JPWO2005020967A1 - Electrical drug delivery formulation - Google Patents

Abstract

When a drug holding layer containing a drug that is unstable in a dissolved state is placed adjacent to a non-polarizable electrode, it is induced by increased drug stability during storage and metal ions derived from the electrode. Provided is an electrical drug transfer formulation that can prevent the appearance change (coloring) of a drug holding layer, prevent electrode components from adhering to the skin, and obtain a high bioavailability of the drug. The electric drug transfer formulation (1) comprises an electrode supporting substrate (5), an electrode layer (2) disposed on the electrode supporting substrate (5), and a drug holding disposed on the electrode layer (2). A layer (3) and a lid material (4) covering the drug holding layer (3) are provided. Here, the drug retaining layer (3) includes a metal chelating agent and / or an electrolyte that reacts with the electrode layer (2) to form a hardly soluble compound.

Description

  The present invention relates to an electrical drug delivery formulation suitable for transdermal or transmucosal application.

  In the present application, “electric drug transport” means a method of transdermally or transmucosally administering a drug regardless of whether it is charged or uncharged by applying an electromotive force to the drug holding layer. In iontophoresis, which is a form of an electric drug transfer device, anode and cathode iontophoresis electrodes are adhered to the skin at regular intervals, for example, and the current generated from the current generator is applied to the electrodes. The treatment is configured to be conducted by guiding, allowing drug administration by electromigration, electroosmosis, or a combination of both. In addition, electroporation, which is another method, temporarily forms a hole in the skin surface by applying an electric field, and allows the drug to be transcutaneously (actively due to the potential gradient) through the hole. To be administered. In the present application, the electric drug transfer is not limited to the above-described method, and any drug administration method including an electric transfer process is interpreted as including all.

  Such an electric drug transfer formulation used for electric drug transfer has a structure in which a drug holding layer and an electrode layer are adjacent to each other, and the drug holding layer maintains the blood concentration of the drug in the body for a certain period of time. For this purpose, in addition to a predetermined amount of medicinal ingredients designed in advance, various additives are encapsulated as necessary to maintain stable medicinal effects.

  In general, the dosage form is a drug-separated packaging type in which the stability of the drug is taken into consideration, and a drug in a separate package is attached to the electrode layer at the time of application, when the drug is held in the drug retention layer in a dry state and dissolved at the time of application It can be broadly divided into three types: a dissolution-integrated packaging type, and a drug-integrated packaging type that is held in a state where the impregnated member is impregnated with a chemical solution, or is held in a state pre-mixed in a hydrophilic gel base such as a water soluble polymer . However, in the medical field, from the viewpoint of operability, a form (drug integrated packaging type) in which the dissolved drug is held in advance in the preparation is most desired. In this case, ensuring the stability of the drug in the drug holding layer is a very big problem, and many proposals have been made so far for the purpose of solving this problem.

For example, Patent Document 1 or Patent Document 2 discloses an iontophoretic preparation containing an anesthetic drug lidocaine and a vasoconstrictor epinephrine. In the case of this preparation, epinephrine is easily oxidized, and drug stabilization is achieved by combining an antioxidant such as sodium pyrosulfite and sodium metabisulfite and a metal chelating agent such as disodium edetate. Further improvement of stability by pH control and nitrogen substitution has been proposed. These two techniques are drug stabilization methods that focus on only the drug retaining layer. However, in the actual drug decomposition mechanism, an elution component from the electrode is involved. The above two techniques do not pay any attention to this point, and there are no examples of countermeasures actually taken on this point.
WO 00/30621 JP-T-2001-505197

On the other hand, many reports have been made regarding 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 hydrocortisone phosphate is administered, drug stability decreases due to pH fluctuations due to water electrolysis. As a solution for this, for example, Patent Document 3 discloses an electrode composition for iontophoresis in which a substance that suppresses electrochemical decomposition of a drug is laminated between a drug-containing layer and an electrode. It has been proposed to improve the electrochemical stability of drugs.
Sandesh C.I. Seth, international journal of pharmaceuticals, 106, 7-14 (1994) JP 11-99209 A

