WO2002096465A1

WO2002096465A1 - Medicinal compositions for percutaneous absorption

Info

Publication number: WO2002096465A1
Application number: PCT/JP2002/005188
Authority: WO
Inventors: Takeshi Nagai; Hitoshi Yamauchi; Eiichi Mafune; Hiroaki Kubota
Original assignee: Saitama Daiichi Pharmaceutical Co., Ltd.; Daiichi Suntory Pharma Co., Ltd.
Priority date: 2001-05-31
Filing date: 2002-05-29
Publication date: 2002-12-05
Also published as: JP4317693B2; JPWO2002096465A1

Abstract

Medicinal compositions containing the following components: (1) an antiarrhythmic such as disopyramide, mexiletine, propafenone, flecainide or pilscicainide, and (2) one or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerol fatty acid esters, terpenes, lower alcohols, polyhydric alcohols and amine compounds. When such a composition is adhered to the skin, the antiarrhythmic can be continuously absorbed percutaneously and thus arrhythmic can be efficaciously prevented over a long time or the occurrence of arrhythmic can be efficaciously prevented.

Description

Pharmaceutical composition for transdermal absorption

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. Background technology Ming ''

New dosage forms are known that control drug delivery to the systemic circulatory system by transdermal absorption of the drug. By 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. Because 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.

For example, percutaneous absorption preparations containing the sodium channel blocker lidocaine perazimarin (Patent Nos. 3115625, JP-A-6-45051, JP-A-7-76526, etc.), β-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. However, the above formulation containing lidocaine is used exclusively as a local anesthetic, and not for the purpose of arrhythmia treatment. For a formulation containing ajmaline, 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. Further, 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. In addition, 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.

That is, the present invention relates to a medicament or composition for transdermal absorption, comprising the following components:

(1) Antiarrhythmic drugs, and

(2) 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

And a pharmaceutical composition comprising:

According to a preferred embodiment of the present invention, 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. Octanol, lauryl alcohol, jetanol amide laurate, deglyceryl laurate, 1-menthol, ethanol, propylenedaricol, 1,3-butanediol, Selected from the group consisting of diisopropanolamine and triethanolamine

There is provided a pharmaceutical composition as described above, which is one or more substances.

In another aspect, according to the present invention, there is provided a pharmaceutical composition for transdermal absorption, comprising the following components:

(1) Antiarrhythmia-drugs,

(2) one or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes,

(3) One or more substances selected from the group consisting of lower alcohols, polyhydric alcohols, and amine compounds

A pharmaceutical composition comprising:

A pharmaceutical composition for transdermal absorption, comprising:

(1) antiarrhythmic drugs,

(3) one or more substances selected from the group consisting of lower alcohols and polyhydric alcohols; and

(4) A pharmaceutical composition comprising one or more amine compounds is provided.

According to preferred aspects of these inventions,

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. Certain of the above pharmaceutical compositions; The above pharmaceutical composition comprising a combination of a lower alcohol and a polyhydric alcohol; the above pharmaceutical composition wherein the lower alcohol is ethanol, and the polyhydric alcohol is propylene dalicol and / or 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.

Is provided. '

In a particularly preferred embodiment, one or two or more selected from the group consisting of (1) an antiarrhythmic drug, (2) octanol, 1-menthol, lauryl alcohol, diethanolamide laurate, and deglyceryl laurate Substance, (3) ethanol, (4) amine compound selected from the group consisting of diisopropanolamine and triethanolamine, (5) polyvalent selected from the group consisting of propylene glycol and 1,3-butanediol A pharmaceutical composition as described above comprising an alcohol is provided. .

