JPH11116470A - Dermal administration preparation containing idebenone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an idebenone-containing dermal administration preparation enabling the efficient absorption of the idebenone, having excellent stability and contact touch and facilitating the application of the idebenone to dementia by processing the idebenone exhibiting excellent medicinal actions on cranial nerve diseases into the dermal administration preparation. SOLUTION: This dermal administration preparation contains idebenone, and is used for preventing and treating dementia, especially senile dementia of Alzheimer type. The dermal administration preparation is preferably administered in the form of cataplasm, patch or tape. The preparation is preferably administered once a day, and the idebenone is administered at a dose of about 0.3-1000 mg/each time. The idebenone is preferably contained in the preparation in an amount of about 0.1-20 wt.% based on the total weight of the preparation, or in an amount of about 0.3-50 mg/cm<2> in the case of the cataplasm. The idebenone which is easily metabolized in digestive tracts and livers and is difficult to reach a brain as target organ by an oral administration method can thereby exhibit a strong medicinal effect even at a small administration dose.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a transdermal preparation containing idebenone for the prevention and treatment of dementia.

[0002]

2. Description of the Related Art The increase in the aging population is accompanied by an increase in cancer, various adult diseases and central illnesses, and has become a major social problem. In particular, how to treat patients with dementia, a central disease, is a truly urgent issue. Dementia patients, especially Alzheimer's disease (hereinafter sometimes referred to as Alzheimer's disease)
As for a method for treating a patient or a method for suppressing the progression of dementia, a sufficiently satisfactory effective means has not been found so far. Idebenone has an immunostimulatory effect and a tissue metabolism activating effect in the body including the brain, and decreases in motivation due to chronic cerebral circulatory disorder accompanying sequelae of cerebral infarction and cerebral hemorrhage, emotional disorder, language disorder, or cerebrovascular disorder It has been reported as a remedy for neurological symptoms, memory and learning disorders. Also,
It is thought that by acting on the mitochondrial electron transport system, the production of lipid peroxide is suppressed, and the mitochondrial function, energy metabolism, and nerve function are prevented. It also eliminates reactive oxygen species (ROS) constantly produced in vivo by its antioxidant action,
It is considered that Alzheimer's dementia is prevented and treated by suppressing senile plaque formation, neurofibrillary tangles, and nerve cell death in the brain, which are thought to be involved in S (Biochem. Biophys. Res. Commun. 125 , 1046-1052
Page, 1984, J. Pharmacol. Exp. Ther., 260, 1132-
1140, 1989). JP-A-3-81218 (US
P 5,059,627) and JP-A-7-61923 (EP-A-629400) describe that idebenone is effective as a therapeutic agent for Alzheimer's senile dementia. In the former, the dose of idebenone is described as 0.1 mg to 500 mg per adult per day. The latter describes that idebenone is administered at a high dose of 150 mg or more per adult per day. Further, Arch. Gerontol. Geriat
r., 15, 1992, pp. 249-259, describe that the efficacy of idebenone in Alzheimer-type senile dementia patients was confirmed by administering 90 mg of idebenone per adult per day. I have. Generally, long-term continuous oral dosing is required in the prevention and treatment of dementia. For example, in patients with Alzheimer's dementia in the very early stage, the patient should continue taking the drug two or three times a day despite having almost no symptoms. It is difficult for a patient to continue taking oral preparations regularly, which requires a great deal of effort by a caregiver to keep the patient taking the oral preparation, which is a factor of lowering compliance. On the other hand, Japanese Patent Application Laid-Open No. 4-99719 discloses various kinds of bases for external patches comprising at least one selected from the group consisting of fatty acids, derivatives thereof, and animal and plant fats and oils, polyhydric alcohols and water. It describes the preparation of a topical patch for a drug. However, there is no description that application to a prophylactic / therapeutic agent for dementia, particularly idebenone, gives favorable results. Also, JP-A 1-27
No. 9818 discloses carbewax ointment, white petrolatum ointment and cream containing idebenone as formulation examples of a graying agent containing idebenone. However, although various reports have been reported on the target disease and dosage form of idebenone, the optimal dosage form for each disease is not known, especially for dementia.
Absorption rate, stability, toxicity, burden on patients, ease of administration,
In view of industrial production and the like, a formulation which is clinically applicable as a medicine and has excellent effects has not yet been obtained.
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 diseases, and a formulation suitable therefor.