In general, in an electric drug transfer formulation, polarizable electrodes such as platinum, gold, carbon, and titanium, and nonpolarizable electrodes such as silver, copper, silver chloride, and copper chloride are used for the electrode layer. In particular, in an iontophoretic preparation, both a polarizable electrode and a non-polarizable electrode can be used. However, when a polarizable electrode is used, electrolysis occurs and the pH of the drug retaining layer changes. Therefore, drug decomposition (hydrolysis) is likely to occur. Therefore, most iontophoresis preparations use non-polarizable electrodes with little pH fluctuation from the viewpoint of safety to living bodies. However, the non-polarizable electrode is a component that undergoes a chemical change and has a strong ionization tendency. Therefore, depending on the conditions of the drug retaining layer (pH, electrolytic mass), the metal ions of the electrode component may become drug substances even in a non-energized state. There is a risk of release to the retaining layer. About this free metal ion, the metal ion reaches the skin at an early stage and is easily absorbed in the living body, and it is easy to generate harmful effects. It has been pointed out that it interferes. For example, Patent Document 4 discloses an iontophoresis preparation in which an ion exchange membrane is installed in an electrode part, and Patent Document 5 discloses an iontophoresis in which an ion exchange resin is dispersed in a drug holding layer adjacent to a non-polarizable electrode. Although lacesis preparations are disclosed, none of the preparations is intended to remove free metal ions that are competing for drug absorption, and the effects on drug stability have not been studied.
Japanese Patent No. 2636290 JP-A-10-66733

  As described above, there is no case in which the composition of the drug retaining layer has been studied by paying attention to the influence of the electrode component of the non-polarizable electrode on the compounding component of the drug retaining layer during storage of the preparation.

  Therefore, the object of the present invention is to increase the drug stability during storage and to further improve the metal derived from the electrode when a drug holding layer containing a drug that is unstable in a dissolved state is adjacent to the non-polarizable electrode. It is possible to prevent the appearance change (coloring) of the drug holding layer induced by ions, while preventing the adhesion of electrode components to the skin, and to obtain a high bioavailability of the drug. It is to provide a drug delivery formulation.

  The inventors of the present invention diligently studied to solve the above-described problems with regard to the electric drug delivery formulation. As a result, it was found that the metal ions as the electrode component promoted the oxidative decomposition of the drug and additives, causing the appearance change such as coloring of the drug holding layer and the decrease in drug stability. The present inventors have found that the above-mentioned problems can be solved by taking measures against the above, and have reached the present invention. Therefore, in the present invention, the drug of the metal ion is obtained by chemically reacting the metal ion to be eluted from the electrode layer (non-polarizable electrode) into the drug holding layer during the storage of the drug with an anion to change it into a hardly soluble compound. An electrolyte that prevents migration to the holding layer and / or a metal chelating agent that selectively traps the eluted metal ions are blended in the drug holding layer. Thereby, the movement of free metal ions from the electrode layer is specifically prevented, the problem of stability due to the oxidation of the preparation is solved, and the decrease in content and coloring of medicinal ingredients and additives can be suppressed.

  That is, the present invention is a transdermal or transmucosal electric drug transfer formulation comprising a drug holding layer containing a medicinal component and an electrode layer disposed adjacent to the drug holding layer, the drug holding layer Is an electrical drug delivery formulation comprising a metal chelating agent and / or an electrolyte that reacts with the electrode layer to form a poorly soluble compound. Here, the electrolyte may contain or generate anions, and the electrode layer may contain a non-polarizable metal component. The non-polarizable metal component can be silver or a mixture containing silver.

The poorly soluble compound can have a solubility in water of 10 g / dm ³ or less or a solubility product (Ksp) of 1 × 10 ⁻² or less, and the standard electrode potential (25 ° C.) of the oxidation-reduction reaction of the hardly soluble compound is -1V to + 2V. The metal chelating agent can be edetic acid or a salt thereof. The compounding amount of the metal chelating agent is preferably 0.001 to 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.

  The medicinal component can include a steroid hormone. The steroid hormone may be at least one selected from the group consisting of dexamethasone phosphate, dexamethasone acetate, dexamethasone metasulfone benzoate, hydrocortisone succinate, hydrocortisone phosphate, prenizolone succinate, betamethasone phosphate and salts thereof.

