WO1999007355A1

WO1999007355A1 - Idebenone-containing preparation for percutaneous administration

Info

Publication number: WO1999007355A1
Application number: PCT/JP1998/003576
Authority: WO
Inventors: Yasutaka Igari; Yasuyuki Suzuki; Shigeru Toyoda
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1997-08-12
Filing date: 1998-08-11
Publication date: 1999-02-18
Also published as: AU8562998A

Abstract

An idebenone-containing preparation for percutaneous administration which is effective in the prevention and treatment of dementia and is useful for efficiently and easily administering idebenone.

Description

Description Transdermal formulation containing technical field

The present invention relates to a preparation for transdermal administration containing idebenone for the prevention and treatment of dementia. Background art

The growing elderly population is a major social problem, with the rise of cancer, various adult diseases and central illness. In particular, how to treat patients with dementia, a central illness, is a truly urgent task. No fully satisfactory and effective means have been found so far for the treatment of dementia patients, especially Alzheimer-type dementia (hereinafter sometimes referred to as Alzheimer's disease) patients, or methods for suppressing the progress of dementia. .

Idebenone has an immunity-promoting effect and an activity of activating tissue metabolism in the body including the brain, and causes a decrease in motivation, emotional disorders, language impairment or It has been reported to improve neurological symptoms, memory and learning disorders caused by cerebrovascular disorders. It is also thought that by acting on the mitochondrial electron transport system, it suppresses the production of lipid peroxide, preventing mitochondrial dysfunction, energy metabolism, and neurological dysfunction. In addition, its antioxidant action eliminates reactive oxygen species (ROS), which are constantly produced in the body, and suppresses senile plaque formation, neurofibrillary tangles, and neuronal cell death in the brain, which are thought to involve ROS. Is considered to prevent and treat Alzheimer's dementia (Biochem. Biophys. Res. Commun. 125, 1046-1052, 1984, J. Pharmacol. Exp. Ther., 260, 1132 -P. 1140, 1989).

JP-A-3-81218 (USP 5,059,627) and JP-A-7-61923 (EP-A-629400) disclose idebenone as a therapeutic agent for Alzheimer's senile dementia. It is stated to be effective. former States that the dose of idebenone is 0.1 mg to 500 mg per adult per day. In the latter, it is stated that idebenone is administered at a high dose of 15 O mg or more per adult per day. Furthermore, Arch. Gerontol. Geriatr., Vol. 15, pp. 249-259, 1992 states that idebenone was administered to Alzheimer's senile dementia patients by administering 9 Omg per day per adult per day. It has been described that the effectiveness of was confirmed.

In general, prophylaxis and treatment of dementia requires long-term, continuous oral administration. For example, in patients with Alzheimer's dementia in the very early stage, patients should continue taking the drug 2 or 3 times a day despite having few symptoms. Makes it difficult for patients to continue taking oral medications regularly, which requires a great deal of effort by caregivers to keep patients taking them, which is a factor in reducing compliance .

On the other hand, Japanese Unexamined Patent Publication No. Hei 9-19719 discloses a base for external patch comprising at least one selected from the group consisting of fatty acids, derivatives thereof and animal and vegetable oils and fats, polyhydric alcohol and water. It is described that the preparation of external patches of various drugs is carried out by using the method. However, there is no description that the application of the drug for the prevention and treatment of dementia, especially idebenone, produces favorable results.

Japanese Patent Application Laid-Open No. 1-2799818 discloses carbewax ointment containing idebenone, white cerin ointment and Creams are described.

However, although there have been various reports on the target disease and dosage form of idebenone, the optimal dosage form for each disease has not been known. Absorption rate, stability, toxicity, especially for patients with dementia Considering the burden, ease of administration, industrial production, etc., there has not yet been obtained a formulation that is clinically applicable as a drug and has excellent effects. The present invention provides, for the first time, a clinically useful administration method of idebenone, which exhibits an excellent action as a drug for cranial nerve disease, and a formulation suitable therefor. Disclosure of the invention The present inventors have made intensive efforts to search for an efficient and simple dosage form of idebenone, and as a result, produced the first transdermal preparation for the prevention and treatment of dementia. It has excellent properties as a clinical medicine, such as having stability, good contact feeling, easy application, idebenone being efficiently absorbed, safe and capable of achieving patient compliance. Based on this, the present invention has been completed.

That is, the present invention

(1) a percutaneous administration preparation for the prevention and treatment of dementia comprising idebenone,

(2) the preparation according to (1), wherein the dementia is Alzheimer's dementia; (3) the preparation according to (1), which is a patch;

(4) The preparation according to (1), which is a patch,

(5) The preparation according to the above (1), which is a tape preparation,

(6) The preparation according to (1), wherein the preparation is administered once every 1 to 7 days.

(7) The preparation according to (1), which is administered once a day,

(8) The formulation according to (1), wherein the amount of idebenone is about 0.1 to about 20% by weight of the total weight of the formulation.

(9) The preparation according to the above (1), wherein the amount of idebenone is about 1 to about 10% by weight based on the total weight of the preparation.

(10) Idebe the amount of non is about 0.3 to about 5 Omg Roh cm ² (3) patch according,

(11) The amount of idebenone is from about 0.4 to about 2 OmgZcm ^2.

