JPH07165569A - Ameliorant for cerebral function - Google Patents

Abstract

PURPOSE:To obtain an ameliorant for cerebral functions, containing ephedrine as an active ingredient and having cerebral neuron protecting actions and high safety. CONSTITUTION:This ameliorant for the cerebral functions contains ephedrine or its salt (e.g. l-ephedrine) or Ephedra sinica which is a plant containing the ephedrine or its extract as an active ingredient. The ameliorant is useful as a therapeutic agent for cerebral angiopathy for mental, nervous and subjective symptoms, activity disorder in daily living, etc. The ameliorant can be prepared as an oral agent such as a tablet, a capsule, a granule, a fine granule or a powder or a parenteral agent such as an injection or a suppository. The daily dose thereof for an adult is 2.5-25mg (the dose is twice in the case of dl- ephedrine hydrochloride) expressed in terms of U-ephedrine hydrochloride at a time administered 1-3 times in the case of the oral agent and 25-40mg (40mg in the case of dl-ephedrine hydrochloride) at a time in the case of the injection. When the active ingredient is the Ephedra sinica or its extract, the dose for an adult is 1.5-9g as the active ingredient and orally administered in several portions.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for improving brain function, which comprises ephedrine or a salt thereof, a plant containing the same, or an extract thereof as an active ingredient.

[0002]

2. Description of the Related Art Although the mortality rate due to stroke has decreased due to recent advances in emergency medical care and blood pressure control, cerebrovascular disorders that inevitably lead to long-term sequelae after onset remain a life threatening disease. With the rapid aging of population, it is desired to develop a drug that can protect nerve cells from ischemia more safely and effectively.

On the other hand, mahuang is the rhizome of Ephedra sinica Staph or other plants of the same genus (Ephedraceae) and has been used as an antitussive and expectorant drug for a long time. In addition, ephedrine is known as the main component of mahuang, sympathomimetic action,
It has central excitatory action, bronchodilator action, anti-inflammatory action, etc.,
It is used as a sympathomimetic, bronchodilator, pressor, and local vasoconstrictor.

[0004] However, there is no case where mahuang or its extract or ephedrine has been used as a cerebral function improving agent for the treatment of cerebrovascular disorders and the like.

[0005]

An object of the present invention is to provide a brain function improving agent which is highly safe and has a cerebral nerve cell protecting effect.

[0006]

It is well known that nerve cells that control the functions of the central nervous system easily undergo necrosis due to ischemia or oxygen deficiency. As a result of a search for effective drugs using the protection of hippocampal CA1 cells showing extremely high sensitivity as an index, it was found that ephedrine or a crude drug containing the same or an extract thereof has a cerebral nerve cell protective effect, and based on this finding, The invention was completed.

That is, the present invention is a brain function improving agent containing ephedrine or a salt thereof, or mahuang or an extract thereof as an active ingredient. In the present invention, ephedrine includes l-ephedrine, d-ephedrine, d
Any of 1-ephedrine, 1-pseudoephedrine, d-pseudoephedrine, and dl-pseudoephedrine may be used, but 1-ephedrine is particularly preferable, and the hydrochloride is preferable as the salt.

The active ingredient of the brain function-improving agent of the present invention is not particularly limited as long as it contains ephedrine or a salt thereof. For example, the compound itself of ephedrine or a salt thereof or a plant containing them, mahuang or The extract is mentioned. Further, a crude drug containing ephedrine other than mahuang or a salt thereof or an extract thereof may be used. Further, a mixed crude drug containing mahuang as a constituent crude drug or an extract thereof may be used.

Examples of the crude drug extract include various aqueous solvent extracts, and it is preferable to use a water extract. As a concrete example of preparation of the extract,
An example is a method of extracting with ~ 20 times the amount of hot water and filtering the resulting extract. This extract can be dried if necessary and used as a dry powder. Among the active ingredients of the present invention, specific examples of the production of mahuang extract are shown below.

Concrete Example 1 To 24 g of Hemp yellow, 240 ml of distilled water was added and decocted until the amount became half, the obtained extract was filtered and then freeze-dried.
5.4 g of dried extract was obtained. Example 2 To 240 g of mahuang, 4.8 L of purified water was added and heated to 10
Extraction was carried out for 1 hour after reaching 0 ° C. The obtained extract was centrifuged and the residue was separated to obtain a solution.

A 0.3 μm membrane fill of this solution
Sterile and clarified with a filter (manufactured by Toyo Roshi Kaisha, Ltd.). Obtained
The filtrate was filtered with diafilter G-10T (Bioengine
Ultrafiltration using Aling Co .: molecular weight cut off 10,000)
I had This ultrafiltration is performed on the lower surface of a container with an internal volume of 2.0 L.
Set a membrane with a diameter of 152 mm to the pressure of 3 kg / cm ²
And add about 2 L of purified water as the liquid in the container is concentrated.
It carried out so that it added. As a result, the ultrafiltrate
Got

Next, the fact that the active ingredient of the present invention has a cerebral nerve cell protecting action will be described with reference to experimental examples. Experimental Example Male gerbils (body weight 70 to 85 g) were used in the experiment. Cerebral ischemia was loaded by occluding the bilateral common carotid arteries of the animals that had been fasted overnight for 4 minutes. One week after resumption of blood flow, FAM (40% formalin: acetic acid: methanol = 1: 1)
The cells were fixed by perfusion at 1: 8) and embedded in paraffin according to a conventional method. A 5 μm frontal section including the dorsal hippocampus was stained with cresyl violet, and the number of nerve cells remaining in the pyramidal cell layer in the hippocampal CA1 region was counted. Furthermore, the length of the hippocampal CA1 region was measured from the photograph of the hippocampus using an image analyzer, and the number of pyramidal cells remaining per 1 mm was calculated. Each test drug was dissolved or suspended in purified water to 10 ml / kg, and was orally administered twice for 7.5 hours and 1.5 hours before ischemia.

