JP2000219623A - Tacky gel composition for iontophoresis and device therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a tacky gel composition used for an iontophoresis capable of delivering a basic medicine into a living body efficiently and provide a device for it. SOLUTION: This composition contains a basic medicine, an acidic polymer, a multi-functional epoxy compound, water, a polyhydric alcohol and/or a gelatin, and the ratio of the basic medicine to the acidic polymer is preferably (10:1)-(1:10). Also, the basic medicine is preferably in a free state.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an adhesive gel composition for iontophoresis, which is applied to a transdermal or transmucosal membrane and uses an electric driving force to deliver a basic drug into the body, and a device therefor.

[0002]

2. Description of the Related Art Iontophoresis
Oresis) is a percutaneous and transmucosal absorption promotion system using an electric driving force. The principle is that molecules charged positively in the electric field generated between the anode and the cathode by energization mainly exit from the anode to the cathode. Promotes permeation of drug molecules through the skin barrier based on the force with which negatively charged molecules exit the cathode and travel to the anode [Journal of Controlled Release (Journal of Controlled Release).
rolled Release) 18, 1992,
213-220; Advanced Drug Delivery Review
very Review) 9th volume, 1992, 119
Page; Pharmashutical Research (Pharma)
Ceutical Research), vol. 3, 1986
318-326].

[0003] Conventionally, as adhesive compositions used in transdermal therapeutic systems (TTS), those containing lipophilic bases such as natural rubbers, synthetic rubbers, acrylics and silicones have been widely known. I have. Further, as a hydrophilic pressure-sensitive adhesive, a poultice containing a hydrophilic base such as sodium polyacrylate or carboxyl vinyl polymer is known. Further, an adhesive composition obtained by crosslinking a methoxyethylene maleic anhydride copolymer with a polyfunctional epoxy compound in order to increase the adhesive strength is disclosed in JP-A-56-154421 or JP-A-59-204117. .
As an external patch containing a basic drug, an adhesive gel containing lidocaine or a salt thereof as a base containing a water-soluble polymer, water and a water retention agent as essential components is disclosed in JP-A-4-305523.
No. 6,009,045.

On the other hand, as a base used for administration of a drug by iontophoresis, it is essential to use a water-soluble base, as disclosed in JP-A-58-10050 or JP-A-63-92360. As disclosed in the gazette, a karaya gum base, a polyvinyl alcohol base and the like are conventionally known. These bases have low adhesiveness of the gel and have a problem of compliance in use. Further, since the adhesive composition based on a water-soluble polymer cross-linked with a metal decreases the cohesive strength of the gel and reduces the adhesive strength when energized, a maleic anhydride copolymer or maleic anhydride may be used as an improvement. A pressure-sensitive adhesive composition containing an acid copolymer, a polyfunctional epoxy compound and a polyhydric alcohol is disclosed in
Japanese Patent Application Laid-Open No. 5-97662 discloses a base comprising a copolymer of acrylic acid and acrylamide. However, with these base compositions, the addition of an electrolyte necessary for iontophoresis raises new problems such as a change in physicochemical properties and temporal stability due to a decrease in cohesive strength of the gel and a decrease in adhesive strength. In particular, the tendency becomes stronger when a basic drug or a salt is blended.

Further, as a base for iontophoresis, an adhesive gel composition having low impedance and improved salting out and polarization is disclosed in Japanese Patent Application Laid-Open No. 9-268991. In this base composition for iontophoresis,
For example, moderate viscosity and low electrical resistance can be maintained even when a salt such as sodium chloride is blended, but the physicochemical properties, The adhesive strength and stability over time are not sufficient.

[0006]

However, the conventional lipophilic adhesive composition requires an organic solvent,
There is a problem that a large amount of heat is required at the time of production and a surfactant is required as seen in an emulsion-type acrylic pressure-sensitive adhesive. Further, such a lipophilic pressure-sensitive adhesive composition has relatively high skin irritation, and has a problem in the working environment at the time of production. Further, a cataplasm using such a lipophilic pressure-sensitive adhesive has not yet obtained a sufficient adhesive strength.

The conventional hydrophilic pressure-sensitive adhesive compositions disclosed in JP-A-56-154421 and JP-A-59-204117 have a low viscosity at the time of plastering, so that the thickness of the composition cannot be controlled. There was a problem that it was difficult. Further, in these bases, the physicochemical properties of the gel are significantly changed by the addition of an electrolyte such as a salt. In addition, Japanese Unexamined Patent Application Publication No.
No. 305523 discloses a metal cross-linkable adhesive composition containing lidocaine as a basic drug.
However, the pressure-sensitive adhesive composition based on a water-soluble polymer cross-linked with a metal, in addition to the fact that the cohesive force of the gel is reduced upon energization and the cohesive force is reduced during iontophoresis, in particular, the adhesive composition from the anode In iontophoresis, there is a problem in safety due to transfer of metal ions to the skin.

On the other hand, conventional karaya gum-based bases and polyvinyl alcohol-based bases for iontophoresis disclosed in the above-mentioned JP-A-58-10050 and JP-A-63-92360 are: The effect of the electrolyte on the gelation is small, and the conductivity during energization can be ensured.
However, these bases have problems in that they have low adhesive strength, poor compliance in use, and are inferior in stability over time.

In the conventional hydrophilic pressure-sensitive adhesive composition disclosed in Japanese Patent Application Laid-Open No. 63-92683, the amount of the base polymer is increased so that plastering becomes possible due to the low viscosity at the time of plastering. There is a problem that the base polymer must be neutralized with an alkali to dissolve the base polymer. Therefore, in these conventional hydrophilic pressure-sensitive adhesive compositions, there is a problem that the diffusion resistance of the drug is increased or the transport number is reduced, and the permeability of the drug is substantially reduced.

Further, a base comprising a copolymer of acrylic acid and acrylamide disclosed in JP-A-5-97662 and a methoxymaleic anhydride copolymer disclosed in JP-A-9-268991 or In the adhesive composition comprising a methoxymaleic acid copolymer and a cross-linked N-vinylacetamide, when a neutral electrolyte or a component is added, properties such as adhesive strength are not impaired. The solubility of a drug to which a component that causes an increase in the pH of the drug is added decreases, thereby decreasing the absorbability.
Further, when an acidic pH adjuster such as hydrochloric acid is added to suppress a change in the pH of the gel, there is a problem that the moldability and the adhesive strength of the gel are also reduced.

Accordingly, an object of the present invention is to provide an adhesive gel composition for iontophoresis and an apparatus therefor, which can solve the above problems and can efficiently deliver a basic drug into the body. is there.