[0003]

Means for Solving the Problems The present inventors have made intensive efforts to search for an efficient and simple dosage form of idebenone, and as a result, have produced the first transdermal administration preparation for the preventive treatment of dementia. It has surprisingly good stability, good contact feeling and easy application, idebenone is efficiently absorbed,
It has been found that it has excellent properties as clinical medicine, such as being able to achieve safety and patient compliance,
Based on this, the present invention has been completed. That is, the present invention relates to (1) a preparation for transdermal administration for the prevention and treatment of dementia containing idebenone, (2) the preparation according to (1), wherein the dementia is Alzheimer-type dementia, and (3) a patch. (1) the preparation according to the above (1), (4) a patch,
(5) a preparation according to (1), which is a tape; (6) a preparation according to (1), which is administered once every 1 to 7 days; (7) a preparation, once per day The formulation according to (1) and (8) the amount of idebenone is about 0.5% of the total weight of the formulation.
1 to about 20% by weight of the preparation according to the above (1),
(9) The preparation according to (1), wherein the amount of idebenone is about 1 to about 10% by weight of the total weight of the preparation, and (10) the above-mentioned preparation, wherein the amount of idebenone is about 0.3 to about 50 mg / cm ^2. The patch according to (3), wherein (11) the amount of idebenone is about 0.4 to about 20 mg / cm ^2.
The patch described in (12), wherein the dose of idebenone is about 0.3.
To about 1000 mg / dose, (13) the dose of idebenone is from about 1 to about 500 mg / dose.
mg / dose of the preparation according to the above (1), (14) a preparation of the above (1), wherein the dose of idebenone is about 2 to about 200 mg / dose, and (15) idebenone as a preventive and therapeutic agent for dementia. The present invention relates to a method for transdermal administration, (16) Use of idebenone for producing a transdermal administration preparation for prevention and treatment of dementia, and the like.

[0004] 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.
It is a known compound described in JP-B-62-3134. Idebenone is disclosed in, for example, Japanese Patent Application Laid-Open
, 63-264436, 56-7734, 56-147746 and the like 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 an 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, a single dose that can be freely adjusted, and applied on the skin, for example, Ointments (including creams), lotions (including suspensions and emulsions), liquids, sprays and the like. 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 preparation of the present invention is, for example, a patch, preferred embodiments include idebenone, a solvent (preferably ethanol), a base (preferably higher (C _12-22 ) fatty alcohol, more preferably stearyl alcohol) and a humectant ( Preferably, the patch contains 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. The amount of the humectant is preferably 20 to 35 parts by weight. When the preparation of the present invention is, for example, a tape preparation, a preferred embodiment is idebenone,
Base (preferably higher ( _C12-22 ) fatty acid alcohols,
Further preferred is a tape containing a stearyl alcohol), a humectant (preferably propylene glycol) and an 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 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.

[0005] The preparation of the present invention can be produced by a method known per se, for example, the method described in the Japanese Pharmacopoeia or a method analogous thereto. Specific examples are described below. "Coating agent" (eg, ointment, lotion, liquid, spray, etc.)
Can be produced according to a conventional method by blending idebenone together with a solvent, a suspending agent, an emulsifier, a propellant, a base and the like known per se in the field of formulation. If necessary, a transdermal absorption controlling component, a humectant, a preservative, an anti-inflammatory agent and the like may be added. The “solvent” is a liquid component constituting “ointment”, “lotion”, “liquid”, and “spray”, and is particularly defined as a water-soluble solvent. Specific examples include water, lower alcohols (eg, ethanol), alkanediols having 2 to 5 carbon atoms (eg, glycerin), and alkanetriols having 2 to 5 carbon atoms (eg, propylene glycol). 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-mentioned "suspension agent" is mainly blended with the "suspension agent" contained in the "spray agent" and the "lotion agent", and separates two-phase liquids (eg, water and isopropyl myristate). When mixed by shaking, it indicates a component that functions to temporarily maintain a uniform state and a fat-soluble solvent that forms an oil phase thereof. Examples of the “component” (the former) include gelling components (eg, sodium alginate, dried aluminum hydroxide gel, agar, etc.), thickeners (eg, xanthan gum, locust bee gum, etc.), aluminum magnesium silicate, Light silicic anhydride, crystalline cellulose, surfactants (eg, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene higher alcohol ether, polyoxyethylene alkyl aryl ether, polyoxy Nonionic surfactants such as ethylene castor oil derivatives and block polymer type nonionic surfactants (Pluronic L-62, L-64, F-68); Ionic surfactants such as sodium lauryl sulfate (SLS) Agent) And the like, and the compounding amount in the preparation is about 0 to 50%. Examples of the “fat-soluble solvent” (the latter) include higher fatty acid alcohols (eg, cetanol, stearyl alcohol, behenyl alcohol, oleyl alcohol, etc.), higher fatty acid esters (eg, isopropyl myristate, tri (caprylic acid, capric acid) glyceride) Etc.), fats and oils (eg,
Soybean lecithin, carnauba wax, beeswax, olive oil, rapeseed oil, etc.), and these may be used alone or in combination of two or more. The amount of the “lipid-soluble solvent” in the preparation is about 0 to 80%.