In the present invention, in each of the above pharmaceutical compositions, it is preferable that 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. Further, the antiarrhythmic drug has the following formula (I):

AXBN (R ^a ) (R ² )

(Wherein, 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:

Is represented by the formula (I), particularly preferred antiarrhythmic agents used in the pharmaceutical compositions of the present invention, disopyramide [- (2 - Jie isopropyl aminoethyl) _ _alpha - Hue sulfonyl - 2 - pyridine Nasetoamido, mexiletine [2- (2,6-dimethylphenoxy) -1-methylethylamine], propafenone [(±) -2,-[2-hydroxy-3- (propylamino) propoxy [3] -Phenylpropiophenone], flecainide [(Sat) -N- (2-piperidylmethyl) -2,5_bis (2,2,2-trifluoroethoxy) -benzamide], Pirjikai An antiarrhythmic drug selected from the group consisting of dido [N- (2,6-dimethylphenyl) -8-pyrrolitidinyl acetoamide] and salts thereof, and hydrates and solvates thereof .

Other examples of particularly preferred antiarrhythmic drugs include the following formula (II):

(Wherein, 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, and 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.

In another aspect, the present invention provides a method for preventing and / or treating arrhythmia, the method including transdermally administering any of the above pharmaceutical compositions. From yet another perspective, 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.

Further, according to the present invention, there is provided a composition for promoting percutaneous absorption of an antiarrhythmic drug, comprising the following components:

(a) one or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes; and (b) one or more substances selected from the group consisting of lower alcohols, polyhydric alcohols, and amine compounds; and

A composition for promoting transdermal absorption of an antiarrhythmic drug, comprising:

(a) one or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes; and

(b) one or more substances selected from the group consisting of lower alcohols and polyhydric alcohols, and

(c) one or more amine compounds

There is provided a composition comprising:

Further, according to the present invention, there is provided the use of the above-mentioned substance or the above-mentioned composition for promoting the transdermal absorption of an antiarrhythmic drug for the production of the above-mentioned pharmaceutical composition for transdermal absorption. BEST MODE FOR CARRYING OUT THE INVENTION

The specification of Japanese Patent Application No. 200-161-545 (filed on May 31, 2001) and the entire disclosure of the claims are referred to in this specification. Include in disclosure.

The pharmaceutical composition of the present invention is a pharmaceutical composition for percutaneous absorption containing an antiarrhythmic drug as an active ingredient. 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. In a more preferred pharmaceutical composition, 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. (B) one or more substances selected from the group consisting of lower alcohols, polyhydric alcohols, and amine compounds. In a more preferred pharmaceutical composition, 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 The composition is characterized by containing one or more substances selected from the group consisting of: and (c) a composition containing one or more amine compounds.

As 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. Preferably, 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.

As used herein, “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.

As used herein, “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.

In the present specification, “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. Examples of triterpenes include glycyrrhetinic acid. Preferred terpenes include 1-menthol.

As used herein, "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.

In the present specification, "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.

In this specification, 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. For example, 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. Particularly preferably, 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. One or selected

Two or more substances, (3) ethanol, (4) an amine compound selected from the group consisting of diisopropanolamine and triethanolamine, (5) propylene dalicol and

The above-mentioned pharmaceutical 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.For example, 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. In addition, 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.

As an example of a preferable antiarrhythmic drug, an antiarrhythmic drug represented by the above formula (I) can be mentioned. Α represents an aryl group which may be substituted, and the aryl group may be either a monocyclic or condensed-ring aryl group. For example, 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. For example, 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 Examples of are, for example, 2,6-dimethylphenyl, 2,5-di (2,2,2-triphenyloleoethoxy) phenyl, 2- (3-phenylpropanoyl) phenyl And the like.

When X represents —C (R ³ ) (CONH ₂ ) —, 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. As the alkyl group represented by 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. When both 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.

Among the antiarrhythmic agents represented by the formula (I), particularly preferred antiarrhythmic agents include disopyramide [α- (2-diisopropylaminoethyl) -α-phenyl-2-pyridinepyridine amide] and mexiletine [2 -(2, 6 dimethylphenoxy) -tomethylethylamine, propafenone [(±) -2 '_ [2-hydroxy-3- (propylamino) propoxy] _3-phenylpropiophenone, flecainide [(Earth) -Ν- (2-piperidylmethyl) -2,5-bis (2,2,2-trifluoethoxy) -benzamide], pilgicide [Ν- (2,6-dimethylphenyl) -8-pyrrolididinyl acetoamide (or 8- (2 ', 6'-dimethylanilino) carbonylmethylpyrrolitidine)].