(3) the patch described in,

(12) The formulation according to (1), wherein the dose of idebenone is about 0.3 to about 100 Omg / dose,

(13) The preparation according to the above (1), wherein the dose of idebenone is about 1 to about 50 OmgZ times,

(14) The preparation according to (1), wherein the dose of idebenone is about 2 to about 20 OmgZ times,

(15) transdermal administration of idebenone as a prophylactic and therapeutic agent for dementia, and And

(16) Use of idebenone for producing a preparation for transdermal administration for prevention and treatment of dementia. BEST MODE FOR CARRYING OUT THE INVENTION

Idebenone is a general name of 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone, and is disclosed in JP-A-56-97223 and JP-B-62-3134. And the like.

Idebenone can be produced, for example, by the method described in JP-A-51-128932, JP-A-63-264436, JP-A-56-7734, JP-A-56-147746, or a method analogous thereto.

The preparation of the present invention may be in any form as long as the desired effect can be achieved with a preparation capable of transdermally administering the active ingredient, and examples thereof include a liniment and a patch.

The “coating agent” is a generic term for a dosage form characterized by being applied in a liquid or semi-solid form, having a fixed form, being capable of freely adjusting a single dose, and being applied on the skin. Examples include ointments (including creams), lotions (including suspensions and emulsions), liquids, and sprays.

The “patch” is a generic term for a transdermal dosage form having a fixed shape and capable of defining a single dose, and includes, for example, patches, plasters, tapes and the like. The patch indicates that the drug holding layer and the adhesive layer are separately arranged on the application surface, and the tape indicates that the drug holding layer and the adhesive layer are uniformly mixed.

The preparation of the present invention is preferably a patch or the like from the viewpoint of controlling the dose. More preferred are a patch and a tape.

When the formulations of the present invention is, for example, patches, preferred embodiment, Idebe non solvent (preferably ethanol), base (preferably higher (C ₁₂ - ₂₂₎ fatty alcohol, more preferably stearyl alcohol) and A patch containing a humectant (preferably propylene glycol). The amount of idebenone is preferably 5 to 10 parts by weight. The amount of the solvent is preferably 10 to 20 parts by weight. The amount of the base is preferably 20 to 35 parts by weight. 20 humectants And preferably 35 parts by weight.

When the formulations of the present invention is, for example, tape agent, preferred embodiment, Idebe non, base (preferably higher (C _{1 2 2 2)} fatty alcohols, more preferably steer Lil alcohol), humectant (preferably propylene Glycol) and adhesive. The amount of idebenone is preferably 5 to 10 parts by weight. The amount of the base is preferably 20 to 30 parts by weight. The blending amount of the humectant is preferably 20 to 30 parts by weight. The amount of the adhesive is preferably 20 to 30 parts by weight. The preparation of the present invention can be produced according to a method known per se, for example, the method described in the Japanese Pharmacopoeia or a method analogous thereto. Specific examples are described below.

“Applying agents” (eg, ointments, lotions, solutions, sprays, etc.) contain idebenone with solvents, suspending agents, emulsifiers, propellants, bases, etc., which are known per se in the pharmaceutical field And it can be manufactured according to a conventional method. If necessary, a transdermal absorption controlling ingredient, a humectant, a preservative, an anti-inflammatory agent and the like may be added.

The “solvent” is a liquid component constituting an “ointment”, “lotion”, “liquid”, and “spray”, and is particularly defined as a water-soluble solvent. Specifically, water, lower alcohols (eg, ethanol, etc.), alkanediols having 2 to 5 carbon atoms (eg, glycerin, etc.), alkanetriols having 2 to 5 carbon atoms (eg, propylene glycol, etc.), etc. No. These may be used alone or in combination of two or more. The amount of the “solvent” in the preparation is about 0 to 90%.

The above "suspension agent" is mainly blended with the "suspension agent" contained in the "spray agent" and the "lotion agent", and is a separated two-phase liquid (eg, water and isopropyl myristate, etc.) The term refers to a component capable of temporarily maintaining a uniform state when mixed by shaking, and a fat-soluble solvent that forms its oil phase. Examples of the “component” (the former) include a gelling component (eg, sodium alginate, dried aluminum hydroxide gel, agar, etc.), a thickener (eg, xanthan gum, mouth-to-mouth gum, etc.), aluminum silicate Magnesium, light caustic anhydride, crystalline cellulose, surfactant (eg, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene higher alcohol ether, polyoxyethylene alkyl Nonionic surfactants such as luaryl ether, polyoxyethylene castor oil derivatives, block polymer type nonionic surfactants (pull nicks L_62, L-64, F-68); Ionic surfactants such as rilsulfate (SLS), etc., and the blending amount in the preparation is about 0 to 50%. Examples of the “fat-soluble solvent” (the latter) include higher fatty acid alcohols (eg, ceanol, stearyl alcohol, behenyl alcohol, oleyl alcohol, etc.), higher fatty acid esters (eg, isopropyl myristate, tri Glycerides, etc.), oils and fats (eg, soybean lecithin, carnauba wax, salami beeswax, olive oil, rapeseed oil, etc.). These may be used alone or in combination of two or more. Good. The compounding amount of the “lipid-soluble solvent” in the preparation is about 0 to 80%.