  According to the present invention, in an electric drug transfer formulation in which an electrode layer and a drug holding layer containing a medicinal component are adjacent to each other, it is possible to specifically prevent the movement of free metal ions from the electrode. It is possible to reduce the content of medicinal ingredients and additives and to suppress coloration of the drug retaining layer, and to realize long-term quality assurance of the preparation.

It is an exploded view which shows one structural example of the electrical drug delivery formulation (electrode) which concerns on this invention. It is sectional drawing of the electric drug delivery formulation of FIG. It is a graph which shows the drug absorptivity in the Example and comparative example of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Electric drug transfer formulation 2 Electrode layer 3 Drug holding layer 4 Lid material 5 Electrode support base material

Embodiments of the present invention will be described in detail below.
FIG. 1 is an exploded view showing an example of the configuration of an electric drug transfer preparation (electrode) according to the present invention, and FIG. 2 is a cross-sectional view of the electric drug transfer preparation shown in FIG. As shown in the figure, the electrical drug transfer formulation 1 includes an electrode support base 5, an electrode layer 2 disposed on the electrode support base 5, a drug holding layer 3 disposed on the electrode layer 2, a drug And a lid material 4 covering the holding layer 3. The electrode layer 2 is connected to an electrode terminal 6 for connection to an external power source.
The electrode composition of the electrode layer of the present invention may be any as long as it can be used for an electric drug transfer formulation, and examples thereof include platinum, silver, silver chloride, copper, copper chloride, titanium, nickel, stainless steel, carbon and the like. However, when considering the electrolysis of the drug, it is preferable to use nonpolarizable electrodes such as silver, silver chloride, copper, and copper chloride, and the present invention is more suitable when the nonpolarizable electrode is used. Highly effective.
Furthermore, in addition to the medicinal component, the drug retaining layer of the present invention contains an anion containing an anion that reacts with a metal chelating agent or an electrode component to form a poorly soluble compound. The effect is suppressed.

  Metal chelating agents include ethylenediaminetetraacetic acid (EDTA) and its sodium, potassium, calcium disodium, diammonium, and triethanolamine salts (TEA-EDTA), hydroxyethylethylenediamminetetraacetic acid (HEDTA) and its Trisodium salts and mixtures thereof are included, but not limited thereto. Moreover, 0.001-1 mass% is preferable with respect to the total mass of a composition, and, as for the compounding quantity of the metal chelating agent, More preferably, it is 0.01-0.5 mass%. If the blending amount is less than 0.001% by mass, a sufficient free metal ion scavenging effect cannot be obtained, whereas if it is 1% by mass or more, it becomes a competitive ion of the drug and reduces drug absorption, and metal There is concern about the effect of the chelating agent itself on the human body.

  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, but other electrolytes in the drug holding layer can be used. It is preferable to select one that has little buffering or reaction with the components. For example, electrolytes having chloride ions are sodium chloride, potassium chloride, calcium chloride, zinc chloride, aluminum chloride, ammonium chloride, stannous chloride, ferric chloride, magnesium chloride, benzalkonium chloride, benzethonium chloride, hydrochloric acid , Arginine hydrochloride, triethanolamine hydrochloride and the like, and examples of the electrolyte having bromide ions include sodium bromide, potassium bromide, calcium bromide and the like. Further, examples of the electrolyte having iodide ions include potassium iodide and sodium iodide. Examples of the electrolyte having sulfate ions include sulfuric acid, zinc sulfate, aluminum sulfate, potassium aluminum sulfate, potassium sulfate, calcium sulfate, copper sulfate, and magnesium sulfate. Examples of the electrolyte having sulfide ions include sodium sulfide and potassium sulfide. Electrolytes having phosphate ions are phosphoric acid, calcium monohydrogen phosphate, sodium monohydrogen phosphate, potassium monohydrogen 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, sodium carbonate, and the like. The electrolyte may be used either in the form of an anhydride or hydrate alone or in the form of an addition salt of a medicinal component.