[0006] The above-mentioned "emulsifier" is partially common to the suspending agent, but is mainly used for "spray", "cream" contained in "ointment", "emulsion" contained in "lotion" and the like. To form a component having the function of maintaining a uniform state by forming an emulsion of two-phase liquids having low compatibility (eg, water and isopropyl myristate) from the time of manufacture until the expiration date, and the oil phase thereof 1 shows a fat-soluble component. Specific examples include gelling components (eg, sodium alginate, polyvinyl alcohol, dried aluminum hydroxide gel, etc.), thickeners (eg, curdlan, agar, mucin, gelatin, pectin, carrageenan, chitin, chitosan,
Locust bingham, tragacanth gum, xanthan gum, pullulan, sucralfate, etc.), aluminum magnesium silicate, light anhydrous silicic acid, crystalline cellulose,
Higher alcohols (eg, cetanol, stearyl alcohol, behenyl alcohol, oleyl alcohol, etc.), higher fatty acid esters (eg, isopropyl myristate, tri (caprylic acid, capric acid) glyceride, etc.), fats and oils (eg, soy lecithin, cetanol, poly) Oxyethylene hydrogenated castor oil, carnauba wax, beeswax, 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 Nonionic surfactants (nonionic surfactants such as Pluronic L-62, L-64, F-68; ionic surfactants such as sodium lauryl sulfate (SLS)); May be used alone or in combination of two or more. The compounding amount of the “emulsifier” in the preparation is about 0 to 70%.

[0007] The above-mentioned "propellant" is a general term for a component which is mainly blended with a "propellant", is charged at a high pressure into a device such as a spray at a boiling point or below normal temperature, and is capable of injecting the contents by the pressure. It is called “propellant”. Specific examples include Freon (eg, Freon 11, Freon 12, Freon 113, etc.), Freon substitute, liquefied petroleum gas, carbon dioxide and the like, and these may be used alone or in combination of two or more. The compounding amount of the “propellant” in the preparation is about 0 to 99%. Further, a propellant can also be produced by mechanically inhaling and discharging air without using a propellant (propellant). The “base” is a general term for compounds that 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. As the "base of ointment", for example, vaseline,
Solid paraffin, olive oil, sesame oil, cottonseed oil, solid paraffin, liquid paraffin, lanolin, higher fatty acid alcohols (eg, cetanol, 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 (caprylic / capric acid) glycerides, etc.), lipids (eg, soybean lecithin, dipalmitoylphosphatidylcholine, distearylphosphatidylcholine, etc.),
Oily bases such as silicone oil; water, macrogol (eg,
Macro Goal 400, Macro Goal 600, Macro Goal 1000, Macro Goal 1500, Macro Goal 40
00, Macrogol 6000, etc.), C2-C5 alkanediol (eg, glycerin), C2-C5 alkanetriol (eg, propylene glycol, 1,3
-Butylene glycol, etc.), polyvinyl alcohol (P
VA), polyacrylic acid (PAA), carboxyvinyl polymer, superabsorbent resin (eg, block polymer of PVA and PAA (eg, Sumikagel SP-510 manufactured by Sumitomo Chemical Co., Ltd.))
And the like. These may be used alone or in combination of two or more, and may be semisolid in the final preparation. The compounding amount in the preparation of the “base of ointment” is
It is about 0 to 99%.

The "base" of the "base of the lotion" and the "base of the propellant" 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 / capric acid))
Glycerides, etc.), liquid oils (eg, olive oil, liquid lanolin, liquid paraffin, etc.), and these may be used alone or in combination of two or more. The "base of lotion agent"
The amount of the “spray base” in the preparation is 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 preparation may be any one that exhibits a water-soluble liquid. The amount of the “liquid base” in the preparation is from 0 to 99%
It is about.

