WO1999007355A1 - Preparation contenant de l'idebenone pour administration par voie percutanee - Google Patents

Preparation contenant de l'idebenone pour administration par voie percutanee Download PDF

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Publication number
WO1999007355A1
WO1999007355A1 PCT/JP1998/003576 JP9803576W WO9907355A1 WO 1999007355 A1 WO1999007355 A1 WO 1999007355A1 JP 9803576 W JP9803576 W JP 9803576W WO 9907355 A1 WO9907355 A1 WO 9907355A1
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WIPO (PCT)
Prior art keywords
idebenone
preparation
acid
dementia
weight
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PCT/JP1998/003576
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English (en)
Japanese (ja)
Inventor
Yasutaka Igari
Yasuyuki Suzuki
Shigeru Toyoda
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Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU85629/98A priority Critical patent/AU8562998A/en
Publication of WO1999007355A1 publication Critical patent/WO1999007355A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

  • the present invention relates to a preparation for transdermal administration containing idebenone for the prevention and treatment of dementia.
  • Alzheimer's disease Alzheimer-type 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).
  • ROS reactive oxygen species
  • 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.
  • prophylaxis and treatment of dementia requires long-term, continuous oral administration.
  • 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.
  • 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.
  • 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.
  • a percutaneous administration preparation for the prevention and treatment of dementia comprising idebenone,
  • the amount of idebenone is from about 0.4 to about 2 OmgZcm 2.
  • 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.
  • Idebe non solvent preferably ethanol
  • base preferably higher (C 12 - 22) fatty alcohol, more preferably stearyl alcohol
  • 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.
  • 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.
  • 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.
  • the “component” examples 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%.
  • a gelling component eg, sodium alginate, dried aluminum hydroxide gel, agar, etc.
  • fat-soluble solvent examples 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%.
  • 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.
  • gelling components eg, sodium alginate, polyvinyl alcohol, dried hydroxylamine gel, etc.
  • thickeners eg, force-doran, agar, mucin, gelatin, pectin, carrageenan, chitin, chitosan
  • 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 ⁇ Barrow, Beeswax, etc.), surfactants (eg, polyoxyethylene
  • 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.
  • 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.
  • specific examples include a base for an ointment, a lotion and a base for a spray.
  • 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 1500,
  • 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%.
  • liquid base examples 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%.
  • 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,
  • preservatives examples 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%.
  • the “humectant” examples 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%.
  • anti-inflammatory agent examples 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.
  • 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.
  • 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.
  • “paste base” examples 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., al
  • 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%.
  • 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).
  • low compatibility e.g, water and myristine
  • a fat-soluble component that forms an oil phase
  • a component that has the function of maintaining a uniform state and a gel-forming component eg, alginic acid
  • 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, etc.
  • the amount of the “transdermal absorption controlling ingredient” in the preparation is about 0 to 80%.
  • “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%.
  • the “humectant” examples 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%.
  • anti-inflammatory agent examples 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%.
  • adheresive examples 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.
  • 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.
  • 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%.
  • the “support” examples include a polymer film (eg, polyethylene, vinyl acetate copolymer, polyethylene phthalate, etc.), woven fabric, nonwoven fabric, paper, aluminum foil and the like.
  • a polymer film eg, polyethylene, vinyl acetate copolymer, polyethylene phthalate, etc.
  • woven fabric e.g., woven fabric, nonwoven fabric, paper, aluminum foil and the like.
  • 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.
  • 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
  • a color close to a skin color which may be appropriately selected according to race
  • release control film examples include a porous polyethylene film (eg, Hipore manufactured by Asahi Kasei Corporation) and a porous polypropylene film (eg, Duragard manufactured by Polyplastics).
  • the above “paste solvent” examples 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.
  • 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.
  • 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.
  • 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.
  • the paste may be coated or impregnated on a support such as a nonwoven fabric and then transferred to a backing.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the preparation of the present invention 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • the unchanged substance can be efficiently delivered to the brain as in the case of intravenous administration.
  • the dosage can be reduced, and the dosage of idebenone can be adjusted by the application area. Patients can easily take medication.
  • 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.
  • Example 2 (Tape preparation) 40 parts by weight of ethanol
  • 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.
  • Example 3 (Tape preparation) 40 parts by weight of ethanol
  • 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)
  • Styrene block copolymer 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)
  • 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)
  • Example 9 30 parts by weight of ethanol
  • 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.
  • 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.
  • 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%
  • the formulation was secured with a cloth bandage to ensure close contact.
  • 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.