[0012]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object and have reached the present invention. The adhesive gel composition for iontophoresis according to the present invention comprises a base It contains a sex drug, an acidic polymer, a polyfunctional epoxy compound, water, a polyhydric alcohol and / or gelatin. Here, the weight ratio of the basic drug to the acidic polymer is preferably set to 10: 1 to 1:10. The acidic polymer is polyacrylic acid, methoxyethylene maleic anhydride copolymer, methoxyethylene maleic acid copolymer, isobutylene maleic anhydride copolymer,
It is composed of one or a combination of two or more selected from the group consisting of isobutylene maleic acid copolymer, carboxyvinyl polymer and carboxymethyl cellulose.

The basic drug is preferably in a free form.
Examples of the basic drug include a local anesthetic, and preferably a combination of a local anesthetic and a vasoconstrictor. here,
Lidocaine is used as a local anesthetic, and epinephrine is used as a vasoconstrictor. In this case, the weight ratio of lidocaine to epinephrine is preferably 1000: 1 to 2: 1. The amount of lidocaine is 1% by weight to 20%.
% By weight, the amount of epinephrine is 0.001% by weight or more
It is preferably 0.5% by weight. In addition, it is desirable to include an antioxidant. The antioxidant comprises one or a combination of two or more selected from the group consisting of sodium pyrosulfite, sodium bisulfite and oxyquinoline sulfate. Here, the compounding amount of the antioxidant is 0.001% by weight.
It is preferable to set it to 1.0% by weight. The iontophoresis device according to the present invention includes a donor electrode, a reference electrode, and a power supply device electrically connected to the donor electrode and the reference electrode. At least one of a pulse DC and a pulse depolarized DC, wherein the current amount is 0.
It is configured to be 5 to 2.0 mA · min / cm ² .

According to this constitution, a matrix-type adhesive gel composition for iontophoresis and a device for efficiently delivering a basic drug can be obtained. In this adhesive gel composition and its device, without causing a decrease in drug transport number due to the gel composition,
Excellent gel moldability and adhesiveness, and low skin irritation,
It also has the advantage that it can be manufactured easily and inexpensively by plastering or filling.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, preferred embodiments of an adhesive composition for iontophoresis containing a basic drug according to the present invention and a device therefor will be described in detail. The adhesive gel composition according to the present invention contains an acidic polymer, a polyfunctional epoxy compound, water, a polyhydric alcohol and / or gelatin, and a basic drug, and adjusts the weight ratio of the acidic polymer to the basic drug. Thereby, an iontophoresis composition excellent in moldability and adhesiveness is provided without lowering the drug transport number. For example, the acidic polymer in the adhesive gel composition is preferably a water-soluble polymer, for example, polyacrylic acid, methoxyethylene maleic anhydride copolymer, methoxyethylene maleic acid copolymer, isobutylene maleic anhydride copolymer, isobutylene Maleic acid copolymer, carboxyvinyl polymer and carboxymethylcellulose can be used as a base polymer with one or a combination of two or more selected from the group consisting of a base polymer, it is possible to have adhesion to skin or mucous membranes, In addition, by using a polyfunctional epoxy compound as a crosslinking agent, it is possible to suppress a decrease in cohesive strength of the composition. In addition, by adding a free form of a basic drug to neutralize the carboxyl group of the base polymer, the decrease in cohesive force is suppressed without the need for adding a pH regulator, etc., and the pH is increased to reduce skin irritation. And competition between the drug and hydrogen ions during iontophoresis energization is reduced, and the permeability of the drug is increased. Furthermore, the addition of polyhydric alcohol makes it possible to increase the cohesive strength, water retention and drug solubility of the pressure-sensitive adhesive composition, and the addition of gelatin improves the formability of the gel, making it easier to paste and cut during production. become.

As described above, by combining the basic drug and the acidic polymer according to the present invention, the pH of the base can be adjusted to a weak acid to a neutral, and an appropriate gel moldability and adhesiveness can be obtained. On the other hand, in a base composition comprising a combination of a basic drug and a basic polymer or a neutral polymer, the pH of the gel greatly changes to the basic side, and in addition to the solubility of the drug and the solubility of the drug, Absorption decreases as dissociation of the compound decreases. Further, when an acidic pH adjuster such as hydrochloric acid is added, the gel forming ability and the tackiness are reduced. In addition, a base composition using a neutral polymer such as polyvinyl alcohol or polyvinylpyrrolidone as a base polymer has a problem in that the adhesive force is insufficient and compliance in use is poor.

The weight ratio of the basic drug to the acidic polymer in the present invention is not particularly limited as long as the pH of the base can be adjusted from a weak acid to a neutral, but it is not limited. 10: 1 which does not affect the properties and release properties
１ ： 1: 10 is desirable. More preferably, 5: 1 to 1:
5, more preferably 3: 1 to 1: 3. In this range, the gel is adjusted to a slightly acidic to neutral pH of 3-7. By adjusting the pH and the adhesive strength to such a level, the skin is less irritating and a suitable adhesiveness is obtained, so that it is suitable in terms of usability, practicality, and viscosity at the time of production.

The acidic polymer according to the present invention is not particularly limited as long as it is a hydrophilic adhesive base which can be produced without a solvent and has a low irritancy to the skin and a moderate adhesive force. , Containing acidic polymers include polyacrylic acid, methoxyethylene maleic anhydride copolymer, methoxyethylene maleic anhydride copolymer, isobutylene maleic anhydride copolymer, isobutylene maleic acid copolymer,
A carboxyvinyl polymer or carboxymethylcellulose is included. By using these acidic polymers as the base polymer, it is possible to suppress the decrease in the transport number, that is, the decrease in the drug permeability due to the competing ions. The amount of the acidic polymer in the present invention is preferably 1 to 20% by weight, more preferably 1 to 10% by weight. The above compounding amount is 1% by weight
If it is less than 20%, it tends to have no gel moldability and the adhesiveness is low. If it exceeds 20% by weight, the cohesive strength is so strong that it tends to be unfavorable in terms of production such as plaster or filling.

Further, as a polymer added for purposes other than imparting tackiness, for example, as a tackifier or binder, agar, starch, mannan, xanthan gum, locust bean gum, carrageenan, gellan gum, tamarind gum, card Orchid, pectin, furceleran, guar gum, alginic acid, sodium alginate,
Examples include polysaccharides such as tara gum, karaya gum, gum arabic, cellulose and derivatives thereof, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, and the like, and these are used alone or in combination of two or more.

Examples of the polyfunctional epoxy compound used in the present invention include sorbitol polyglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, ethylene glycol diglycidyl ether, and polyethylene glycol diglycidyl ether. Propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether and the like. The compounding amount of the polyfunctional epoxy compound according to the present invention is preferably 0.01 to 2% by weight based on the whole base.
If the amount is less than 0.01% by weight, gel formability tends not to be obtained, and if it exceeds 2% by weight, tackiness tends to be lost.

