WO2002069967A1 - Compositions a absorption percutanee - Google Patents

Compositions a absorption percutanee Download PDF

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Publication number
WO2002069967A1
WO2002069967A1 PCT/JP2002/001812 JP0201812W WO02069967A1 WO 2002069967 A1 WO2002069967 A1 WO 2002069967A1 JP 0201812 W JP0201812 W JP 0201812W WO 02069967 A1 WO02069967 A1 WO 02069967A1
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Prior art keywords
group
methyl
oxothiazolidine
hydrogen atom
compound
Prior art date
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PCT/JP2002/001812
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English (en)
Japanese (ja)
Inventor
Kazuhiro Inoue
Junichi Okada
Original Assignee
Sankyo Company, Limited
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Publication date
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Publication of WO2002069967A1 publication Critical patent/WO2002069967A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a composition for preventing or treating angina pectoris, comprising a transdermal absorption promoting compound and a thiazolidinone-based antianginal compound or a pharmacologically acceptable salt thereof as active ingredients. Or their use in the manufacture of a medicament for the treatment, a method of preventing or treating angina pectoris by administering a pharmacologically effective amount thereof to a warm-blooded animal, or a method of producing them. .
  • the thiazolidinone-based antianginal active compound represented by the general formula (XIII) or a pharmacologically acceptable salt thereof can be made into a transdermal formulation to maintain its effective blood concentration, to maintain its efficacy, and to reduce the number of administrations. It is expected to have various clinical benefits such as improved compliance.
  • transdermal absorption preparation a preparation described in JP-A-11-279060 is known.
  • the skin permeability of the thiazolidinone antianginal active compound represented by the general formula (XIII) or a pharmacologically acceptable salt thereof is extremely small, and the amount required for exerting the medicinal effect is percutaneously. It was difficult to absorb.
  • percutaneous absorption promoting compounds compounds that promote percutaneous absorption of drugs ⁇ hereinafter referred to as “percutaneous absorption promoting compounds”.
  • Transdermal absorption-promoting compounds known to exhibit skin absorption-promoting action are highly toxic to the skin, such as skin irritation, and are impractical for use in pharmaceutical preparations.
  • Low percutaneous absorption-promoting compounds generally have a strong percutaneous absorption-promoting effect only for certain drugs, and have almost no percutaneous absorption-promoting effect for many other drugs.
  • a transdermal absorption promoting compound having low toxicity and a strong absorption promoting effect on the thiazolidinone antianginal active compound represented by the general formula (XIII) has not been known so far. .
  • the present inventors have conducted intensive studies over many years on the improvement of the transdermal absorbability of a thiazolidinone-based anti-anginal activity compound or a pharmacologically acceptable salt thereof.
  • a compound or a pharmacologically acceptable salt thereof By combining a compound or a pharmacologically acceptable salt thereof with a specific terpene-based transdermal absorption-enhancing compound, it has been found that transdermal absorbability is remarkably improved, and that toxicity to the skin is low.
  • the present invention relates to a composition for the prevention or treatment of angina pectoris, comprising a percutaneous absorption promoting compound and a thiazolidinone antianginal compound or a pharmacologically acceptable salt thereof as active ingredients (particularly for topical administration).
  • Topical compositions their use for the manufacture of a medicament for the prevention or treatment of angina, and a method for preventing or treating angina, in which a pharmacologically effective amount thereof is administered to a warm-blooded animal. Or, about their manufacturing methods.
  • the present invention
  • R 1 is a hydrogen atom, a C 6 alkyl group, substituted or unsubstituted.
  • Aryl group the substituent is a C 6 alkyl group, a C 6 alkoxy group or a halogen atom
  • a substituted or unsubstituted C 6 — a substituted or unsubstituted C 6 —.
  • Ariru eleven C 6 alkyl group (the substituent, Ci one C 6 alkyl group, a C "C 6 alkoxy group or a halogen atom.) Indicates,
  • R 2 represents a hydrogen atom or a C 6 alkyl group
  • n 1 or 2.
  • composition for preventing or treating angina comprising as an active ingredient
  • the terpene compound is neomenthol, (-)-carveol, ⁇ -terpineol, 3-forcene, (-)-menthone, (+)-pulegone, L — (-)-acetoxy
  • the composition according to (1) which is ⁇ -menthane, 1,8-cineole or j6-pinene.
