasing the current density of electrolysis, the current density can be appropriately adjusted in order to obtain the target deposition amount. For example, it is 0.1-100 mA / cm < ² > normally, Preferably it is 0.1-20 mA / cm < ² >. The thickness of the polyanionic water-soluble polysaccharide deposit is preferably 0.05 mm to 5 cm, more preferably 0.1 mm to 1 cm, and most preferably 0.2 mm to 5 mm.

  The concentration of the polyanionic water-soluble polysaccharide in the solution is not particularly limited, but is preferably 0.01 to 5%, more preferably 0.01 to 3%, and most preferably 0. 0.1 to 3%.

Examples of the polyanionic water-soluble polysaccharide that can be used in the production method of the present invention are those that can be bonded to a passive film made of the oxide, such as alginate, gellan, gellan gum, xanthan chitosan, and carrageenan. In particular, those having a carboxyl group are preferable, and examples thereof include alginates. Examples of the alginate include sodium alginate, potassium alginate, ammonium alginate, and calcium alginate, and sodium alginate is particularly preferable.
Alginate has a carboxyl group in its molecule, and as described later, it can form a strong bond with a passive film made of oxide by having a carboxyl group. It is also considered advantageous for the gelation of the alginate itself. Furthermore, among polyanionic water-soluble polysaccharides, alginate can be cross-linked with a metal ion such as calcium and gelled. Does not dissolve.
Alginic acid is a linear polymer in which β-D-mannuronic acid (M block) and α-L-guluronic acid (G block), which is its C-5 epimer, are (1-4) linked. COO ⁻ having a deprotonated carboxyl group ionically bonds with the oxide to form a strong bond with the conductor. In addition, alginic acid is considered to be gelled by bonding with a hydrogen bond of a carboxyl group (COOH).

  Examples of the solvent that dissolves the polyanionic water-soluble polysaccharide include ketones such as acetone or ethyl methyl ketone, alcohols such as ethanol or methanol, water, or a mixture thereof. An aqueous solution in which a polyanionic water-soluble polysaccharide is dissolved in water is preferred.

  In addition to the polyanionic water-soluble polysaccharide deposition step, the method for producing an iontophoresis electrode of the present invention includes a step of crosslinking the polyanionic water-soluble polysaccharide deposited on a conductor using metal ions. Can be included. That is, the manufacturing method comprises (a) immersing a conductor capable of forming a passive oxide film, connected to the positive electrode, in a solution containing a polyanionic water-soluble polysaccharide, and electrolyzing, A step of depositing a polyanionic water-soluble polysaccharide on the conductor, and (b) a step of crosslinking the polyanionic water-soluble polysaccharide deposited on the conductor using a metal ion. By the crosslinking step (b), the polyanionic water-soluble polysaccharide can be further gelled.

In the crosslinking step (b), the polyanionic water-soluble polysaccharide deposited on the conductor is crosslinked using metal ions. As the metal ion, a divalent cation is preferable, and for example, Ca ⁺⁺ can be used. Alginic acid is a linear polymer in which β-D-mannuronic acid (M block) and α-L-guluronic acid (G block), which is its C-5 epimer, are (1-4) linked, and have 6 residues The G block composed of the above can form a stable complex with a divalent cation (for example, Ca ⁺⁺ ) to form a three-dimensional gel.
Specifically, the gel in which the polyanionic water-soluble polysaccharide is deposited can be crosslinked by immersing it in an aqueous solution of a divalent cation, such as a calcium chloride solution.

  In the method for producing an iontophoresis electrode of the present invention, in addition to the polyanionic water-soluble polysaccharide deposition step (a) and the crosslinking step (b), a cationic agent is added to the polyanionic water-soluble polysaccharide. The step of bonding can be included. That is, the manufacturing method comprises (a) immersing a conductor capable of forming a passive oxide film, connected to the positive electrode, in a solution containing a polyanionic water-soluble polysaccharide, and electrolyzing, A step of depositing a polyanionic water-soluble polysaccharide on the conductor, (b) a step of crosslinking the polyanionic water-soluble polysaccharide deposited on the conductor using a metal ion, and (c) the polyanionic water-soluble polysaccharide. A step of binding a cationic drug to the saccharide can be included.

