WO2002096465A1 - Compositions medicinales pour absorption percutanee - Google Patents

Compositions medicinales pour absorption percutanee Download PDF

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Publication number
WO2002096465A1
WO2002096465A1 PCT/JP2002/005188 JP0205188W WO02096465A1 WO 2002096465 A1 WO2002096465 A1 WO 2002096465A1 JP 0205188 W JP0205188 W JP 0205188W WO 02096465 A1 WO02096465 A1 WO 02096465A1
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Prior art keywords
group
fatty acid
pharmaceutical composition
alcohols
substances selected
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PCT/JP2002/005188
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English (en)
Japanese (ja)
Inventor
Takeshi Nagai
Hitoshi Yamauchi
Eiichi Mafune
Hiroaki Kubota
Original Assignee
Saitama Daiichi Pharmaceutical Co., Ltd.
Daiichi Suntory Pharma Co., Ltd.
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.)
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Application filed by Saitama Daiichi Pharmaceutical Co., Ltd., Daiichi Suntory Pharma Co., Ltd. filed Critical Saitama Daiichi Pharmaceutical Co., Ltd.
Priority to JP2002592974A priority Critical patent/JP4317693B2/ja
Publication of WO2002096465A1 publication Critical patent/WO2002096465A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to a pharmaceutical composition for transdermal absorption. More specifically, the present invention relates to a pharmaceutical composition for transdermal absorption containing an antiarrhythmic drug as an active ingredient.
  • New dosage forms are known that control drug delivery to the systemic circulatory system by transdermal absorption of the drug.
  • transdermally administering the drug pain at the time of injection can be avoided, or delay in the onset of the drug effect due to gastrointestinal absorption or variation in the drug effect due to the first-pass effect can be avoided.
  • percutaneous administration can be easily adjusted and its efficacy can be rapidly eliminated by discontinuing administration, transdermal administration is attracting attention as a safe and less burdensome method for patients.
  • percutaneous absorption preparations containing the sodium channel blocker lidocaine perazimarin Patent Nos. 3115625, JP-A-6-45051, JP-A-7-76526, etc.
  • ⁇ -blockers Percutaneous absorption preparations containing certain atenolol, bupranolol, pindolol and the like (JP-A-8-310946, JP-A-2509585, JP-A-7-76526, etc.) are known.
  • the above formulation containing lidocaine is used exclusively as a local anesthetic, and not for the purpose of arrhythmia treatment.
  • transdermal absorption is promoted in combination with a specific absorption enhancer, but the absorption enhancement effect may not always be sufficient depending on the type of base.
  • a composition for promoting percutaneous absorption in which a higher alcohol such as octanol or lauryl alcohol is combined with ethanol or a polyhydric alcohol is known (International Publication W000 / 53226, International Publication TO00 / 53184). It has not been put into practical use as a transdermal preparation for the treatment of arrhythmias. Disclosure of the invention
  • An object of the present invention is to provide a preparation for transdermal absorption containing an antiarrhythmic drug as an active ingredient. More specifically, an object of the present invention is to stably absorb an antiarrhythmic drug percutaneously by applying it to the skin, effectively suppress arrhythmia over a long period of time, or effectively prevent the occurrence of arrhythmia. It is to provide a formulation.
  • the present inventors have made intensive efforts to solve the above problems, and as a result, are selected from the group consisting of higher alcohols, fatty amides, glycerin fatty acid esters, terpenes, lower alcohols, polyhydric alcohols, and amine compounds. It has been found that combining the substance with an antiarrhythmic drug enhances the transdermal absorption of the antiarrhythmic drug.
  • one or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes, and selected from the group consisting of lower alcohols, polyhydric alcohols, and amine compounds It has been found that a composition comprising one or more substances in combination significantly enhances the percutaneous absorption of antiarrhythmic drugs.
  • the present invention has been completed based on the above findings.
  • the present invention relates to a medicament or composition for transdermal absorption, comprising the following components:
  • composition comprising:
  • one or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, terpenes, lower alcohols, polyhydric alcohols, and amine compounds are used.
  • composition as described above, which is one or more substances.
  • composition for transdermal absorption comprising the following components:
  • a pharmaceutical composition comprising:
  • a pharmaceutical composition for transdermal absorption comprising:
  • a pharmaceutical composition comprising one or more amine compounds is provided.
