WO2005020967A1

WO2005020967A1 - Electric drug transport preparation

Info

Publication number: WO2005020967A1
Application number: PCT/JP2004/012091
Authority: WO
Inventors: Seiji Tokumoto; Mitsuru Kuribayashi; Toshio Yoshida; Kazutaka Inoue; Kenji Mori
Original assignee: Hisamitsu Pharmaceutical Co., Inc.
Priority date: 2003-08-29
Filing date: 2004-08-24
Publication date: 2005-03-10
Also published as: JPWO2005020967A1

Abstract

An electric drug transport preparation in which stability of a drug is enhanced during storage and a variation in appearance (coloring) of a drug holding layer due to metal ions derived from an electrode can be prevented during preparation under such a state that the drug holding layer containing a drug unstable under dissolved state adjoins a nonpolarizable electrode, and a high biological utilization rate of a drug can be attained by preventing adhesion of the electrode component to skin. The electric drug transport preparation (1) comprises an electrode supporting substrate (5), an electrode layer (2) arranged on the electrode supporting substrate (5), a drug holding layer (3) arranged on the electrode layer (2), and a cover material (4) covering the drug holding layer (3). The drug holding layer (3) contains an electrolyte reacting with a metal chelating agent and/or the electrode layer (2) to form a hard-to-dissolve compound.

Description

Specification

Electrical drug delivery formulation

Technical field

The present invention relates to an electropharmaceutical drug transfer preparation suitable for transdermal or transmucosal application.

^ Scenic technology

[0002] In the present application, "electric drug transfer" means a method of applying a transdermal or transmucosal drug, whether charged or uncharged, by applying an electromotive force to a drug holding layer. In iontophoresis, which is a form of an electric drug transfer device, an iontophoresis electrode for an anode and a cathode is attached to, for example, the skin at regular intervals, and the current generated by a current generator is applied to the electrode. The drug is administered by electromigration, electroosmosis, or a combination of the two. In addition, another method, electroporation, forms a temporary hole in the skin surface by the application of an electric field through which the drug can be passed either transdermally or actively (under the influence of a potential gradient). It is administered. Note that, in the present application, the electric drug transfer is not limited to the above method, but is interpreted to include all drug administration methods including an electric transfer process.

[0003] Such an electropharmaceutical drug transfer preparation used for electropharmaceutical drug transfer has a structure in which a drug holding layer and an electrode layer are adjacent to each other. For the purpose of maintaining for a certain period of time, in addition to a certain amount of pre-designed medicinal ingredients, various additives are enclosed as necessary to maintain stable medicinal properties.

[0004] In general, the form of the preparation is determined by taking into account the stability of the drug and taking the drug in a separate package, which is attached to the electrode layer at the time of application of a separately packaged drug. Dissolution-integrated packaging type for use when dissolving, and drug-integrated packaging type in which the impregnating member is held in a state in which the drug solution is impregnated or in a state in which it is previously mixed with a hydrophilic gel base such as a water-soluble polymer. Can be roughly divided into two. However, in the medical field, from the viewpoint of operability, a form in which a dissolved drug is preliminarily held in a preparation (drug integrated package type) is most desired. in this case, Ensuring the stability of the drug in the drug-retaining layer is a very important task, and many proposals have been made to solve this problem.

For example, Patent Literature 1 or Patent Literature 2 discloses an iontophoresis preparation comprising a lidocaine anesthetic and a vasoconstrictor epinephrine. In the case of this formulation, because epinephrine is easily oxidized, drug stabilization is achieved by mixing an antioxidant such as sodium pyrosulfite and sodium metabisulfite, and a metal chelating agent such as disodium edetate. At the same time, further improvement in stability by pH control and nitrogen replacement has been proposed. These two technologies are drug stabilization methods that focus only on the drug holding layer. However, in the actual drug decomposition mechanism, components eluted from the electrode are involved. The above two technologies do not pay attention to this point at all, and there is no example where measures have been taken for the actual point.

Patent Document 1: W 100Z30621

Patent Document 2: Japanese Translation of PCT International Publication No. 2001-505197

[0006] On the other hand, many reports have been made on the interaction between an electrode and a drug in an energized state. For example, Non-Patent Document 1 reports that when iontophoresis of hydrocortisone sodium succinate and sodium hydroconoretisone sodium phosphate is administered, drug stability decreases due to pH fluctuation due to electrolysis of water. I have. As a solution, for example, Patent Document 3 discloses an electrode composition for iontophoresis in which a substance that suppresses the electrochemical decomposition of a drug is laminated between a drug-containing layer and an electrode. This has been proposed to improve the electrochemical stability of the drug.