The cationic drug binding step (c) is difficult to perform simultaneously with the polyanionic water-soluble polysaccharide deposition step (a), but may be performed before, simultaneously with, or after the crosslinking step (b). it can. In this binding step (c), the cationic drug is bound to the polyanionic water-soluble polysaccharide by electrostatic interaction.
For example, when the bonding step (c) is performed before the crosslinking step (b), the gelled polyanionic water-soluble polysaccharide is immersed in a solution containing a cationic drug in the deposition step (a). Can also be combined. Further, after the deposition step (a), a cationic agent can be added to the electrolytic cell, the anode and the cathode can be reversed, and the cationic agent can be bound to the gelled polyanionic water-soluble polysaccharide.
Further, when the binding step (c) is performed simultaneously with the crosslinking step (b), the cationic agent is mixed with the metal ion at the same time by mixing the cationic agent with the divalent cation solution. It can be bound to a gel of a polyanionic water-soluble polysaccharide.
Further, when the bonding step (c) is performed after the crosslinking step (b), the metal crosslinking gel obtained in the crosslinking step (b) is bonded by immersing it in a solution containing a cationic drug. be able to.

  Furthermore, the iontophoresis electrode obtained by the production method of the present invention can be freeze-dried. Freeze drying can be performed by a conventional method using a freeze dryer. Freeze drying enables long-term storage and facilitates transportation. Freeze-drying can be carried out with either an iontophoresis electrode composition containing a cationic drug or an iontophoresis electrode composition containing no cationic drug, but when returned to a gel In addition, since it can be used without penetrating the drug, it is preferable to freeze-dry the iontophoresis electrode composition containing the cationic drug.

<< Adhesion between conductor and gel >>
The mechanism by which the conductor and the polyanionic water-soluble polysaccharide can be firmly bonded by the production method of the present invention has not been elucidated in detail, but can be considered as follows. However, the present invention is not limited by the following description.
The conductor used in the production method of the present invention is capable of forming a passive oxide film on its surface. The oxide is considered to be positively charged under weak acidity, and to this, a negatively charged group of the polyanionic water-soluble polysaccharide, for example, COO ⁻ is bound by an ionic bond. That is, it is considered that the interface between the conductor and the polyanionic water-soluble polysaccharide is controlled by the ionic bond, and a strong bond is formed.
On the other hand, a gel of polyanionic water-soluble polysaccharide is considered to be formed by hydrogen bonding of protonated groups of polyanionic water-soluble polysaccharide, for example, COOH.

  Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but these do not limit the scope of the present invention.

Example 1
In Example 1, an iontophoresis electrode composition was prepared using sodium alginate as the polyanionic polysaccharide.
Sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity: 300 to 400 mPa · s) was dissolved in ultrapure water to prepare a 1% aqueous solution. To 2 g of this sodium alginate aqueous solution, 20 mL of a 1 mol / L calcium chloride aqueous solution was added, poured into a rectangular mold, and gelled into a film. The obtained electrode gel composition for iontophoresis had a thickness of about 0.5 mm and a length of 2.5 cm × width of 4 cm. This gel composition was thoroughly washed with ultrapure water to remove excess calcium solution. The produced electrode gel composition for iontophoresis is shown in FIG. In order to examine the adhesion, it was affixed to human skin. This gel composition showed sufficient adhesion to the skin. When applied to the joint part, the joint movement was followed and sufficient adhesion to the skin was obtained.