The polyhydric alcohol used in the present invention includes, for example, ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1,3-butylene glycol, glycerin, D-sorbitol and D-mannitol. And the like, and sugar alcohols and the like, among which polyethylene glycol and glycerin are preferred. These may be used alone or in combination of two or more. The blending amount of the polyhydric alcohol according to the present invention is preferably 10 to 60% by weight. If the amount is less than 10% by weight, sufficient cohesion tends not to be obtained, and if it exceeds 60% by weight, tackiness tends to be lost.

The water used in the present invention is necessary for swelling the stratum corneum of the skin, improving the permeability of the drug, and obtaining conductivity. The water content is preferably 10 to 80% by weight, more preferably. Is desirably in the range of 20 to 50% by weight.

The gelatin contained in the pressure-sensitive adhesive composition according to the present invention may be either acid-treated or alkali-treated, and the amount of gelatin is preferably 0.1 to 15% by weight. If the amount is less than 0.1% by weight, sufficient cohesion tends not to be obtained, and if it exceeds 15% by weight, appropriate tackiness tends not to be obtained. Further, if necessary, the electrolyte, a pH adjuster, a stabilizer, a thickener, a wetting agent, as long as the gel formability, adhesiveness and drug absorbability are not affected.
Surfactants, solubilizers, absorption promoters and the like may be added. For example, examples of the electrolyte include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, a cation exchange resin, and an anion exchange resin. The amount of the electrolyte according to the present invention is not particularly limited.

The basic drug used in the present invention is not particularly limited as long as it has a pharmacological activity, and examples thereof include antibiotics, antifungal agents, inotropic agents, therapeutic agents for arrhythmias, and vasodilators. , Diuretics, antihypertensives, antihyperlipidemics, cardiovascular agents, antiplatelet agents, hemostatic agents, anticoagulants, antitumor agents, antipyretics, analgesics, anti-inflammatory agents, antitussives, sedatives, Muscle relaxants, antiepileptics, antidepressants, antiulcers, antiallergics, antidiabetic agents, antituberculosis agents, hormonal agents,
Narcotic antagonists, bone resorption inhibitors, angiogenesis inhibitors, local anesthetics and the like are used.

As an example, any of a free form and a salt of a basic drug may be used as long as they do not affect the formability and adhesiveness of the gel, but the free form is preferable. As antibiotics, for example, gentanmycin, lipidomycin, sisomicin, tetracycline, ampicillin, cefotiam, cefazolin, thienacine, sulfazecin,
Streptomycin, kanamycin, rifampicin and the like are used. Examples of antifungal agents include amphotericin B, itraconazole, fluconazole, 2-
[(1R, 2R) -2- (2,4-difluorophenyl-2-hydroxy-1-methyl-3- (1H-1,2,
4-triazol-1-yl) propyl] -4- [4-
2,2,3,3-tetrafluoropropoxy] phenyl] -3 (2H, 4H) -1,2,4-triazolone and the like are used. Dopamine, dobutamine, ubidecarenone and the like are used as inotropic agents. Examples of the antiarrhythmic agent include procainamide, lidocaine, phenytoin, propranol, metoprolol, verapamil, diltiazem, oxyprenol and the like. As the vasodilator, for example, nicardipine, verapamil, papaverine, trazoline and the like are used. As the diuretic, for example, acetazolamide, methazolamide, chlorothiazide, furosemide, triamterene, amiloride, aminometrozine and the like are used. As antihypertensives, for example, hydralazine, budralazine, prazosin,
Doxazosin, carteolol, clonidine, enalapril, captopril, delapril, manidipine, pinacidil, minoxidil and the like are used. As the circulatory solvent, for example, ethylephrine, dihydroergotamine and the like are used. As an antiplatelet agent, for example, ticlopidine or the like is used. Epinephrine or the like is used as a hemostatic agent. As the antitumor agent, for example, 6-mercaptopurine, cytarabine, bleomycin, actinomachine D, mitomachine C, adriamycin, procarbazine, doxorubicin and the like are used.

Examples of antipyretics, analgesics or anti-inflammatory agents include tiaramid, emorfazone, buprenorphine, eptazosin, pentazocine, butorphanol,
Tramazole, meperidine, morphine, hydromorphine, fentanyl and the like are used. As the muscle relaxant, for example, eperisone, tizanidine, chlorphenesin, tolperisone and the like are used. Examples of the antidepressant include amitriptyline, imipramine, clomipramine, desipramine, maprotiline and the like. Examples of antitussive expectorants include amproxol,
Bromhexine, ephedrine, salbutamol, tulobuterol, formoterol, azelastine, ketotifen, codeine, picoperidamine and the like are used.
As the sedative, for example, chlorpromazine, fluphenazine, atropine and the like are used. As the muscle relaxant, for example, dantrolene, eperisone, tizanidine, tolperisone, pridinol, tubocurarine and the like are used. As the antiepileptic agent, for example, phenytoin, ethosuximide and the like are used. As the antidepressant, for example, imipramine, phenelzine and the like are used.

As the anti-ulcer agent, for example, cimetidine, famotidine and the like are used. Examples of antiallergic agents include diphenylhydramine, chlorpheniramine, cyproheptadine, ketotifen, epinastine,
Tripelenamine, clemizole and the like are used. As a therapeutic agent for diabetes, for example, tolbutamide, chlorpropamide, glibenclomide, acetohexamide, midaglizole, glymidine, glipizide, metformin and the like are used. As the antituberculous agent, for example, streptomycin, kanamycin, isoniazid, ethambutol, pyrazinamide and the like are used. Examples of narcotic antagonists include protamine, naloxone, levallorphan,
Nalorphine or the like is used. As the bone resorption inhibitor, for example, raloxifene, alendronate and the like are used.

Examples of the local anesthetic include lidocaine,
Tetracaine, procaine, benzocaine, etidocaine, prilocaine, dibucaine, bupivacaine, proparacaine, phenacaine, cocaine, oxybuprocaine, propitocaine, ethyl aminobenzoate, orthocaine, oxesazein, mepivacaine or chloroprocaine are used.

The basic drug used in the present invention includes the above-mentioned local anesthetics, and a more preferred basic drug includes a combination of a local anesthetic and a vasoconstrictor. Lidocaine is a typical local anesthetic,
It is used for nerve block therapy for shingles neuralgia and postherpetic neuralgia due to surface / infiltration / transmission anesthesia, and for pain relief at the time of puncture of a venous indwelling needle. In the iontophoresis composition comprising the acidic polymer and the basic drug according to the present invention, the local anesthetic effect of lidocaine can be reduced by shortening the action time, enhancing the effect and maintaining the action by using the vasoconstrictor epinephrine in combination. It is. This is due to the fact that in the base composition of the present invention, the competing ionic species coexisting in the base were small and the drug was effectively absorbed.