The above-mentioned "emulsifier" is common to some suspending agents, but is mainly blended in "cream" contained in "spray", "ointment", "emulsion" contained in "lotion", etc. A component that has the function of maintaining a uniform state by forming an emulsion from a two-phase liquid with low compatibility (eg, water and isopropyl myristate, etc.) from the time of manufacture to the expiration date, and a fat-soluble component that forms its oil phase The components are shown. Specific examples include gelling components (eg, sodium alginate, polyvinyl alcohol, dried hydroxylamine gel, etc.), thickeners (eg, force-doran, agar, mucin, gelatin, pectin, carrageenan, chitin, chitosan) , Oral cast bingham, tragacanth gum, xanthan gum, pullulan, sucralfate, etc.), aluminum magnesium gayate, light caffeic anhydride, crystalline cellulose, higher alcohols (eg, ceanol, stearyl alcohol, behenyl alcohol) , Oleyl alcohol, etc.), higher fatty acid esters (eg, isopropyl myristate, tri (caprylic acid, dextrin acid), etc.), fats and oils (eg, soybean lecithin, seanol, polyoxyethylene hydrogenated castor oil) , Carna ゥ Barrow, Beeswax, etc.), surfactants (eg, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene higher alcohol ether, polyoxyethylene alkyl aryl ether, polyoxyethylene castor oil Derivatives, block polymer type Non-ionic surfactants such as on-ionic surfactants (pull nicks L_62, L-64, F-68); ionic surfactants such as sodium radicalyl sulfate (SLS) These components may be used alone or in combination of two or more. The blending amount of the “emulsifier” in the preparation is about 0 to 70%. The above-mentioned “propellant” is mainly blended with “propellant”, and is a general term for components that can be injected at high pressure into equipment such as sprays at a boiling point of below normal temperature and that can spray the contents by the pressure. This is what is called " Specific examples include CFCs (eg, Freon 11, Freon 12, Freon 113, etc.), alternative freons, liquefied petroleum gas, carbon dioxide, etc. These may be used alone or in combination of two or more. I do not care. The compounding amount of the “propellant” in the preparation is about 0 to 99%. Sprays can also be produced by mechanically inhaling and discharging air without using propellants.

The above-mentioned “base” is a general term for compounds which are mixed with the above-mentioned coating composition for the purpose of dissolving or uniformly dispersing idebenone in a preparation and have an excipient role in a solid preparation. Hereinafter, specific examples include a base for an ointment, a lotion and a base for a spray.

Examples of “bases for ointments” include petrolatum, solid paraffin, olive oil, sesame oil, cottonseed oil, solid paraffin, liquid paraffin, lanolin, and higher fatty acid alcohols (eg, SENONOL, stearyl alcohol, oleyl alcohol) ), Higher fatty acids (eg, myristic acid, palmitic acid, stearic acid, oleic acid, etc.) Fatty acid esters (eg, beeswax, beeswax, whale wax, isopropyl myristate, isopropyl palmitate, tri (capric acid capric acid) ) Dali-cerides, etc.), lipids (eg, soybean lecithin, dipalmitoylphosphatidylcholine, distearylphosphatidylcholine, etc.), oily bases such as silicone oil; water, macrogols (eg, macrogol 40) 0, macro goal 6 0 0, macro goal 100000, Macrogol 1500, Macrogol 400, Macrogol 600,000) Alkanediol with 2 to 5 carbon atoms (eg, glycerin), 2 to 5 carbon atoms Alkanetriol (eg, propylene glycol, 1,3-butyl blend, etc.), polyvinyl alcohol (PVA), polyacrylic acid (P AA), carboxyvinyl polymer, superabsorbent resin (eg, block polymer of PVA and PAA (eg, Sumikagel 3-510 manufactured by Sumitomo Chemical Co., Ltd.), etc.). These may be used alone or in combination of two or more, and the final preparation may be semisolid. The amount of the “base of ointment” in the preparation is about 0 to 99%.

Examples of the “base” of the “base of lotion” and “base of spray” include, for example, water, lower alcohols (eg, ethanol), alkanediols having 2 to 5 carbon atoms (eg, glycerin). Etc.), liquid esters (eg, isopropyl myristate, tri (caprylic acid), glyceride), liquid fats (eg, olive oil, liquid lanolin, liquid paraffin, etc.), and the like. Two or more of them may be used in combination, and it is sufficient that the final preparation is liquid. The compounding amounts of the “mouth base” and “propellant base” in the preparation are each about 0 to 99%.

Examples of the “liquid base” include water, lower alcohols (eg, ethanol, etc.), and alkanediols having 2 to 5 carbon atoms (eg, glycerin, etc.). These may be used alone or in combination of two or more. The final drug product may be a water-soluble liquid. The amount of the “liquid base” in the preparation is about 0 to 99%.

The above-mentioned “transdermal absorption controlling ingredient” is compounded for the purpose of acting on the skin surface, mainly the stratum corneum to promote the absorption of the drug. Specific examples include phospholipids (eg, lecithin, etc.), solid paraffin, beeswax, carnauba wax, hydrogenated castor oil, lanolin, vaseline, polyvinyl alcohol, polyvinylpyrrolidone, polyethylenedaricol, glycerin fatty acid ester, cholesterol, carbopol, and porphyrin Xymethylcellulose, carboxyethylcellulose, silicone resin, lower alcohols (eg, ethanol, isopropyl alcohol, etc.), aliphatic carboxylic acids having 6 to 20 carbon atoms (eg, cabronic acid, caprylic acid, capric acid, lauric acid) Acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidonic acid, etc.) and salts thereof, aliphatic alcohols having 6 to 20 carbon atoms (eg, n-butyl alcohol, n-cetyl alcohol, etc.) , Carbon number 2 ~ 2 0 fatty alcohols and carbon Esters with aliphatic carboxylic acids of numbers 6 to 20 (eg, isopropyl myristate, etc.), esters of aliphatic alcohols with 2 to 20 carbon atoms and alkanediols with 2 to 5 carbon atoms (glycerin, etc.) (E.g., tri (force prillic acid / force pric acid) dali seride, etc.), alkanediol with 2-5 carbon atoms (eg, glycerin), alkanetriol with 2-5 carbon atoms (eg, propylene glycol, etc.), pyrrolidone Derivatives (eg, N-methylpyrrolidone, etc.), d-limonene, 1-menthol, surfactants (eg, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, polyoxyxylene high-grade Alcohol ether, polyoxetylene alkyl aryl ether, polyoxye Non-ionic surfactants, such as forage castor oil derivatives, block polymer type non-ionic surfactants (pull nicks L-62, L-64, F-68); sodium radicalyl sulfate ( SLS) and the like, and these may be used alone or in combination of two or more. The amount of the “transdermal absorption controlling ingredient” in the preparation is about 0 to 80%.