  • One or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes are octanol, laurinoleanol, lauric acid diethanolamide, lauric acid deglyceryl, and 1 above-mentioned pharmaceutical composition which is one or more substances selected from the group consisting of menthol;
  • One or more substances selected from the group consisting of lower alcohols and polyhydric alcohols are one or more substances selected from the group consisting of ethanol, propylene glycol, and 1,3-butanediol.
  • the above pharmaceutical composition, wherein the amine compound is one or more amine compounds selected from the group consisting of disopropanolamine and triethanolamine.
  • the antiarrhythmic drug is an antiarrhythmic drug capable of binding sodium channel.
  • the molecular weight of the antiarrhythmic drug is preferably, for example, 200 or more and 500 or less, and the pKa of the antiarrhythmic drug is preferably 7 or more.
  • the antiarrhythmic drug has the following formula (I):
  • A represents an optionally substituted aryl group
  • X is an oxygen atom, one NH—CO—, one CO—NH—, or one C (R 3 ) (CONH 2 ) —
  • R 3 is R represents a hydrogen atom or a monovalent substituent
  • B represents an optionally substituted alkylene group having 2 or 3 carbon atoms
  • R 1 and R 2 each independently represent a hydrogen atom or an alkyl group Wherein R 1 and Z or R 2 may form a ring together with a substituent on the alkylene represented by B), and it is also preferable that the antiarrhythmic agent is represented by the formula:
  • R 11 represents a hydrogen atom or a lower alkyl group
  • R 12 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom
  • R 13 represents a lower alkyl group, a lower alkoxy group.
  • An amino group or a halogen atom and the most preferred antiarrhythmic drug is pyridicanide [N- (2,6-dimethylphenyl) -8-pyrrolidine [Tidinyl acetoamide] and salts thereof, and hydrates and solvates thereof.
  • the present invention provides a method for preventing and / or treating arrhythmia, the method including transdermally administering any of the above pharmaceutical compositions.
  • a substance that promotes transdermal absorption of antiarrhythmic drugs comprising higher alcohols, fatty acid amides, glycerin fatty acid esters, terpenes, lower alcohols, polyhydric alcohols, and amine compounds
  • a substance selected from the group is provided by the present invention.
  • composition for promoting percutaneous absorption of an antiarrhythmic drug comprising the following components:
  • composition for promoting transdermal absorption of an antiarrhythmic drug comprising:
  • composition comprising:
  • the pharmaceutical composition of the present invention is a pharmaceutical composition for percutaneous absorption containing an antiarrhythmic drug as an active ingredient.
  • an antiarrhythmic drug As the substance for promoting percutaneous absorption of the antiarrhythmic drug, higher alcohols, fatty amides, glycerin It is characterized by containing one or more substances selected from the group consisting of fatty acid esters, terpenes, lower alcohols, polyhydric alcohols, and amine compounds.
  • the fibrous component that promotes percutaneous absorption of an antiarrhythmic drug is selected from the group consisting of (a) higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes.
  • the composition for promoting transdermal absorption of an antiarrhythmic drug is selected from the group consisting of ( a ) higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes.
  • One or more substances, (b) from lower alcohols and polyhydric alcohols is characterized by containing one or more substances selected from the group consisting of: and (c) a composition containing one or more amine compounds.
  • the “higher alcohol” a monohydric alcohol having about 8 to 12 carbon atoms can be used.
  • the higher alcohol p-structure is not particularly limited, and may be linear or branched, and may contain one or more unsaturated bonds.
  • a linear, saturated alcohol can be used. More specifically, for example, octanol, nonanol, decanol, decanol, or benzyl alcohol can be used, and preferred higher alcohols include octanol or benzyl alcohol.
  • fatty acid amide means a compound that forms an amide bond with an amine compound at a carboxyl group of a fatty acid.
  • the type of the fatty acid constituting the fatty acid amide is not particularly limited, but, for example, a saturated or unsaturated fatty acid having about 6 to 18 carbon atoms, preferably about 8 to 16 carbon atoms is preferable. Any of a chain or a branched fatty acid may be used. More specifically, examples of the fatty acid include capric acid, oleic acid, caprylic acid, lauric acid, myristic acid, pentadecanoic acid, and palmitic acid. Of these, capric acid or lauric acid is more preferable.
  • the type of the amine compound is not particularly limited, either, but aminoamine is preferred, and diethanolamine is preferred. Preferred fatty acid amides include lauric diethanolamide.
