STABILIZED COMPOSITIONS CONTAINING NOOTROPIC DRUGS

Abstract: The present invention provides a stable composition of an antidementia medicament. Specifically, it is a stabilized composition of an antidementia medicament comprising an antidementia medicament and an organic acid. As the organic acid, tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid, citric acid and the like are particularly preferable.

Description: Field of Industrial Application The present invention relates to a stabilized composition of an antidementia medicament, especially, donepezil and also to a method of stabilizing donepezil. Prior Art Along with the emergence of a recent social problem concerning care of senile dementia, remedies for the senile dementia have been energetically developed. Among these, donepezil has an acetylcholine esterase inhibitory effect and is highly evaluated for its usefulness as a remedy for slight to medium degree of Alzheimer's dementia. Because donepezil is a basic medicament, it is provided as a salt of hydrochloric acid. While, when medicaments are administered to patients, an appropriate dosage form is selected from tablets, capsule agents, powders, granules, ointments, injections, syrups and the like. In pharmaceutical preparations, various ideas are carried out corresponding to each dosage form. For example, percutaneous administration is known as one of the routes of administration to patients to whom chemicals can be orally administered with difficulty. In general, a medicament which is a salt has inferior penetrability into the skin; therefore medicaments are frequently made into a free form to formulate these drugs in percutaneous pharmaceuticals. However, the stability of a medicament differs depending on the state of the medicament such as a salt state and a free state. The state of the medicament sometimes causes a hindrance to pharmaceutical preparations. There is the case where an antidementia medicament, particularly, donepezil becomes unstable to light and/or heat when it is prepared and hence attention must be paid. In view of this situation, the inventors of the present invention have conducted intensive studies to increase the stability to light and/or heat and, as a result, found that the subject can be solved by the following means and completed the present invention. EP- 1 025 858 A1 representing prior art according to Art. 54(3) and (4) EPC describes pharmaceutical compositions comprising donepezil hydrochloride and organic acids such as citric acid and benzoic acid. EP-0 535 645 A2 refers to medicaments useful for the treatment of memory dysfunctions comprising carbamate derivatives of 4-amino-3-isoxazolidinones, 3-amino-1-hydroxpyrrolidin-2-ones and 1-amino-1-cyclopropanecarboxylic acid analogs and pharmaceutically acceptable acid addition salts thereof. EP-0 653 427 A1 refers to galanthamine derivatives and pharmaceutically acceptable acid addition salts thereof for the treatment of memory dysfunctions. US-A-5,177,070 discloses the use of galanthamine and pharmaceutically acceptable salts thereof for the treatment of senile dementia of the Alzheimer type. Finally, WO 97/03987 A reveals citric acid, tartaric acid, mesyllic acid and tosyllic acid for the preparation of pharmaceutically acceptable acid addition salts of compounds used in the treatment of senile dementia of the Alzheimer type. Disclosure of the Invention The present invention refers to a stabilized composition of an antidementia medicament comprising donepezil and an organic acid selected from tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid and citric acid. The present invention also refers to a method of stabilizing an antidementia medicament comprising donepezil by adding an organic acid as specified above to donepezil. The structural formula of donepezil is as follows: Regarding the organic acids, mesyllic acid, salicylic acid and citric acid are preferred. The organic acids may be used singly or by mixing two or more. Citric acid has a particularly excellent effect on the heat stability of donepezil. Although no particular limitation is imposed on the ratio of donepezil to the organic acid, the amount of the organic acid is usually 0.1 to 10 parts by weight, preferably 0.2 to 5 parts by weight and more preferably 0.2 to 2 parts by weight to 1 part by weight of donepezil. The composition of the present invention may be used in a form such as tablets, granules, powders, ointments, injections or syrups. Each form is produced by a conventionally known method. For example, the granules can be produced as follows: the antidementia medicament is mixed with fillers such as lactose, mannitol, corn starch and crystal cellulose, a binder such as hydroxypropyl cellulose and polyvinylpyrrolidone dissolved in a solvent such as water is added thereto, mixed, kneaded and then granulated using an extrusion granulator. The ointments can be used together with the so-called ointment bases such as liquid paraffin, hydrogenated oil, vegetable oil, squalene, higher alcohols, higher fatty acid, esters of higher fatty acid, glycerol, water, antiseptics and dyes, and may be produced by a usually used method. Syrups are prepared by dissolving the antidementia medicament together with a sweetener such as sucrose, xylitol, mannitol and glucose in water. Further, a flavoring agent such as vanilla essence may be added if necessary. According to the present invention, the stability of donepezil is significantly increased. The effects of the present invention will be shown by way of concrete examples. Stabilization Test Examples An ethanol/water (1/1) solution containing 1 mg/ml of donepezil was prepared. Tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid and citric acid are respectively added to the solution in an amount by mol equivalent to donepezil. 