Examples of the above-mentioned "preservatives" include benzoic acid, sodium benzoate, benzyl benzoate, ethanol, sodium edetate, benzalkonium chloride, salicylic acid, salicylate, isobutyl para-hydroxybenzoate, isopropyl para-benzoate, and para-oxy benzoate. And ethyl butyl, butyl para-hydroxybenzoate, propyl para-hydroxybenzoate, methyl para-hydroxybenzoate, phenol, benzyl alcohol, boric acid, borax, 1-menthol, and the like. These may be used alone or in combination of two or more. The compounding amount of the "preservative" in the preparation is about 0 to 20%.

Examples of the “humectant” include glycerin, propylene glycol, urine, amino acids (eg, 1-proline and the like), and these may be used alone or in combination of two or more. The blending amount of the “humectant” in the preparation is about 0 to 50%.

Examples of the above-mentioned "anti-inflammatory agent" include glycyrrhetinic acid, diphenhydramine and the like, and these may be used alone or in combination of two or more. The compounding amount of the “anti-inflammatory agent” in the preparation is about 0 to 10%. The above-mentioned "paste" (eg, patch, plaster, tape, etc.) is a suitable carrier using an agent, an emulsifier, a transdermal absorption controlling component, a preservative, a moisturizer, an anti-inflammatory agent, an adhesive, etc. It can be manufactured by absorbing or adhering to (backing) and, if necessary, controlling the release of drug from the preparation, by controlling the release of the drug, according to a conventional method. If necessary, idebenone may be dissolved and dispersed in a solvent in advance.

The above-mentioned “base” is a general term for compounds that are incorporated into the above-mentioned patches for the purpose of dissolving or uniformly dispersing idebenone in the preparation and have an excipient role in solid preparations. Hereinafter, specific examples will be given.

Examples of “paste base” include petrolatum, solid paraffin, olive oil, sesame oil, cottonseed oil, liquid paraffin, lanolin, higher fatty acid alcohols (eg, ceanol, stearyl alcohol, oleyl alcohol, etc.), Higher fatty acids (eg, myristic acid, palmitic acid, stearic acid, oleic acid, etc.), fatty acid esters (eg, beeswax, beeswax, spermaceti, isopropyl myristate, isopropyl palmitate, tri ) Glycerides, etc.), lipids (eg, soybean lecithin, dipalmitoylphosphatidylcholine, distearylphosphatidylcholine, etc.), oily bases such as silicon oil; for example, water, macrogols (eg, macrogol) 400, Macro Goal 600, Macro Goal 100 000, macrogol 1500, macrogol 4 000, macrogol 600 000, etc., alkanediol with 2 to 5 carbon atoms (eg, glycerin, etc.), 2 to 5 carbon atoms Alkantriol (eg, propylene glycol, 1,3-butylene glycol, etc.), polyvinyl alcohol (PVA), polyacrylic acid (PAA), lipoxyvinyl polymer, super absorbent resin (eg, PVA and PAA Block polymer

(E.g., Sumikagel SP-5110 manufactured by Sumitomo Chemical Co., Ltd.) and the like, and these may be used alone or in combination of two or more.The final formulation has a semi-solid form. I just need. Of these, oil-based bases are preferred. More preferred are aliphatic alcohols and fatty acid esters. The amount of the “base” in the preparation is about 0 to 99%.