The hardly soluble compound of the present invention preferably has a solubility in water of 10 g / dm ³ or less, or a solubility product (Ksp) of 1 × 10 ⁻² or less, more preferably a solubility of 1 g / dm ³ or less or a solubility product. (Ksp) 1 × 10 ⁻⁵ or less. When the solubility is 10 g / dm ³ or more, or the solubility product (Ksp) is 1 × 10 ⁻² or more, re-dissolution of the hardly soluble compound is likely to occur, and thus a sufficient function may not be exhibited. In addition, the poorly soluble compound is not crystallized and precipitated in the drug retaining layer, but is essentially crystallized in the 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 electricity is applied to the hardly soluble compound is preferably −1 V to +2 V, more preferably −0.5 V to + 1V. A standard electrode potential (25 ° C.) of −1 V or less not only increases the polarization at the electrode surface but also induces electrical skin irritation. Further, at +2 V or more, there is a problem that self-reduction tends to occur.

As the hardly soluble compound corresponding to the above, for example, 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. 5 mg / dm ³ (25 ° C., standard electrode potential +0.07 V), silver iodide (solubility product 8.5 × 10 ⁻¹⁷ (25 ° C.), standard electrode potential −0.15 V), silver cyanide (solubility product) 1.6 × 10 ⁻¹⁴ (25 ° C.), standard electrode potential −0.017 V), silver carbonate (solubility product 8.1 × 10 ⁻¹² (25 ° C.), standard electrode potential +0.47 V), silver sulfide (solubility) 6.151 × 10 ⁻¹⁰ mg / dm ³ (10 ° C., standard electrode potential −0.71 V), silver phosphate (solubility product 6.44 × 10 ⁻³ (20 ° C.), standard electrode potential +0.34 V) , Silver sulfate (solubility 0.84 g / 100 g (25 ° C.), standard Electrode potential + 0.65V)), and the like.

  Moreover, 0.001-1 mass% is preferable with respect to the total mass of a composition, and, as for the compounding quantity of the electrolyte of this invention, More preferably, it is 0.01-0.5 mass%. If the blending amount is less than 0.001% by mass, the effect of capturing 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 drug absorption.

  The drug holding layer is divided into an impregnation type that holds a drug solution soaked in an impregnation member, and a matrix type that holds the drug in a gel-like or semi-solid form having a shape-retaining property. In the impregnation type, for example, a non-woven fabric, absorbent cotton, gauze, paper, a synthetic resin continuous foam or a sponge such as an absorbent resin, a porous material, or the like is stored in a state where the drug solution is held. On the other hand, in the matrix type, a hydrophilic base is suitably used. For example, polyacrylic acid, polyacrylic acid partial neutralized product, polyacrylic acid complete neutralized product, methoxyethylene maleic anhydride copolymer and neutralized product. , Methoxyethylenemaleic acid copolymer and neutralized product, carboxyvinyl polymer, starch polyacrylate, polyacrylamide and polyacrylamide derivatives, N-vinylacetamide, N-vinylacetamide and acrylic acid and / or acrylate Ionic synthetic polymers such as polymers, nonionic synthetic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, and polyethylene oxide, as well as gum arabic, tragacanth gum, locust bin gum, guar gum, echo gum, karaya gum, agar, starch, carrageenan, algi Acid, alginate, propylene glycol alginate, dextran, dextrin, amylose, gelatin, collagen, pullulan, pectin, amylopectin, starch, chitin, chitosan, albumin, casein, methylcellulose, ethylcellulose, propylcellulose, ethylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose , Natural resins such as hydroxypropylmethylcellulose, hydroxypropyl starch and semi-synthetic resins, and water is added to form a gel or a solid, or glycerin, ethylene glycol, diethylene glycol, triethylene glycol, Glycols such as polyethylene glycol, propylene glycol, polypropylene glycol, 1,3-pro Diols such as N-diol, 1,4-butanediol, sugar alcohols such as D-sorbitol, xylitol, mannitol, erythritol, and the like, and flexible plasticizing, or a flexible film having self-retaining properties and skin adhesion What was shape | molded in the sheet-like gel is mentioned. In addition, preservatives, buffering agents, pH adjusting agents, and the like can be added as necessary, but the blending amount is set so as not to lower the drug absorbability upon administration in consideration of competition with the drug.