Non-Special Noon Document 1: Sandesh C. beth, international journal of pharmaceutics, 106, 7-14 (1994)

Patent Document 3: JP-A-11-99209

[0007] In general, in an electropharmaceutical drug delivery system, a polarizable electrode such as platinum, gold, carbon or titanium, or a non-polarizable electrode such as silver, copper, silver chloride or copper chloride is used for the electrode layer. In particular, an iontophoresis preparation can use both a polarizable electrode and a non-polarizable electrode.However, when a polarizable electrode is used, electrolysis occurs and the pH of the drug-retaining layer changes. Drug degradation (hydrolysis) is likely to occur. Therefore, in iontophoresis preparations, In most cases, non-polarizable electrodes with little pH fluctuation are used from the viewpoint of safety to living organisms. However, the non-polarizable electrode is a component that undergoes a chemical change and has a strong tendency to ionize. There is a risk of release in the retaining layer. Regarding this free metal ion, the point that the metal ion easily reaches the skin and is easily absorbed into the living body and causes harmfulness, and that the free metal ion becomes a competitive ion of the drug ion, and It is pointed out that it inhibits sex. For example, Patent Literature 4 discloses an iontophoresis preparation having an ion-exchange membrane at the electrode portion, while Patent Literature 5 discloses an ion-exchange resin in which an ion-exchange resin is dispersed in a drug holding layer adjacent to a non-polarizable electrode. Although tophoresis preparations have been disclosed, all preparations are intended to remove free metal ions that compete with drug absorption, and have not been studied for their effects on drug stability.

Patent Document 4: Patent No. 2636290

Patent Document 5: JP-A-10-66733

[0008] As described above, there is no case in which the composition of the drug-retaining layer is studied by focusing on the effect of the electrode component of the non-polarizable electrode on the compounding component of the drug-retaining layer during storage of the preparation. Disclosure of the invention

Problems to be solved by the invention

[0009] Therefore, an object of the present invention is to increase the drug stability during storage when a drug holding layer containing a drug unstable in a dissolved state is commercialized adjacent to a non-polarizable electrode. It is possible to prevent the appearance change (coloring) of the drug holding layer induced by the metal ions derived from it, and to prevent the electrode components from adhering to the skin and to obtain a high bioavailability of the drug. It is an object of the present invention to provide an electropharmaceutical drug delivery preparation that can be used.

Means for solving the problem

[0010] The present inventors have conducted intensive studies on an electropharmaceutical drug delivery formulation to solve the above-mentioned problems. As a result, it was found that metal ions, which are electrode components, promoted the oxidative decomposition of drugs and additives, and caused changes in appearance such as coloring of the drug holding layer and a decrease in drug stability. The present inventors have found that the above problem can be solved by taking measures against the eluting components, and have reached the present invention. Therefore, in the present invention During storage of the drug product, the metal ion that elutes from the electrode layer (non-polarizable electrode) to the drug holding layer is chemically reacted with an anion to convert it into a hardly soluble compound, thereby forming a metal ion drug holding layer. An electrolyte that prevents the migration to the metal and / or a metal chelating agent that selectively traps the eluted metal ions is blended in the drug holding layer. As a result, the transfer of free metal ions from the electrode layer is specifically prevented, the stability problem due to the oxidation of the preparation is solved, and the reduction in the content of the medicinal component and additives and coloring can be suppressed.

[0011] That is, the present invention relates to a transdermal or transmucosal electric drug transfer preparation comprising a drug-retaining layer containing a medicinal component, and an electrode layer disposed adjacent to the drug-retaining layer, The above-mentioned drug-retaining layer is an electropharmaceutical drug delivery preparation containing a metal chelating agent and / or an electrolyte which reacts with the electrode layer to form a poorly soluble compound. Here, the electrolyte may contain or generate an anion, and the electrode layer may contain a non-polarizable metal component. The non-polarizable metal component can be silver or a mixture containing silver.

[0012] The flame-soluble compound, the water solubility 10 g / dm ³ or less or a solubility product (Ksp) can be 1 X 1 0- ² or less, the standard electrode potential of the redox reaction of the hardly soluble compound ( 25 ° C) can be -IV— + 2V. Further, the metal chelating agent can be edetic acid or a salt thereof. The compounding amount of the metal chelating agent is preferably 0.001-1% by mass. The electrolyte preferably generates at least one of halide ions (excluding fluorine ions), sulfide ions, sulfate ions, and phosphate ions when dissolved. The amount of the electrolyte is preferably 0.001 to 1% by mass.

[0013] The medicinal component may include a steroid hormone. The steroid hormone, dexamethasone phosphate, dexamethasone acetate, dexamethasone benzoate metasulfone, hydroconoretisone succinate, hydroconoretisone phosphate, prenizolone succinate, at least selected from the group consisting of betamethasone phosphate and salts thereof. Can be one. The invention's effect

According to the present invention, the transfer of free metal ions from an electrode can be specifically prevented in an electric drug transfer preparation in which an electrode layer and a drug holding layer containing a medicinal component are adjacent to each other. In addition, it is possible to reduce the content of medicinal components and additives, whose stability due to oxidation is a problem, and to suppress the coloring of the drug holding layer, thereby realizing long-term quality assurance of the preparation.

Brief Description of Drawings

FIG. 1 is an exploded view showing one configuration example of an electric drug transfer preparation (electrode) according to the present invention.

FIG. 2 is a cross-sectional view of the electric drug transfer preparation of FIG. 1.

FIG. 3 is a graph showing drug absorbability in Examples and Comparative Examples of the present invention.