Another example of a preferable antiarrhythmic drug includes the antiarrhythmic drug represented by the above formula (II). This antiarrhythmic drug is described in Japanese Patent Publication No. 4-46956, the disclosure of which is incorporated herein by reference. 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, and 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 (Ι · Ι) 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 ', 5, -dimethylanilino) carbonylmethylpyrrolitidine, 8- (2', 6'- Methylanilino) carbonylmethylpyrrolitidine, 8- (3 ', 4'-dimethinoleanilino) carbonylmethylpyro-V-tidine, 8- (3,5'-dimethylanilino) carbo-noremethinolepyrrolidine, 8- (2 ,, 5, -Dimethoxyanilino) carponylmethylpyrrolitidine, 8- (2,, 6, -dicopeniaurino) carbonylmethylpyrrolididine, 8- (2 ', 6'-Jetylar-lino) potassylmethylpyrrolidine And 8- (2 ', 4', 6'-trimethylarino) carbomethylpyrrolitidine. A particularly preferred antiarrhythmic drug is 8- (2 ', 6'-dimethylanilino) carbonylmethylpyrrolitidine [alias: Ν- (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. When the antiarrhythmic drug has an asymmetric carbon, Pure stereoisomers, such as diastereoisomers, any mixture of stereoisomers, racemates and the like. For example, when the above-mentioned preferred antiarrhythmic drug is used, a salt form such as pilsicainide hydrochloride, propafenone hydrochloride, mexiletine hydrochloride, or flecainide acetate is preferable. For example, 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.

In a more preferred embodiment, 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.

In a further preferred embodiment, 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及Pi polyalcohol One or two or more substances selected from the group consisting of 5 to 80% by weight, preferably about 20 to 60% by weight, based on the total weight of the composition. 0.1 to 20 weight of the above amine compound based on the total weight of the composition. / ₀ , preferably about 1 to 5% by weight. 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. For example, 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. In the production of the pharmaceutical composition of the present invention, 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. It is possible to choose. For example, aqueous bases such as macrogol; oil-based bases such as petrolatum and liquid paraffin; gum arabic, gelatin, 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 The power that can be used as an additive for pharmaceuticals. It should be noted that 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. When 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. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Test Example 1: Skin permeation test

The extirpated skin of Yucatan micropig (minipita) is sandwiched between vertical diffusion cells (Franz-type diffusion cells, applicable area: 0.95 cm ² ) circulating water at 37 ° C, and a receiver (true). 4 ml of isotonic phosphate buffer solution (H7.4) was added to the (peel) side and stirred with a magnetic stirrer. 0.5 ml of each sample was applied to the donor (keratin) side, the solution in the receiver was collected over time, and the drug concentration in the solution was measured by high performance liquid chromatography. The amount was determined. Each sample was blended and mixed according to the composition shown in Table 1 to obtain a sample for a permeation test. The results are shown in Table 1 (all percentages in the table are% by weight).

table 1

PIL: Pinoresid hydrochloride DP: Diisopropanolamine

Oct: Octanol EtOH: ethanol 1-M: 1 menthol

PG: Propylene glycol NMP: N-methyl-2-pyrrolidone

BG: 1,3-butylene glycol (1,3-butanediol). Test Example 2: Skin permeation test No. 2

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. 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. ). In addition, Table 3 shows the results of similar tests conducted with the components in the composition changed (all percentages in the table are% by weight). Table 2

PIL: Pilsicainide hydrochloride DP: Disopropanolamine

Oct: I'm crazy about Etano EtOH: Ethanor

BG: 1,3-butylene glycol (1,3-butanediol)

PG ··· propylene glycol PVP: Polybutylpyrrolidone (gelling agent) Table 3

PIL: Pildicainide hydrochloride DP: Diisopropanolamine

EtOH: Ethanore

BG: 1,3-butylene glycol (1,3-butanediole) Test Example 3: Skin permeation test No. 3

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.