[0009] The above-mentioned "transdermal absorption controlling ingredient" is used for the skin surface,
It is mainly formulated to act on 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, petrolatum, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol,
Glycerin fatty acid ester, cholesterol, carbopol, carboxymethylcellulose, carboxyethylcellulose, silicone resin, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), carbon number 6-20
Aliphatic carboxylic acids (eg, caproic acid, caprylic acid, capric acid, lauric 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-octyl alcohol, n-cetyl alcohol, etc.), aliphatic alcohols having 2 to 20 carbon atoms and carbon number Ester (e.g., isopropyl myristate, etc.) with an aliphatic carboxylic acid having 6 to 20 carbon atoms and alkanediol (e.g., glycerin) having 2 to 5 carbon atoms with an aliphatic alcohol having 2 to 20 carbon atoms (e.g., tri (Caprylic acid / capric acid) glyceride, etc.), alkanediol having 2 to 5 carbon atoms (eg, glycerin), alkanetriol having 2 to 5 carbon atoms (eg, propylene glycol), pyrrolidone derivative (eg, N-methyl) Pyrrolidone, etc.), d-limonene, l-menthol,
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 Nonionic surfactants such as nonionic surfactants (Pluronic L-62, L-64, F-68); and ionic surfactants such as sodium lauryl sulfate (SLS). May be used alone or in combination of two or more. The amount of the “transdermal absorption controlling ingredient” in the preparation is from 0 to 80%
It is about.

The above "preservatives" include, for example, benzoic acid, sodium benzoate, benzyl benzoate, ethanol, sodium edetate, benzalkonium chloride, salicylic acid, salicylate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, Examples include ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, phenol, benzyl alcohol, boric acid, borax, 1-menthol, and the like, alone or in combination of two or more. Good. The amount of the "preservative" in the preparation is from 0 to 2
It is about 0%. Examples of the "humectant" include glycerin, propylene glycol, urea, amino acids (eg, 1-proline and the like), and these may be used alone or in combination of two or more. The compounding amount of the “humectant” in the preparation is about 0 to 50%. The above "inflammation inhibitor"
Examples thereof include glycyrrhetinic acid and diphenhydramine, 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 from 0 to 10
%.

The above-mentioned "patches" (eg, patches, plasters,
Tapes, etc.) are absorbed or adhered to an appropriate carrier (backing) using idebenone as a base, an emulsifier, a transdermal absorption controlling component, a preservative, a humectant, an anti-inflammatory agent, an adhesive, etc. If necessary, a release-controlling film can be provided for the purpose of controlling the release of the drug from the preparation, and can be produced according to a conventional method. If necessary, idebenone may be dissolved and dispersed in a solvent in advance. The “base” is a generic term for compounds that are mixed with the above-mentioned patch for the purpose of dissolving or uniformly dispersing idebenone in a preparation and have an excipient role in a solid preparation. Hereinafter, specific examples will be described. As the "base for patch", for example, petrolatum, solid paraffin, olive oil, sesame oil, cottonseed oil, liquid paraffin,
Lanolin, higher fatty acid alcohols (eg, cetanol, stearyl alcohol, oleyl alcohol, etc.), higher fatty acids (eg, myristic acid, palmitic acid, stearic acid, oleic acid, etc.), fatty acid esters (eg, beeswax, beeswax, whale wax, Isopropyl myristate,
Oily bases such as isopropyl palmitate, tri (caprylic / capric acid) glyceride, etc., lipids (eg, soybean lecithin, dipalmitoylphosphatidylcholine, distearylphosphatidylcholine, etc.), and silicone oil; Water, macrogol (eg, macrogol 4
00, macrogol 600, macrogol 1000, macrogol 1500, macrogol 4000, macrogol 6000, etc.), alkanediol having 2 to 5 carbon atoms (eg, glycerin), alkanetriol having 2 to 5 carbon atoms (eg, Propylene glycol, 1,3-butylene glycol, etc.), polyvinyl alcohol (PVA), polyacrylic acid (PAA), carboxyvinyl polymer, superabsorbent resin (eg, block polymer of PVA and PAA (eg, Sumikagel manufactured by Sumitomo Chemical Co., Ltd.) And aqueous bases such as SP-510, etc.). These may be used alone or in combination of two or more, and may be a semi-solid in the final preparation. Of these, oil-based bases are preferred. More preferred are aliphatic alcohols and fatty acid esters. The compounding amount of the “base” in the preparation is about 0 to 99%.

The above-mentioned "emulsifier" includes 2
Phase liquids (eg, water and isopropyl myristate)
From the time of manufacture to the expiration date, a component that functions to maintain a uniform state by forming an emulsion and a fat-soluble component that forms the oil phase thereof, for example, a gelling component (eg,
Sodium alginate, polyvinyl alcohol, dried aluminum hydroxide gel, agar, etc.), thickeners (eg, curdlan, agar, mucin, gelatin, pectin, carrageenan, chitin, chitosan, locust bingham,
Tragacanth gum, xanthan gum, pullulan, sucralfate, etc.), aluminum magnesium silicate, light silicic anhydride, crystalline cellulose, higher alcohols (eg, cetanol, stearyl alcohol, behenyl alcohol, oleyl alcohol, etc.), higher fatty acid esters (eg, isopropyl myristate) , Tri (caprylic acid,
(Capric acid) glyceride, etc.), fats (eg, soybean lecithin, polyoxyethylene hydrogenated castor oil, carnauba wax, beetle wax, etc.), surfactants (eg, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, poly) Oxyethylene fatty acid ester, polyoxyethylene higher alcohol ether, polyoxyethylene alkyl aryl ether,
Polyoxyethylene castor oil derivative, block polymer type nonionic surfactant (Pluronic L-62, L
-64, F-68); ionic surfactants such as sodium lauryl sulfate (SLS)). These can be used alone or 2
More than one species may be used in combination. The amount of the “emulsifier” in the preparation is about 0 to 90%.

