JP2002275061A - Antidepressant.antianxiety agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antidepressant and an antianxiety agent by identifying an active component of a plant of the family Lamiacetae participating in the development of antidepressing action and antianxiety action and using an extract of a plant such as beefsteak plant as an active component. SOLUTION: The antidepressant and antianxiety agent contain rosmarinic acid as an active component.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an antidepressant and an anxiolytic.

[0002]

2. Description of the Related Art Lamiaceae plants have been medicated for a long time, but perilla is a herbal medicine that has been used for a long time and is described in the name of Su in Chinese foods of Nanabe. Kin Kampo is used in Chinese herbs, such as Shiboku-yu (this morning's experience), Mysterious hot water (Saidai's secret), Koso-san (Japanese medicine pharmacy), and Sanso drinking (Japanese medicine pharmacy). It is one of the essential drugs. According to the famous doctor's separate book, "Be careful, except the cold, warm the inside,"
It is mainly used for bronchitis with neurological symptoms, fever due to qi's balance, headache, cough, etc. Its pharmacological action has long been used as a soothing agent as a tranquilizer, and is sometimes known as a light stimulant. And the perylaldehyde (perilla) which is an aroma component of the aqueous extract and the essential oil.
Studies have also been conducted on the effect of ldehide on the nervous system (Pharmaceutical Journal 101 (7) 642-648).
(1981)).

According to such research reports, perilaldehyde has not been shown to act as a gas-suppressing effect as an inhibitory effect on the momentum of rats, and therefore, the effect of perilla as a gas-suppressing agent is a mixture of several components. It is concluded that the effect of perylaldehyde appears to be an effect, in addition to the synergistic effect caused by perylaldehyde.

[0004]

As mentioned above, although perilla has been used as a tranquilizer or a mild stimulant in terms of herbal medicine, antidepressants and anxiolytic agents have been used. The efficacy of the drug as a drug has not been elucidated, and much research has not been conducted on what components of perilla have antidepressant and anxiolytic effects.

Accordingly, an object of the present invention is to elucidate an active ingredient involved in the expression of an antidepressant action and an anxiolytic action of a Labiatae plant, and to provide an antidepressant and an anxiolytic agent comprising a plant extract such as perilla as an active ingredient. Is to provide.

[0006]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have compared the effects of various perilla extraction fractions on mice, and found that they have an antidepressant effect on the rosmarinic acid-rich fraction. They found that they had an anxiolytic effect, and completed the present invention.

[0007] That is, the present invention is an antidepressant comprising rosmarinic acid as an active ingredient.

[0008] The present invention is also an anti-anxiety agent comprising rosmarinic acid as an active ingredient.

[0009] The antidepressant and anxiolytic of the present invention may be a plant extract containing rosmarinic acid, and a rosmarinic acid-containing plant soluble in water and / or a polar organic solvent as an active ingredient. The effect of can be obtained. Here, the rosmarinic acid-containing plant is not particularly limited, but is preferably a perilla, a moray eel, a persimmon, a oyster, a cypress, a kawamidori, a kasou, a rensenso, an emisoso, a sage,
Oregano, thyme, basil, majorana, lemongrass,
It can be suitably selected from the group consisting of rosemary, peppermint, and mint.

Rosmarinic acid contained in rosmarinic acid-containing plants such as perilla is represented by the following formula: It is a compound represented by these.

Rosmarinic acid has an antioxidant effect (Hegn
auer, R.:"Chemotaxonomie der Pflanzen, "Birk-hause
r Verlag, Basel, Stuttgart, Bd. 4, p327-8, 1966), as well as anti-inflammatory effects (Wirtz-Peitz, F. et al .: Rosmarinic
acid-phospolipid complex.Ger. 2952115, 1981 [Chem.
Abstr. 95, 192388p, 1981]), and it is believed that the effects of various perilla combinations on various inflammations and asthma may involve rosmarinic acid.
In addition, it has been reported that rosmarinic acid is involved as a vegetable and herb inhibitory active substance against the enzyme hyaluronidase which increases vascular permeability during inflammation and participates in allergic reactions (hyaluronidase inhibitory action of vegetables and herbs. Journal of the Japanese Society of Agricultural Chemistry, 73 (extra edition), 1
38, 1999). However, it has been found for the first time in the present invention that rosmarinic acid is an active ingredient involved in the expression of an antidepressant action and an anxiolytic action.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The dosage and formulation of the antidepressant and anxiolytic of the present invention will be described. The antidepressant and anxiolytic of the present invention may be used pure rosmarinic acid as it is, but a water-soluble fraction of a rosmarinic acid-containing plant,
A soluble fraction in a polar organic solvent or a mixed solvent of a polar organic solvent and water may be contained as an active ingredient. In the fractionation from the water extract with a polar organic solvent-water mixed solvent,
Preferably polar organic solvent: water 20-80: 80-20
(Capacity ratio). Further, the polar organic solvent is preferably methanol or ethanol.