  • composition according to (1) wherein the terpene compound is Neomen! 3-yl, 3-carene, (+)-pulegone or 1,8-cineole.
  • composition according to (1) wherein the terpene compound is (+)-pulegone or 1,8-cineole.
  • R 1 is a hydrogen atom, a C 4 alkyl group, a phenyl group, a phenyl group having a substituent (the substituent is a methyl group, a methoxy group, a fluorine atom or a chlorine atom), a benzyl group, a substituent A benzyl group (the substituent is a methyl group, a methoxy group, a fluorine atom or a chlorine atom); a phenethyl group or a phenethyl group having a substituent (the substituent is a methyl group, a methoxy group, a fluorine atom or A chlorine atom.)
  • R 2 is a hydrogen atom or a C 4 alkyl group
  • R 1 is a hydrogen atom, a methyl group, a 4-methoxyphenyl group or a benzyl group,
  • R 2 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group, wherein the composition according to any one of (1) to (4), and
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom, a methyl group, a propyl group, a butyl group or an isobutyl group,
  • composition according to any one of (1) to (4), wherein n is 1.
  • "one C 6 alkyl group” in R 1 and “C” C 6 alkyl group "moiety one C 6 alkoxy group in R 1 is a straight-chain or branched having 1 to 6 alkyl carbons refers to radicals such as methyl, Echiru, propyl, isopropyl, heptyl, s- Bed chill, Isopuchiru, t-heptyl, pentyl or hexyl group obtained, preferably, Ci be single C 4 alkyl group More preferably, it is a methyl or ethyl group, and particularly preferably, a methyl group.
  • the “C 6 — aryl group” for R 1 is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and may be, for example, a phenyl or naphthyl group, preferably a phenyl group. .
  • Aryl—one C 6 alkyl group” for R 1 is C 6 —.
  • a C 6 alkyl group to which an aryl group is bonded, and “C 6 -C 10 aryl group” and “—C 6 alkyl group” are as defined above.
  • Such a group may be, for example, a benzyl, phenyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, diphenylmethyl, 1-naphthylmethyl or 2-naphthylmethyl group, preferably a phenylene Roux (d one C 4 alkyl) group, more preferably a benzyl or phenethyl group, particularly preferred Is a benzyl group.
  • a benzyl, phenyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, diphenylmethyl, 1-naphthylmethyl or 2-naphthylmethyl group preferably a phenylene Roux (d one C 4 alkyl) group, more preferably a benzyl or phenethyl group, particularly preferred Is a benzyl group.
  • the “halogen atom” in R 1 can be, for example, a fluorine, chlorine, bromine or iodine atom, and is preferably a fluorine or chlorine atom.
  • Compound (II) can react with an acid to form a salt.
  • Such salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or carbonic acid; acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, apple Acids or salts with carboxylic acids such as benzoic acid; salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid; or glutamic acid or aspartic acid
  • a salt with such an acidic amino acid can be used, preferably a salt with an inorganic acid or carboxylic acid, and particularly preferably a salt with hydrochloric acid.
  • the antianginal active compound (XIII) has an asymmetric carbon and therefore has an isomer.
  • these isomers and a mixture of these isomers are all represented by a single formula, that is, the general formula (XIII), but the present invention relates to these isomers and their isomers It also includes mixtures of isomers.
  • the anti-anginal active compound (XIII) or a pharmacologically acceptable salt thereof absorbs water, adsorbs water, or hydrates when left in the air or recrystallized. In some cases, a solvate may be obtained by adding an appropriate solvent, and such hydrates and solvates are also included in the present invention.
  • the percutaneous absorption promoting compounds represented by the formulas (I) to (XII) can be used alone or in combination.
