Percutaneously applicable preparation containing donepezil hydrochloride

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.

Description: Field of the Invention The present invention relates to a percutaneously applicable preparation containing an antidementia medicament, a percutaneous absorption promoter for an antidementia medicament, or a rectum applicable preparation. Prior Art Recently, with an increase in old people, sufferers from dementia such as Alzheimer's disease have been increasing. Care thereof and the like have been put into social problems. On the other hand, the development of therapeutic medicaments of dementia has rapidly advanced. For example, donepezil hydrochloride has been widely used as a therapeutic medicament for Alzheimer's disease, from slight to middle degrees, which has acetylcholine esterase inhibiting activity. Hitherto, in many cases these therapeutic medicaments for dementia have orally been administered in the form of a tablet or the like. As manners for administering a medicament to a patient or the like, there are known percutaneous administration, injection administration, rectum administration and the like, as well as oral administration in the form of a tablet, a capsule, a syrup, a granule, and the like. A suitable manner is selected dependently on the disease thereof and the nature of the medicament. There may be cases in which it becomes difficult to take an antidementia medicament orally when the condition of dementia gets worse because a dementia patient takes the medicament. Therefore, it is especially useful to administrate the medicament percutaneously in the form of an ointment or the like, in the case of a patient whose condition gets worse. However, in general the skin cannot be penetrated by medicaments, and thus it is difficult to cause a sufficiently efficacious amount to be absorbed from the skin into the body. In order to overcome such difficulty, researches have been so far made on many percutaneous absorption promoters. However, their effects vary dependently on medicaments, and thus it is very difficult to predict percutaneous absorption of a specific medicament from past data. Moriearty PL in CNS Drugs vol. 4 nr. 5 p.323-334 (1995) discloses transdermal delivery of cholinesterase inhibitors. As other administration dosage form than oral administration, a rectum applicable preparation can be proposed. The rectum applicable preparation is also called a suppository, and is a preparation that a solid medicament is inserted from the anus to cause the medicament to be absorbed into the rectum. The design for the preparation needs to be conducted considering complex factors such as physical chemistry properties of the medicament, reactivity with a basis, and the like. Thus, it is difficult to produce an optimum rectum applicable preparation by only expansion of the prior art. Disclosure of the Invention The present invention is a percutaneously applicable preparation containing donepezil HCl. The present invention is a percutaneously applicable preparation containing donepezil HCl, 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 is also a percutaneous absorption promoter for an antidementia medicament, which is selected from a higher alcohol, a lactate of a higher alcohol, an ester of a higher fatty acid and a lower alcohol and an ester of a fatty acid having 6 - 18 carbon atoms and propyleneglycol. The present invention is a method of promoting a percutaneous absorption of an antidementia medicament, which comprises administering donepezil HCl to a person suffering from dementia either percutaneously, together with at least one selected from a higher alcohol, a lactate of a higher alcohol, an ester of a higher fatty acid and a lower alcohol, and an ester of a fatty acid having 6-18 carbon atoms and propyleneglycol, and use of donepezil HCl for manufacturing the preparation as defined above. Detailed Description of the Invention The antidementia medicament in the present invention means donepezil hydrochloride. The structural formulae of this compound is as follows. 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 donepezil HCl 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%. 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. 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 300g (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 0.785cm 2 . At a receiver side, 3ml 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 3ml. Stirring was conducted with stirrers at both sides of the receiver and donor. 200 µl 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. Brief Description of the Drawings Fig. 1 is a graph showing an effect that 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 has on skin permeability of the medicament. Fig. 2 is a graph showing an effect that a higher alcohol has on skin permeability of the medicament. Fig. 3 is a graph showing an effect that an ester lactate of a higher alcohol has on skin permeability of the medicament. Preparation of the sample solution To 90ml of propyleneglycol were added 5ml of purified water, and then 5 g of donepezil hydrochloride were added to the mixture and stirred. To this suspension was added dropwise 4N NaOH, and then pH of the mixture was adjusted to pH 7. Next, distilled water was added to the mixture so that the total volume would be 100ml. Thus, a donepezil hydrochloride /propyleneglycol solution (referred to as solution A, hereinafter) was prepared. Comparative sample 1: 2ml of propyleneglycol were added to 8ml of the solution A to prepare a sample. The present invention sample 1: 1.7ml of propyleneglycol and 0.3ml of propyleneglycol monocaprylate (Trade name: Cefzol 218) were added to 8ml of the solution A to prepare a sample. The present invention sample 2: 1.7ml of propyleneglycol and 0.3ml of diisopropyl adipate were added to 8 ml of the solution A to prepare a sample. The present invention sample 3: 1.7ml of propyleneglycol and 0.3ml of isopropyl myristate were added to 8ml of the solution A to prepare a sample. The present invention sample 4: 1.7ml of propyleneglycol and 0.3ml of diethyl sebacate were added to 8ml of the solution A to prepare a sample. The present invention sample 5: 1.7ml of propyleneglycol and 0.3ml of isopropyl palmitate were added to 8 ml of the solution A to prepare a sample. The present invention sample 6: 1.7ml of propyleneglycol and 0.3ml of decanol were added to 8 ml of the solution A to prepare a sample. The present invention sample 7: 1.7ml of propyleneglycol and 0.3ml of lauryl alcohol were added to 8ml of the solution A to prepare a sample. The present invention sample 8: 1.7ml of propyleneglycol and 0.3ml of myristyl alcohol were added to 8ml of the solution A to prepare a sample. The present invention sample 9: 1.7ml of propyleneglycol and 0.3ml of melted cetyl alcohol were added to 8ml of the solution A to prepare a sample. The present invention sample 10: 1.7ml of propyleneglycol and 0.3ml of stearyl alcohol were added to 8ml of the solution A to prepare a sample. The present invention sample 11: 1.7ml of propyleneglycol and 0.3ml of melted myristyl lactate were added to 8 ml of the solution A to prepare a sample. The present invention sample 12: 1.7ml of propyleneglycol and 0.3ml of cetyl lactate were added to 8ml of the solution A to prepare a sample. The results are shown in Figs. 1 to 3. From the figures, it is evident that the percutaneously applicable preparation according to the present invention causes the skin permeability of the medicament to remarkably increase. Examples The following will describe the present invention in detail referring to Examples, but the present invention is not limited to these Examples. Example 1 Propyleneglycol was heated to 60°C and then donepezil hydrochloride was added thereto and dispersed and dissolved therein. To the mixture, was added a mixture of cetyl lactate and Plastibase (trade name) which were beforehand heated to 60°C. The mixture was cooled to room temperature while being stirred, so as to obtain an oily ointment preparation having the following composition. Donepezil hydrochloride 5% by weight Cetyl lactate 10 Propyleneglycol 15 Plastibase 70 Example 2 Donepezil hydrochloride was added to myristyl lactate and dispersed therein. On the other hand, sorbitantrioleate and white Vaseline were heated to 60°C and then were uniformly mixed. To this, the above-mentioned stirred homogenous product of myristyl lactate and donepezil hydrochloride was added. The whole amount thereof was homogeneously stirred and mixed, and then was cooled to room temperature, so as to obtain an oily ointment having the following composition. Donepezil hydrochloride 1.5% by weight Myristyl lactate 5% by weight Sorbitantrioleate 3% by weight White Vaseline 90.5% by weight Example 3 Lauryl alcohol, polyoxyethylene (20) sorbitan monooleate, the Japanese Pharmacopoeia macrogol ointment and a preservative were heated to 60°C and then were homogeneously mixed. Thereafter, donepezil hydrochloride was added to the mixture and then the resultant mixture was sufficiently mixed while being cooled, so as to obtain a hydrophilic ointment having the following composition. Donepezil hydrochloride 2% by weight Lauryl alcohol 3% by weight Polyoxyethylene (20) sorbitan monooleate 2% by weight The Japanese Pharmacopoeia macrogol ointment 92.9% by weight Preservative (methylparaben) 0.1% by weight Example 4 Squalane, isopropyl myristate, stearic acid, monoglyceride stearate, sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate and myristyl lactate were heated to 70°C and then were homogeneously dissolved. Donepezil hydrochloride was added to the mixture and then the resultant mixture was stirred to be homogenous. To the mixture were gradually added propyleneglycol, a preservative agent and purified water that were separately heated to 60°C. The resultant mixture was cooled to about 30°C while being stirred, so as to obtain an O/W type creamy preparation having the following composition. Donepezil hydrochloride 2% by weight Squalane 8% by weight Isopropyl myristate 4% by weight Stearic acid 4% by weight Monoglyceride stearate 4% by weight Sorbitan palmitate 1.5% by weight polyoxyethylene (20) sorbitan monostearate 0.5% by weight Myristyl lactate 5% by weight Propyleneglycol 5% by weight Preservative (methylparaben) 0.1% by weight