The above-mentioned “emulsifier” includes two-phase liquids with low compatibility (eg, water and myristine). (E.g., isopropyl acid) from the time of manufacture to the expiration date, and a fat-soluble component that forms an oil phase, and a component that has the function of maintaining a uniform state and a gel-forming component (eg, alginic acid). Sodium, polyvinyl alcohol, dried aluminum hydroxide gel, agar, etc.), thickeners (eg, carrageenan, agar, mucin, gelatin, pectin, carrageenan, chitin, chitosan, locust bingham, tragacanth, xanthan gum, pullulan , Sucraral phosphate, etc.), aluminum magnesium silicate, light caustic anhydride, crystalline cellulose, higher alcohols (eg, cetanol, stearyl alcohol, behenyl alcohol, oleyl alcohol, etc.), higher fatty acid esters (eg, myristin) Acid iso Ropir, tri (capric acid, glyceride, etc.), fats and oils (eg, soybean lecithin, polyoxyethylene hydrogenated castor oil, carnauba wax, salamisimi wax, etc.), surfactants (eg, polyoxyethylene sorbitan) Fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene higher alcohol ether, polyoxyethylene alkylaryl ether, polyoxyethylene castor oil derivative, block polymer type 1 nonionic surfactant (pull Non-ionic surfactants such as mouth nicks L-62, L-64, and F-68); ionic surfactants such as sodium radicalyl sulfate (SLS)). These may be used alone or in combination of two or more. The amount of the "emulsifier" in the preparation is about 0 to 90%. The “transdermal absorption controlling component” is a component formulated for the purpose of acting on the skin surface, mainly the stratum corneum to promote the absorption of the drug, and includes, for example, phospholipids (eg, lecithin), solids Paraffin, beeswax, carnaupa wax, hydrogenated castor oil, lanolin, petrolatum, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, glycerin fatty acid ester, cholesterol, carbopol, carboxymethylcellulose, carboxyethyl cellulose, silicone resin, lower alcohol (eg , Ethanol, isopropyl alcohol, etc.), aliphatic carboxylic acids having 6 to 20 carbon atoms (eg, cabronic acid, capric acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidone) Acid etc.) Beauty salts thereof, aliphatic alcohols with carbon number 6-2 0 (e.g., n- old rot Alcohols, n-cetyl alcohol, etc.), esters of aliphatic alcohols having 2 to 20 carbon atoms and aliphatic carboxylic acids having 6 to 20 carbon atoms (eg, isopropyl myristate, etc.), 2 to 2 carbon atoms Esters of aliphatic alcohols of 0 and alkane diols of 2 to 5 carbon atoms (such as glycerin) (eg, tri (force prillic acid / protic acid) glyceride, etc.), alkane diols of 2 to 5 carbon atoms (eg, glycerin) Etc.), alkanetriols with 2 to 5 carbon atoms (eg, propylene glycol), pyrrolidone derivatives (eg, N-methylpyrrolidone), d-limonene, 1-menthol, surfactants (eg, polyoxyethylene sorby) Even fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene higher alcohol Nonionics such as cellulose ethers, polyoxyethylene alkyl ether reel ethers, polyoxyethylene castor oil derivatives, block polymer type nonionic surfactants (pull nicks L-62, L-64, F-688) Surfactants; ionic surfactants such as sodium radicalyl sulfate (SLS)), and these may be used alone or in combination of two or more. The amount of the “transdermal absorption controlling ingredient” in the preparation is about 0 to 80%. Examples of the above-mentioned "preservatives" include benzoic acid, sodium benzoate, benzyl benzoate, ethanol, sodium edetate, benzalkonium chloride, salicylic acid, salicylate, isoptyl para-hydroxybenzoate, isopropyl para-benzoate, and para-oxy benzoate. And ethyl butyl, butyl para-hydroxybenzoate, propyl para-hydroxybenzoate, methyl para-hydroxybenzoate, phenol, benzyl alcohol, boric acid, borax, 1-menthol, and the like. These may be used alone or in combination of two or more. The compounding amount of the "preservative" in the preparation is about 0 to 20%.

Examples of the “humectant” include glycerin, propylene glycol, urine, amino acids (eg, 1-proline and the like), and these may be used alone or in combination of two or more. Of these, propylene glycol is preferred. The compounding amount of the “humectant” in the preparation is about 0 to 50%.

Examples of the above-mentioned "anti-inflammatory agent" include glycyrrhetinic acid, diphenhydramine and the like, and these may be used alone or in combination of two or more. The "inflammation prevention The amount of the “agent” in the preparation is about 0 to 10%.

Examples of the “adhesive” include, for example, an acrylic adhesive (eg, at least two kinds of 2-ethylhexyl acrylate, vinyl acetate, ethyl acrylate, methacrylate, methoxyl acrylate, and acrylic acid). Copolymers (eg, Nippon Riki-Vide Co., Ltd. £ 300, etc.), natural and synthetic rubbers (eg, polyisobutylene (PIB), neoprene, polybutadiene, polyisoprene, etc.), polysiloxane, polyurethane, styrene r Soprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), etc., may be used alone or in combination of two or more. For example, PIB and SIS may be used in combination, and the mixing ratio thereof is preferably from 1: 1 to 1: 4. The amount of the "adhesive" in the tape preparation is about 0 to 70%. Examples of the “support” include a polymer film (eg, polyethylene, vinyl acetate copolymer, polyethylene phthalate, etc.), woven fabric, nonwoven fabric, paper, aluminum foil and the like. When the “polymer film” is transparent, a change in the color (yellow-brown) of idebenone can be directly confirmed, and when idebenone is not absorbed due to a skin disorder or the like, the change is directly confirmed. It is possible to more reliably carry out preventive treatment, such as by re-attaching the product. When the “polymer film” is colored, for example, when it is colored with a color close to a skin color (which may be appropriately selected according to race), the color of idebenone can be masked, and The advantage is that the surrounding people are not aware that the treatment is being performed.

Examples of the above-mentioned "release control film" include a porous polyethylene film (eg, Hipore manufactured by Asahi Kasei Corporation) and a porous polypropylene film (eg, Duragard manufactured by Polyplastics).

Examples of the above “paste solvent” include water, lower alcohols (eg, ethanol), alkanediols having 2 to 5 carbon atoms (eg, glycerin), alkanetriols having 2 to 5 carbon atoms (eg, propylene). Glycol and the like). These may be used alone or in combination of two or more. Of these, preferred are ethanol, propylene glycol, glycerin and the like. The amount of the “solvent” in the preparation is about 0 to 90%. The “tape agent” and “patch agent” produced using the above components may be non-aqueous or hydrated. Preferred are non-aqueous tapes and non-aqueous patches.