Explanation of symbols

[0016] 1 Electrical drug transfer formulation

2 Electrode layer

3 Drug retention layer

4 Lid material

5 Electrode support substrate

BEST MODE FOR CARRYING OUT THE INVENTION

An embodiment of the present invention will be described in detail below.

FIG. 1 is an exploded view showing one configuration example of the electric drug transfer preparation (electrode) according to the present invention, and FIG. 2 is a cross-sectional view of the electric drug transfer preparation of FIG. As shown in the figure, the electrodrug transfer preparation 1 comprises an electrode supporting substrate 5, an electrode layer 2 disposed on the electrode supporting substrate 5, a drug holding layer 3 disposed on the electrode layer 2, And a lid member 4 that covers the holding layer 3. The electrode layer 2 is connected to an electrode terminal 6 for connecting to an external power supply.

The electrode composition of the electrode layer of the present invention is not particularly limited as long as it can be used for an electropharmaceutical drug delivery system. Examples thereof include platinum, silver, silver chloride, copper, copper chloride, titanium, nickel, stainless steel, and carbon. However, in consideration of the electrolysis of the drug, it is preferable to use non-polarizable electrodes such as silver, silver chloride, copper, and copper chloride.The present invention particularly uses non-polarized electrodes. Higher efficacy in some cases.

Furthermore, the drug-retaining layer of the present invention comprises, in addition to the medicinal component, a metal chelating agent or an electrolyte containing an anion that forms a poorly soluble compound in response to the electrode component, thereby forming a compound component of the electrode component. To reduce the impact on the environment.

[0018] Metal chelating agents include ethylenediaminetetraacetic acid (EDTA) and its sodium and potassium salts, Powers include, but are not limited to, calcium disodium salt, diammonium salt, and triethanolamine salt (TEA_EDTA), hydroxyethylethylenediamminetetraacetic acid (HEDTA) and its trisodium salt, and mixtures thereof. Further, the compounding amount of the metal chelating agent is preferably 0.001-1% by mass, more preferably 0.01 0.5% by mass, based on the total mass of the composition. If the amount is less than 0.001% by mass, a sufficient effect of trapping free metal ions cannot be obtained. If the amount is 1% by mass or more, it becomes a competitive ion of the drug, which decreases the absorption of the drug and reduces the metal chelate. There is concern about the effect of the drug itself on the human body.

[0019] The electrolyte used in the present invention can be used as long as it reacts with the electrode component to form a hardly soluble compound and can suppress the migration of the metal component to the drug holding layer. It is preferable to select one that has little buffer and little reaction with other components. For example, electrolytes containing chloride ions include sodium chloride, potassium chloride, potassium chloride, zinc chloride, aluminum chloride, ammonium chloride, stannous chloride, ferric chloride, magnesium chloride, and benzalkonium chloride. Benzene, sodium chloride, hydrochloric acid, arginine hydrochloride, triethanolamine hydrochloride, and the like. Further, the electrolyte having a bromide ion includes sodium bromide, potassium bromide, calcium bromide, and the like. Further, the electrolyte having iodide ions includes potassium iodide and sodium iodide. Examples of the electrolyte having sulfate ions include sulfuric acid, zinc sulfate, aluminum sulfate, aluminum potassium sulfate, potassium sulfate, calcium sulfate, copper sulfate, and magnesium sulfate. Examples of the electrolyte having sulfide ions include sodium sulfide and potassium sulfide. In addition, electrolytes having phosphate ions include phosphoric acid, calcium monohydrogen phosphate, sodium monohydrogen phosphate, potassium hydrogen phosphate, tricalcium phosphate, trisodium phosphate, dipotassium hydrogen phosphate, hydrogen phosphate Disodium and the like. Examples of the electrolyte having carbonate ions include ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, and sodium carbonate. The electrolyte may be used in the form of an anhydride or a hydrate alone, in the form of an addition salt of a medicinal component, or in a different form.

[0020] In addition, sparingly soluble compounds of the present invention have a solubility in water 10 g / dm ³ or less, or solubility product (Ksp) l X 10- ² is preferably from it preferably tool is less than the solubility lg / dm ³ Below or Kaidoseki (Ksp) l X 10- ⁵ is less than or equal to. Solubility 10 g / dm ³ or more or a solubility product (Ksp) l X 10 - ² or more, it becomes liable to occur redissolution of poorly soluble compounds, it may not exhibit a sufficient function. In addition, the poorly soluble compound is not one that crystallizes and precipitates in the drug holding layer but crystallizes essentially in a form of being laminated on the electrode surface.As a result, the insulating property on the electrode surface is increased. Become. Therefore, the standard electrode potential (25 ° C) of the electrode reaction (oxidized type ~~ ^ reduced type) when applying electricity to the hardly soluble compound is preferably -IV- + 2V, more preferably. Is -0.5V- + 1V. At standard electrode potentials below -IV (25 ° C), not only does the polarization on the electrode surface increase, but it also induces electrical skin irritation. At + 2V or more, there is a problem that self-reduction is likely to occur.