The above-mentioned “transdermal absorption controlling ingredient” is used for
It is a component that is mainly formulated for the purpose of acting on the stratum corneum to promote the absorption of the drug, such as phospholipids (eg, lecithin), solid paraffin, beeswax, carnauba wax, hardened castor oil, lanolin, petrolatum, Polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, glycerin fatty acid ester, cholesterol, carbopol, carboxymethylcellulose, carboxyethylcellulose, silicone resin, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), aliphatic carboxylic acid having 6 to 20 carbon atoms ( For example, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidonic acid, etc. and salts thereof, and aliphatic alcohols having 6 to 20 carbon atoms (eg, n-octyl alcohol) Le, n- cetyl alcohol), 6 aliphatic alcohols and the carbon number of 2 to 20 carbon atoms
Ester (eg, isopropyl myristate, etc.) with an aliphatic carboxylic acid having 20 carbon atoms, and ester (eg, tri (capryl) with an aliphatic alcohol having 2 to 20 carbon atoms and an alkanediol having 2 to 5 carbon atoms (such as glycerin) Acid / capric acid) glyceride, etc.), alkanediol having 2 to 5 carbon atoms (eg, glycerin), alkanetriol having 2 to 5 carbon atoms (eg, propylene glycol), pyrrolidone derivative (eg, N-methylpyrrolidone, etc.) ), D-limonene, l
-Menthol, 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 derivative, Block polymer type nonionic surfactant (Pluronic L-62, L-64, F
-68); ionic surfactants such as sodium lauryl sulfate (SLS)), and these may be used alone or in combination of two or more. The compounding amount of the “transdermal absorption controlling ingredient” in the preparation is about 0 to 80%.

Examples of the above "preservatives" include benzoic acid, sodium benzoate, benzyl benzoate, ethanol, sodium edetate, benzalkonium chloride, salicylic acid, salicylate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, Examples include ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, phenol, benzyl alcohol, boric acid, borax, 1-menthol, and the like, alone or in combination of two or more. Good. The amount of the "preservative" in the preparation is from 0 to 2
It is about 0%. Examples of the "humectant" include glycerin, propylene glycol, urea, 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%. The above "inflammation inhibitor"
Examples thereof include glycyrrhetinic acid and diphenhydramine, 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 from 0 to 1
It is about 0%.

Examples of the "adhesive" include, for example, acrylic adhesives (eg, 2-ethylhexyl acrylate, vinyl acetate, ethyl acrylate, methacrylate, methoxyethyl acrylate, at least two copolymers of acrylic acid (eg, Nippon Carbide PE-300
), Natural and synthetic rubbers (eg, polyisobutylene (PIB), neoprene, polybutadiene, polyisoprene, etc.), polysiloxane, polyurethane, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene Block copolymer (SB
S) and the like, and these 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 from 0 to 7
It is about 0%. 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 (yellowish brown) of idebenone can be directly confirmed,
In addition, when idebenone has not been absorbed due to a skin disorder or the like, it can be confirmed directly, and the preventive treatment can be performed more reliably, for example, by replacing the preparation. 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),
This has the advantage that the color of idebenone can be masked and that the surrounding people are not aware that the drug is being treated. Examples of the above “release control membrane” include a porous polyethylene membrane (eg, Hipore manufactured by Asahi Kasei Corporation) and a porous polypropylene membrane (eg, Durag manufactured by Polyplastics)
ard etc.).

Examples of the "solvent for the patch" include water, lower alcohols (eg, ethanol, etc.),
5 alkanediols (eg, glycerin, etc.), 2 carbon atoms
To 5 alkanetriols (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. Preferably, it is a non-aqueous tape or non-aqueous patch.