  • glycerin fatty acid ester refers to an ester of glycerin and a fatty acid.
  • the type of fatty acid constituting the glycerin fatty acid ester is not particularly limited, but is preferably, for example, a saturated or unsaturated fatty acid having about 6 to 18 carbon atoms, preferably about 8 to 16 carbon atoms, and is linear or branched. Any chain fatty acid may be used. More specifically, examples of the fatty acid include acetic acid, oleic acid, acetic acid, lauric acid, myristic acid, pentadecanoic acid, and palmitic acid, and among them, capric acid or lauric acid is more preferable.
  • Preferred glycerin fatty acid esters include glyceryl de-laurate. Can be.
  • terpenes is used to mean monoterpenes, chain terpene alcohols, triterpenes and the like.
  • Monoterpenes include, for example, cineol, 1-menthenole, menthone, d-limonene, nerolidol, a-terbineole, and linear terpene alcohols include geraniol.
  • triterpenes include glycyrrhetinic acid.
  • Preferred terpenes include 1-menthol.
  • lower alcohol means an alcohol having 6 or less carbon atoms.
  • the lower alcohol is preferably a lower alkanol composed of a straight chain, a branched chain, a ring or a combination thereof, but may contain one or more unsaturated bonds.
  • Examples of the lower alcohol include ethanol, propanol, and isopropanol, and ethanol is particularly preferable.
  • polyhydric alcohol means a dihydric or higher alcohol, and for example, a dihydric or trihydric alcohol is preferable.
  • Polyhydric alcohols include, for example, propylene glycol, 1,3-butanediol, ethylene glycol ', diethylene glycol, 1,3-propylene glycol, triethylene glycol, dipropylene glycol, 1,41 Butanediol, glycerin and the like can be used, and more preferably, propylenedaricol, glycerin, 1,3-butanediol and the like can be mentioned. Of these, propylene dalicol or 1,3-butanediol is preferred.
  • the type of the “amine compound” is not particularly limited, and any compound having an amino group may be used.
  • the amine compound may have one or more substituents other than the amino group.
  • amino alcohol and the like can be suitably used, and diethanolamine, diisopropanolamine, triethanolamine and the like are preferable.
  • Particularly preferred amine compounds are diisopropanolamine or triethanolamine.
  • the combination of the above components in a preferred composition is selected from the group consisting of (1) an antiarrhythmic agent, (2) octanol, 1-menthol, lauryl alcohol, diethanolanol laurate, and deglyceryl laurate.
  • Two or more substances (3) ethanol, (4) an amine compound selected from the group consisting of diisopropanolamine and triethanolamine, (5) propylene dalicol and
  • composition containing a polyhydric alcohol selected from the group consisting of 1,3-butanediol can be mentioned.
  • the type of antiarrhythmic drug contained in the pharmaceutical composition of the present invention can be appropriately selected by those skilled in the art.
  • an antiarrhythmic drug having a sodium channel binding ability an antiarrhythmic having a molecular weight of 200 or more and 500 or less
  • a drug or an antiarrhythmic drug having a pKa of 7 or more, preferably 9 to 11, can be suitably used.
  • the pharmaceutical composition of the present invention can suitably contain a water-soluble antiarrhythmic drug.
  • antiarrhythmic drugs are classified into Group I (a sodium channel blocker), Group II (a blocker), Group III (a potassium channel blocker, and a group IV (a calcium antagonist)) according to the Vaughan Williams classification.
  • As an active ingredient of the pharmaceutical composition it is preferable to use an antiarrhythmic drug classified into Group I.
  • an antiarrhythmic drug represented by the above formula (I) can be mentioned.
  • ⁇ represents an aryl group which may be substituted, and the aryl group may be either a monocyclic or condensed-ring aryl group.
  • a phenyl group, a naphthyl group and the like can be used, and a phenyl group can be preferably used.
  • the type, number, and substitution position of the substituents on the aryl ring are not particularly limited.
  • an alkyl group eg, methyl group, ethyl group
  • an alkoxy group eg, methoxy group, ethoxy group
  • a halogenated alkyl group eg, Trifluoromethyl group, halogenated alkoxy group (2,2,2-trifluoroethoxy group, etc.
  • alkanoyl group acetyl group, propanoyl group, 3-phenylpropanoyl group, etc.
  • halogen Atom fluorine atom, chlorine atom, etc.