  • transdermal absorption enhancing compounds represented by the formulas (I) to (XII) or a combination thereof (i) neomenthol, (-) one carveol, ⁇ -terpineol, 3-forcen, (-)-menthone, (+)-pulegone, L-(-)-acetoxy- ⁇ -menthan, 1,8 —Cineol or i3-pinene or a combination thereof. More preferably,
  • Neomenthol 3-forcene, (+)-pulegone or 1,8-cineole or a combination thereof. More particularly preferably,
  • R 1 is a hydrogen atom, a C 4 alkyl group, a phenyl group, a phenyl group having a substituent (the substituent is a methyl group, a methoxy group, a fluorine atom or a chlorine atom), a benzyl group, A benzyl group having a group (the substituent is a methyl group, a methoxy group, a fluorine atom or a chlorine atom), a phenethyl group or a phenethyl group having a substituent (the substituent is a methyl group, a methoxy group, a fluorine atom) An atom or a chlorine atom.)
  • (b) is a compound wherein the compound is a hydrogen atom or a 1 C 4 alkyl group. More preferably,
  • R 2 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group. Even more preferably,
  • composition of the present invention is preferably a composition in which the above-mentioned ⁇ to (i V ) ′ transdermal absorption promoting compound and (a) to (h) anti-anginal active compound are appropriately combined.
  • Suitable compounds in the general formula (XIII) can be specifically exemplified in Table 1.
  • Compound No. 159 (4R) —N— (2-nitroxicetyl) -12-oxothiazolidin—4_carpoxamide.
  • the terpene compounds represented by the structural formulas (I) to (XII) are known substances.
  • the anti-anginal active compound represented by the general formula (XIII) is a known compound or a known method [for example, Japanese Patent Publication No. 7-80859 (EP 506434) or Japanese Patent Application Laid-Open No. 9-176137 (EP 812835). ) Etc.].
  • Example 1 Example 1
  • Transdermal absorption-enhancing compound (XI) To 5 ml of 1,8-cineole, add 25 mg of the anti-anginal compound of Compound No. 1 and irradiate with ultrasound for about 10 minutes at room temperature, and A composition containing the compound No. 1 anti-anginal active compound was obtained. Comparative Example 1
  • transdermal absorption enhancing compounds (XIV) To 5 ml of the following control transdermal absorption enhancing compounds (XIV) to (XXIII), add 25 mg of the compound No. 159 anticardioactive compound, and irradiate ultrasonic waves at room temperature for about 10 minutes to obtain the transdermal absorption enhancing compounds (XIV) to A composition comprising (XXIII) and the compound No. 159, an antianginal compound, was obtained.
  • the structural formula of the compound used in Comparative Example 1 is shown below.
  • a 6-week-old hairless mouse (purchased by Hoshino Test, male) was sacrificed by vertebral transection, The skin was stripped from the part. The peeled skin was lightly washed with physiological saline (0.9 w / w%), cut into a circular shape with a diameter of 3.2 cm, and fixed in a Franz type permeation cell (1.5 cm in diameter). Charged with test composition 1ml of liquid to one side Donna, 0.02 M isotonic phosphate buffer solution as receptor one-pack the receptor side (pH 7.2, prepared with NaH 2 P0 4 and Na 2 HPO 4) filled with 10ml Was. Figure 1 shows the equipment used.
  • the temperature of the receptor chamber was maintained at 37 ° C. and stirred with a magnetic stirrer.
  • One receptor solution was sampled at predetermined time intervals, and immediately supplemented with an equal volume of 0.02M phosphate buffer (pH 7.2).
  • the amount of skin permeation per unit area at each time point was calculated.
  • the amount of skin permeation increases in proportion to time after the lag time (LT: hr), a certain time until skin permeation reaches a steady state, so the slope of the proportional part and the area of the intercept indicate the area per unit area.
  • the skin permeation rate (Flux: g / hr-cm 2 ) and lag time were calculated.
  • the ratio of the skin permeation rate of the compound obtained by administering the composition containing the transdermal absorption enhancing compound to the skin permeation rate of the compound obtained by administering the control solution was determined as an enhancement ratio (Enhancement Ratio: ER). And was shown as an index of the absorption promoting effect obtained in the present invention.
  • Table 2 shows the results of the tests thus obtained.
  • a composition containing only the antianginal active compound of Compound No. 159, that is, 25 mg of the antianginal active compound of Compound No. 159 is added to 5 ml of purified water and irradiated with ultrasonic waves at room temperature for about 10 minutes. The resulting composition was administered.
  • a composition containing only the anti-anginal active compound of compound No. 1, that is, 25 mg of the anti-anginal active compound of compound No. 1 is added to 5 ml of purified water and irradiated with ultrasonic waves at room temperature for about 10 minutes. The resulting composition was administered.
