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Title:  Percutaneously applicable preparation and suppository containing an antidementia medicament

United States Patent:  6,521,639

Issued:  February 18, 2003

Inventors:  Murahashi; Naokazu (Ibaraki, JP); Kato; Akira (Ibaraki, JP); Sugaya; Yukiko (Ibaraki, JP); Ando; Hidenobu (Gunma, JP)

Assignee:  Eisai Co., Ltd. (Tokyo, JP)

Appl. No.:  628006

Filed:  July 28, 2000

Abstract

The present invention provides a percutaneously applicable preparation containing an antidementia medicament, wherein the antidementia medicament is incorporated a higher alcohol, a lactate of a higher alcohol, an ester of a higher fatty acid and a lower alcohol, or an ester of a fatty acid having 6-18 carbon atoms and propyleneglycol. The present invention also provides a rectum applicable preparation containing an antidementia medicament, wherein the antidementia medicament is incorporated a tiriglyceride of a fatty acid and/or a water-soluble macromolecule.

DETAILED DESCRIPTION OF THE INVENTION

The antidementia medicament in the present invention means prophylactic agents or preventives and therapeutic agents or remedies for dementia such as cerebrovasular dementia and Alzheimer's disease. Specific example thereof can include donepezil, TAK-147, CP118954 revastigmine, metrifonate, galanthamine and the like. Donepezil is generally used in the form of donepezil hydrochloride, as a therapeutic agent for Alzheimer's disease from slight to middle degrees. Chemical name thereof is 1-benzyl-4-(5,6-dimethoxyindanone-2-yl)methylpyperidine. Chemical names of TAK-147 and CP118954 are 3-[1-(phenylmethyl)pyperidine-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepine -8-yl)-1-propane fumarate, and 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-pyperidinyl]ethyl]-6H-pyrrolo[4,5-f]- 1,2-benzisoxazole-6-one maleate, respectively.

A higher alcohol in the present invention means a straight chain or branched, saturated or unsaturated alcohol having 10 or more carbon atoms, and can include, for example, decanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol and the like. Moreover, a lactate of a higher alcohol in the present invention is an ester of the above-mentioned higher alcohol and lactic acid, and can include, for example, myristyl lactate, cetyl lactate, lauryl lactate and the like. The ester of a higher fatty acid and a lower alcohol means an ester of a straight chain or branched, saturated or unsaturated fatty acid having 12 or more carbon atoms and a lower alcohol having 3 or less carbon atoms, and can include, for example, diisopropyl adipate, diethyl sebacate, isopropyl myristate, isopropyl palmitate, and the like. Specific examples of esters of a fatty acid having 6-18 carbon atoms and propyleneglycol in the present invention can include propyleneglycol monocaprylate, propyleneglycol monocaproate, propyleneglycol dicaprylate, and the like. It is available as Cefzol (trade name).

Concerning the mixing ratio of the antidementia medicament to such a substance in the present invention, the substance is in an amount of generally 0.1-10 parts by weight, preferably 0.2-5 parts by weight, and more preferably 0.5-3 parts by weight per part by weight of the antidementia medicament.

The dosage form of the percutaneously applicable preparation according to the present invention is not especially limited, if the dosage form makes application to the skin possible. Examples of the dosage form can include an ointment preparation, a creamy preparation, an adhesive preparation, a lotion preparation, and the like.

In order to prepare these dosage forms, any basis material which is generally used can be used. Examples of an oily basis material can include white Vaseline, purified lanoline, squalane, silicone, fluid paraffin, plant oil, waxes and the like. An aqueous basis material may be water, a lower alcohol, a polyhydric alcohol, a water-soluble macromolecule and the like. The adhesive preparation may be a basis material usually used, examples of which can include, as polymer compositions, ones having adhesiveness such as natural rubber, synthetic rubbers, styrene/isoprene/styrene block copolymers, polyacrylate resins, polyisobutylene resins; and soft polyamide resins, polyvinyl alcohols, polyacrylic resins, and the like. Furthermore, a surfactant, a stabilizer, a preservative or the like may be appropriately incorporated, if necessary. In a conventionally used manner, a percutaneously applicable preparation such as an ointment preparation or an adhesive preparation can be produced. The percentage of the medicament in these percutaneously applicable preparations is usually from 0.1 to 5%.

On the other hand, in the case that the present invention is a rectum applicable preparation, it can be produced by dispersing the medicament into an oily basis such as cacao oil or triglyceride of a fatty acid having from a middle chain to a long chain, or a hydrophilic basis such as macrogol, or the like, in a heating and melting manner or the like. The ratio of the antidementia medicament to the basis is not especially limited. However, the weight of a suppository is usually from 1 to 3 g, and the medicament is contained in an amount of from 0.5 to 50 mg. In general, a rectum applicable preparation is also called a suppository, and according to the form thereof, it can also be administrated into the vagina.

The present invention makes it possible to achieve body circulation of an antidementia medicament that is hardly absorbed from the skin by percutaneous administration thereof, and has an especially great advantage for dementia patients who have difficulty in taking any medicament. It is also a preparation which is excellent in safety since administration can be immediately stopped in the case that an undesired effect is revealed. On the other hand, it is said that in the case of a rectum applicable preparation an absorption rate generally becomes lower than that in the case of oral administration. In spite of it, the rectum applicable preparation has exhibited an increased absorption several times as much as the absorption in the case of oral administration, according to a basis.

Next, the effect of the present invention was confirmed by the following method.

An HWY/S1c male rat (hairless rat) having a body weight of about 300 g (9-10 weekly ages) was put under an anesthetic. After it was checked that its skin had no injuries, the whole of the abdominal skin was stripped off. This was cut into suitable sizes, and then the cut pieces were set to a perpendicular type, in-vitro, diffusing cell having a transmission area of 0.785 cm2. At a receiver side, 3 ml of a pH 7.4 phosphoric acid buffer solution were used. At the donor side, a sample solution described in the following was respectively injected in an amount of 3 ml. Stirring was conducted with stirrers at both sides of the receiver and donor. 200 .mu.l of solutions from the solution at the receptor side were respectively sampled at intervals to determine the quantity of donepezil. The determination of the quantity was performed by high-speed liquid chromatography using an ODS column.

Claim 1 of 5 Claims

What is claimed is:

1. A percutaneously applicable preparation comprising an antidementia medicament and a percutaneous absorption promoter wherein the percutaneous absorption promoter is a lactate of a higher alcohol and wherein the antidementia medicament is donepezil hydrochloride.

 


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