  • hydroxyl group amino group (may be substituted by alkyl group, alkanoyl group, etc.).
  • Aryl groups having substituents are, for example, 2,6-dimethylphenyl, 2,5-di (2,2,2-triphenyloleoethoxy) phenyl, 2- (3-phenylpropanoyl) phenyl And the like.
  • R 3 represents a hydrogen atom or a monovalent substituent.
  • the type of the monovalent substituent is not particularly limited, but is preferably, for example, a heteroaryl group (such as a pyridyl group). Particularly preferred is a 2-pyridyl group.
  • a substituent may be present on the alkylene group having 2 or 3 carbon atoms represented by B, but the type, substitution position, and number of the substituent are not particularly limited. Preferred substituents include, for example, lower alkyl groups, amino groups, hydroxyl groups and the like.
  • R 1 or R 2 for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like are preferable.
  • R 1 and R 2 represent an alkyl group, they may be the same or different.
  • the type of the ring formed by R 1 and / or R 2 and the substituent on the alkylene represented by B is not particularly limited, and may be a monocyclic or polycyclic ring structure. Examples thereof include a piperidine ring and a pyrrolidine ring.
  • antiarrhythmic agents include disopyramide [ ⁇ - (2-diisopropylaminoethyl) - ⁇ -phenyl-2-pyridinepyridine amide] and mexiletine [2 -(2, 6 dimethylphenoxy) -tomethylethylamine, propafenone [( ⁇ ) -2 '_ [2-hydroxy-3- (propylamino) propoxy] _3-phenylpropiophenone, flecainide [(Earth) - ⁇ - (2-piperidylmethyl) -2,5-bis (2,2,2-trifluoethoxy) -benzamide], pilgicide [ ⁇ - (2,6-dimethylphenyl) -8-pyrrolididinyl acetoamide (or 8- (2 ', 6'-dimethylanilino) carbonylmethylpyrrolitidine)].
  • R 11 and R 12 are both hydrogen atoms, and R 13 is a methyl group, a methoxy group, an amino group, a chlorine atom, or a bromine
  • R 11 is a hydrogen atom
  • R 12 and R 13 are each independently a methyl group, an ethyl group, a methoxy group, or a chlorine atom
  • R 11 R 12 and R 13 are all The case where it is a methyl group is preferable.
  • R 11 is a hydrogen atom, is particularly preferred if R 12 and R 1 3 are each independently a methyl group, on the benzene ring in this case: the substitution position of 12 and R 13 are the 2-position and 6-position Is preferred.
  • Preferred anti-arrhythmic drugs included in the formula ( ⁇ ⁇ ⁇ ) include 8- (2′-methylanilino) carbonylmethylpyrrolididine, 8- (4′-methylanilino) carbonylmethylpyrrolididine, (2, -Cuproauryno) carbonylmethylpyrrolitidine, 8- (2, -Promoyurino) carbonylmethylpyrrolididine, 8- (2'-methoxyanilino) carbonylmethylpyrrolidine, 8- (3, -Methoxyanilino) carbonylmethyl Pyrrolitidine, 8- (4, -methoxyanilino) carbo-normethylpyrrolitidine, 8- (2'-aminoanilino) propyl methylpyrrolitidine, 8_ (2 ', 3, _dimethylanilino) Carbonylmethylpyrrolitidine, 8- (2,4, -dimethylanilino) carbonylmethylpyrrolitidine, 8- (2 '
  • a particularly preferred antiarrhythmic drug is 8- (2 ', 6'-dimethylanilino) carbonylmethylpyrrolitidine [alias: ⁇ - (2,6-dimethylphenyl) -8-8-pyrrolitidinylacetamide: pildicainide].
  • the antiarrhythmic drug contained in the pharmaceutical composition of the present invention includes, in addition to a substance in free form, a substance in the form of a physiologically acceptable salt, or a hydrate or solvate of a substance in free or salt form An object may be used.
  • the type of the solvent that forms the solvate is not particularly limited, and examples thereof include ethanol, acetone, and tetrahydrofuran.
  • Pure stereoisomers such as diastereoisomers, any mixture of stereoisomers, racemates and the like.
  • a salt form such as pilsicainide hydrochloride, propafenone hydrochloride, mexiletine hydrochloride, or flecainide acetate is preferable.
  • hydrochloride monomonohydrate is preferable.