[0021] Examples of the poorly soluble compound corresponding to the above include, when a silver-containing electrode is used, silver chloride (solubility 30 mg / dm ³ (25 ° C), standard electrode potential +0.22 V), silver bromide (Solubility 5.5mg / d

3/1

m '(25 ° C), standard electrode potential + 0.07V), silver iodide (solubility product 8.5 X 10 — “(25 ° C), standard electrode potential-0.15V), cyanide silver (solubility product 1.6 X 10- ¹⁴ (25 ° C), the standard electrode potential - 0.017V), silver carbonate (solubility product ^{8.1 X 10- 12 (25 ° C} ), the standard electrode potential + 0.47 V), silver sulfide (solubility 6.151 X ¹⁰ "10 ^{mg / dm 3 (10 ° C} ), the standard electrode potential - 0.71V), silver phosphate (solubility product ^{6.44 X 10- 3 (20 ° C} ), standard electrostatic electrode potential + 0.34 V), silver sulfate (solubility 0.84g / 100g (25 ° C), standard electrode potential + 0.65V)).

[0022] The amount of the electrolyte of the present invention is preferably 0.001-1% by mass, more preferably 0.01-0.5% by mass, based on the total mass of the composition. If the amount is less than 0.001% by mass, the effect of trapping free metal ions cannot be obtained, whereas if it is 1% by mass or more, it becomes a competitive ion of the drug and decreases the drug absorption.

The drug holding layer is classified into an impregnating type in which a drug solution is impregnated into an impregnating member and holding the same, and a matrix type in which the drug is held in a gel-like or semi-solid state having shape-retaining properties. In the impregnated type, for example, a drug solution is stored in a sponge such as a nonwoven fabric, absorbent cotton, gauze, paper, synthetic resin continuous foam or an absorbent resin, a porous material, or the like so as to be held. On the other hand, in the matrix type, a hydrophilic base is preferably used, for example, polyacrylic acid, partially neutralized polyacrylic acid, completely neutralized polyacrylic acid, methoxyethylene anhydrous maleic acid copolymer and neutralized Product, methoxyethylene maleic acid copolymer and neutralization Products, carboxyvinyl polymers, polyacrylic acid starch, polyacrylamide and polyacrylamide derivatives, N-vieracetoamide, and copolymers of N-vieracetamide with acrylic acid and / or acrylate Synthetic polymers, nonionic synthetic polymers such as polyvinyl alcohol, polybutylpyrrolidone, and polyethylene oxide, as well as arabia gum, tragacanth gum, locust bingham, guar gum, echo gum, karaya gum, agar, starch, carrageenan, alginic acid, and alginate , Alginate propylene glycol, dextran, dextrin, amylose, gelatin, collagen, punorellan, actin, amylopectin, starch, chitin, chitosan, albumin, casein, methylcellulose Natural resins such as etinoresenolerose, propinoresenolerose, etinoremethinoresenolerose, hydroxymethinoresenolerose, hydroxyethinoresenolerose, hydroxypropyl pinoremethinoresenolerose, and hydroxypropyl starch; Semi-synthetic resins can be mentioned, and these are added to water to form gels or solids, and glycerin, ethylene glycol, ethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol And diols such as 1,3-propanediol and 1,4-butanediol, and sugar alcohols such as D-sorbitol, xylitol, mannitol, and erythritol. Soft and skin-adhesive Examples thereof include those formed into a soft film or sheet gel. If necessary, preservatives, buffering agents, pH adjusters, etc. can be added.However, the amount of the preservatives should be such that the drug absorbability at the time of administration should not be reduced in consideration of competition with the drug. I do.