  • Figure 1 shows the device used for the skin permeability test.
  • composition containing the percutaneous absorption promoting compounds (I) to (XII) and the antianginal active compound (XIII) of the present invention has an excellent effect of the percutaneous absorption promoting compound and has low toxicity. Therefore, it is useful as an external preparation for topical administration to prevent or treat angina in warm-blooded animals (particularly humans).
  • the composition of the present invention comprises an oil-based base, a water-soluble base, an adhesive used for a tape, a film base, a gel base, or an interface between an oil-based base and a water-soluble base, which are commonly used for external preparations. It may contain an emulsion base to which an activator has been added.
  • oil base examples include vegetable oils such as cottonseed oil, sesame oil and olive oil; waxes such as carnauba wax and beeswax; higher hydrocarbons such as white petrolatum, liquid paraffin and plastic base; fatty acids such as stearic acid and palmitic acid And esters thereof; higher alcohols such as ceanol; and silicones such as silicon fluid or silicone rubber.
  • water-soluble base examples include a solution or a polymer hydrogel of polyvinyl alcohol, propyloxyvinyl polymer, a cellulose derivative, etc .; polyethylene glycol (Macrogol, Pharmacopoeia) or a polyethylene glycol-polypropylene glycol copolymer; or propylene.
  • Glycol 1,3-butylene glycol, ethanol or glycerin.
  • the adhesive used in the tape include a methacrylate copolymer, a natural rubber-based adhesive or a synthetic rubber-based adhesive such as synthetic isoprene; or a silicone polymer-based adhesive.
  • An adhesive and the like can be given.
  • the material of the film base include polyethylene, polypropylene, polyethylene-vinyl acetate copolymer, PET, and aluminum laminate.
  • the gel base include dry agar, gelatin, aluminum hydroxide, and cayic acid.
  • surfactant used in the emulsion base examples include anionic surfactants such as fatty acids, saponins, fatty acid sarcosides, alcohol sulfates and alcohol phosphates, and cationic surfactants such as quaternary ammonium salts and heterocyclic amines.
  • anionic surfactants such as fatty acids, saponins, fatty acid sarcosides, alcohol sulfates and alcohol phosphates
  • cationic surfactants such as quaternary ammonium salts and heterocyclic amines.
  • An amphoteric surfactant such as alkyl betaine or lysolecithin; or a non-ionic surfactant such as polyoxyethylene alkyl ether, polyoxetylene sorbitan fatty acid ester or sucrose fatty acid ester.
  • the composition of the present invention may contain, if necessary, commonly used additives such as a surfactant, a thickener, a stabilizer, a pH adjuster or a preservative.
  • a surfactant include anionic surfactants such as fatty acid,, saponin, fatty acid sarcoside, alcoholic ester and alcoholic phosphate; cationic surfactants such as quaternary ammonium salt or heterocyclic amine; alkyl.
  • amphoteric surfactants such as betaine and lysolecithin; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester and sucrose fatty acid ester.
  • thickener examples include cellulose derivatives such as carboxymethylcellulose; polycarboxylic acids such as polyacrylic acid or methoxymethylene maleic anhydride copolymer; and nonionic water-soluble polymers such as polyvinylpyrrolidone or polyvinyl alcohol.
  • stabilizer examples include antioxidants such as ascorbic acid and sodium pyrosulfite; and chelating agents such as EDTA.
  • the adjusting agent examples include a phosphate buffer and sodium hydroxide.
  • the preservative examples include alkenyl quaternary ammonium salts such as parabens, benzalkonium chloride, and benzethonium chloride.
  • the composition of the present invention is used as an external preparation, but the external preparation is not particularly limited as long as it is absorbed by application to the skin and is expected to have a pharmacological effect. , Lotions, ointments, creams, gels, sols, aerosols, haptics, plasters or tapes.
  • the composition of the present invention is prepared by a conventional method using the above-mentioned various bases, pressure-sensitive adhesives and other additives which are added as required.
  • Lower limit of the ratio of the use of the terpene compound (I) Nojiru (XII) to the antianginal active compound (XIII) in the composition of the present invention [weight ratio when the antianginal active compound (XIII) is set to 1] Is 0.5 (preferably 1) and the upper limit is 200 (preferably 40, most preferably 3).