Preferred production methods of the preparation of the present invention include:
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 are added to the solvent as needed before mixing the base.
When the preparation of the present invention is a patch, (1) the obtained plaster is applied to a non-woven fabric as needed while being spread to a certain thickness, and then transferred to a backing such as a polyester film. Next, the resulting transferred product is attached to a slightly larger polyester film coated with an adhesive component in advance, or (2) the obtained plaster is
It is manufactured by transferring to a part of a backing such as a polyester film coated with an adhesive component in advance.
When the preparation of the present invention is a tape, an adhesive component such as 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 applied 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 of the total weight of the preparation is preferable. Is from about 0.1 to about 20% by weight, more preferably from 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 / cm ² , preferably about 0.3 to about 200 mg / cm ² .
About 50 mg / cm ² , more preferably about 0.4 to about 20
mg / cm 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 preventing or treating Alzheimer's dementia for adults, about 0.3 to about 10% as idebenone.
00 mg / dose, preferably about 1 to about 500 mg / dose, more preferably about 2 to about 200 mg / dose. The number of administrations 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 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. Of these, the back part is more preferable.

The preparations of the present invention may contain other active ingredients such as central nervous drugs [eg, anxiolytics, sleep-inducing drugs, schizophrenia drugs, as well as idebenone as long as they do not attenuate each other's efficacy. Parkinson's disease drug, anti-dementia drug (eg, anti-acetylcholinesterase drug, cerebral circulation improver, cerebral metabolic activator, etc.), antihypertensive drug, diabetes drug, anti-hyperlipidemic drug, etc. May be used together. The other active ingredient and idebenone may be mixed according to a means known per se, and may be administered as a preparation or separately to the same subject at the same time or with a time lag as in the preparation of the present invention. . By the preparation of the present invention, the effective amount of idebenone is transdermally absorbed. 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 prophylactic / therapeutic agent for dementia such as Alzheimer's dementia, as well as other cerebral nervous system diseases, diabetes (eg, diabetes due to pancreatitis or pancreatic disorder), diabetic complications (eg, , Nephropathy, neuropathy, retinopathy, arteriosclerosis, thrombosis, cataract, iritis, etc.), allergic diseases (eg, bronchial asthma, allergic rhinitis, etc.), and mammals ( Eg, humans, monkeys, dogs, cats, rats, etc.). Since idebenone has a lipid peroxide production inhibitory action by acting on the mitochondrial electron transport system, it is a preventive and remedy for skin disorders caused by lipid peroxide, a preventive and remedy for skin aging, a preventive and remedy for skin wrinkle formation, sunburn Remedies, burn remedies,
It can be safely transdermally administered as an agent for preventing or treating mitochondrial encephalomyopathy. Since the preparation of the present invention is easy to administer, for example, it is possible to continue treatment without knowing the surrounding people in an early stage patient, and to provide care in a patient whose symptoms are apparent. The patient can easily administer the drug to the patient, and by observing the state of application, it is possible to easily confirm whether or not the drug treatment is being performed reliably. Therefore, the burden on patients and their caregivers in medical institutions, nursing homes, or home care can be significantly reduced.

Idebenone is susceptible to metabolism in the gastrointestinal tract and liver, and oral administration, which is generally used, increases the required dosage to deliver an effective amount of idebenone to the target organ, the brain. In rats, the ratio of unchanged substance in the brain and plasma at the peak after oral administration was about 4%.
However, when administered intravenously, the unchanged body was rapidly transferred to the brain, and the same ratio was about 75% 10 minutes after administration,
It is about 18% in 30 minutes, and the drug transfer to the target organ brain is more efficient than oral administration. Therefore, in the preparation of the present invention, since the first-pass effect in the digestive tract and liver can be avoided, not only can the dosage be reduced, but also idebenone can be directly transferred into the systemic bloodstream by transdermal administration. As a result, the unchanged substance can be efficiently delivered to the brain similarly to intravenous administration. When idebenone is orally administered as a tablet, the amount of idebenone that migrates into the systemic blood is restricted for the above reasons, and the amount of idebenone increases, so the tablet size increases or the number of tablets to be administered increases. Inconvenience such as increase occurs. On the other hand, the dosage of the formulation of the present invention can be reduced, and the dosage of idebenone can be adjusted with the applied area.Moreover, even for elderly patients who are difficult to swallow with a large tablet or a plurality of tablets. Dosing is easier.

Further, a part of the drug (idebenone) is stored in the skin where the transdermal preparation of the present invention is administered,
Since the drug is supplied into the bloodstream for a while after the transdermal preparation is removed, the drug treatment is continued even if the patient is forgotten to administer the drug. Also, when idebenone is orally administered, an absorption peak generally exists, and the blood concentration varies with each administration. In the case of idebenone acting on the central nervous system, a strong drug effect can be obtained at a small dose by maintaining a substantially constant blood idebenone concentration, but the formulation of the present invention releases idebenone at a substantially constant rate. Because it can be used, it is a preparation having a strong drug effect at a smaller dose than oral administration.

[0022]

The present invention will be described in more detail with reference to the following Examples and Experimental Examples, which should not be construed as limiting the present invention.