The polyacrylic acid, methoxyethylene maleic anhydride copolymer, methoxyethylene maleic acid copolymer, isobutylene maleic anhydride copolymer, isobutylene maleic acid copolymer in the iontophoresis composition for local anesthesia according to the present invention. The weight ratio of the acidic polymer consisting of one or a combination of two or more selected from the group consisting of a polymer, a carboxyvinyl polymer and carboxymethylcellulose and a basic drug consisting of lidocaine and epinephrine is adjusted so that the pH of the base is weak acid to medium. The combination is not particularly limited as long as it is a combination that can be adjusted to the property.
1:10 is desirable. More preferably, 5: 1 to 1: 5
And more preferably from 3: 1 to 1: 3. Further, the weight ratio of the basic drug lidocaine to epinephrine is not particularly limited, but is preferably 1000: 1 to 2: 1. Gels prepared in this range are adjusted to a weakly acidic to neutral pH of 3-7. By adjusting the pH and the adhesive strength to such a level, the skin is less irritating and a suitable adhesiveness is obtained, so that it is suitable in terms of usability, practicality, and viscosity at the time of production.

Further, the amount of lidocaine according to the present invention is 1 to 20% by weight, more preferably 1 to 10% by weight. The amount of epinephrine is 0.001.
% To 0.5% by weight, more preferably 0.01 to 0.5% by weight.
% To 0.5% by weight. If the amount of lidocaine is less than 1% by weight, sufficient absorbency cannot be obtained, and if the amount exceeds 20% by weight, cohesive strength tends to be strong, which tends to be unfavorable in the production of plasters and the like. When the amount of epinephrine is less than 0.001% by weight, the effect of lidocaine tends not to be enhanced, and when the amount exceeds 0.5% by weight, a threshold value of the drug effect is obtained.

Further, the antioxidant according to the present invention is added for the purpose of preventing the oxidation of epinephrine. The type of the antioxidant is not particularly limited, but it is preferably a water-soluble antioxidant, and a substance having a small number of competing ionic species is preferred. . For example, L-ascorbic acid, erythorbic acid, citric acid, sodium edetate, sodium pyrosulfite, sodium hydrogen sulfite, oxyquinoline sulfate and the like are used, and one or a combination of two or more selected from the group is used. Can be
In particular, since sodium bisulfite or oxyquinoline sulfate exerts an antioxidant action in a trace amount, it is useful in that it can be added without impairing the physicochemical properties of the adhesive gel.
The blending amount of sodium bisulfite or oxyquinoline sulfate is preferably 0.001% by weight to 1.0% by weight, more preferably 0.001% by weight to 0.5% by weight, and particularly preferably 0.001% to 0.5% by weight. 3% by weight is preferred.

The composition of the reference electrode constituting the iontophoresis device to be described later is the same as that of the adhesive gel composition of the donor electrode containing the drug as described above, and is made of an acidic polymer, a polyfunctional epoxy compound or a metal compound. An electrolyte is added to a base component composed of one or two of them, water, polyhydric alcohol and / or gelatin to further improve conductivity. The crosslinking agent used for the reference electrode in the present invention is not particularly limited, but at least one of a polyfunctional epoxy compound and a metal compound is selected, and such a metal compound includes aluminum hydroxide, aluminum silicate, and water. Examples include magnesium oxide and calcium hydroxide. Examples of the electrolyte include chlorides, phosphates or sulfates of sodium, potassium, calcium, and magnesium, cation exchange resins, and anion exchange resins. Further, the electrolyte includes a pH adjuster. Examples of such a pH adjuster include amines such as triethanolamine and diethanolamine, salts of acidic polymers such as sodium hydroxide, sodium polyacrylate and sodium carboxymethylcellulose, and basic polymers. As the physicochemical properties of such a reference electrode, it is desirable to have similar viscosity, moldability, adhesiveness, etc., as with the donor electrode. That is,
It is preferable that the gel of the reference electrode is adjusted to a weakly acidic to neutral pH of 3 to 7 and has the same adhesive strength. By exhibiting the same level of tackiness as the donor electrode, the skin is less irritating and a suitable tackiness is obtained. further,
With respect to the adhesiveness when the donor electrode, the reference electrode, and the power supply device connected thereto are applied to the skin, a well-balanced preparation without discomfort at the time of application can be obtained. Also,
Since the base compositions of the donor electrode and the reference electrode are similar, they are also effective in terms of production such as plaster and filling properties.

The iontophoresis device according to the present invention is not limited to the number of donor electrodes and reference electrodes, but may include at least one pair of donor electrodes and reference electrodes, and electrically connect these donor electrodes and reference electrodes. And a single power supply device. Adhesive gels are respectively laminated on the donor electrode and the reference electrode. The electrode used in the present invention is not particularly limited as long as it is made of a conductive electrode material that can be generally used in iontophoresis. Examples of such a conductive material include silver, silver chloride, aluminum, zinc, copper, iron, carbon, platinum, titanium, and stainless steel. Among them, silver or silver
Silver chloride has good electrical properties such as resistance, and if it is manufactured using a paste material, it is inexpensive and has high productivity.

The present device is useful for transdermally administering a drug by iontophoresis using various applicators applicable to the skin. FIG.
FIG. 1 is a schematic view showing a cross section of an example of an applicator provided with the adhesive gel composition according to the present invention. As shown in FIG. 1, the basic part of the applicator includes a backing (made of polyethylene terephthalate) 1, an electrode (silver paste) 2 laminated thereon, an adhesive gel 3 disposed on the electrode 2, and an adhesive gel. And a liner (made of polyethylene terephthalate) 4 covering the same. In addition, the electrode 2 is provided with an electrode printing section so that the electrode 2 can be connected to the electrode device directly or by a connector or the like. The device thus configured is used by removing the liner 4 immediately before use and affixing the adhesive gel 3 so that the surface of the adhesive gel 3 directly contacts the skin.

The method of reinforcing this device, namely the composition of the backing, the structure of the donor and reference electrodes,
The integral type on the same support or the separation type configuration on two or more types of supports is not particularly limited. Further, the numbers of the donor electrodes and the reference electrodes are not limited, and at least one or more of each may be used. Also,
The form of such a device may be any form, such as, but not limited to, a rectangle, a circle, an oval, a square, a heart, a jaw, and the like.
The size and the color are not particularly limited as long as they have practicality. FIG. 2 is a schematic diagram showing an example of an iontophoresis device provided with the adhesive gel composition according to the present invention. As shown in FIG. 2, the apparatus comprises a backing 5, a donor electrode 6 and a reference electrode 7 laminated thereon.
And a donor electrode side composition 8 disposed on the donor electrode 6
And a reference electrode-side composition 9 disposed on the reference electrode 7, and a liner 10 covering both the compositions 7 and 8.
And a power supply device 11. Power supply 11
The donor electrode 6 is connected to one of the electrodes, and the reference electrode 7 is connected to the other electrode. When using this device, the liner 10 is removed, and the donor electrode side composition 6 and the reference electrode side composition 7 are attached so that the surfaces thereof directly contact the skin.

