JPH10338631A - Anti-anxiety agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent extremely effective to improve and treat uneasy nerve syndromes and related diseases generated by psychogenic disturbance. SOLUTION: This agent is obtained by including magnolol or a pharmaceutically acceptable salt thereof and/or honokiaol or a pharmaceutically acceptable salt thereof as an active ingredient, both of which have an anti-anxiety effect at an administration amount much smaller than that which generates a calmative action but does not have any side effect which benzodiazepin-based anti- anxiety agent have, and are hence extremely safe.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel anxiolytic agent which is a therapeutic agent for anxiety and related diseases.

[0002]

2. Description of the Related Art The general clinical effect of anxiolytic drugs is that they cause anxiety and nervousness as a psychogenic disorder that causes neurosis and psychosomatic disorders, and do not cause sleepiness or decreased consciousness. It is intended to alleviate and improve in quantity. Currently, benzodiazepines are widely used in clinical practice as anxiolytics, but side effects such as physical dependence and central muscle relaxation by the drugs have been pointed out as serious problems.

[0003] That is, in the treatment of patients with anxiety such as neurosis in the foreground, benzodiazepines are used as an auxiliary means, and although it is desirable to use the minimum required amount in the shortest possible period, Increasing reports of drug dependence, abuse, and long-term indifference have been reported. Therefore, there is a need for a drug that does not exhibit side effects such as a hypnotic action and a muscle relaxing action, as well as amnesia, tolerance, dependence, and the like.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug which does not exhibit the side effects of conventional anxiolytic drugs and has an excellent anxiolytic effect.

[0005]

Means for Solving the Problems The present inventors have searched for active ingredients for the action from Saiboku-to, a Chinese herbal preparation having an anxiolytic action, and found that magnolol and honokiol contained in the preparation were: It was found to be the active substance. These are 2,000- to 5,000-fold more potent than Saiboku-to, and have no side effects (effects such as muscle relaxation, sedation, hypnosis, dependence, and amnesia) of benzodiazepine drugs within the effective amount. Was found.

That is, the present invention relates to magnolol or a pharmaceutically acceptable salt thereof and / or honokiol or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the active ingredient of the present invention”) as an active ingredient. It is intended to provide an anxiolytic agent characterized by containing.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Magnolol (Magnolol) used as an active ingredient in the anxiolytic of the present invention
l) is 5,5'-di-2-propenyl- [1,1 '
-Biphenyl] -2,2'-diol, and honokiol is 3 ', 5-di-2-propenyl- [1,1'-biphenyl] -2,4'-diol.

These may be those fractionated and purified from Saiboku-to, but may be present in other natural products, and may be separated and purified from them as a single product, or may be commercially available. May be used.

In order to prepare the anxiolytic agent of the present invention, the active ingredient of the present invention is formulated as it is or together with a conventional pharmaceutical carrier, and tablets, capsules, granules, fine granules, powders,
Oral preparations such as liquid preparations and parenteral preparations such as injection preparations, drops and suppositories may be used.

In order to exhibit the desired effect as an oral preparation, it depends on the age, weight and degree of the disease of the patient.
It is appropriate to take g several times a day.

[0011] Pharmaceutical carriers can be selected according to the administration form and dosage form. In the case of oral preparations, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like are used. It is manufactured according to the usual method. In addition, in preparing an oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter,
Flavoring agents, coloring agents, fragrances and the like can be added. Specific examples thereof include the following.

(Binder) starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol. (Disintegrant) Starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose.

(Surfactant) sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80. (Lubricant) Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

(Fluidity promoter) Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate. In addition, suspensions,
They can also be administered as emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents.

[0015] On the other hand, in order to exhibit the desired effect as a parenteral preparation, it depends on the age, weight and degree of disease of the patient. It is suitable to administer by intravenous injection, intravenous injection by drip, subcutaneous injection, intramuscular injection or the like up to 1 g.

This parenteral preparation is produced according to a conventional method,
As the diluent, 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 and the like can be generally used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added.

Also, from the viewpoint of stability, this parenteral preparation can be frozen after filling into a vial or the like, water is 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, a tonicity agent,
Stabilizers, preservatives, soothing agents and the like may be added. Examples of other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, and are produced according to a conventional method.

[0018]

The anxiolytic agent of the present invention exhibits an excellent anxiolytic effect as shown in the test examples described later. In addition, the active ingredients of the present invention are all known to be contained in crude drugs such as Koboku and the like. For example, oral administration of 0.1 to 100 mg / kg to mice for 3 consecutive weeks As is clear from the fact that no deaths were observed, the safety is high. At the same time, it does not show any side effects (dependence, tolerance) seen with benzodiazepines, so it is an extremely safe drug.