The rosmarinic acid-containing plant is not particularly limited, but is preferably a perilla, a moray eel, an oyster, a scallop, a sprouts, a kawamidori, a kagosou, a rensenso, an emisoso, a sage, an oregano,
It is a plant selected from the group consisting of thyme, basil, majorana, lemongrass, rosemary, peppermint, and gypsophila, more preferably perilla.

The rosmarinic acid, the water-soluble fraction of a rosmarinic acid-containing plant, or the soluble fraction in an ethanol-water mixed solvent can be administered as it is or together with a conventional pharmaceutical carrier. The administration form is not particularly limited and is appropriately selected as needed. Examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, and parenteral preparations such as injections and suppositories. .

In order to obtain the desired effect as an oral preparation, it is usually appropriate to take 0.1 to 10 mg of rosmarinic acid several times a day for adults, depending on the age, weight and degree of disease of the patient. It is.

In the present invention, oral preparations such as tablets, capsules, granules and the like can be produced by a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, constarch, inorganic salts and the like.

In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavor, and the like are appropriately used in addition to the above-mentioned excipients. Can be.
Specific examples are shown below.

Examples of the binder include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone,
Macro goals can be used.

As a disintegrant, starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose and the like can be used.

As the surfactant, sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate and the like can be used.

As the lubricant, talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol and the like can be used.

Examples of the fluidity promoter include light anhydrous silicic acid,
Dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like can be used.

The antidepressant of the present invention can also be administered as a suspension, emulsion, syrup, or elixir. These various dosage forms contain a flavoring agent and a coloring agent. You may.

Rosmarinic acid, a water-soluble fraction of a rosmarinic acid-containing plant, or a polar organic solvent or a polar organic solvent
In order to obtain the intended effect using a soluble fraction in a water-mixed solvent as a parenteral drug, the age of the patient, the body weight, although it depends on the degree of the disease, usually 0.01 to 1 mg of rosmarinic acid in an adult.
Intravenous, intravenous, subcutaneous, and intramuscular injections are appropriate.

This parenteral preparation is produced according to a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation can be frozen after filling into a vial or the like, water can be removed by a usual freeze-drying technique, and a liquid preparation can be prepared from the freeze-dried product immediately before use. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, and are prepared according to a conventional method.

[0027]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be specifically described below based on embodiments. (Antidepressant) The various perilla extract fractions (A to D, F) and rosmarinic acid (E) shown in FIG. 1 and below are each dissolved in distilled water, and then an antidepressant effect confirmation test shown below is performed. 1 hour before the test session, the mice were orally administered to a mouse depression model (ICR male mice (body weight: 30 to 35 g; Charles River Japan)) at the dosages shown in FIGS. The effects were compared. In addition, FIG.
7. In D.7, W. Indicates distilled water, and DSP indicates desipramine. Further, each column is S.P. E. FIG. The mean by M is shown, * P <0.05, ** P <0.01 (vs. distilled water control).

A. Perilla water extract B. Perilla water extract elution part C.I. Perilla water extract water-methanol (50/50) elution part Part of perilla water extract methanol elution Rosmarinic acid (pure) F. C water-methanol (70/30) elution part

The test for confirming the antidepressant development effect was performed in a water tank (diameter 1).
9cm, height 25cm, water depth 15cm, water temperature 24 ± 1
° C) by a forced swimming test. The forced swimming test was performed in two sessions, a conditioning session and a test session. In the conditioning session, mice were subjected to a 15 minute forced swim in the aquarium, and the test session was transferred 24 hours later. In the test session, put the mouse in the water tank again and set the immobility time to Super Mex (Muromachi Kikai Co., Ltd.)
For 5 minutes. The measured immobility time data are shown as the mean ± standard error, and the one-way analysis of variance and Dunnet's test
nett's test).