When the iontophoresis device according to the present invention is used, for example, for local anesthesia, a DC voltage is applied between the electrodes of the device by using at least one of DC, pulse DC, and pulse depolarization DC. It can be performed by energizing. As the power supply, a power supply capable of applying a continuous DC voltage or a pulse DC voltage is preferable. The frequency of the pulse DC voltage is preferably 0.1 to 200 kHz, more preferably 1 to 100 kHz, and particularly preferably 5 to 80 kHz.
It is appropriately selected from the range of Hz. The on / off ratio of the pulse DC voltage is from 1/100 to 20 /
1, preferably 1/50 to 15/1, more preferably 1/30 to 10/1.

In this case, the energization time is not particularly limited, but is preferably 60 minutes or less, more preferably 30 minutes or less, and further preferably 15 minutes or less. The current amount total current is 0.25~5.00mA · min / cm ^2, more preferably from to the 0.5~2.0mA · min / cm ^2. Here, the amount of current means the product of the current used for the permeation of the drug and time, and when a pulse DC or a pulse depolarized DC is applied, the current indicates a transmission current.

[0039]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples based on experimental examples, but the present invention is not limited to these examples. In the following description, “%” means “% by weight” unless otherwise specified. In the experimental examples, the physical properties of the gel were evaluated according to the respective criteria shown in Table 1 based on the moldability, body feel, and adhesiveness. The pH of the gel surface was measured using an electrode for surface pH measurement (Horiba, 6261-).
10C electrode). An elasticity value (manufactured by San Kagaku, Rheometer CR-200D) and a bodily sensation value (exudation) were used as an index of moldability, and a probe tack value (probe tack tester, manufactured by Rigaku Corporation) was used as an index of adhesiveness.

[0040]

[Table 1]

Further, the pharmacological effect of the preparation containing a local anesthetic was also evaluated. Before the start of the experiment, the back of the guinea pig was shaved with a clipper and an electric razor, and the skin surface was thoroughly wiped with gauze soaked in slightly warm water. The right or left side of the center of the back was stimulated with a stimulating needle, and the site where the skin contraction reaction appeared reliably was designated as the adhesive gel application site, and the control electrode was applied to the other hair removal sites. A drug-containing adhesive gel (donor electrode, 6 cm ² ) was connected to the anode side, and an electrode containing sodium chloride (reference electrode, 6 cm ² ) was connected to the cathode side, and current supply was started. Energization is DC current 0.1m
A / cm ² for 15 minutes. After completion of the energization, the site to which the donor electrode was applied was stimulated six times with a stimulating needle, and changes in the skin contraction response were observed over time. The local anesthesia effect was determined based on the anesthesia effect immediately after power-on, from-to ++ shown in Table 2. The sustainability of the anesthesia effect was as follows. Things that last,
Those with almost no effect were evaluated as x.

[0042]

[Table 2]

<Experimental Example 1> Table 3 shows examples of combinations of basic drugs and acidic or neutral polymers in the present invention. Examples 1 and 2, using lidocaine or lidocaine hydrochloride as a basic drug, polyacrylic acid as an acidic polymer, and polyvinyl alcohol as a neutral polymer,
The adhesive compositions of Comparative Examples 1 and 2 were prepared.

[0044]

[Table 3]

Example 1 8 parts by weight of polyacrylic acid 40 parts by weight of glycerin 0.1 part by weight of ethylene glycol diglycidyl ether 43.9 parts by weight of water 8 parts by weight of lidocaine While heating the components in this formulation to 50 ° C. The mixture was stirred until uniform, and finally a crosslinking agent was added at 40 ° C. to obtain a pressure-sensitive adhesive composition of the present invention. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Example 2 8 parts by weight of polyacrylic acid 40 parts by weight of glycerin 0.1 part by weight of ethylene glycol diglycidyl ether 43.9 parts by weight of water 8 parts by weight of lidocaine hydrochloride The components in this formulation were heated to 50 ° C. Then, the mixture was stirred until uniform, and finally a crosslinking agent was added at 40 ° C. to obtain a pressure-sensitive adhesive composition of the present invention. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

(Comparative Example 1) Polyvinyl alcohol 12 parts by weight Water 80 parts by weight Lidocaine 8 parts by weight The components in this formulation were stirred and dissolved until uniform while heating, and the solution was placed on a release-treated PET liner for 1 hour.
It was plastered with a thickness of mm, and was freeze-crosslinked at -80 ° C to obtain a comparative adhesive composition of the present invention. The completed adhesive composition was cut into an appropriate shape and used for the test.

(Comparative Example 2) Polyvinyl alcohol 12 parts by weight Water 80 parts by weight Lidocaine hydrochloride 8 parts by weight The components in this formulation were stirred and dissolved until uniform while heating.
It was plastered with a thickness of mm, and was freeze-crosslinked at -80 ° C to obtain a comparative adhesive composition of the present invention. The completed adhesive composition was cut into an appropriate shape and used for the test.

Table 4 shows the adhesive compositions of Examples 1 and 2 and Comparative Examples 1 and 2 evaluated for pH, moldability, sensation and adhesiveness. As a result, in the combination of the basic drug and the acidic polymer in Examples 1 and 2, excellent physical properties were obtained in terms of gel moldability and adhesiveness. In addition, the pH of the gel became 5 or less, and the basic drug was present in a dissociated state, suggesting that the basic drug was present in an ion form advantageous for iontophoresis. On the other hand, Comparative Examples 1 and 2
, Suggesting that the drug solubility may decrease and the abundance in the ionic form may decrease, and the viscosity of the gel was remarkably low.

[0050]

[Table 4]

<Experimental Example 2> Table 5 shows composition examples using a neutralizing agent in the combination composition examples of the basic drug and the acidic polymer in the present invention. The adhesive compositions of Comparative Examples 3 to 5 were prepared using lidocaine hydrochloride as a basic drug and adding sodium hydroxide as a neutralizing agent.