The drug contained in the composition of the present invention can be used in any therapeutic field as long as it exists in a dissolved state in the drug holding layer and dissociates into cations or anions. Particularly, a bioactive substance having a molecular weight of 1 × 10 ^{2 to} 1 × 10 ⁶ is widely used. For example, antiallergic, anesthetic, analgesic, antiasthmatic, anticonvulsant, antitumor, antipyretic, antiarrhythmic, antihypertensive, diuretic, vasodilator, antiemetic, central nervous system agitation Drugs, diagnostics, hormones, anti-inflammatory drugs, antidepressants, antipsychotics, immunosuppressants, muscle relaxants, antivirals, antibiotics, antithrombotic agents, bone resorption inhibitors, bone formation promoters For example, the power is not limited to these. These may be used alone or in combination as needed. Examples of various drugs that can dissociate into cations include bacampicillin, sultamicillin, cefpodoxime proxetil, ceftereram pivoxil, cefmenoxime, cefetiam, doxycycline, minocycline, tetrasacrine, erythromycin, rokitamycin, amylicin, Anorebekacin, Astromycin, Dibekacin, Gentamicin, Isepamicin, Kanamycin, Micronomacyin, Sissomycin, Streptomycin, Tobramycin, Ethambutol, Isoureacid, Fluconazole, Flucytosine, Miconazole, Acyclovir, Chloramphenicol, Clindamycin, Fosfomycin, noncomycin, aclarubicin, bleomycin, cytarabine, dacanolevacine, dimustine, ぺ promyci , Pro-luvazine, vinblastine, vincristine, vindesine, calcitonins, patatilide hormone (PTH), granulocyte colony formation stimulating factor (G-CSF), mecamermin, alimemazine, chlorpheniram, clemastine, mequitazine, azelastine, ketotifen, Oxatomide, methylmethionine sulfonium chloride, conorechitin, kymostad, gabexate, nafamostat, mizoribine, piroxicam, progourmetacin, emorfazone, thiaramid, buprenorphine, enolegotamine, phenacetin, rilmazahon, triazolam, zopiclone , Nitrazepam, clonazepam, amantadine, bromocriptine, chlorpromazine, snoretopride, chlororesazepoxide, cloxazolam, diazepam, Etizolam, oxosazolam, amitriptyline, imipramine, noretriptyline, setiptiline, ticlovidine, atotopin, panclodinium bromide, tizanidine, pyridostigmine bromide, dobutamine, dopamine, benidipine, diltiazem, dicardipine, verapamil Aceptolol, Atenolol, Carteolol, Metopyrolol, Nipradilol, Pindolol, Propranolol, Dipyridamole, Nicorandil, Tradipir, Azimarin, Aprindine, Dibenzoline, Disopyramide, Flecaide, Isoprenaline, Lidocaine, Mexiletine, Proamide Tetracaine, Sibucaine, Propafenone, Quinidine, Hydrochlorothiazide, Triclomouth thiazide, Tribamide, Azosemide, A Suralol, budralazine, bunazosin, forcedralazine, clonidine, delapril, enalapril, guanethidine, hydralazine, labetaronole, prazosin, reserpine, terazosin, perazipir, nicomol, epinephrine, etilefrin, midodrine, panoberenoleno, renopine , Mabterone, Propoterol, Salbutamol, Terbutaline, Allobuterol, Tipudine, Nmbroxol, Bromhexine, Cimetidine, Famotidine, Ranitidine, Roxatidin acetate, Benexate, Omebulanore, Pirenzepine, Snorepiride, Cisapride, Domperidone, Metoclopramide, Trimebutine, Codine, Monolehine, Fentaninole, Petitidine, Petitidine, Xetine Listed powers are not limited to these.

Examples of various drugs that can be dissociated into anions include amoxicillin, ampicillin, aspoxycillin, benzylpenicillin, methicillin, piperacillin, sulbenicillin, ticarcillin, cefaclor, cefedroxyl, cefelexin, cefatrizine, cefixime, ceflazine, cefradixin, and ceflozine. Cefamandole, cefazolin, cefmetazole, cefminotas, cefperazone, cefotaxime, cefotaten, cefoxitin, cefpyramid, cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, cefzonam, aztreonam, carmonam, promoximexime Loxacin, Enoxasin, Naliditasic acid, Norfloxacin, Ofloxacin, Vidarazon, Fluorourashi Nore, methotrexate, levothyroxine, liothyronine, amlexanox, cromoglycic acid, tranilast, gliclazide, insulins, prostaglandins, benzbromarone, rubazochrome, tranexamic acid, alkolofenac, aspirin, diclofenac, inbumetafen, inbufenfen Ketoprofen, mefenamic acid, sulindac, thiaprofenic acid, tolmetin, sulpyrine, oral benzalit, penicillamine, amobarbital, pentobarbital, phenobarbital, thiopental, funetren, valproic acid, droxidopa, acetazolamide, bumetanide, canlenic acid, Ethacrynic acid, aracepril, captopril, lisinopurinole, methinoredono, clofibrate, pravastatin Probuconore, anoreprostadil, aminophylline, theophylline, carbocysteine, dexamethasone phosphate, dexamethasone acetate, dexamethasone methacrylate benzoate, hydrocortisone succinate, hydrocortisone phosphate, prenizolone succinate, betamethasone succinate and salts thereof. Not limited. Suitable drugs in the present invention include drugs that are extremely difficult to maintain drug stability due to hydrolysis and oxidative degradation, and drugs that have a remarkable change in appearance (color) over time. More preferred drugs include water-soluble steroid compounds. Representative compounds include dexamethasone phosphate and Xamethasone, dexamethasone methansulfonate, hydrocortisone succinate, hydrocortisone phosphate, prenisolone succinate, betamethasone phosphate and salts thereof. Example

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. Tables 1, 2, and 3 show the amounts of the drug-retaining layers in Examples and Comparative Examples of the present invention.

[Table 1]

00

(Table 1) Examples 1-10

Component 1 2 3 4 5 6 7 8 9 10 Drug Dexamethasone sodium phosphate 3 3 2 1 3 3 3 3 3 3

Phosphorus ® Hetamethasonaton ¹ J

Ionic synthetic molecule sodium polyacrylate

Polyacrylic USB

N vinyl acetate / acrylic) #

Nonionic synthetic polymer Polyvinyl alcohol 15 17 17 17 15 15 15 15 15 15

Polyethylene oxide '

Natural polymer gelatin

Carrageenan

Polyhydric alcohols Glycerin 10-10 10 10 10-10 10 1Q-10-.