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 retaining layer and dissociates into a cation or an anion. A physiologically active substance of × 10 ² to 1 × 10 ⁶ is widely used. For example, antiallergic agents, anesthetics, analgesics, antiasthma drugs, anticonvulsants, antitumor drugs, antipyretic drugs, antiarrhythmic drugs, antihypertensive drugs, diuretics, vasodilators, antiemetics, central nervous system stimulants, Examples include diagnostic agents, hormonal agents, anti-inflammatory agents, antidepressants, antipsychotics, immunosuppressants, muscle relaxants, antiviral agents, antibiotics, antithrombogenic agents, bone resorption inhibitors, osteogenesis promoters, etc. However, it is not limited to these. These may be used alone or in combination as necessary.

Examples of various drugs that can dissociate into cations include bacampicillin, sultamicillin, cefpodoxime proxetyl, cefteleram pivoxil, cefmenoxime, cefetiam, doxycycline, minocycline, tetrasacrine, erythromycin, rokitamycin, amikacin, arukacin, , Dibekacin, gentamicin, isepamicin, kanamycin, micronomacyin, sisomycin, streptomycin, tobramycin, ethambutol, isoniaside, fluconazole, flucytosine, miconazole, acyclovir, chloramphenicol, clindamycin, fosfomycin, vancomycin, aclarubicin, bleomycin, cytarabine , Dacarbazine, nimustine, peplomycin, proca Vadine, vinblastine, vincristine, vindesine, calcitonins, patachilide hormone (PTH), granulocyte colony-stimulating factor (G-CSF), mecasermine, alimemazine, chlorphenirum, clemastine, mequitazine, azelastine, ketotifen, oxatomide, methyl Methionine sulfonium chloride, colchicine, camostad, gabexate, nafamostat, mizoribine, piroxicam, pro gourmet tacin, emorphazone, tiaramid, buprenorphine, ergotamine, phenacetin, rilmazafone, triazolam, zopiclone, nitrazepam, clonazepam, promanthazine, bromothrazine Chlordiazepoxide, cloxazolam, diazepam, etizola , Oxazolam, amitriptyline, imipramine, nortriptyline, cetipitrine, ticlopidine, atropine, pancuronium bromide, tizanidine, pyridostigmine bromide, dobutamine, dopamine, benidipine, diltiazem, nicardipine, verapamil, acetrol, atenolol, cartelolol, metrolol, ditrolol , Propranolol, dipyridamole, nicorandil, tradipir, ajmarin, aprindine, dibenzoline, disopyramide, flecainide, isoprenaline, lidocaine, mexiletine, procaine, procainamide, tetracaine, sibucaine, propaphenone, quinidine, hydrochlorothiazide, trichlorothiazide, palymidrazol , Budra Razine, bunazosin, cadralazine, clonidine, delapril, enalapril, guanethidine, hydralazine, labetalol, prazosin, reserpine, terazosin, uradipir, nicomol, epinephrine, ethylephrine, midodrine, papaverine, clenbuterol, butenolol tertetrol Tipepdin, ambroxol, bromhexine, cimetidine, famotidine, ranitidine, roxatidine acetate, benexate, omepral, pirenzepine, sulpiride, cisapride, domperidone, metoclopramide, trimebutine, codeine, morphine, fentanyl, trothrin, oxybutrin And salts thereof, The present invention is not limited to these.
Examples of various drugs that can dissociate into anions include amoxicillin, ampicillin, aspoxillin, benzylpenicillin, methicillin, piperacillin, sulfenicillin, ticarcillin, cefaclor, cephedroxyl, ceferexin, cephatridin, cefixime, cefradine, cefradine, cefazoline, , Cefmetazole, cefminox, cefoperazone, cefotaxime, cefotaten, cefoxitin, cefpyramide, cefthrosin, ceftazidime, ceftizoxime, ceftriaxone, cefzonam, aztreonam, carmonam, flomoxefine, latamoflocinoc , Vidarazone, fluorouracil, Totrexate, levothyroxine, liothyronine, amlexanox, cromoglycic acid, tranilast, gliclazide, insulins, prostaglandins, benzbromarone, carbazochrome, tranexamic acid, alcolofenac, aspirin, diclofenac, ibuprofen, indomethacin, ketoprofen acid, ketoprofen acid , Sulindac, thiaprofenic acid, tolmethine, sulpyrine, lobenzalite, penicillamine, amobarbital, pentobarbital, phenobarbital, thiopental, phenitolene, valproic acid, droxidopa, acetazolamide, bumetanide, canlenic acid, ethacrylic acid, araceptril, captopril, methyl Clofilablate, pravastatin, probucol, a These include, but are not limited to, prostadil, aminophylline, theophylline, carbocysteine, dexamethasone phosphate, dexamethasone acetate, dexamethasone metasulfone benzoate, hydrocortisone succinate, hydrocortisone phosphate, prenizolone succinate, betamethasone phosphate and salts thereof. It is not a thing. Suitable drugs in the present invention include drugs that are very difficult to maintain drug stability due to hydrolysis and oxidative degradation, and drugs whose appearance change (coloring) over time is remarkable. More preferable drugs include water-soluble steroid compounds. Representative compounds include dexamethasone phosphate, dexamethasone acetate, dexamethasone metasulfone benzoate, hydrocortisone succinate, hydrocortisone phosphate, plenisolone succinate, betamethasone phosphate and salts thereof.