  • Examples of a method for preparing a composition containing the terpene compounds (I) to (XII) and the antianginal compound (XIII) include the following. When preparing liquid sprays, lotions, sols or aerosols, the terpene compounds (I) to (XII) and the anti-anginal active compound (XIII) can be mixed with water, propylene glycol, 1,3-butylene.
  • the above additives can be added as needed.
  • the terpene compounds (I) to (XII) and the antianginal active compound (XIII) are added to the water-soluble base, the oil base and / or water, vegetable oil or the like. It is obtained by mixing with a solvent usually used in the technical field, adding a surfactant if necessary, and subjecting it to an emulsification treatment. If necessary, the above additives can be added.
  • a terpene compound (I) to (XII) which may contain the above additives if necessary
  • an antianginal active compound ( ⁇ ) are used as the adhesive. Both are obtained by coating on the film base.
  • a solution containing the terpene compounds (I) to (III), the antianginal active compound (XIII), and the gel base if necessary, the above additives may be contained
  • the composition of the present invention is a composition containing a terpene compound (I) to (XII) for the prevention or treatment (preferably treatment) of angina pectoris, and an antianginal active compound (XIII).
  • Compositions containing may be used topically, simultaneously or at staggered times.
  • a preparation method for preparing a composition containing the terpene compounds (I) to (XII) for example, the following ones can be mentioned.
  • terpene compounds (I) to (XII) use terpene compounds (I) to (XII) with water, propylene glycol, 1,3-butylene glycol, ethanol or glycerin, etc. It is obtained by simply dissolving or dispersing in a solvent.
  • the above additives can be added.
  • the terpene compounds (I) to (XII) It is obtained by mixing with a soluble base, the oil base and Z or an appropriate solvent, and subjecting the mixture to an emulsification treatment with the surfactant as necessary. If necessary, the above additives can be added.
  • a terpene compound (I) to (XII) (which may contain the additive if necessary) is added together with the pressure-sensitive adhesive to the film base.
  • a solution containing the terpene compounds (I) to (XII) and the gel base (if necessary, the additive may be contained) is poured into a mold. It can be obtained by subjecting it to a crosslinking treatment or a drying operation according to the conditions.
  • a preparation method for preparing a composition containing the antianginal active compound (XIII) include the following. When preparing liquid sprays, mouthwashes, sols or aerosols, the antianginal activating compound (XIII) is simply added to a solvent such as water, propylene glycol, 1,3-butylene glycol, ethanol or glycerin. It is obtained by dissolving or dispersing.
  • the above additives can be added.
  • the antianginal active compound (XIII) is mixed with the water-soluble base, the oil-based base, and a suitable solvent, and if necessary, the surfactant is added. By emulsification. If necessary, the above-mentioned additives can be added.
  • an antianginal compound (XIII) (which may contain the above additives if necessary) is applied onto the film base together with the adhesive.
  • Is obtained by In the case of a gel it is obtained by pouring a solution containing the antianginal active compound (XIII) and the gel base into a mold and subjecting it to a crosslinking treatment or a drying operation as necessary.
  • the site of administration of the composition of the present invention is not particularly limited, and can be appropriately selected according to the pharmacological or pharmacokinetic properties of the indication and the active ingredient.
  • skin on the chest, abdomen, and back And the like for example, skin on the chest, abdomen, and back And the like.
  • a method for administering the composition of the present invention for example, when used as a liquid spray, lotion, sol or aerosol, the composition is directly administered to the skin, or impregnated with lint cloth or gauze. And administration to the skin.
  • the composition of the present invention When the composition of the present invention is used as an ointment or cream, the composition may be applied directly to the skin, or may be applied to a lint cloth, gauze, or the like and applied to the skin. In the case of haptics, plasters or tapes, they can be applied as they are to the skin.
  • the composition of the present invention When the composition of the present invention is used as a gel, the composition may be applied as it is, or may be applied to the skin by applying it to a backing film such as lint cloth, gauze or adhesive tape.
  • the composition of the present invention When the composition of the present invention is used as a composition containing the terpene compounds (I) to (XII) and a composition containing the antianginal active compound (XIII), the composition may be administered simultaneously or at the same time.