  • the blending amount of each component in the pharmaceutical composition of the present invention is not particularly limited. And one or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, terpenes, lower alcohols, polyhydric alcohols, and amine compounds based on the total weight of the composition. 1-90% by weight, preferably 20-70% by weight. / 0 can be blended.
  • the antiarrhythmic agent can be blended in an amount of 1 to 70% by weight, preferably about 10 to 60% by weight, based on the total weight of the composition. And 0.5 to 50% by weight, preferably 1 to 20% by weight, based on the total weight of the composition, of one or more substances selected from the group consisting of, and terpenes, lower alcohol, polyhydric alcohol, and One or more substances selected from the group consisting of amine compounds can be added at a ratio of about 5 to 80% by weight, preferably about 20 to 60% by weight, based on the total weight of the composition.
  • the antiarrhythmic agent can be blended in an amount of 1 to 70% by weight, preferably about 10 to 60% by weight, based on the total weight of the composition.
  • Higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes 0.5 to 50% by weight relative to the total weight of the composition of one or more kinds of substances selected from the group consisting of, the group preferably of 1 to 20 weight 0/0, lower alcohol ⁇ Pi polyalcohol
  • the form of the pharmaceutical composition of the present invention is not particularly limited as long as it is a form suitable as a preparation for transdermal absorption.
  • ointments, creams, liquids, lotions, liniments, cataplasms, plasters (plasters), tapes, patches, gels, liza-par formulations, etc. Can be prepared.
  • the preparation method of the pharmaceutical composition of the present invention is not particularly limited, either, and a well-known and commonly used preparation method can be adopted according to the formulation form.
  • one or more additives for pharmaceutical preparations can be used, and the necessity and type thereof are appropriately determined by those skilled in the art according to the type of the pharmaceutical form.
  • aqueous bases such as macrogol
  • oil-based bases such as petrolatum and liquid paraffin
  • gum arabic such as petrolatum and liquid paraffin
  • methinoresenorelose ethylsenorelose
  • canoleboxy methinoresenorelose hydroxypropinole cellulose
  • Water-soluble polymers such as hydroxypropylmethylcellulose, polyacrylic acid, polyvinyl alcohol, and polybierpi oralidone
  • antioxidants such as erisorbic acid, sodium erisorbate, hydroxyanisole, sodium anhydrous sulfite
  • preservatives coloring agents
  • coloring agents The power that can be used as an additive for pharmaceuticals.
  • these additives for pharmaceutical preparations need to be selected so as not to impair the transdermal absorbability of the pharmaceutical composition of the present invention. By doing so, it is possible to select the desired pharmaceutical additives.
  • the antiarrhythmic drug becomes unstable in acid or alkali, it is preferable to prepare the pharmaceutical composition so as to be in the vicinity of mesophilic.
  • An acrylic pressure-sensitive adhesive was applied to the polyethylene porous film (drug release controlling film) and dried, and a release liner was coated on the pressure-sensitive adhesive surface to form a laminated film.
  • a depression is created in the support film by heat and pressure, and 0.1 ml of the sample solution or sample gel is dropped into the depression, and
  • the laminated membrane prepared in (1) was placed with the polyethylene porous membrane down, and the periphery was heat-sealed to obtain a test preparation.
  • the skin permeability of the drug was tested in the same manner as in Test Example 1, except that each preparation was applied to the donor (keratinous) side of the skin and a sample was applied.
  • Table 2 The results are shown in Table 2 (all percentages in the table are given in weight percent, and "cumulative skin penetration” is the cumulative amount (g / cra 2 ) of the drug permeating the skin. ).
  • Table 3 shows the results of similar tests conducted with the components in the composition changed (all percentages in the table are% by weight).
  • PIL Pilsicainide hydrochloride DP: Disopropanolamine
  • PIL Pildicainide hydrochloride DP: Diisopropanolamine
  • the drug skin permeability was tested in the same manner as in Test Example 1 except that the exfoliated skin of a hairless mouse skin was used instead of Yucatan micropig (minipita). The results are shown in Table 4.
  • the pharmaceutical composition of this invention can percutaneously absorb the antiarrhythmic drug which is an active ingredient continuously, can suppress arrhythmia effectively over a long period of time, or can prevent the onset of arrhythmia effectively.