  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. In addition, Table 1, Table 2, and Table 3 show the compounding amount of the drug retaining layer in the examples and comparative examples of the present invention.

Example 1
After 15% by mass of polyvinyl alcohol (completely saponified product, manufactured by Kuraray) was dispersed in 10% by mass of glycerin, water was added and dissolved by heating. Separately, 3% by mass of dexamethasone sodium phosphate and 0.1% by mass of disodium edetate were dissolved in water. Both preparations were kneaded while defoaming with a vacuum kneader. The obtained composition (drug holding layer) is a polyester terephthalate film on which an electrode layer is printed after 0.8 g is filled in a convex molded container (diameter 24 mm, depth 1.5 mm) made of release polyester terephthalate. The preparation of this example was obtained by pasting and freezing at −40 ° C. and then thawing at 5 ° C.

(Examples 2 to 15)
Gels were prepared in the same manner as in Example 1 for the components listed in Table 1 or Table 2.
(Example 16)
39.8% by weight of gelatin (made by Nitta Gelatin), 3% by weight of D-sorbitol solution (made by Nikken Chemical), 0.3% by weight of polyethylene glycol monostearate (MYS10, made by Nikko Chemicals) Added and dissolved by heating. Separately, 2% by mass of polyvinyl alcohol (partially saponified product, manufactured by Kuraray) and 1.5% by mass of polyethylene oxide (coagulant, manufactured by Dow Chemical) were dispersed in 12% by mass of glycerin. Both preparations were kneaded while defoaming with a vacuum kneader. Next, sodium polyacrylate (F-480 ss, manufactured by Showa Denko) 2 mass%, polyacrylic acid partially neutralized product (NP-700, manufactured by Showa Denko) 0.5 mass%, methyl parahydroxybenzoate 0.18 mass %, A preparation prepared by dispersing 0.02% by mass of propyl parahydroxybenzoate in 10% by mass of glycerin, 3% by mass of dexamethasone sodium phosphate and 0.2% by mass of calcium chloride dihydrate dissolved in 15% by mass of water The prepared products were sequentially added and dissolved uniformly. Finally, a preparation prepared by dispersing 0.37% by mass of dry aluminum hydroxide gel (manufactured by Kyowa Chemical) in 3% by mass of glycerin and 0.1% by mass of ethylene glycol diglycidyl ether are added and kneaded until uniform. did. The obtained composition (drug holding layer) is a polyester terephthalate film on which an electrode layer is printed after 0.8 g is filled in a convex molded container (diameter 24 mm, depth 1.5 mm) made of release polyester terephthalate. The preparation of this example was obtained by pasting.