As a preferable production method of the preparation of the present invention, for example, idebenone is dissolved or uniformly dispersed in a solvent such as propylene glycol and then mixed with a base such as stearyl alcohol to obtain a plaster. Additives such as preservatives and humectants, if necessary, should be added to the solvent before mixing the base. When the preparation of the present invention is a patch, (1) the obtained plaster is applied to a nonwoven fabric as needed while being spread to a certain thickness, and then transferred to a backing such as a polyester film. Next, the obtained transferred product is pasted on a slightly larger polyester film coated with an adhesive component in advance, or (2) The obtained plaster is coated on a polyester film in which the adhesive component is coated in advance. It is manufactured by transferring to a part of the backing. When the preparation of the present invention is a tape, an adhesive component such as a polyalkyl vinyl ether is added to the obtained plaster, mixed uniformly, and transferred to a backing such as a polyester film while spreading to a certain thickness. When the paste is in a sol form and it is difficult to maintain the form, the paste may be coated or impregnated on a support such as a nonwoven fabric and then transferred to a backing.

When the preparation of the present invention is a patch or a tape, these may be cut into a suitable size to achieve the purpose before use.

The amount of idebenone used in the present invention in the preparation is not particularly limited as long as the desired pharmacological effect can be exhibited. For example, about 0.1 to about 60% by weight, preferably about 0.1 to about 20% by weight, more preferably about 1 to about 10% by weight. When the preparation of the present invention is a patch, the compounding amount of idebenone per unit area is, for example, about 0.1 to about 200 mg Zcm ² , preferably about 0.3 to about 5 Omg / cm 2, more preferably about 0.4 to about 2 mg / cm 2. is a OmgZcm ^2.

The application of the preparation of the present invention to the skin (including mucous membranes) of the body varies depending on the condition of the patient, but when administered as an agent for the prophylactic or therapeutic treatment of Alzheimer's dementia in adults, about 0.1% as idebenone. 3 to about 100 OmgZ, preferably about 1 to about 500 mgZ, more preferably about 2 to about 20 OmgZ. Dosing times The number is, for example, once every 1 to 7 days, preferably once a day (patch, application, spraying, etc.). The administration period of the preparation of the present invention is usually 1 month to 5 years, and it may be administered for a longer period of time to suppress the progress of symptoms. Preferably it is 3 months to 4 years, more preferably 6 months to 2 years. In such a long-term administration, the preparation of the present invention can be easily administered without burdening the patient.

When the preparation of the present invention is a patch or a tape, the preparation may be cut into a convenient size for application and two or more sheets may be applied to the same or different places on the body. The place to be affixed is not particularly limited, but is preferably a site with less body hair. For example, it is applied to the inside of the upper arm, the back, the inside of the thigh, and the like. Of these, the back part is more preferred.

In addition, the preparations of the present invention may contain other active ingredients in addition to idebenone, such as central nervous drugs [eg, anxiolytics, sleep-inducing drugs, schizophrenia drugs, Parkinson, as long as they do not attenuate each other's efficacy. Drugs for anti-dementia drugs, anti-dementia drugs (eg, anti-acetylcholinesterase drugs, cerebral circulation improving drugs, cerebral metabolic activators, etc.), antihypertensive drugs, anti-diabetic drugs, anti-hyperlipidemic drugs, etc. May be used together. The other active ingredient and idebenone are mixed according to a method known per se, and are then administered to the same subject as a preparation or separately prepared at the same time or with a time lag as in the preparation of the present invention. Is also good.

By the preparation of the present invention, idebenone is transdermally absorbed in its effective amount. In the present invention, the toxicity is extremely low, and almost no side effects or toxicity are observed even after long-term administration. Therefore, the preparation of the present invention can be used as a preventive / therapeutic agent for dementia such as Alzheimer's dementia, as well as other cerebral nervous system diseases, diabetes (eg, S-extractitis or diabetes due to Teng's disease), diabetic, etc. It can be used as a prophylactic or therapeutic agent for complications (eg, nephropathy, neuropathy, retinopathy, arteriosclerosis, thrombosis, cataract, iritis, etc.) and allergies (eg, bronchial asthma, allergic rhinitis, etc.) It can be safely transdermally administered to mammals (eg, humans, monkeys, dogs, cats, rats, etc.). Since idebenone has a lipid peroxide production inhibitory effect by acting on the mitochondrial electron transport system, it prevents and treats skin disorders caused by lipid peroxide, prevents and treats skin aging, and reduces the formation of skin wrinkles. It can also be safely transdermally administered as a prophylactic / therapeutic agent, a sunburn therapeutic agent, a burn therapeutic agent, a mitochondrial encephalomyopathy preventive / therapeutic agent, and the like. Since the preparation of the present invention is easy to administer, for example, in an early stage patient, treatment can be continued without being known to surrounding people, and in a patient whose symptoms are manifest, Caregivers can easily administer medication to patients, and by observing the state of application, it is possible to easily confirm whether or not drug treatment is being performed reliably. Therefore, the burden on patients and their caregivers at medical institutions, nursing homes or home care can be significantly reduced.

Idebenone is susceptible to metabolism in the gastrointestinal tract and liver, and generally required oral administration increases the required dosage to deliver an effective amount of idebenone to the target organ, the brain . In rats, the ratio of unchanged drug in the brain and plasma at the peak after oral administration is about 4%, but when administered intravenously, the unchanged drug is rapidly transferred to the brain. The ratio is about 75% at 10 minutes after administration and about 18% at 30 minutes after administration, and the drug transfer to the target organ brain is more efficient than oral administration.

Therefore, in the preparation of the present invention, the first-pass effect in the gastrointestinal tract and liver can be avoided, so that not only can the dosage be reduced, but also idebenone can be directly translocated into the systemic bloodstream by transdermal administration. As a result, the unchanged substance can be efficiently delivered to the brain as in the case of intravenous administration.