D-sorbitol solution (70W

Crosslinking agent Dried aluminum hydroxide gel

Ethylene glycol diglycidyl ether

Metal chelating agent disodium edetate 0.1 0.1 0.05 0.05 0.05 0.1

Ide M¾tetrasodium 0.1

Electrolyte Sodium chloride 0.1 0.1 0.1 0.1 0.1 0.05 0.01 0.05

Calcium chloride (dihydrate) 0.1 Sodium sulfide

Sodium sulfate

Disodium hydrogen phosphate

Surfactant Monostearin Polyethylene glycol

Preservative methyl parapen _t 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18

Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 Omizu 71.7 69.7 70.7 71.7 71.6 71.65 71.7 71.74 71.65 71.6

(Table 2) Examples 11-20

o

(Table 3) Comparative Example 1-10

Ingredient 1 2 3 4 5 6 7 8 9 10 Drug Dexamethasone sodium phosphate 3 3 3 3 3 3 3 3 3 Henometazono sodium linoleate

Ionic synthetic polymer Sodium polyacrylate 1.8

Polyacrylic acid partially neutralized 0,45

N-vinylacetamito '/ acrylic acid copolymer 5 Nonionic synthetic polymer Polyvinyl alcohol 15 15 15 15 15 15 15 15 2 3

Polyethylene oxide '1.5 Natural polymer Gelatin 3

Carrageenan 2.5 Polyhydric alcohols Glycerin 10 10 10 10 10 10 _ „10 1_0 _ 30 30

D-Sorbitol solution (70W 3 crosslinking agent Dried aluminum hydroxide gel ― ―

Ethylene glycol diglycidyl ester 0.1 0.1 Metal chelating agent

Tetrasodium edetate

Electrolyte Sodium chloride 1

Sodium hydroxide 0.2

Sodium sulfate 0.2

Sodium fluoride 0.2

Sodium nitrate 0.2

iiffiiH "Thorium 0.2

Surfactant Polyethylene glycol monostearate 0.3 0.4 Preservative Methyl parapene 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18

Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 Purified water 74.8 71.8 71.6 71.6 71.6 71.6 71.6 70.8 55.15 55.3

Polyvinyl alcohol (completely saponified product, manufactured by Kuraray Co., Ltd.) was 15 mass ^_0/0 was dispersed in glycerin 10 weight ^_0/0, it was dissolved by heating the addition of water. Separately, dexamethasone sodium phosphate 3% by mass and disodium edetate 0.1% by mass were dissolved in water. Both preparations were kneaded while defoaming with a vacuum kneader. 0.8 g of the obtained composition (drug holding layer) was filled into a peeled polyester terephthalate convex molded container (diameter 24 mm, depth 1.5 mm), and a polyester terephthalate film on which an electrode layer was printed was pasted. They were combined, frozen at 40 ° C, and thawed at 5 ° C to obtain the preparation of this example.

(Example 2-15)

Gels were prepared in the same manner as in Example 1 for the components described in Table 1 or Table 2. (Example 16)

Gelatin in water 39.83 wt% (manufactured by Nitta Gelatin) 2 Weight ^_0/0, D-sorbitol solution (manufactured by Nikken Chemicals) 3 weight ^_0/0, polyethylene glycol monostearate (MYS10, manufactured by Nikko Chemicals) 0.3 weight ⁰ / ₀ was added and heated and dissolved. Separately, 2% by mass of Polyvier alcohol (partial Keni-Daimono, manufactured by Kuraray) and 1.5% by mass of polyethylene oxide (coagulant, manufactured by Dow Chemical) were dispersed in 12% by mass of glycerin to prepare. Both preparations were kneaded while defoaming with a vacuum kneading machine. Next, 2% by mass of sodium polyacrylate (F-480ss, manufactured by Showa Denko), 0.5% by mass of polyacrylic acid partially neutralized product (NP-700, manufactured by Showa Denko), 0.18% by mass of methyl parahydroxybenzoate, is dissolved 0.02 wt% propyl benzoate glycerin 10 mass ^_0/0 preparations dispersed in, and dexamethasone sodium phosphate 3 wt ^_0/0, 0.2 wt% Shioi匕calcium dihydrate in 15% by weight of water The prepared preparations were sequentially added and uniformly dissolved. Finally, a 0.37 mass% dry water aluminum oxide gel (manufactured by Kyowa Chemical) was添Ka卩glycerin 3 mass tone was dispersed in% product and ethylene glycol diglycidyl Honoré ether 0.1 ^_0/0, until uniform kneading I combined. 0.8 g of the obtained composition (drug holding layer) was filled in a convex molded container (diameter 24 mm, depth 1.5 mm) made of peeled polyester terephthalate, and then a polyester terephthalate film on which an electrode layer was printed was filled. By laminating, the preparation of this example was obtained.