Therefore, according to the anxiolytic of the present invention, anxiety can be removed without causing side effects, and therefore, it is extremely advantageous as an anxiolytic. Furthermore, since the active ingredient of the present invention has an effect of enhancing a benzodiazepine drug, it is possible to reduce the dose of the benzodiazepine drug by taking the active ingredient at the same time.

[0020]

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Experimental Example 1 Anti-anxiety effect of honokiol and magnolol In this experiment, the anxiolytic effect was examined by an elevated plus maze experiment and a locomotor activity measurement experiment.

(1) Experimental animals For the experiments, ddY male mice (Nippon Medical Science Research Institute)
Was used. Mice were purchased at the age of 6 weeks, and then caged with polycarbonate (30 wood floors).
(W) × 20 (D) × 15 (H) cm) within 10-11
Each animal was bred with solid feed (MF: Oriental yeast) and tap water. The environment inside the animal breeding room is 14 hours light: 10 hours dark (artificial lighting; 5 am to 7 pm),
Room temperature was adjusted to 22 ± 2 ° C. and humidity to 50 ± 2%.

(2) Experimental apparatus Elevated cross maze apparatus: two closed arms and two open arms orthogonal to each other (each 6 (W) × 30)
(L) cm) and a platform (9 × 9 cm) where they intersect. The closed arms have black opaque side walls (10 (H) cm) and the floor is gray opaque. The open arms have no side walls and the floor is transparent. The platform floor is gray opaque.
This device was installed at a height of 40 cm.

Spontaneous locomotion measuring apparatus: Measured with a Gunma University-type ambulometer (AMB-10; Ohara Medical Industry) having an acrylic resin measuring cage having a diameter of 20 cm. This device uses a microswitch to record minute vibrations of the measuring cage caused only by the horizontal movement (relocation movement) of the mouse. The feature is that no turning movement is recorded.

(3) Administration method Drug administration is performed using a solvent (distilled water containing 1% Tween-80) and honokiol (0.19 and 0.38 mg / k).
g) and magnolol (0.49 and 0.98 mg)
/ Kg) was orally administered once a day for 7 days, and the above measurement experiment was performed on the day after the final administration. The mice were placed on the central maze platform and the cumulative time spent in the open arm for 5 minutes was measured. Immediately after the completion of the elevated plus maze experiment, the locomotor activity of the mice was measured with an ambulometer for 5 minutes.

When the general activity is significantly affected by the drug, the chance level of the shift to the open arm changes, and there is a risk of being mistaken for a change in the anxiolytic effect. Changes in locomotor activity due to the administration of the above drugs were also studied. Table 1 shows the results.

[0027]

[Table 1]

As is apparent from the results, a significant anxiolytic effect was observed. In addition, no significant change in spontaneous exercise was observed, indicating that the determination of the anxiolytic effect was not hindered. During this experiment, benzodiazepine-based anxiolytic drugs did not show any behavioral changes and symptoms (particularly muscle relaxation, sedation / hypnosis, etc.) that were visually observed without exception.

Example 1 Tablet: An anxiolytic (tablet) was produced by the following formulation and manufacturing method. [Prescription] Dextrin 40 g Crystalline cellulose 20 g Carboxymethylcellulose calcium 5 g Polyethylene glycol 6000 5 g Honokiol 30 g Total 100 g [Production method] According to the above-mentioned formula, are mixed uniformly and compression-molded with a tablet machine to obtain one tablet of 100 mg. Was. One tablet contains 30 mg of honokiol, and 1 to 20 tablets per day for adults are divided into several doses.

Example 2 Granules: An anxiolytic (granule) was produced according to the following formulation and production method. [Prescription] Dextrin 82 g Polyethylene glycol 6000 2.5 g Carboxymethylcellulose calcium 5 g Light anhydrous silicic acid 0.5 g Magnolol 10 g Total 100 g [Production method] After mixing uniformly according to the above-mentioned prescription, compression molding is performed by a compression molding machine. It was pulverized by a crusher and sieved to obtain granules. 1 g of this granule contains 1 magnolol
It contains 00mg, and adults take 0.3 to 6g a day in several doses.

Example 3 Capsules: An anxiolytic (capsule) was produced according to the following formulation and manufacturing method. [Manufacturing method] According to the above-mentioned formula, is mixed uniformly,
00 mg was filled into a No. 2 capsule. This capsule 1
The capsule contains 20 mg of honokiol, and the adult takes 1 to 30 capsules a day in several doses.

Example 4 Injection: An anxiolytic (injection) was produced according to the following formulation and production method. [Preparation method] Dissolve and according to the above formula,
The resulting solution was added to and emulsified to obtain an injection.

Claims (1)

[Claims] 1. An anxiolytic agent comprising as an active ingredient magnolol or a pharmaceutically acceptable salt thereof and / or honokiol or a pharmaceutically acceptable salt thereof.