  • the administration with a difference can be appropriately selected.
  • the composition containing the terpene compounds (I) to (XII) and the composition containing the antianginal active compound (XIII) are administered at the same time, the two compositions are respectively different from each other (preferably). Suitably, it may be administered locally.
  • the composition containing the terpene compounds (I) to (XII) and the composition containing the antianginal active compound (XIII) are administered at different times, the terpene compounds (I) to (X)
  • the composition containing XII) or the composition containing the antianginal active compound (XIII) is administered topically immediately (within 5 minutes) or after a certain period of time (5 to 24 hours).
  • the other composition may be administered at the same or a different (preferably adjacent) location as the first administration.
  • the composition containing the terpene compounds (I) to (XII) and the composition containing the antianginal active compound (XIII) are administered with a local time lag.
  • preferred embodiments are: The composition containing the compounds (I) to (XII) is administered to the skin, and after 5 minutes to 24 hours (preferably 30 minutes to 3 hours), the administered composition is removed, and The topical administration of the composition containing the cardioactive compound (XIII) is substantially the same as the topical site initially administered.
  • the upper limit of the dosage of the antianginal active compound * ( ⁇ ) of the composition of the present invention per adult is 100 mg (preferably 500 mg, more preferably 100 mg), and the lower limit is 0.1 mg. (Preferably lmg, more preferably lOmg) and is administered topically once to 10 times daily.

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Abstract

L'invention concerne des compositions à durée illimitée à usage topique contenant comme principe actif des composés de type terpène et des composés exerçant un effet antiangineux, représentés par la formule générale (XIII), ou des sels de ceux-ci acceptables sur le plan pharmaceutique. Dans cette formule, R1 représente hydrogène, C¿1-6? alkyle, etc. ; R?2¿ représente hydrogène, C¿1-6? alkyle ; et n est égal à 1 ou 2. Ces compositions sont très efficaces grâce à leurs composés d'accélération de l'absorption percutanée et sont utilisés comme agent thérapeutiques ou préventifs contre l'angine.
PCT/JP2002/001812 2001-03-01 2002-02-27 Compositions a absorption percutanee WO2002069967A1 (fr)

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JP2001-056198 2001-03-01

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0535237A1 (fr) * 1991-03-20 1993-04-07 Hisamitsu Pharmaceutical Co., Inc. Composition soulageant les irritations cutanees et preparation pour administration percutanee a usage externe contenant ladite composition
US5298516A (en) * 1991-03-27 1994-03-29 Sankyo Company, Limited Thiazolidone compounds and method of using the same as a vasodilator
WO1995015118A1 (fr) * 1993-11-30 1995-06-08 Imarx Pharmaceutical Corp. Microspheres gazeuses pour application topique et sous-cutanee
EP0682942A1 (fr) * 1993-01-21 1995-11-22 Yamanouchi Pharmaceutical Co. Ltd. Nouvelle preparation absorbable par voie percutanee
EP0812835A1 (fr) * 1995-03-02 1997-12-17 Sankyo Company Limited Derives de thiazolidinone optiquement actifs
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JPH11246407A (ja) * 1997-12-25 1999-09-14 Sankyo Co Ltd 経皮吸収組成物
JPH11279060A (ja) * 1998-03-26 1999-10-12 Sankyo Co Ltd 経皮吸収組成物

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EP0535237A1 (fr) * 1991-03-20 1993-04-07 Hisamitsu Pharmaceutical Co., Inc. Composition soulageant les irritations cutanees et preparation pour administration percutanee a usage externe contenant ladite composition
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EP0682942A1 (fr) * 1993-01-21 1995-11-22 Yamanouchi Pharmaceutical Co. Ltd. Nouvelle preparation absorbable par voie percutanee
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JPH10120566A (ja) * 1996-08-29 1998-05-12 Sankyo Co Ltd 光学活性なチアゾリジノン誘導体を有効成分とする狭心症予防剤または治療剤
JPH11246407A (ja) * 1997-12-25 1999-09-14 Sankyo Co Ltd 経皮吸収組成物
JPH11279060A (ja) * 1998-03-26 1999-10-12 Sankyo Co Ltd 経皮吸収組成物

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