Example 2
In Example 2, an iontophoresis electrode was prepared using sodium alginate as the polyanionic polysaccharide and aluminum as the metal electrode.
Sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity: 300 to 400 mPa · s) was dissolved in ultrapure water to prepare a 1% aqueous solution. To 2 g of this sodium alginate aqueous solution, 20 mL of an about 1 mol / L calcium chloride aqueous solution was added and poured into a rectangular mold together with the aluminum electrode to form a film. The obtained electrode gel composition for iontophoresis had a thickness of about 0.5 mm and a length of 2.5 cm × width of 4 cm. The gel composition in the iontophoresis electrode was sufficiently washed with ultrapure water to remove excess calcium solution. The produced electrode for iontophoresis is shown in FIG. In order to examine the adhesion, it was affixed to human skin. This gel composition showed sufficient adhesion to the skin. When applied to the joint part, the joint movement was followed and sufficient adhesion to the skin was obtained.

Example 3
In Example 3, the electrode gel composition for iontophoresis prepared according to the procedure of Example 1 was freeze-dried to prepare an electrode composition for freeze-dried iontophoresis.
The electrode gel composition for iontophoresis obtained by the procedure of Example 1 was frozen at −20 ° C. using a deep freezer. The frozen electrode gel composition for iontophoresis was set in a freeze dryer (manufactured by VirTis) and freeze-dried in 12 hours to obtain an electrode composition for freeze-dried iontophoresis.

Example 4
In Example 4, the adhesion of the electrode composition for iontophoresis of the present invention and the electrode composition for freeze-dried iontophoresis in the oral mucosa of pigs was examined.
Except that the concentration of the aqueous solution of sodium alginate was changed from 1% to 0.5% or 2%, the procedure of Example 1 was repeated to obtain an electrode composition for 0.5% iontophoresis and 2% ions. An electrode composition for tophoresis was obtained. Moreover, the operation of Example 3 was repeated except that the concentration of the aqueous solution of sodium alginate was changed from 1% to 0.5% or 2%, and an electrode composition for 0.5% freeze-dried iontophoresis was used. And the electrode composition for 2% freeze-drying iontophoresis was obtained.

  The four types of iontophoresis electrode compositions were applied to the intraoral mucosa of pigs, and the adhesion was observed. Anesthetize pig, electrode composition for 0.5% iontophoresis, electrode composition for 2% iontophoresis, electrode composition for 0.5% lyophilized iontophoresis, and for 2% lyophilized iontophoresis The electrode composition was applied to the oral cavity of pigs. The two freeze-dried iontophoresis electrode compositions were applied in a freeze-dried state without supplying water. Immediately after application, the adhesion after 1 hour and 2 hours was observed with an endoscope. The results are shown in Table 1.

  As shown in Table 1, the gel composition at any concentration showed good adhesion immediately after application and 1 hour later. 2 hours after application, good adhesion was exhibited except for the electrode composition for 0.5 or 2% freeze-dried iontophoresis. The 0.5 or 2% freeze-dried iontophoresis electrode composition slightly deteriorated in adhesion after 2 hours. This is probably because the dried electrode composition for iontophoresis was not sufficiently gelled only by saliva in the oral cavity. Therefore, in the electrode composition for lyophilized iontophoresis, it is considered desirable to supply moisture before use.