(All percentages in the table is the weight ^_0/0).

Table 4

1-M: 1-menthol EtOH: ethanol

PG: Propylene Dali Cornole Industrial Applicability

ADVANTAGE OF THE INVENTION 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.

Claims

The scope of the claims

1. A pharmaceutical composition for transdermal absorption, comprising:

(1) antiarrhythmic drugs, and

A pharmaceutical composition comprising:

2. 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 octanol, lauryl alcohol, phenol laurate, One or two or more substances selected from the group consisting of glyceryl delaurate, menthol, ethanol, propylene glycol, 1,3-butanediol, diisopropanolamine, and triethanolamine 2. The medicament or composition according to claim 1, wherein

3. A pharmaceutical composition for transdermal absorption, comprising:

(1) antiarrhythmic drugs,

A pharmaceutical composition comprising:

4. A medicament for percutaneous absorption, comprising:

(1) antiarrhythmic drugs,

(3) One or more selected from the group consisting of lower alcohols and polyhydric alcohols The above substances, and

(4) One or more amine compounds

A pharmaceutical composition comprising:

5. One or more substances selected from the group consisting of higher alcohols, fatty acid amides, glycerin fatty acid esters, and terpenes are octanol, laurinole alcohol, ethanolamide laurate, deglycol laurate, and 5. The pharmaceutical composition according to claim 3, which is one or more substances selected from the group consisting of one menthol.

6. 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 ^ thanol, propylene glycol, and 1,3-butanediol. The pharmaceutical composition according to any one of claims 3 to 5, which is two or more substances.

7. The pharmaceutical composition according to any one of claims 3 to 5, comprising a combination of a lower alcohol and a polyalcohol.

8. The pharmaceutical composition according to claim 7, wherein the lower alcohol is ethanol, and the polyhydric alcohol is propylene glycol and / or 1,3-butanediol.

9. The amine compound according to any one of claims 3 to 8, wherein the amine compound is one or more amine compounds selected from the group consisting of diisopropanolamine and triethanolamine. Pharmaceutical compositions.

10. The medicament or composition according to any one of claims 1 to 9, wherein the antiarrhythmic drug is an antiarrhythmic drug capable of binding to sodium channels.

11. The antiarrhythmic drug has the following formula (I):

AXB-NiR ¹ ) (R ² )

(Wherein, A represents an optionally substituted aryl group; X is an oxygen atom, _NH—CO—, —CO—NH—, or one C (R ³ ) (CONH ₂ ) — (R ³ is hydrogen B represents an atom or a monovalent substituent); B represents an optionally substituted C2 or C3 alkyl atom; R ¹ and R ² each independently represent a hydrogen atom or an alkyl group, but R ¹ and / or R ² may form a ring together with a substituent on the alkylene represented by B) The pharmaceutical composition according to any one of claims 1 to 10, represented by the formula:

12. The antiarrhythmic drug is selected from the group consisting of disoviramide, mexiletine, propafenone, flecainide, pilsicainide and salts thereof, and hydrates and solvates thereof. Item 10. The pharmaceutical composition according to any one of Items 10 to 10.

1 3. The antiarrhythmic drug has the following formula (II):

(Wherein, R ¹¹ represents a hydrogen atom or a lower alkyl group; ¹² represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, and R ¹³ represents a lower alkyl group, a lower alkoxy group. The drug or the composition according to any one of claims 1 to 10, which is an 8-substituted pyrrolizidine derivative represented by the following formula:

14. Any one of claims 1 to 10 wherein the antiarrhythmic drug is selected from the group consisting of pilsicainide and its salts, and hydrates and solvates thereof.

Item 2. The pharmaceutical composition according to Item 1. .