Claims: A percutaneously applicable preparation comprising donepezil hydrochloride and at least one selected from the group consisting of a higher alcohol, a lactate of a higher alcohol, an ester of a higher fatty acid and a lower alcohol and an ester of a fatty acid having 6-18 carbon atoms and propyleneglycol. The preparation as claimed in Claim 1, wherein the higher alcohol is a straight chain or branched, saturated or unsaturated alcohol having 10 or more carbon atoms. The preparation as claimed in Claim 1, wherein the higher alcohol is at least one selected from the group consisting of decanol, lauryl alcohol, myristyl alcohol, cetyl alcohol and stearyl alcohol. The preparation as claimed in Claim 1, wherein the lactate of the higher alcohol is at least one selected from the group consisting of myristyl lactate, cetyl lactate and lauryl lactate. The preparation as claimed in Claim 1, wherein the ester of the higher fatty acid and the lower alcohol is at least one selected from the group consisting of diisopropyl adipate, diethyl sebacate, isopropyl myristate and isopropyl palmitate. The preparation as claimed in Claim 1, wherein the ester of the fatty acid having 6-18 carbon atoms and propyleneglycol is at least one selected from the group consisting of propyleneglycol monocaprylate, propyleneglycol monocaproate and propyleneglycol dicaprylate. Use of donepezil hydrochloride for manufacturing a percutaneously applicable preparation (according to any one of claims 1-6) for the treatment of dementia.

Inventors: ANDO HIDENOBU, KATO AKIRA, MURAHASHI NAOKAZU, SUGAYA YUKIKO, ANDO, HIDENOBU, KATO, AKIRA, MURAHASHI, NAOKAZU, SUGAYA, YUKIKO
Applicants: EISAI CO LTD, EISAI CO., LTD.
Application year: 1999
Main classification: A61K9
IPC codes: A61K9, A61K47