Example 5
In this Example 5, release of lidocaine from an electrode composition for iontophoresis using sodium alginate was performed using the experimental cell described in FIG. 6 (described in Kinoshita et al. Paper: T. Kinoshita, T. Shibaji and M. Umino, J. Med. Dent. Sci., 50, 71 (2003)).
First, an electrode composition for iontophoresis containing a drug was prepared using sodium alginate as a polyanionic polysaccharide and lidocaine hydrochloride as a cationic drug. Sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity: 300 to 400 mPa · s) was dissolved in ultrapure water to prepare a 0.3% aqueous solution. Lidocaine hydrochloride was dissolved in this aqueous sodium alginate solution to a concentration of 1%. 20 mL of a 1 mol / L calcium chloride aqueous solution was added to 8 g of the lidocaine hydrochloride-containing alginic acid aqueous solution and poured into a cylindrical rectangular mold having a diameter of 20 mm and a height of 10 mm to cause gelation (FIG. 5). The obtained columnar gel was sufficiently washed with ultrapure water to remove excess calcium solution, and then stored in a 1% lidocaine hydrochloride aqueous solution. The obtained lidocaine-containing iontophoresis electrode composition was set on the donor side (23) of the glass cell (25) of the experimental system, as shown in FIG. 3 mL of ultrapure water was placed on the acceptor side (24) of the glass cell, and a cellophane film (21) was placed between them as a skin model. The test voltage was a rectangular wave with an alternating current of 20 V and a duty cycle of 80%, and energized for 60 minutes. The concentration of lidocaine hydrochloride in the ultrapure water on the acceptor side was obtained by collecting 20 μL of liquid every 10 minutes, diluted 40-fold with ultrapure water, and then absorbance at 262 nm using an ultraviolet-visible spectrophotometer. Was measured and the concentration was calculated. As a control, the release due to spontaneous diffusion of lidocaine to the acceptor side when no voltage was applied was measured. The results are shown in FIG. The release of lidocaine to the acceptor side was almost doubled compared to the case of natural diffusion without applying a voltage.

Example 6
In Example 6, an iontophoresis electrode containing an iontophoresis electrode composition was produced using aluminum as a conductor. Alginic acid was deposited on the anode aluminum using a polystyrene cell (FIG. 8).
First, sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity 80 to 120 mPa · s) was dissolved in ultrapure water to prepare a 0.5% aqueous solution. Next, 20 mL of the prepared sodium alginate aqueous solution was added to the polystyrene cell. Aluminum having a thickness of 0.1 mm (manufactured by Nilaco Corporation) was used for the anode, and platinum having a thickness of 0.1 mm (manufactured by Nilaco Corporation) was set on the cathode. The distance between the electrodes was 10 mm, and a DC stabilized power source (P4K-80, manufactured by Matsusada Precision Co., Ltd.) was used as the power source. The current density was set to 0.5, 1, 1.5, or 3.0 mA / cm ² and energized for 60, 120, 300, or 600 seconds, respectively. The energized electrode was washed with ultrapure water and dried in a dryer set at 37 ° C. for 24 hours.

<< Comparative Example 1 >>
In this comparative example 1, an iontophoresis electrode containing an iontophoresis electrode composition was produced using platinum as a conductor.
Specifically, the operation of Example 6 was repeated except that platinum was used instead of aluminum for the anode.

<< Comparative Example 2 >>
In this Comparative Example 1, an iontophoresis electrode containing an iontophoresis electrode composition was produced using silver as a conductor.
Specifically, the operation of Example 6 was repeated except that silver was used instead of aluminum for the anode.

  When the aluminum of Example 6, platinum of Comparative Example 1, and silver of Comparative Example 2 are used as conductors, deposits can be confirmed on all the metals (anodes) after energization under the above energization conditions. It was. However, in aluminum, the alginic acid deposit was firmly bonded to the aluminum, but in platinum and silver, the deposit was easily peeled off by washing with ultrapure water. Therefore, the following analysis of the physical properties of the deposit was performed on the iontophoresis electrode using aluminum of Example 6.

[Characteristics of deposits when aluminum is used as a conductor]
FIG. 9 shows the appearance of an electrode using aluminum after energization for 60, 120, 300, or 600 seconds at a current density of 3.0 mA / cm ² . By energization, deposits were confirmed on the aluminum anode electrode, and the amount of deposition increased with the energization time.