[0052]

[Table 5]

Comparative Example 3 Polyacrylic acid 8 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Water 42.9 parts by weight Sodium hydroxide 1.0 part by weight Lidocaine hydrochloride 8 parts by weight The components were mixed and stirred while heating to 50 ° C until uniform, and finally a crosslinking agent was added at 40 ° C to obtain the pressure-sensitive adhesive composition of the present invention. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Comparative Example 4 Polyacrylic acid 8 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Water 41.9 parts by weight Sodium hydroxide 2.0 parts by weight Lidocaine hydrochloride 8 parts by weight The components were mixed and stirred while heating to 50 ° C until uniform, and finally a crosslinking agent was added at 40 ° C to obtain the pressure-sensitive adhesive composition of the present invention. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

(Comparative Example 5) 8 parts by weight of polyacrylic acid 40 parts by weight of glycerin 0.1 part by weight of ethylene glycol diglycidyl ether 39.9 parts by weight of water 4.0 parts by weight of sodium hydroxide 8 parts by weight of lidocaine hydrochloride The components were mixed and stirred while heating to 50 ° C until uniform, and finally a crosslinking agent was added at 40 ° C to obtain the pressure-sensitive adhesive composition of the present invention. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

As shown in Table 6, the combination of polyacrylic acid, which is an acidic polymer, and lidocaine, which is a basic drug, as in Example 1, shows excellent physical properties in both moldability and adhesiveness. The composition shown in No. 2 has a low pH and is slightly inferior in moldability. Therefore, the adhesive compositions of Comparative Examples 3 to 5 were obtained by adding sodium hydroxide as a pH adjuster. As a result, when the pH of the gel was increased, the moldability and body feel of the gel were improved, but the tendency of the adhesiveness to decrease was observed. Furthermore, using the adhesive compositions of Examples 1 and 2 and Comparative Examples 3 to 5, the local anesthetic effect of the guinea pig by the pin-licking method was evaluated. As a result, as shown in Table 6, compared with the pressure-sensitive adhesive composition of Example 1, in Comparative Examples 4 and 5, a decrease in drug efficacy was observed. This is probably because the local anesthetic effect was reduced due to competition between the drug and the sodium ion of the sodium hydroxide as a pH regulator added to improve the gel formability.

[0057]

[Table 6]

<Experimental Example 3> Comparison of the crosslinking agent in the adhesive gel composition of the present invention and the effect of the addition of polyhydric alcohol were evaluated. As shown in Table 7, lidocaine and epinephrine were used as basic drugs, and a polyfunctional epoxy compound or a metal compound was used as a crosslinking agent.
Was prepared. Further, an adhesive composition of Example 4 to which gelatin was added was prepared.

[0059]

[Table 7]

(Example 3) Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Water 45.6 parts by weight Lidocaine 8 parts by weight Epinephrine 0.1 part by weight Sodium bisulfite 0.3 part by weight The mixture was stirred while heating until uniform, and finally epinephrine, an antioxidant and a crosslinking agent were added at 40 ° C. to obtain a pressure-sensitive adhesive composition of the present invention. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

(Example 4) Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 5 parts by weight Water 40.5 parts by weight Lidocaine 8 parts by weight Epinephrine 0.1 parts by weight Bisulfite 0.3 parts by weight of sodium The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally, epinephrine, an antioxidant and a crosslinking agent were added at 40 ° C. to obtain a comparative adhesive composition. . It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Comparative Example 6 Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Aluminum hydroxide 1 part by weight Gelatin 5 parts by weight Water 39.6 parts by weight Lidocaine 8 parts by weight Epinephrine 0.1 part by weight Sodium bisulfite 0.3 Parts by weight The components in this formulation were mixed and stirred while heating to 50 ° C until uniform, and finally epinephrine, an antioxidant and a crosslinking agent were added at 40 ° C to obtain a comparative adhesive composition. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

As shown in Table 8, the pressure-sensitive adhesive compositions of Examples 3 and 4 were excellent in gel moldability, body feel and tackiness. On the other hand, in Comparative Example 6, the gel moldability was low,
Bleeding was observed and the feeling was bad. Further, Comparative Example 6
In this case, epinephrine reacted with aluminum, and coloring of the gel was observed during storage. On the other hand, the pharmacological effect was high in Examples 3 and 4, while a high local anesthetic effect was recognized, but in Comparative Example 6, a tendency to decrease was observed. Here, the composition of Example 4 to which gelatin is added has an advantage that handling at the time of production such as plaster or cutting is easy.

[0064]

[Table 8]

<Experimental Example 4> The influence of the weight ratio of a local anesthetic and an acidic polymer on the moldability, adhesiveness and pharmacological effect of the adhesive gel composition of the present invention was evaluated. As shown in Table 9, lidocaine as a basic drug is 2 to 12%,
The adhesive compositions of Examples 5 to 10 and Comparative Examples 7 to 9 were prepared in a range of 0.1% epinephrine and 2% to 8% polyacrylic acid as an acidic polymer.

[0066]

[Table 9]

Example 5 Polyacrylic acid 4 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 47.5 parts by weight Lidocaine 4 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Example 6 Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 45.5 parts by weight Lidocaine 4 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Example 7 8 parts by weight of polyacrylic acid 40 parts by weight of glycerin 0.1 part by weight of ethylene glycol diglycidyl ether 4.0 parts by weight of gelatin 43.5 parts by weight of water 4 parts by weight of lidocaine 0.1 part by weight of epinephrine 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Example 8 Polyacrylic acid 4 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 47.5 parts by weight Lidocaine 4 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Example 9 Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 41.5 parts by weight Lidocaine 8 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Example 10 Polyacrylic acid 8 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 39.5 parts by weight Lidocaine 8 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Comparative Example 7 Polyacrylic acid 8 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 45.5 parts by weight Lidocaine 2 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Comparative Example 8 Polyacrylic acid 2 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 45.5 parts by weight Lidocaine 8 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Comparative Example 9 Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4.0 parts by weight Water 37.5 parts by weight Lidocaine 12 parts by weight Epinephrine 0.1 parts by weight 0.3 parts by weight of sodium hydrogen sulfite The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally at 40 ° C., epinephrine, an antioxidant and a crosslinking agent were added to prepare a comparative adhesive composition. Obtained. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

As shown in Table 10, the pressure-sensitive adhesive compositions of Examples 5 to 10 were all excellent in moldability, tackiness and pharmacological effects. On the other hand, in the composition of Comparative Example 7, the amount of the polymer was small and the pressure-sensitive adhesive composition was incomplete in moldability.
With the weight ratio between the acidic polymer and the basic drug in Comparative Examples 8 and 9, sufficient neutralization could not be performed, and moldability was not sufficient. In particular, in Comparative Example 8, the dissolution of the basic drug was insufficient, and crystals were observed in the gel. The adhesiveness of such an adhesive composition was extremely low.