【Example】

Example 1 (Tape preparation) Idebenone 10 parts by weight Stearyl alcohol 30 parts by weight Propylene glycol 30 parts by weight Polyalkylvinyl ether 30 parts by weight After mixing the above amounts of idebenone and propylene glycol, stearyl alcohol is added, and the mixture is stirred to obtain a uniform paste. Was prepared and mixed with a polyalkyl vinyl ether as an adhesive component to obtain a uniform plaster. The obtained plaster was applied to a polyester release liner so as to have a thickness of 100 μm, and after forming a plaster layer, it was transferred to a polyester film to obtain a patch containing idebenone 10% (w / w). Was.

Example 2 (Tape preparation) Idebenone 5 parts by weight Ethanol 40 parts by weight Water 10 parts by weight Isopropyl myristate 20 parts by weight Propylene glycol 5 parts by weight Tween 80 10 parts by weight Polyalkyl vinyl ether 10 parts by weight Idebenone and ethanol in the above amounts After mixing, isopropyl myristate and propylene glycol were added, water and Tween 80 were further added, and after uniform mixing and stirring,
It was mixed with a polyalkyl vinyl ether as an adhesive component to obtain a substantially uniform plaster. The resulting paste is applied to a polyester release liner so as to have a thickness of 100 μm. After forming a paste layer, the paste is transferred to a polyester film to obtain a idebenone 5% (W / W) compounding tape. Was.

Example 3 (Tape preparation) Idebenone 5 parts by weight Ethanol 40 parts by weight Water 10 parts by weight Isopropyl myristate 5 parts by weight Glycerin 30 parts by weight Polyalkylvinyl ether 10 parts by weight After mixing the above amounts of idebenone and ethanol, myristic acid Isopropyl and glycerin were added, water was further added, and a uniform plaster was prepared by mixing and stirring, followed by mixing with a polyalkylvinyl ether as an adhesive component to obtain a uniform plaster. The obtained plaster was applied to a polyester release liner so as to have a thickness of 100 μm, and after forming a plaster layer, it was transferred to a polyester film and idebenone 5% (W /
W) A compounded tape was obtained.

Example 4 (Tape preparation) Agarose 1 part by weight Xanthan gum 0.5 part by weight Idebenone 5 parts by weight Ethanol 40 parts by weight Water 10 parts by weight Isopropyl myristate 5 parts by weight Glycerin 30 parts by weight Polyalkyl vinyl ether 8.5 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, and then mixed with the adhesive component polyalkylvinyl ether to obtain a substantially uniform plaster. The obtained plaster was applied to a polyester release liner so as to have a thickness of 100 μm, and after forming a plaster layer, it was transferred to a polyester film and idebenone 5%
A (W / W) compounding tape was obtained.

Example 5 (Tape preparation) (Aqueous phase) Propylene glycol 15% Sumikagel NP-510 0.5% Purified water 26.5% (Oil phase) Idebenone 8% Tween 20 5% Isopropyl myristate 10% Styrene-isoprene -Styrene block copolymer (SIS) 35% Propylene glycol dissolved in purified water
NP-510 was added to the aqueous phase, idebenone, Tween
n20, isopropyl myristate and adhesive (SI
S) was mixed to form an oil phase. The previously obtained aqueous phase and oil phase were sufficiently mixed, applied on a polyethylene sheet so that the thickness of the dried paste was about 100 μm, and dried at 80 ° C. for 5 minutes. After drying, the tape was covered with a separator to produce an idebenone-containing tape preparation.

Example 6 (Ointment cream) Idebenone 5% Tri (caprylic / capric acid) glyceride 40% Sorbitanic acid monooleate 1.2% Polyoxyethylene sorbitanic acid monooleate 1.8% 1,3-butylene glycol 10% Carboxyvinyl polymer 0.3% Propyl parahydroxybenzoate 0.1% Methyl paraoxybenzoate 0.1% 1N sodium hydroxide 1.25 ml Purified water Add 100% tri (caprylic acid / capric acid) glyceride to 80 ° C The mixture was heated, and idebenone and sorbitanic acid monooleate dissolved therein were used as an oil phase. The purified water was heated to 80 ° C., and a solution in which propyl parahydroxybenzoate, methyl paraoxybenzoate, polyoxyethylene sorbitanate monooleate, 1,3-butylene glycol and carboxyvinyl polymer were dissolved was used as an aqueous phase. The oil phase is added while stirring the aqueous phase, and the temperature is lowered to room temperature while stirring. 1N
Sodium hydroxide was added to produce an idebenone-containing ointment cream.