(Examples 17 to 18)
A gel was prepared in the same manner as in Example 16 for the components listed in Table 2.
Example 19
30% by mass of water, 5% by mass of N-vinylacetamide / acrylic acid copolymer (GE-167, Showa Denko), 21% by mass of glycerin, polyethylene glycol monostearate (MYS10, manufactured by Nikko Chemicals) 0.4% by mass Was added and dissolved by heating. Separately, 3% by mass of polyvinyl alcohol (partially saponified product, manufactured by Kuraray), 0.18% by mass of methyl parahydroxy benzoate, and 0.02% by mass of propyl parahydroxy benzoate were dispersed in 9% by mass of glycerin to prepare. Both preparations were kneaded while defoaming with a vacuum kneader. Next, a preparation prepared by adding 3% by mass of gelatin (made by Nitta Gelatin) to 13% by mass of water and dissolving by heating, 3% by mass of dexamethasone sodium phosphate, 0.2% by mass of sodium chloride, 12.2% by mass of water The preparations dissolved in% were sequentially added and dissolved uniformly. Finally, 0.1% by mass of ethylene glycol diglycidyl ether was added and kneaded until uniform. The obtained composition (drug holding layer) is a polyester terephthalate film on which an electrode layer is printed after 0.8 g is filled in a convex molded container (diameter 24 mm, depth 1.5 mm) made of polyester terephthalate which has been subjected to a release treatment. The preparation of this example was obtained by pasting.
(Example 20)
Gels were prepared in the same manner as in Example 19 for the components listed in Table 2.
(Comparative Examples 1-8)
Gels were prepared in the same manner as in Example 1 for the components listed in Table 3.
(Comparative Example 9)
Gels were prepared in the same manner as in Example 16 for the components listed in Table 3.
(Comparative Example 10)
Gels were prepared in the same manner as in Example 19 for the components listed in Table 3.

(Experimental example 1: Observation of appearance change)
The gel compositions (4.5 cm ² ) of Examples 1 to 20 and Comparative Examples 1 to 10 are nonpolarizable electrodes (silver / silver chloride (1: 1): a mixture of silver and silver chloride) or polarizable electrodes ( The preparation on which the polyester film printed with carbon was mounted was packaged in aluminum and used as an evaluation sample. The electrode of this example is a donor / reference electrode. This experimental example was stored at 40 ° C., and the degree of appearance change of the drug retaining layer was examined. The results are shown in Table 4. Table 4 lists main generated salts that are considered to be generated by the reaction between the electrolyte of the drug holding layer and the electrode layer.

In the results shown in Table 4, in Comparative Example 1 containing no drug, the drug retaining 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 (silver / In the case of silver chloride, coloring was confirmed, but not in the polarizable electrode (carbon). This result suggests that clear coloration occurs in a system containing a drug using a non-polarizable electrode (silver / silver chloride).
On the other hand, in Examples 1 to 20 in which a metal chelating agent and an electrolyte were blended in consideration of coloring prevention, no clear coloring of the drug retaining layer was observed even in a system in which a non-polarizable electrode (silver / silver chloride) was installed. However, in Comparative Examples 3 to 7, it was not possible to prevent coloring by itself even though the electrolyte was blended.

The cause can be determined to be due to the difference in mobility of the anion to be generated (interaction with other components) and the solubility and solubility product of the salt formed by reaction with the electrode layer. Incidentally, in Comparative Example 3, silver hydroxide, which is a hardly soluble salt, was planned to be produced, but it seems that the salt was not produced because the hydroxide ions were buffered. (For the solubility and solubility product of the product salts listed in Table 4, refer to the detailed description column. Incidentally, silver hydroxide (solubility 2.65 mg / dm ³ (25 ° C.), silver nitrate (solubility 241 g / 100 g (25 ° C.) .)

  From the above results, in preparations with non-polarizable electrodes (silver / silver chloride), by adding an electrolyte that generates metal ions and / or anions that react with the electrode layer to form poorly soluble compounds. It is obvious that the coloring can be suppressed and prevented, and the influence of the electrode layer is suppressed.

(Experimental Example 2: Drug Stability Test) A formulation in which a polyester film printed with a silver / silver chloride paste was mounted on the gel compositions (4.5 cm ² ) of Examples 1, 5 and Comparative Example 2 of the present invention was prepared. It stored at 50 degreeC in the state which gave the aluminum package, and examined the degree of the time-dependent change of a medicinal ingredient (dexamethasone sodium phosphate). The results are shown in Table 5.