2 to 7 showing the obtained results, perilla water extract (A) (FIG. 2), perilla water extract water / methanol (50/50) elution part (C) (FIG. 4) And C showed significant effects in the water-methanol (70/30) eluted part (F) (FIG. 7). In addition, a significant effect was also observed in rosmarinic acid pure product (E) (FIG. 6), which is a main component of the perilla water extract 50% methanol elution part.

On the other hand, the perilla water extract water elution part (B)
(FIG. 3), the perilla water extract methanol elution part (D) (FIG. 5) did not show a significant effect.

(Anxiolytic) Rosmarinic acid was dissolved in physiological saline, and then 30 minutes before the test session of the fear conditioning stress test shown below, the ddY male mouse ( (Body weight: 30 to 35 g: Tokyo experimental animal) was administered intraperitoneally, and its anxiolytic effect was compared with that of administration of physiological saline alone. In FIG. 8, each column shows the S.M. E. FIG. Mean values by M are shown, * P <0.05 (vs saline control).

As an experimental device for the fear conditioning stress test, a wooden box with a stainless steel grid floor connected to an electric shock foot shock stimulator (30 cm in length, 25 cm in height, divided into three sections) was used. The test was conducted in a conditioning session and a test session. In the conditioning session, mice were loaded with a 6 minute electric shock stress stimulus (1.2 mA at 10 second intervals for 1 second) in the device,
After 24 hours, the test session was started. In the test session, the mouse was put into the apparatus again, and the immobility time was measured for 6 minutes with Supermex (Muromachi Kikai Co., Ltd.). The measured data were shown as mean ± standard error, and a one-way analysis of variance and Dunnett's test were used for a statistically significant difference test with the symmetric group.

As is clear from FIG. 8 showing the obtained results, the administration of rosmarinic acid showed a significant effect on anxiety resolution.

[0035]

As described above, the antidepressants and anxiolytics of the present invention exhibit good antidepressant and anxiolytic effects by using rosmarinic acid as an active ingredient.

[Brief description of the drawings]

FIG. 1 is a flowchart showing a perilla extraction process.

FIG. 2 is a graph showing the results of a forced swimming test of perilla water extract (A).

FIG. 3 is a graph showing the results of a forced swimming test of a perilla water extract water elution portion (B).

FIG. 4 is a graph showing the results of a forced swimming test of a perilla water extract water / methanol (50/50) elution part (C).

FIG. 5 is a graph showing the results of a forced swimming test of a perilla water extract methanol elution part (D).

FIG. 6 is a graph showing the results of a forced swimming test of rosmarinic acid (pure product) (E).

FIG. 7 is a graph showing a forced swimming test result of a water-methanol (70/30) elution part (F) of C.

FIG. 8 is a graph showing the results of a fear conditioning stress test for rosmarinic acid.

Continued on the front page (72) Inventor Masaaki Hayashi 6-1-1 Shinjuku, Shinjuku-ku, Tokyo Tokyo Medical University Pharmacology Department (72) Inventor Masato Inatsu 6-1-1 Shinjuku, Shinjuku-ku, Tokyo Tokyo Medical University Pharmacology Course (72) Inventor Tomoko Yamada 6-1-1 Shinjuku, Shinjuku-ku, Tokyo Tokyo Medical University Pharmacology Course (72) Inventor Junichi Miyamoto 6-1-1 Shinjuku, Shinjuku-ku, Tokyo Tokyo Medical University Pharmacology Department (72) Inventor Teruhiko Matsumiya 6-1-1 Shinjuku, Shinjuku-ku, Tokyo Tokyo Medical University Pharmacology Department F-term (reference) 4C088 AB38 AC01 BA08 CA08 MA52 NA14 ZA05 ZA12 4C206 AA01 DA21 DB20 MA05 MA72 NA14 ZA05 ZA12

Claims (4)

[Claims] 1. An antidepressant comprising rosmarinic acid as an active ingredient. 2. The antidepressant according to claim 1, wherein a soluble fraction of a rosmarinic acid-containing plant in water and / or a polar organic solvent is an active ingredient. 3. An anxiolytic agent comprising rosmarinic acid as an active ingredient. 4. The anti-anxiety agent according to claim 3, wherein a soluble fraction of a rosmarinic acid-containing plant in water and / or a polar organic solvent is used as an active ingredient.