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  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Préparation contenant de l'idébénone pour administration par voie percutanée, efficace pour la prévention et le traitement de la démence et utile pour administrer efficacement et facilement de l'idébénone.
PCT/JP1998/003576 1997-08-12 1998-08-11 Preparation contenant de l'idebenone pour administration par voie percutanee WO1999007355A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU85629/98A AU8562998A (en) 1997-08-12 1998-08-11 Idebenone-containing preparation for percutaneous administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP21774997 1997-08-12
JP9/217749 1997-08-12

Publications (1)

Publication Number Publication Date
WO1999007355A1 true WO1999007355A1 (fr) 1999-02-18

Family

ID=16709155

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/003576 WO1999007355A1 (fr) 1997-08-12 1998-08-11 Preparation contenant de l'idebenone pour administration par voie percutanee

Country Status (2)

Country Link
AU (1) AU8562998A (fr)
WO (1) WO1999007355A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6756045B1 (en) 1999-07-09 2004-06-29 Birgit Neudecker Topically applied idebenone-containing agent with protective and regenerative effect
WO2006100017A1 (fr) 2005-03-21 2006-09-28 Santhera Pharmaceuticals (Schweiz) Ag Derive de quinone 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4- benzoquinone pour le traitement de dystrophies musculaires
EP2108366A1 (fr) 2008-04-09 2009-10-14 Santhera Pharmaceuticals (Schweiz) AG Dérivé de quinone 2,3-dimethoxy-5-méthyl-6-(10-hydroxydecyl)-1,4-benzoquinone pour le traitement des maladies respiratoires dans la dystrophie musculaire
EP2246048A1 (fr) 2009-04-30 2010-11-03 Santhera Pharmaceuticals (Schweiz) AG Dérivé de quinone 2,3-dimethoxy-5-méthyl-6-(10-hydroxydecyl)-1,4-benzoquinone pour le traitement de la sclérose en plaques progressive primaire
WO2021186061A1 (fr) 2020-03-19 2021-09-23 Bemido Sa Idébénone pour le traitement du syndrome de détresse respiratoire aiguë (ards) chez des patients chez lesquels on a diagnostiqué une infection à coronavirus

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5697223A (en) * 1979-12-30 1981-08-05 Takeda Chem Ind Ltd Tissue metabolism activator
EP0377520A2 (fr) * 1989-01-06 1990-07-11 ELAN CORPORATION, Plc Utilisation de la nicotine pour la fabrication d'un kit utilisé dans le traitement des maladies susceptibles de ce traitement
JPH0381218A (ja) * 1989-08-24 1991-04-05 Takeda Chem Ind Ltd 神経成長因子分泌誘導剤
EP0561597A1 (fr) * 1992-03-16 1993-09-22 INDENA S.p.A. Dérivés de physostigmine, leur usage et formulations pharmaceutiques les contenant
JPH0761923A (ja) * 1993-06-18 1995-03-07 Takeda Chem Ind Ltd アルツハイマー病治療剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5697223A (en) * 1979-12-30 1981-08-05 Takeda Chem Ind Ltd Tissue metabolism activator
EP0377520A2 (fr) * 1989-01-06 1990-07-11 ELAN CORPORATION, Plc Utilisation de la nicotine pour la fabrication d'un kit utilisé dans le traitement des maladies susceptibles de ce traitement
JPH0381218A (ja) * 1989-08-24 1991-04-05 Takeda Chem Ind Ltd 神経成長因子分泌誘導剤
EP0561597A1 (fr) * 1992-03-16 1993-09-22 INDENA S.p.A. Dérivés de physostigmine, leur usage et formulations pharmaceutiques les contenant
JPH0761923A (ja) * 1993-06-18 1995-03-07 Takeda Chem Ind Ltd アルツハイマー病治療剤

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6756045B1 (en) 1999-07-09 2004-06-29 Birgit Neudecker Topically applied idebenone-containing agent with protective and regenerative effect
WO2006100017A1 (fr) 2005-03-21 2006-09-28 Santhera Pharmaceuticals (Schweiz) Ag Derive de quinone 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4- benzoquinone pour le traitement de dystrophies musculaires
EP2108366A1 (fr) 2008-04-09 2009-10-14 Santhera Pharmaceuticals (Schweiz) AG Dérivé de quinone 2,3-dimethoxy-5-méthyl-6-(10-hydroxydecyl)-1,4-benzoquinone pour le traitement des maladies respiratoires dans la dystrophie musculaire
EP2246048A1 (fr) 2009-04-30 2010-11-03 Santhera Pharmaceuticals (Schweiz) AG Dérivé de quinone 2,3-dimethoxy-5-méthyl-6-(10-hydroxydecyl)-1,4-benzoquinone pour le traitement de la sclérose en plaques progressive primaire
WO2010124713A1 (fr) 2009-04-30 2010-11-04 Santhera Pharmaceuticals (Schweiz) Ag Dérivé quinone 2,3-diméthoxy-5-méthyl-6-(10-hydroxydécyl)-1,4-benzoquinone pour le traitement d'une sclérose en plaques progressive primaire
WO2021186061A1 (fr) 2020-03-19 2021-09-23 Bemido Sa Idébénone pour le traitement du syndrome de détresse respiratoire aiguë (ards) chez des patients chez lesquels on a diagnostiqué une infection à coronavirus

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Publication number Publication date
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