(Examples 17-18)

Gels were prepared in the same manner as in Example 16 for the components described in Table 2. (Example 19) In water 30 wt% N-Bulle § Seto amide / acrylic acid copolymer (GE-167, manufactured by Showa Denko) 5 Weight ^_0/0, glycerin 21 weight ^_0/0, polyethylene glycol monostearate (MYS10, sunlight Kemi It was added Karuzu Ltd.) _{_0.4} wt%, dissolved by heating. Separately, 3% by mass of polybutyl alcohol (partially saponified product, manufactured by Kuraray), 0.18% by mass of methyl parahydroxybenzoate, and 0.02% by mass of propyl parahydroxybenzoate were dispersed in 9% by mass of glycerin. Both preparations were kneaded while defoaming with a vacuum kneader. Next, a preparation prepared by adding 3% by mass of gelatin (manufactured by Nitta Gelatin) to 13% by weight of water and dissolving by heating, and 3% by mass of dexamethasone sodium phosphate and 0.2% by mass of sodium chloride dissolved in 12.2% by mass of water. The prepared preparations were sequentially added and uniformly dissolved. Finally, ethylene glycol diglycidyl Honoré ether 0.1 ^_0/0 was added Caro, kneaded until uniform. 0.8 g of the obtained composition (drug holding layer) was filled in a convex molded container (diameter 24 mm, depth 1.5 mm) made of peeled polyester terephthalate, and a polyester terephthalate film on which an electrode layer was printed was pasted. Together, the preparation of this example was obtained.

(Example 20)

Gels were prepared in the same manner as in Example 19 for the components described in Table 2.

(Comparative Examples 11-8)

Gels were prepared in the same manner as in Example 1 for the components described in Table 3.

(Comparative Example 9)

Gels were prepared in the same manner as in Example 16 for the components described in Table 3.

(Comparative Example 10)

Gels were prepared in the same manner as in Example 19 for the components described in Table 3.

(Experimental example 1: Observation of appearance change)

The gel compositions (4.5 cm ² ) of Example 1-20 and Comparative Example 1-10 were prepared using a non-polarizable electrode (silver / silver chloride (1: 1): a mixture of silver and silver chloride) or a polarizable electrode (carbon ) Was printed on aluminum and the preparation equipped with a polyester film was used as an evaluation sample. The electrode of this embodiment is a dual-purpose electrode for a donor and a reference. This experimental example was stored at 40 ° C, and the degree of change in the appearance of the drug-retaining layer was examined. Table 4 shows the results. Table 4 shows the main salts which are considered to be formed by the reaction between the electrolyte in the drug holding layer and the electrode layer. [0034] [Table 4]

(Table 4)

◎: no coloring 〇: very weak coloring m: obvious coloring X: very strong coloring

[0035] In the results shown in Table 4, in Comparative Example 1 containing no drug, the drug holding layer was not colored regardless of the presence or absence of the electrode, whereas in Comparative Example 2 containing the drug, the non-polarizable electrode was not used. (Silver / silver chloride) The color was confirmed to be colored. The force was not confirmed with the polarizable electrode (carbon). This result is evident for a drug-containing system using non-polarizable electrodes (silver / silver chloride). It indicates that coloring occurs.

On the other hand, in Example 1-20 in which a metal chelating agent and an electrolyte were blended in consideration of prevention of coloring, in the system provided with a non-polarizing electrode (silver / silver chloride), no apparent coloring of the drug holding layer was observed. I got it. However, in Comparative Example 37, it was not possible to prevent coloring alone by using the electrolyte.

[0036] The cause can be determined to be due to the difference in the mobility of the generated anion (interaction with other components) and the difference in the solubility and solubility product of the salt formed by reacting with the electrode layer. By the way, in Comparative Example 3, silver hydroxide, which is a hardly soluble salt, was to be produced.However, since the hydroxide ion was buffered, it had a sufficient force to produce the salt. Seem. (For the solubility and solubility product of the formed salt described in Table 4, see the column of the detailed description. In addition, silver hydroxide (solubility 2.65 mg / dm ³ (25.C), silver nitrate (solubility 241 g / 100 g (25. C).)

[0037] From the above results, in the preparation provided with the non-polarizable electrode (silver / silver chloride), the electrolyte which generates an anion which forms a poorly soluble compound by reacting with the metal chelating agent and / or the electrode layer is used. It is clear that the compounding can suppress and prevent coloring and suppress the influence of the electrode layer.

[0038] (Experiment 2: Drug Stability Test) Example of the present invention 1, was fitted with a polyester film printed silver / silver chloride paste gel composition of Example 5 and Comparative Example 2 (4.5 cm ²⁾ The preparation was stored in an aluminum package at 50 ° C, and the time-dependent change of the active ingredient (dexamethasone sodium phosphate) was examined. Table 5 shows the results.