5 ml of each resulting solution was sealed in a transparent glass sample. The pH of each resulting solution was 5.74, 5.84, 5.73, 5.89, 5.75 and 3.28. The pH of the solution in the case of adding no organic acid was 5.63. Each glass sample was stored at room temperature under 1000Lux for one month to measure the content. While each same solution was separately stored at a cold place for a month and the content was measured to determine the residual ratio under illumination of light. The content was measured by using high performance liquid chromatography. The results are shown in Table 1. Organic acid Storage condition Outward appearance Peak hight Residual ratio (%) not added cold place - 41367 100.0 121°C,20min - 42946 103.8 1000Lux,1month ++ 35139 84.9 tosyllic acid cold place - 42967 100.0 121°C,20min - 44320 103.2 1000Lux,1month + 41856 97.4 mesyllic acid cold place - 43386 100.0 121°C,20min ± 44202 101.9 1000Lux,1month - 43164 99.5 benzoic acid cold place - 42667 100.0 121°C,20min - 43547 102.1 1000Lux,1month ++ 38813 91.0 salicylic acid cold place - 43075 100.0 121°C,20min - 43814 101.7 1000Lux,1month + 43326 100.6 tartaric acid cold place - 44598 100.0 121°C,20min - 43284 97.1 1000Lux,1month - 42926 96.3 citric acid cold place - 42583 100.0 121°C,20min - 43102 101.2 1000Lux,1month - 42346 99.4 As shown in Table 1, the composition according to the present invention was improved in light stability more significantly than the samples to which nothing was added. The compositions containing each of, particularly, mesyllic acid, salicylic acid and citric acid were considered to be almost not decomposed since no peak of the decomposed materials was observed on a chromatogram. Because percutaneous pharmaceuticals such as ointments are frequently exposed to light after they are applied to the skin, the composition according to the present invention is particularly useful. Next, each of citric acid and maleic acid and as a control, hydrochloric acid and phosphoric acid was added to a 5 mg/5 ml donepezil solution in an amount shown in Table 2 and each resulting solution was stored at 60°C for one month to measure the content. The pH was adjusted to 3.75. The results are shown in Table 2. Organic acid The ratio of the area of impurities on a chromatogram (%) Citric acid 0.22mg 0.07 15mg 0.09 30mg 0.10 45mg 0.10 malic acid 15mg 0.10 Control hydrochloric acid 5mg 0.42 phosphoric acid 15mg 0.43 Further, each of citric acid and as a control, hydrochloric acid was added to a 5 mg/5 ml donepezil solution containing 10% of polyvinylpyrrolidone (PVP) in an amount shown in Table 3 and each resulting solution was stored at 60°C for one month to measure the content. The results are shown in Table 3. Organic acid The ratio of the area of impurities on a chromatogram (%) Citric acid 15mg 1.34 45mg 1.26 Control hydrochloric acid 5mg 2.45 It is clear from Tables 2 and 3 that the composition of the present invention is reduced in the ratio of the area of impurities on a chromatogram of high performance liquid chromatography more significantly than the control sample and is increased in stability also to heat. Examples The present invention will be hereinafter described in more detail by referring to Examples, however the present invention is not limited by them. Example 1 5 g of donepezil, 5 g of tosyllic acid, 150 g of lactose, 200 g of mannitol and 20 g of low-substituted hydroxypropyl cellulose were mixed. To the mixture was gradually added 7 g of hydroxypropyl cellulose dissolved in 50 ml of water, which was then mixed and kneaded. The kneaded mixture was charged into an extrusion granulator to produce a granule. The screen was designed to be 0.4 mm. Example 2 500 mg of donepezil, 200 mg of citric acid and 2000 mg of glucose were dissolved in water for injection. The pH of the solution was adjusted to 5.5 by adding 0.1N sodium hydroxide. Then, water for injection was further added to the solution such that the volume was 100 ml. Each 1 ml of the resulting solution was pipetted into an ample. The ample was melt-closed and then sterilized at 121°C for 15 minutes to produce an injection. Example 3 100 mg of donepezil, 300 mg of sodium saccharate and 50 mg of citric acid were dissolved in 50 ml purified water. The pH of the solution was adjusted to 5.5 by adding 0.1N sodium hydroxide. Then, 300 mg of methyl paraben and 20 mg of propyl paraben which were dissolved in a small amount of propylene glycol were added thereto. Purified water was further added such that the total volume of the resulting solution was 100 ml to produce a syrup.

Claims: A stabilized antidementia medicament composition comprising donepezil and an organic acid selected from tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid and citric acid. A method of stabilizing an antidementia medicament comprising donepezil as an active agent, which comprises the step of adding an organic acid selected from tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid and citric acid to donepezil. The method as claimed in Claim 2, wherein the organic acid is added in an amount of 0.1 to 10 parts by weight to one part of donepezil. Use of a combination of donepezil and an organic acid selected from tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid and citric acid for the preparation of an antidementia medicament composition.

Inventors: ANDO HIDENOBU, HARADA TSUTOMU, KATO AKIRA, MURAHASHI NAOKAZU, SUGAYA YUKIKO, ANDO, HIDENOBU, HARADA, TSUTOMU, KATO, AKIRA, MURAHASHI, NAOKAZU, SUGAYA, YUKIKO
Applicants: EISAI CO LTD, EISAI CO., LTD.
Application year: 1999
Main classification: A61K47
IPC codes: A61K47, A61K31, A61K9, A61P25