  In contrast to the experimental example equipped with Comparative Example 2, the experimental example equipped with Example 1 (containing disodium edetate) and Example 5 (containing disodium edetate and sodium chloride) had a high drug residual rate and further decomposed. It is clear that there is a difference in the composition of things. In particular, in Example 1 and Example 5, the production rate of other decomposition products (oxides and the like) is reduced. In addition, it is known that the decomposition mechanism of dexamethasone sodium phosphate is mainly oxidative decomposition and hydrolysis, and metal ions are particularly involved in oxidative decomposition. From this point, it was predicted that the free silver ions had an adverse effect on the drug stability, but it was also confirmed in this experimental example. From this result, since the metal chelating agent and electrolyte of the present example suppress the release of silver ions, it can be determined that the drug stability has been improved.

(Experimental example 3: in vivo drug absorption)
A polyester film printed with a silver chloride paste 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). Further, a reference electrode (anode) was prepared by impregnating a preparation (4.5 cm ² ) in which a PET nonwoven fabric was mounted on the printed surface of an electrode printed with a silver paste with physiological saline.

  At the start of the experiment, the abdomen of an SD rat 7 weeks old (body weight 300 g, N = 4) was shaved, and then the drug product was applied, fixed with eslatex tape (manufactured by Alcare), and connected to a power supply device and a recording device. The cord was connected to the preparation, and energization (constant current: 0.45 mA / patch, energization time: 3 hr) was started. Blood was collected with a syringe from the vaginal vein over time, the plasma was dephosphorylated 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 drug absorptivity in Examples and Comparative Examples of the present invention, where 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) were compared with Comparative Example 2. The drug absorbability was equivalent to that of (unblended). On the other hand, in Comparative Example 8 (containing 1.0% by mass of sodium chloride), the drug absorbability was lowered, and it was found that the compounded electrolyte was a competitive ion for the drug. However, from the viewpoint of drug absorption, it is important to reduce the amount of electrolyte as much as possible.

  INDUSTRIAL APPLICABILITY The present invention can be used for an electric drug transfer formulation that can realize long-term quality assurance as a medical product.

Claims (12)

A transdermal or transmucosal electrical drug transfer formulation comprising a drug holding layer containing a medicinal component and an electrode layer adjacent to the drug holding layer, wherein the drug holding layer is a metal chelating agent and An electrical drug delivery formulation comprising an electrolyte that reacts with the electrode layer to form a poorly soluble compound. The electrical drug delivery formulation according to claim 1, wherein the electrolyte contains or generates an anion. The electrical drug delivery formulation according to claim 1 or 2, wherein the electrode layer contains a non-polarizable metal component. 4. The electric drug transfer formulation according to claim 3, wherein the non-polarizable metal component is composed of silver or a mixture containing silver. 5. The electric drug transfer formulation according to claim 1, wherein the hardly soluble compound has a solubility in water of 10 g / dm ³ or less or a solubility product (Ksp) of 1 × 10 ⁻² or less. . The electric drug transport formulation according to any one of claims 1 to 5, wherein a standard electrode potential (25 ° C) of an oxidation-reduction reaction of the hardly soluble compound is -1 V to +2 V. The electrical drug transfer formulation according to any one of claims 1 to 6, wherein the metal chelating agent is edetic acid or a salt thereof. The electric drug transfer formulation according to any one of claims 1 to 6, wherein the amount of the metal chelating agent is 0.001 to 1% by mass. The electrical material according to any one of claims 1 to 8, wherein the electrolyte generates at least one of halide ions (excluding fluorine ions), sulfide ions, sulfate ions and phosphate ions when dissolved. Drug transfer formulation. The electric drug transfer formulation according to any one of claims 1 to 8, wherein the amount of the electrolyte is 0.001 to 1% by mass. The said medicinal component contains a steroid hormone, The electrical drug transfer formulation in any one of Claims 1-10 characterized by the above-mentioned. The steroid hormone is at least one selected from the group consisting of dexamethasone phosphate, dexamethasone acetate, dexamethasone metasulfone benzoate, hydrocortisone succinate, hydrocortisone phosphate, prenizolone succinate, betamethasone phosphate and salts thereof. The electrical drug transport formulation according to claim 11.

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