[Table 5]

(Table 5)

Experimental Example 1 Example and Comparative Example Residual drug rate Hydrolyzate Other degradation products

50-1 month (Dexame thasone) (oxides, etc.) Experimental example 2-1 Comparative example 2 83. 69¾ 6. 38¾ 2.83¾ Experimental example 2-2 Example 1 87. 15¾ 4. 82¾

Experimental Example 2-3 1 Example 5 88.85¾ 4.26¾ 0.79¾

[0040] In contrast to the experimental example equipped with Comparative Example 2, the experimental example equipped with Example 1 (containing sodium disodium edetate) and Example 5 (containing sodium disodium edetate and sodium chloride) had a higher drug residual ratio. It is clear that there is a difference in the composition of the decomposed product. In particular, in Examples 1 and 5, the generation rates of other decomposition products (oxides and the like) were reduced. In addition, dexamethasium phosphate It is known that oxidative decomposition and hydrolysis are the main reactions in the mechanism of sodium decomposition, and metal ions are particularly involved in oxidative decomposition. From these points, it was expected that the released silver ions would adversely affect drug stability, but this was also confirmed in this experimental example. From this result, it can be determined that the metal chelating agent and the electrolyte of this example suppress the release of silver ions, and thus have improved drug stability.

(Experimental example 3: in vivo drug absorption)

A polyester film on which a silver chloride paste was printed was attached to the gel compositions (4.5 cm ² ) obtained in Example 2, Example 5, Comparative Example 2, and Comparative Example 8, and used as a donor electrode (cathode). A reference electrode (anode) was prepared by impregnating physiological saline solution into a preparation (4.5 cm ² ) in which a PET non-woven fabric was attached to the printed surface of the electrode on which the silver paste was printed.

[0042] At the start of the experiment, the abdomen of a 7-week-old SD rat (body weight 300 g, N = 4) was subjected to shaver treatment, a preparation was applied thereto, fixed with Elatex tape (manufactured by Alcare), and a power supply device and recording were performed. The cord connected to the device was connected to the preparation, and energization (constant current: 0.45 mA / patch, energization time: 3 hr) was started. Blood was collected over time using a syringe from the venous vein, dephosphorylated the plasma with alkaline phosphatase, cleaned up with an ODS cartridge, and quantified by HPLC. The results are shown in FIG. FIG. 3 is a graph showing the drug absorptivity in Examples and Comparative Examples of the present invention, wherein the horizontal axis represents time (hr) and the vertical axis represents serum dexamethasone concentration (ng / ml).

In the results shown in FIG. 3, Example 2 (containing 0.1% by mass of sodium chloride) and Example 5 (containing 0.1% by mass of sodium chloride and 0.1% by mass of disodium edetate) show Comparative Example 2 (Not blended) showed the same drug absorption. On the other hand, in Comparative Example 8 (containing 1.0% by mass of sodium chloride), the drug absorptivity was reduced, and it was found that the compounded electrolyte was a competitive ion of the drug. However, from the aspect of drug absorption, it is important to minimize the amount of electrolyte blended.

Industrial applicability

[0044] The present invention can be used for an electropharmaceutical drug transfer preparation that can realize long-term quality assurance as a medical product.

Claims

The scope of the claims

[I] A transdermal or transmucosal electric drug transfer preparation comprising a drug holding layer containing a drug component and an electrode layer provided adjacent to the drug holding layer, wherein the drug holding layer is made of gold. An electropharmaceutical drug delivery preparation comprising a chelating agent of the genus and an electrolyte which reacts with Z or the electrode layer to form a poorly soluble compound.

[2] The electropharmaceutical drug transfer preparation according to [1], wherein the electrolyte contains or generates an anion.

3. The electropharmaceutical drug delivery preparation according to claim 1, wherein the electrode layer contains a non-polarizable metal component.

4. The electropharmaceutical drug delivery preparation according to claim 3, wherein the non-polarizable metal component is made of silver or a mixture containing silver.

[5] The poorly soluble compound has a solubility in water of 10 g / dm ³ or less or a solubility product (Ksp) of 1 × 1

The electropharmaceutical drug delivery device according to any one of claims 14 to 14, wherein the drug content is 0 to ² or less.

[6] The electric drug transfer according to any one of [15] to [15], wherein a standard electrode potential (25 ° C.) of the oxidation-reduction reaction of the hardly soluble compound is −IV− + 2V. Formulation.

[7] The electropharmaceutical drug delivery preparation according to any one of [16] to [16], wherein the metal chelating agent is edetic acid or a salt thereof.

[8] The compounding amount of the metal chelating agent is 0.001 to 1% by mass.

An electropharmaceutical drug transfer preparation according to any one of 1 to 6.

9. The electrolyte according to claim 11, wherein the electrolyte generates at least one of a halide ion (excluding a fluorine ion), a sulfide ion, a sulfate ion, and a phosphate ion when dissolved.

9. The electropharmaceutical drug delivery preparation according to any one of 8.

[10] The electropharmaceutical drug delivery preparation according to any one of [18] to [18], wherein the blending amount of the electrolyte is 0.0001 1% by mass.

[II] The electropharmaceutical drug transfer preparation according to any one of [110] to [110], wherein the medicinal component contains a steroid hormone.

[12] The steroid hormone power dexamethasone phosphate, dexamethasone acetate, methasulfone The electropharmaceutical drug delivery preparation according to claim 11, which is at least one selected from the group consisting of dexamethasone benzoate, hydrocortisone succinate, hydrocortisone phosphate, prenisolone succinate, betamethasone phosphate and salts thereof. .