[0077]

[Table 10]

<Experimental Example 5> The influence of the weight ratio of lidocaine to epinephrine on the moldability, adhesiveness and pharmacological effect of the adhesive gel composition of the present invention was evaluated. Table 11
As shown in Table 2, the adhesive compositions of Examples 11 to 30 and Comparative Examples 10 to 19 were prepared in the range of 0 to 10% of lidocaine and 0 to 0.5% of epinephrine. The addition amount of the acidic polymer in the composition was adjusted according to the addition amount of the basic drug.

[0079]

[Table 11]

Examples 11 to 15 Polyacrylic acid 4 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 50.1 to 50.59 parts by weight Lidocaine 1 part by weight Epinephrine 0 0.010 to 0.500 parts by weight Sodium bisulfite 0.3 parts by weight The ingredients in this formulation were heated and mixed at 50 ° C. until uniform, and finally at 40 ° C. epinephrine, an antioxidant and a crosslinking agent were added. It was added to obtain a comparative adhesive composition. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Examples 16 to 20 Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 45.1 to 45.59 parts by weight Lidocaine 4 parts by weight Epinephrine 0 0.010 to 0.500 parts by weight Sodium bisulfite 0.3 parts by weight The ingredients in this formulation were heated and mixed at 50 ° C. until uniform, and finally at 40 ° C. epinephrine, an antioxidant and a crosslinking agent were added. It was added to obtain a comparative adhesive composition. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Examples 21 to 25 Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 41.1 to 41.59 parts by weight Lidocaine 8 parts by weight Epinephrine 0 0.010 to 0.500 parts by weight Sodium bisulfite 0.3 parts by weight The ingredients in this formulation were heated and mixed at 50 ° C. until uniform, and finally at 40 ° C. epinephrine, an antioxidant and a crosslinking agent were added. It was added to obtain a comparative adhesive composition. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Examples 26 to 30 Polyacrylic acid 8 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 37.1 to 37.59 parts by weight Lidocaine 10 parts by weight Epinephrine 0 0.010 to 0.500 parts by weight Sodium bisulfite 0.3 parts by weight The ingredients in this formulation were heated and mixed at 50 ° C. until uniform, and finally at 40 ° C. epinephrine, an antioxidant and a crosslinking agent were added. It was added to obtain a comparative adhesive composition. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

(Comparative Examples 10 to 15) Polyacrylic acid 4 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 51.1 to 51.6 parts by weight Epinephrine 0 to 0.500 Parts by weight Sodium bisulfite 0.3 part by weight The components in this formulation are heated and mixed at 50 ° C. until uniform, and finally mixed at 40 ° C. with epinephrine, an antioxidant and a crosslinking agent. I got something. It was plastered to a thickness of 1 mm on a release-treated PET liner, cut into an appropriate shape, and used for the test.

Comparative Example 16 Polyacrylic acid 4 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 50.9 parts by weight Lidocaine 1 part by weight Then, the mixture was stirred while being heated until uniform, and finally a crosslinking agent was added at 40 ° C. to obtain a comparative adhesive composition. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

(Comparative Example 17) Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 45.9 parts by weight Lidocaine 4 parts by weight Then, the mixture was stirred while being heated until uniform, and finally a crosslinking agent was added at 40 ° C. to obtain a comparative adhesive composition. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

Comparative Example 18 Polyacrylic acid 6 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 41.9 parts by weight Lidocaine 8 parts by weight Then, the mixture was stirred while being heated until uniform, and finally a crosslinking agent was added at 40 ° C. to obtain a comparative adhesive composition. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

Comparative Example 19 Polyacrylic acid 8 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 37.9 parts by weight Lidocaine 10 parts by weight Then, the mixture was stirred while being heated until uniform, and finally a crosslinking agent was added at 40 ° C. to obtain a comparative adhesive composition. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

Using the pressure-sensitive adhesive compositions of Examples 11 to 30 and Comparative Examples 10 to 19, comparative tests as shown in Table 12 were conducted. Lidocaine is 0% (Comparative Examples 10 to 15) and 1%
(Comparative Example 16 and Examples 11 to 15) have moldability and adhesive strength, and cannot neutralize polyacrylic acid sufficiently.
A gel with poor moldability was obtained. On the other hand, in the case of the composition to which lidocaine was added at 4% or more, a gel excellent in moldability and adhesiveness was obtained by adjusting the blending amount of polyacrylic acid. The local anesthetic effect was not observed in Comparative Examples 11 to 15 in which lidocaine was not added, and the initial effect was observed in Comparative Examples 16 to 19 in which epinephrine was not added, but the effect was not sustained and disappeared in a short time. did. On the other hand, a remarkable sustaining effect was obtained at an addition concentration of epinephrine of 0.01% or more. That is, when viewed from the ratio of lidocaine to epinephrine, a sustained drug effect in the range of 1000: 1 to 2: 1 was confirmed.

[0090]

[Table 12]

<Experimental Example 6> The effect of the amount of current on the pharmacological effect of the adhesive gel composition of the present invention was evaluated.
Lidocaine 8% and epinephrine 0.1%, current 0.1
At mA / cm ² , as shown in Table 13, within the range of 5 to 30 minutes for the application time, Examples 31 to 34
Comparative Examples 20 to 23 were compared as a non-energized group.

[0092]

[Table 13]

(Examples 31 to 34, Comparative Examples 20 to 23) Polyacrylic acid 8 parts by weight Glycerin 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 39.5 parts by weight Lidocaine 8 parts by weight Epinephrine 0.1 part by weight Sodium bisulfite 0.3 part by weight The components in this formulation are uniformly heated while heating to 50 ° C.
Mix and stir until finally epinephrine, anti-
An oxidizing agent and a crosslinking agent were added to obtain a comparative adhesive composition. Stripping
Spray 1mm thick on release PET liner
It was cut into pieces and used for the test. Before starting the experiment
Remove hair on back with hair clipper and electric razor, soak in warm water
The skin surface was thoroughly wiped with gauze. Middle back midline
Stimulate the right or left side of the heart with a stimulating needle to contract the skin
The area where the reaction appears reliably is the area where the adhesive gel is applied.
A control electrode was affixed to the hair-removed part of the above. Drug-containing adhesive gel
(Donor electrode, 6 cm²) On the anode side with sodium chloride
Containing electrode (reference electrode, 6cm ²) On the cathode side
Each was connected and energization was started. Non-energized group is similar
Only the attaching operation was performed, and the power was not supplied. Energization is DC
Flow 0.1mA / cm²And the application time is 5 to 30 minutes
Was.

As apparent from Table 14, Comparative Examples 20 to 2
In the non-energized state shown in FIG. 3, no local anesthetic action was observed. On the other hand, when electricity was supplied, a local anesthetic effect was observed at an application time of 5 minutes or more, and about 0.5 to 1.5 mA.
-At min / cm ² , an almost stable sustained local anesthetic effect was obtained. On the other hand, the effect was constant at 1.5 mA · min / cm ² or more.

