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WO2005020967A1 - Preparation pour le transport electrique d'un medicament - Google Patents

Preparation pour le transport electrique d'un medicament Download PDF

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Publication number
WO2005020967A1
WO2005020967A1 PCT/JP2004/012091 JP2004012091W WO2005020967A1 WO 2005020967 A1 WO2005020967 A1 WO 2005020967A1 JP 2004012091 W JP2004012091 W JP 2004012091W WO 2005020967 A1 WO2005020967 A1 WO 2005020967A1
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WO
WIPO (PCT)
Prior art keywords
drug
electrode
electropharmaceutical
electrolyte
preparation according
Prior art date
Application number
PCT/JP2004/012091
Other languages
English (en)
Japanese (ja)
Inventor
Seiji Tokumoto
Mitsuru Kuribayashi
Toshio Yoshida
Kazutaka Inoue
Kenji Mori
Original Assignee
Hisamitsu Pharmaceutical Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hisamitsu Pharmaceutical Co., Inc. filed Critical Hisamitsu Pharmaceutical Co., Inc.
Priority to JP2005513430A priority Critical patent/JPWO2005020967A1/ja
Publication of WO2005020967A1 publication Critical patent/WO2005020967A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

Definitions

  • the present invention relates to an electropharmaceutical drug transfer preparation suitable for transdermal or transmucosal application.
  • electro 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a hydrophilic gel base such as a water-soluble polymer.
  • Patent Literature 1 or Patent Literature 2 discloses an iontophoresis preparation comprising a lidocaine anesthetic and a vasoconstrictor epinephrine.
  • drug stabilization is achieved by mixing an antioxidant such as sodium pyrosulfite and sodium metabisulfite, and a metal chelating agent such as disodium edetate.
  • an antioxidant such as sodium pyrosulfite and sodium metabisulfite
  • a metal chelating agent such as disodium edetate.
  • pH control and nitrogen replacement 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
  • 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.
  • 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
  • a polarizable electrode such as platinum, gold, carbon or titanium
  • a non-polarizable electrode such as silver, copper, silver chloride or copper chloride
  • an iontophoresis preparation can use both a polarizable electrode and a non-polarizable electrode.
  • 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.
  • 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.
  • 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.
  • Patent Literature 4 discloses an iontophoresis preparation having an ion-exchange membrane at the electrode portion
  • 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.
  • Patent Document 4 Patent No. 2636290
  • Patent Document 5 JP-A-10-66733
  • 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
  • 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.
  • 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.
  • 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.
  • the present invention relates to a transdermal or transmucosal electric drug transfer preparation
  • a drug-retaining layer containing a medicinal component
  • 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.
  • the electrolyte may contain or generate an anion
  • the electrode layer may contain a non-polarizable metal component.
  • the non-polarizable metal component can be silver or a mixture containing silver.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 1 is an exploded view showing one configuration example of the 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the electrolyte having a bromide ion includes sodium bromide, potassium bromide, calcium bromide, and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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, pun
  • 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.
  • a bioactive substance having a molecular weight of 1 ⁇ 10 2 to 1 ⁇ 10 6 is widely used.
  • 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, ⁇ promyci , Pro-luvazine, vinblastine, vincri
  • 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.
  • 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.
  • Tables 1, 2, and 3 show the amounts of the drug-retaining layers in Examples and Comparative Examples of the present invention.
  • Nonionic synthetic polymer Polyvinyl alcohol 15 17 17 17 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15
  • Metal chelating agent disodium edetate 0.1 0.1 0.05 0.05 0.05 0.1
  • Nonionic synthetic polymer Polyvinyl alcohol 15 15 15 15 15 15 15 2 3
  • Carrageenan 2.5 Polyhydric alcohols Glycerin 10 10 10 10 10 10 _ tart10 1_0 _ 30 30
  • 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.
  • 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.
  • 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.
  • 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]
  • 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.
  • 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.
  • 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).)
  • 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.
  • Example of the present invention 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.
  • Example 1 containing sodium disodium edetate
  • Example 5 containing sodium disodium edetate and sodium chloride
  • the experimental example equipped with Example 1 and Example 5 had a higher drug residual ratio.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • the present invention can be used for an electropharmaceutical drug transfer preparation that can realize long-term quality assurance as a medical product.

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Abstract

L'invention concerne une préparation pour le transport électrique d'un médicament, qui permet: de renforcer la stabilité du médicament pendant le stockage et de prévenir, pendant la préparation, une variation de l'aspect (coloration) de la couche retenant le médicament, ladite variation étant due aux ions métalliques provenant d'une électrode, grâce au fait que la couche contenant un médicament instable à l'état dissous est placée de façon adjacente à une électrode non polarisable; et d'obtenir un taux d'utilisation biologique élevé du médicament si l'on empêche l'élément électrode de coller à la peau. La préparation (1) pour le transport électrique d'un médicament comprend un substrat (5) support d'électrode, une couche d'électrode (2) placée sur le substrat (5), une couche (3) de retenue de médicament placée sur la couche d'électrode (2), et une matière d'enrobage couvrant la couche (3) de retenue de médicament. Cette couche (3) contient un électrolyte réagissant avec un chélateur métallique et/ou la couche d'électrode (2) pour former un composé se dissolvant difficilement.
PCT/JP2004/012091 2003-08-29 2004-08-24 Preparation pour le transport electrique d'un medicament WO2005020967A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996011034A2 (fr) * 1994-10-07 1996-04-18 Hisamitsu Pharmaceutical Co., Inc. Procede d'administration par iontophorese de steroides solubles dans l'eau
JPH09248344A (ja) * 1996-03-17 1997-09-22 Hisamitsu Pharmaceut Co Inc イオントフォレーシス用電極デバイス
JPH1199209A (ja) * 1997-09-26 1999-04-13 Kyowa Hakko Kogyo Co Ltd イオントフォレシス用電極組成物
JP2000219623A (ja) * 1998-11-26 2000-08-08 Hisamitsu Pharmaceut Co Inc イオントフォレ―シス用粘着ゲル組成物及びその装置

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