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Abstract

L'invention concerne des compositions médicinales renfermant les composants suivants : (1) un anti-arythmisant tel que la disopyramide, le mexiletine, la propafénone, le flécaïnide ou le pilscicainide, et (2) une ou plusieurs substances sélectionnées dans le groupe constitué par alcools supérieurs, amides d'acides gras, esters d'acides gras de glycérol, terpènes, alcools inférieurs, polyols et composés amine. Lorsque cette composition est appliquée sur la peau, l'anti-arythmisant est absorbé en continu par voie percutanée, ce qui permet de prévenir efficacement l'arythmie sur une longue période ou de prévenir efficacement l'apparition d'une arythmie.
PCT/JP2002/005188 2001-05-31 2002-05-29 Compositions medicinales pour absorption percutanee WO2002096465A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2002592974A JP4317693B2 (ja) 2001-05-31 2002-05-29 経皮吸収用医薬組成物

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JP2001-164545 2001-05-31
JP2001164545 2001-05-31

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WO2002096465A1 true WO2002096465A1 (fr) 2002-12-05

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006176430A (ja) * 2004-12-22 2006-07-06 Saitama Daiichi Seiyaku Kk ピルジカイニド貼付剤

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EP0089061A2 (fr) * 1982-03-16 1983-09-21 Suntory Kabushiki Kaisha Dérivés de pyrrolizidine substitués en position 8 et leur application
JPH02207024A (ja) * 1989-02-03 1990-08-16 Fsk Corp 経皮吸収製剤
EP0507160A1 (fr) * 1991-03-30 1992-10-07 Teikoku Seiyaku Kabushiki Kaisha Préparation à usage externe pour application sur la peau à base de lidocaine
JPH05310598A (ja) * 1991-04-18 1993-11-22 Mikasa Seiyaku Kk 経皮投与製剤
JPH06145051A (ja) * 1992-02-25 1994-05-24 Nitto Denko Corp 穿刺処理前貼付用の貼付剤および穿刺時疼痛の軽減方法
JPH06256218A (ja) * 1993-03-04 1994-09-13 Lederle Japan Ltd 外用剤
JPH0776526A (ja) * 1993-09-06 1995-03-20 Sansei Seiyaku Kk 乳酸エステルを含有する経皮吸収製剤
JPH08310946A (ja) * 1995-05-19 1996-11-26 Yuutoku Yakuhin Kogyo Kk 経皮吸収製剤
EP0757910A1 (fr) * 1994-04-21 1997-02-12 Hisamitsu Pharmaceutical Co., Inc. Composition de base administree par voie percutanee et composition medicamenteuse administree par voie percutanee obtenue a partir de cette derniere
JPH09169635A (ja) * 1995-12-20 1997-06-30 Sekisui Chem Co Ltd 経皮吸収製剤

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0089061A2 (fr) * 1982-03-16 1983-09-21 Suntory Kabushiki Kaisha Dérivés de pyrrolizidine substitués en position 8 et leur application
JPH02207024A (ja) * 1989-02-03 1990-08-16 Fsk Corp 経皮吸収製剤
EP0507160A1 (fr) * 1991-03-30 1992-10-07 Teikoku Seiyaku Kabushiki Kaisha Préparation à usage externe pour application sur la peau à base de lidocaine
JPH05310598A (ja) * 1991-04-18 1993-11-22 Mikasa Seiyaku Kk 経皮投与製剤
JPH06145051A (ja) * 1992-02-25 1994-05-24 Nitto Denko Corp 穿刺処理前貼付用の貼付剤および穿刺時疼痛の軽減方法
JPH06256218A (ja) * 1993-03-04 1994-09-13 Lederle Japan Ltd 外用剤
JPH0776526A (ja) * 1993-09-06 1995-03-20 Sansei Seiyaku Kk 乳酸エステルを含有する経皮吸収製剤
EP0757910A1 (fr) * 1994-04-21 1997-02-12 Hisamitsu Pharmaceutical Co., Inc. Composition de base administree par voie percutanee et composition medicamenteuse administree par voie percutanee obtenue a partir de cette derniere
JPH08310946A (ja) * 1995-05-19 1996-11-26 Yuutoku Yakuhin Kogyo Kk 経皮吸収製剤
JPH09169635A (ja) * 1995-12-20 1997-06-30 Sekisui Chem Co Ltd 経皮吸収製剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006176430A (ja) * 2004-12-22 2006-07-06 Saitama Daiichi Seiyaku Kk ピルジカイニド貼付剤

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