FIG. 10 shows an FT-IR spectrum of the anode surface that was energized for 60, 120, 300, or 600 seconds at a current density of 0.5 mA / cm ² to deposit alginic acid and dried after the energization. The anode surface after drying was measured for a reflection spectrum by a specular reflection method (incident angle 60 degrees) using an infrared spectrophotometer (FT-IR: manufactured by JASCO Corporation, FT / IR-4100N).
The asymmetric stretching vibration of the carboxyl group was detected in the vicinity of 1600 cm ⁻¹ , which revealed that the deposit was alginic acid. As the energization time increased, a peak attributed to the C═O stretching vibration of the carboxyl group was detected in the vicinity of 1730 cm ⁻¹ and the intensity increased. This shows that the proton was generated at the anode due to electrolysis of water, so that the pH was locally reduced, and the carboxyl group of alginic acid was protonated. It is considered that the protonated carboxyl group formed a hydrogen bond, and alginic acid gelled on the electrode surface.

  FIG. 11 shows the amount of alginic acid deposited on the aluminum electrode with respect to the energization time. The amount of alginic acid deposited was calculated by measuring the weight of the electrode after drying and changing the weight before and after energization. As the energization time increased, the amount of alginic acid deposited increased. In addition, as the current density increased, the amount of alginic acid deposited increased.

FIG. 12 shows an SEM photograph of an aluminum cross section in which alginic acid is deposited at a current density of 0.5 mA / cm ² . The cross section of the electrode after drying was observed using a scanning electron microscope (SEM: manufactured by JEOL Ltd., JSM-5310). The thickness of the alginate layer was 3-5 μm in 60 seconds, 8-10 μm in 120 seconds, 18-20 μm in 300 seconds, and 20-22 μm in 600 seconds, and became thicker as the electrolysis time increased.

  The electrode composition for iontophoresis of the present invention can efficiently absorb a local anesthetic into the skin and can be used for local anesthesia in surgery. In addition, an electrode composition for iontophoresis containing insulin can be used for the treatment of diabetes, and a drug can be introduced into the body without using a needle.

11 ... electrode for iontophoresis;
12 ... metal;
13 ... Electrode composition for iontophoresis;
14 ... Power supply;
15 ... Metal electrode;
21 ... cellophane film;
22 ... bolts;
23 ... Donor side of the glass cell;
24 ... Acceptor side of the glass cell;
25 ... Glass cell;
26 ... platinum plate electrode;
27 ... water bath;
28 ... Acrylic plate.

Claims (7)

An alginate gel is deposited on the conductor by dipping in an alginate-containing solution and electrolysis of an aluminum or aluminum alloy conductor connected to the positive electrode and capable of forming an oxide passivation film. The manufacturing method of the metal electrode for iontophoresis which contains the alginate gelatinized by forming the hydrogen bond in the carboxyl group and the conductor of aluminum or aluminum alloy including the process, and the alginate gel deposited on the conductor. The method for producing a metal electrode for iontophoresis according to claim 1, wherein the alginate is sodium alginate, potassium alginate, or ammonium alginate. The method for producing a metal electrode for iontophoresis according to claim 1 or 2, wherein the alginate gel is freeze-dried. The method for producing a metal electrode for iontophoresis according to any one of claims 1 to 3, wherein the alginate gel is crosslinked by metal ions. The manufacturing method of the metal electrode for iontophoresis as described in any one of Claims 1-4 in which the said alginate gel contains a cationic chemical | medical agent. (A) An alginate gel connected to a positive electrode by immersing an electroconductive aluminum or aluminum alloy conductor capable of forming an oxide passive film connected to the positive electrode in a solution containing an alginate and electrolyzing it. And (b) cross-linking the alginate gel deposited on the conductor using metal ions,
The manufacturing method of the metal electrode for iontophoresis of Claim 4 containing this. (A) An alginate gel connected to a positive electrode by immersing an electroconductive aluminum or aluminum alloy conductor capable of forming an oxide passive film connected to the positive electrode in a solution containing an alginate and electrolyzing it. Depositing,
(B) a step of cross-linking the alginate gel deposited on the conductor using metal ions, and (c) a step of binding a cationic agent to the alginate gel ,
The manufacturing method of the metal electrode for iontophoresis of Claim 5 containing this.