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 at 80 ° C. while heating. Then, stearyl alcohol was dissolved, and the temperature was lowered while stirring. Oleic acid and SIS around 50 ° C
Was added. It was applied on a polyethylene sheet so that the thickness of the dried paste was about 100 μm, and then dried at room temperature. After drying, the tape was covered with a separator to produce an idebenone-containing tape preparation.

Example 8 (Patch) Agarose 1.5 parts by weight Xanthan gum 0.5 parts by weight Idebenone 5 parts by weight Ethanol 40 parts by weight Water 10 parts by weight Isopropyl myristate 5 parts by weight Glycerin 38 parts by weight The above amounts of idebenone and ethanol After mixing, isopropyl myristate, glycerin, agarose and xanthan gum to which water was added were 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 μm, and after forming a paste layer, a paste margin of a polyester film (5 cm × 5 cm) coated with an adhesive beforehand becomes 5 mm. In this manner, a patch containing idebenone 5% (W / W) was obtained.

Example 9 (Patch) Idebenone 5 parts by weight Ethanol 30 parts by weight Stearyl alcohol 40 parts by weight Glycerin 20 parts by weight Macrogol 6000 5 parts by weight After mixing the above amounts of idebenone and ethanol, stearyl alcohol, glycerin and macrogol 600
0 was added and mixed and stirred to obtain a substantially uniform plaster. The obtained plaster was 100 μm thick on a polyester release liner.
After coating and forming a plaster layer, a polyester film (5 cm × 5 c
m) is transferred so that the glue allowance is 5 mm.
% (W / W) combined patch was obtained.

Example 10 (patch) Idebenone 5 parts by weight Ethanol 30 parts by weight Stearyl alcohol 40 parts by weight Glycerin 20 parts by weight Macrogol 6000 5 parts by weight After mixing the above amounts of idebenone and ethanol, stearyl alcohol, glycerin and macrogol 600
0 was added and mixed and stirred to obtain a substantially uniform plaster. The obtained plaster was 100 μm thick on a polyester release liner.
After coating and forming a plaster layer, a polyester film (5 cm × 5 c
m) Transfer the paste so that the paste margin is 8 mm, and add idebenone 5
% (W / W) combined patch was obtained. Further, the plaster surface was covered, and a porous polyethylene membrane (Hipore) was pressure-bonded so as to cover 3 mm of the glue margin, thereby obtaining a patch containing idebenone 5% (W / W).

Experimental Example 1 Seven-week-old male rats (SD strain) were used after fasting from the evening before the drug administration experiment. Before the experiment, pentobarbital sodium (somnopentyl (Pitman-Moore (USA)
Made. 65 mg / kg) was administered intraperitoneally, and the abdominal hair of the rat was carefully shaved with a clipper, followed by a shaver (BRAUN
The hair was completely removed using System 1-2-3, model number BS-5-424C, BRAUN, Germany). The rat was fixed on a fixed base (Natsume Seisakusho, Tokyo) with the abdomen facing upward, and the dehaired abdomen was 70-
The preparation obtained in Example 4 above (9 square centimeters, containing 4.5 mg idebenone) when the alcohol on the skin surface dries carefully three times with absorbent cotton soaked with an 80% ethanol solution (Wako Pure Chemical Industries) Was affixed. The formulation was secured with a cloth bandage to ensure close contact. Blood was collected from the tail of the rat at regular intervals, and the idebenone concentration in the serum after deproteinization was measured. The concentration was measured by HPLC (reverse phase column (C
18), eluent (25: 75 = water: acetonitrile),
UV detection wavelength 280 nm) was used. Idebenone was detected in the serum, indicating that the drug was transferred from the above formulation through the skin and into the blood.

[0033]

EFFECT OF THE INVENTION 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 (16)

[Claims] 1. 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 preparation according to claim 1, which is administered once every 1 to 7 days. 7. The preparation according to claim 1, which is administered once a day. 8. The compounding amount of idebenone is about 0.5% of the total weight of the preparation.
The formulation of claim 1, wherein the formulation is 1 to about 20% by weight. 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 according to claim 3, wherein the amount of idebenone is from about 0.3 to about 50 mg / cm ² . 11. The patch according to claim 3, wherein the amount of idebenone is from about 0.4 to about 20 mg / cm ² . 12. The preparation according to claim 1, wherein the dose of idebenone is about 0.3 to about 1000 mg / dose. 13. The dosage of idebenone is from about 1 to about 50.
The formulation according to claim 1, which is 0 mg / dose. 14. The dosage of idebenone is from about 2 to about 20.
The formulation according to claim 1, which is 0 mg / dose. 15. A method for transdermally administering idebenone as an agent for preventing and treating dementia. 16. Use of idebenone for producing a preparation for transdermal administration for prevention and treatment of dementia.