[0095]

[Table 14]

<Experimental Example 7> In the adhesive gel composition of the present invention, the effect of the added concentration of an antioxidant (sodium bisulfite) on the stability of a vasoconstrictor (epinephrine) was examined.

Example 35 Polyacrylic acid 6 parts by weight Polyethylene glycol 400 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 46.54 parts by weight Lidocaine 3 parts by weight Epinephrine 0.05 parts by weight 0.3 parts by weight of sodium bisulfite 0.01 parts by weight of oxyquinoline sulfate The components in this formulation are heated and mixed at 50 ° C. until uniform, and finally a crosslinking agent is added at 40 ° C. to obtain a comparative adhesive composition. I got something. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

(Example 36) Polyacrylic acid 6 parts by weight Polyethylene glycol 400 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 46.24 parts by weight Lidocaine 3 parts by weight Epinephrine 0.05 parts by weight 0.6 parts by weight of sodium bisulfite 0.01 part by weight of oxyquinoline sulfate The components in this formulation are heated and mixed at 50 ° C. until uniform, and finally a crosslinking agent is added at 40 ° C. to obtain a comparative adhesive composition. I got something. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

Comparative Example 24 Polyacrylic acid 6 parts by weight Polyethylene glycol 400 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 46.85 parts by weight Lidocaine 3 parts by weight Epinephrine 0.05 parts by weight The components in this formulation were mixed and stirred while heating to 50 ° C. until uniform, and finally a crosslinking agent was added at 40 ° C. to obtain a comparative adhesive composition. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

Comparative Example 25 Polyacrylic acid 6 parts by weight Polyethylene glycol 400 40 parts by weight Ethylene glycol diglycidyl ether 0.1 part by weight Gelatin 4 parts by weight Water 45.34 parts by weight Lidocaine 3 parts by weight Epinephrine 0.05 parts by weight 1.5 parts by weight of sodium bisulfite 0.01 part by weight of oxyquinoline sulfate The components in this formulation are heated and mixed at 50 ° C. until uniform, and finally a crosslinking agent is added at 40 ° C. to obtain a comparative adhesive composition. I got something. 1 on release PET liner
It was plastered with a thickness of mm, cut into an appropriate shape, and used for the test.

Using the adhesive gels of Examples 35 and 36 and Comparative Examples 24 and 25, the stability of lidocaine and epinephrine was examined. After storing each adhesive gel at 50 ° C. for 4 weeks, the contents of lidocaine and epinephrine in the adhesive gel were measured. As a result, as shown in Table 15, in each of Examples and Comparative Examples, about 100% of lidocaine could be recovered and was stable in the adhesive gel. On the other hand, epinephrine is about 96% in Example 35, about 84% in Example 36, about 67% in Comparative Example 24, and about 72% in Comparative Example 25, and has a stabilizing effect according to the concentration of sodium bisulfite added. , And a decrease in the stability of epinephrine was observed particularly at high concentrations.

[0102]

[Table 15]

[0103]

As described above, the adhesive gel composition according to the present invention is an adhesive composition applied to the skin or mucous membrane, and comprises an acidic polymer, a polyfunctional epoxy compound, water, It contains a polyhydric alcohol and / or gelatin and a basic drug, and does not cause a decrease in drug transport number, which is a drawback of the conventional base, and is excellent in moldability and adhesiveness. Provides a cis composition. According to the present invention, a pressure-sensitive adhesive gel composition for iontophoresis and a device therefor, which ensure a high standard in terms of manufacturability, handleability, skin irritation, stability over time, pharmacological effect, electrical properties and economy, are provided. Obtainable.

[Brief description of the drawings]

FIG. 1 is a schematic view showing a cross section of an example of an applicator in an iontophoresis device according to the present invention.

FIG. 2 is a schematic view showing a cross section of an example of the iontophoresis device according to the present invention.

[Explanation of symbols]

 1, 5 backing 2 electrode 3 adhesive gel 4, 10 liner 6 donor electrode 7 reference electrode 8 donor electrode side composition 9 reference electrode side composition 11 power supply device

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/38 A61K 47/38 47/42 47/42 A61N 1/04 A61N 1/04 1/30 1 / 30 A61P 9/00 A61P 9/00 23/02 23/02

Claims (13)

[Claims] 1. An adhesive gel composition for iontophoresis, comprising: a basic drug, an acidic polymer, a polyfunctional epoxy compound, water, a polyhydric alcohol and / or gelatin. 2. The weight ratio of a basic drug to an acidic polymer is 1
The pressure-sensitive adhesive gel composition for iontophoresis according to claim 1, wherein the ratio is 0: 1 to 1:10. 3. An acidic polymer comprising polyacrylic acid, methoxyethylene maleic anhydride copolymer, methoxyethylene maleic acid copolymer, isobutylene maleic anhydride copolymer, isobutylene maleic acid copolymer, carboxyvinyl polymer and The adhesive gel composition for iontophoresis according to claim 1 or 2, wherein the composition is one or more selected from the group consisting of carboxymethyl cellulose. 4. The adhesive gel composition for iontophoresis according to claim 1, wherein the basic drug is in a free form. 5. The adhesive gel composition for iontophoresis according to claim 4, wherein the basic drug is a local anesthetic. 6. The adhesive gel composition for iontophoresis according to claim 4, wherein the basic drug is a local anesthetic and a vasoconstrictor. 7. The adhesive gel composition for iontophoresis according to claim 6, wherein the local anesthetic is lidocaine and the vasoconstrictor is epinephrine. 8. The method according to claim 7, wherein the weight ratio of lidocaine to epinephrine is 1000: 1 to 2: 1.
The adhesive gel composition for iontophoresis according to the above. 9. The compounding amount of lidocaine is 1% by weight to 20% by weight, and the compounding amount of epinephrine is 0.001% by weight to 0.1% by weight.
The adhesive gel composition for iontophoresis according to claim 7, wherein the content is 5% by weight. 10. The adhesive gel composition for iontophoresis according to claim 7, further comprising an antioxidant. 11. The adhesive for iontophoresis according to claim 10, wherein the antioxidant is one or more selected from the group consisting of sodium pyrosulfite, sodium bisulfite and oxyquinoline sulfate. Gel composition. 12. The content of the antioxidant is 0.001% by weight.
The pressure-sensitive adhesive gel composition for iontophoresis according to claim 10 or 11, wherein the content is from 1.0 to 1.0% by weight. 13. A donor electrode, a reference electrode,
A power device electrically connected to the donor electrode and the reference electrode, wherein the current output from the power device is at least one of DC, pulse DC, and pulse depolarized DC, and the current amount is 0. .25-5.00
An iontophoresis device characterized by mA · min / cm ² .