When idebenone is administered orally as a tablet, the amount of idebenone that is transferred into the whole blood is restricted for the above reasons, and the size of the tablet increases because the dose of idebenone increases. Or inconvenience such as increasing the number of tablets to be administered. On the other hand, in the preparation of the present invention, the dosage can be reduced, and the dosage of idebenone can be adjusted by the application area. Patients can easily take medication.

Furthermore, a part of the drug (idebenone) is stored in the skin where the transdermal administration preparation of the present invention is administered, and the drug remains in the bloodstream for a while after the transdermal administration preparation is removed. Because of the supply, drug treatment is continued even if patients forget to take medication.

In addition, when idebenone is orally administered, an absorption peak generally exists, and the blood concentration varies with each administration. In the case of idebenone, which acts on the central nervous system, maintaining a substantially constant blood level of idebenone provides strong efficacy at a small dose. However, since the formulation of the present invention can release idebenone at a substantially constant rate, it is a formulation having a strong drug effect at a smaller dose than oral administration. Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention should not be limited thereto. Example 1 (Tape preparation)

Idebenone 10 parts by weight

Stearyl alcohol 30 parts by weight

Propylene dalycol 30 parts by weight

30 parts by weight of polyalkyl vinyl ether After mixing the above amounts of idebenone and propylene glycol, add stearyl alcohol, prepare a uniform paste by mixing and stirring, and mix with polyalkyl vinyl ether as an adhesive component to obtain a uniform paste. Body.

The obtained plaster was applied to a polyester release liner so as to have a thickness of 100 im, and after forming a plaster layer, it was transferred to a polyester film and idebenone 10% (w / w) A combined patch was obtained. Example 2 (Tape preparation) 40 parts by weight of ethanol

Water 10 parts by weight

Isopropyl myristate 20 parts by weight

Propylene glycol 5 parts by weight

Tween 8 0 1 0 parts by weight

Polyalkyl vinyl ether 10 parts by weight After mixing the above amounts of idebenone and ethanol, add isopropyl myristate and propylene glycol, add water and Tween 80, and mix uniformly. After the mixing and stirring, the mixture was mixed with a polyalkyl vinyl ether as an adhesive component to obtain a substantially uniform plaster.

The obtained paste is applied to a polyester release liner so as to have a thickness of 100 zm, and after forming a paste layer, it is transferred to a polyester film and idebenone 5% (W / W) A compounded tape was obtained. Example 3 (Tape preparation) 40 parts by weight of ethanol

Water 10 parts by weight

Isopropyl myristate

Glycerin 30 parts by weight

Polyalkyl vinyl ether 10 parts by weight After mixing the above amounts of idebenone and ethanol, add isopropyl myristate and glycerin, further add water, mix and stir to prepare a uniform plaster, and mix with adhesive polyalkyl vinyl ether To give a uniform plaster. The obtained plaster was applied to a polyester release liner so as to have a thickness of 100 m, a plaster layer was formed, and then transferred to a polyester film and idebenone 5% (W / W ) A compounded tape was obtained. Example 4 (Tape preparation)

1 part by weight of agarose

Xanthan gum 0.5 parts by weight Ethanol 40 parts by weight

water

5 parts by weight of isopropyl myristate

Glycerin 30 parts by weight Polyalkyl vinyl ether 8 After mixing the above amounts of idebenone and ethanol, add water to isopropyl myristate, glycerin, agarose, and xanthan gum, mix and stir, mix with polyalkyl vinyl ether as an adhesive component, and make Body. The resulting plaster is applied to a polyester release liner to a thickness of 100 ^ m.After forming a plaster layer, it is transferred to a polyester film and mixed with 5% idebenone (W / W). A tape was obtained. Example 5 (Tape preparation)

(Aqueous phase) Propylene glycol 15%

Sumikagel NP—5 0 0.5%

Purified water 26.5%

(Oil phase) 8%

Twe e n 20 5%

Isopropyl myristate 10%

Styrene and isoprene

Styrene block copolymer (SIS) Dissolve 35% propylene glycol in purified water, add Sumikagel NP-510 to the aqueous phase, mix idebenone, Tween 20, isopropyl myristate and adhesive (SIS). Oil phase. The previously obtained aqueous phase and oil phase were sufficiently mixed, applied to a polyethylene sheet so that the thickness of the dried paste was about 100 / m, and dried at 80 ° C for 5 minutes. After drying, the tape was covered with a separation tray to produce a tape formulation containing idebenone. Example 6 (Ointment cream)

Five %

Tri (force prillic acid force pric acid) glyceride 40% Sorbi-suic acid monooleate 1.2%

Polyoxyethylene sorbic acid monooleate 1.8%

1,3-butylene glycol 10%

Carboxyvinyl polymer 0.3%

Pallax benzoate pill 0.1%

Methyl paraoxybenzoate 0.1%

1N sodium hydroxide 1.25ml

Add purified water and heat 100% tri (cafrillic acid glyceric acid) glyceride to 80.

And a solution of sorbic acid monooleate as an oil phase. The purified water was heated to 80, and the aqueous phase was prepared by dissolving propyl paraoxybenzoate, methyl paraoxybenzoate, polyoxyethylene sorbyconate monooleate, 1,3-butylene glycol and carboxyvinyl polymer. . Add the oil phase while stirring the aqueous phase, and lower to room temperature with stirring. 1N sodium hydroxide was added to produce an ointment cream containing idebenone. Example 7 (Tape preparation)

Idebenone 5% Stearyl alcohol 15% Oleic acid 10% Propylene glycol 35% Styrene-isoprene-styrene block copolymer (SIS) 35% Idebenone and propylene glycol are mixed under heating 80 to dissolve the stearyl alcohol. The temperature was lowered while stirring. At around 50 ° C oleic acid and SIS were added. It was applied to a polyethylene sheet so that the thickness of the dried paste was about 100 zm, and then dried at room temperature. After drying, the tape was covered with a separator to produce an idebenone-containing tape. Example 8 (patch)

Agarose 1.

Xanthan gum 0.

Idebenone 5 parts by weight

40 parts by weight of ethanol

Water 10 parts by weight

5 parts by weight of isopropyl myristate

Glycerin 38 parts by weight After mixing the above amounts of idebenone and ethanol, isopropyl myristate, glycerin, agarose, and xanthan gum to which water was added were mixed and stirred to obtain a substantially uniform plaster.

The obtained plaster was applied to a polyester release liner so as to have a thickness of 100 m. After the plaster layer was formed, a polyester film (5 cm × 5 cm) coated with an adhesive in advance was used. Transfer was performed so that the paste margin was 5 mm to obtain a patch containing idebenone 5% (W / W). Example 9 (patch) 30 parts by weight of ethanol

Stearyl alcohol 40 parts by weight

Glycerin 20 parts by weight

Macrogol 600 After mixing the above amounts of idebenone and ethanol, stearyl alcohol, glycerin and Macrogol 600 were added and mixed and stirred to obtain a substantially uniform plaster.

The obtained plaster is applied to a polyester release liner so that the thickness becomes 100 m. After applying a plaster layer, transfer the polyester film (5 cm x 5 cm) pre-coated with adhesive so that the margin is 5 mm, and 5% idebenone (W / W) A combined patch was obtained. Example 10 (Patch)

5 parts by weight

30 parts by weight of ethanol

40 parts by weight of stearyl alcohol

Daricelin 20 parts by weight

Macrogol 6000 After mixing the above amounts of idebenone and ethanol, stearyl alcohol, glycerin and Macrogol 6000 were added and mixed and stirred to obtain a substantially uniform plaster.

The obtained paste is applied to a polyester release liner so as to have a thickness of 100 m. After the paste layer is formed, the adhesive allowance of the polyester film (5 cm x 5 cm) pre-coated with adhesive is applied. Transfer to 8mm and make idebenone 5%

(W / W) A combined patch was obtained. Furthermore, the surface of the plaster was covered, and a porous polyethylene membrane (Hipore) was crimped so as to cover 3 mm of the glue margin, and a patch containing idebenone 5% (W / W) was obtained. Experimental example 1

Seven-week-old male rats (SD strain) were used after fasting from the evening before the drug administration experiment.

Prior to the experiment, sodium pentobarbital (somnopentyl (Pitman-Moore, USA); 65 mg / kg) was intraperitoneally administered, and the abdominal hair of the rat was carefully shaved using a clipper, followed by shaving (BRAUN System The hair was completely removed using a rat 2-3, model number BS-5-424C, BRAUN, Germany) The abdomen was fixed with the rat facing abdomen upward (Natsume Seisakusho, Tokyo). The 70-80% ethanol solution (Wako Jun (Drugs) was carefully wiped three times with absorbent cotton soaked with water, and when the alcohol on the skin surface was dry, the preparation obtained in Example 4 above (9 square centimeters, containing 4.5 mg idebenone) was applied. . The formulation was secured with a cloth bandage to ensure close contact. Blood was collected from the rat tail at regular intervals, and the serum idebenone concentration was measured after deproteinization. The concentration was measured by HPLC (reverse phase column (C18), eluent (25: 75 = water: acetonitrile), UV detection wavelength 280 nm).

Idebenone was detected in the serum, indicating that the drug was transferred from the above formulation into the blood via the skin. Industrial applicability

The preparation of the present invention can be safely transdermally administered to mammals such as humans as an agent for preventing or treating dementia such as Alzheimer-type dementia.

Claims

The scope of the claims

I. A transdermal preparation containing idebenone for the prevention and treatment of dementia.

2. The preparation according to claim 1, wherein the dementia is Alzheimer-type dementia.

3. The preparation according to claim 1, which is a patch.

4. The preparation according to claim 1, which is a patch.

5. The preparation according to claim 1, which is a tape preparation.

6. The formulation of claim 1, which is administered once every 1 to 7 days.

7. The formulation according to claim 1, which is administered once a day.

8. The preparation according to claim 1, wherein the amount of idebenone is about 0.1 to about 20% by weight based on the total weight of the preparation.

9. The preparation according to claim 1, wherein the amount of idebenone is about 1 to about 10% by weight based on the total weight of the preparation.

10. The patch of claim 3, wherein the amount of idebenone is about 0.3 to about 5 OmgZcm ² .

The patch according to claim 3, wherein the amount of I I. idebenone is about 0.4 to about 2 OmgZcm ² .

12. The formulation of claim 1, wherein the dose of idebenone is about 0.3 to about 100 OmgZ.

13. The formulation of claim 1, wherein the dose of idebenone is about 1 to about 50 Omg / dose.

14. The formulation of claim 1, wherein the dose of idebenone is about 2 to about 20 OmgZ.

15. A method of transdermally administering idebenone as a preventive and therapeutic agent for dementia.

16. Use of idebenone for the manufacture of a transdermal formulation for the prevention and treatment of dementia.