Further, the same operation as above was performed without adding ischemia to the sham operation group, and to the control group was administered only 10 ml / kg of purified water instead of the test drug. The dried extract obtained in Example 1 was used as mahuang.

[0014]

[Table 1]

From the results shown in Table 1, it was confirmed that the active ingredient of the present invention has a cerebral nerve cell protecting action. Therefore, it was suggested that the brain function improving agent of the present invention is useful as a cerebrovascular disorder therapeutic agent for psychiatric symptoms, neurological symptoms, subjective symptoms, disorders of activities of daily living, and the like. As described above, ephedrine or a salt thereof or mahuang or an extract thereof which is an active ingredient of the brain function improving agent of the present invention, as described above, is a sympathomimetic, a bronchodilator, a pressor, a local vasoconstrictor for many years, or It is used as an antitussive expectorant and its safety is established. For example, the acute toxicity [LD ₅₀ (mg / kg)] value of 1-ephedrine hydrochloride in mice was reported to be 143 by intravenous administration, 385 by intraperitoneal administration, and 834 by oral administration (Pharmaceutical Research, 27 , 460 (1955)
etc). In addition, the acute toxicity [LD ₅₀ (mg / kg)] value of the mahuang extract (water extraction) in mice was 62 when administered intraperitoneally.
It was reported to be 0, 78,000 by oral administration (Modern Oriental Medicine, 1 (2), 35 (1988)).

Next, the formulation and dose of the brain function improving agent of the present invention will be described. The brain function-improving agent of the present invention can be formulated by combining ephedrine or a salt thereof, or mahuang or an extract thereof with a known pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. To be

In order to exert the intended effect, it depends on the age, body weight and degree of disease of the patient, but when the active ingredient is ephedrine hydrochloride, it is usually administered as 1-ephedrine hydrochloride in an adult to 1 12.5 to 25 mg (dl
-Double dose for ephedrine hydrochloride) 1-3 times daily,
As an injection, 1-ephedrine hydrochloride is usually used in adults.
25-40mg times (40m for dl-ephedrine hydrochloride)
g) is injected subcutaneously or intramuscularly. In addition, when the active ingredient is mahuang or its extract, it is suitable to administer 1.5 to 9 g of the active ingredient as an active ingredient in adults usually in divided doses several times a day.

Oral agents include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used in a conventional manner. In addition to the above-mentioned excipients, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance and the like can be appropriately used in this type of formulation. Specific examples of each are as shown below.

[Binder] Crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose 2
208, hydroxypropyl methylcellulose 290
6, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose phthalate 2007
31, hydroxypropyl methyl cellulose phthalate 220824, hydroxypropyl methyl cellulose acetate succinate, carmellose sodium, ethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch , Hydroxypropyl starch, pullulan, polyvinylpyrrolidone K25, polyvinylpyrrolidone K3
0, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer S,
Methacrylic acid copolymer LD, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar, gelatin, white shellac, tragacanth, purified white sugar, macrogol 200,
Macrogol 300, Macrogol 6000.

[Disintegrant] Crystalline cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch. , Hydroxypropyl starch, sodium carboxymethyl starch,
Tragant.

[Surfactant] Soybean lecithin, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 100, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 5
0, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene [42] polyoxypropylene [67] glycol, polyoxyethylene [54] polyoxypropylene [39] glycol, polyoxyethylene [105]
Polyoxypropylene [5] glycol, polyoxyethylene [160] polyoxypropylene [80] glycol, polyoxyethylene [196] polyoxypropylene [67] glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate. , Sorbitan monopalmitate, sorbitan monolaurate, polysorbate 40, polysorbate 6
0, polysorbate 65, polysorbate 80, glyceryl monostearate, sodium lauryl sulfate, lauromacrogol.

[Lubricant] Wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dried aluminum hydroxide gel, talc, metasilicic acid. Acid magnesium aluminate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, polyethylene glycol.

[Flowability Accelerator] Hydrous silicon dioxide, light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate. The brain function improving agent of the present invention is a suspension, emulsion, syrup,
It can also be administered as an elixir, and these various dosage forms may contain a flavoring agent and a coloring agent.

On the other hand, parenteral preparations are manufactured by a conventional method,
Generally, 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 used as the diluent. Further, if necessary, a bactericidal agent, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like, frozen, and then water may be removed by an ordinary freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added appropriately.

[0025]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples. Example 1 200 g of the dried extract obtained in Example 1 was mixed with 89 g of lactose and 1 g of magnesium stearate, and the mixture was tabletted with a single-shot tableting machine to give a diameter of 20 mm and a weight of about 2.3.
g slug tablet was prepared, and this was crushed by an oscillator, sized, and sieved to obtain a good granule having 20 to 50 mesh particles.

This granule may be used in a dose of 1 to 1 depending on the symptoms.
4.5 g (corresponding to a dry extract weight of the active ingredient of the present invention of 0.69 to 3.10 g) is taken 3 times a day. Example 2 200 g of the dried extract obtained in Example 1 was mixed with 20 g of microcrystalline cellulose and 5 g of magnesium stearate, and this mixture was tabletted with a single-shot tableting machine to produce a tablet having a diameter of 7 mm and a weight of 225 mg. did. This tablet contains 200 mg of the dry extract of the active ingredient of the present invention in one tablet. This tablet is taken at a dose of 3 to 16 tablets three times a day according to the symptoms.

Example 3 According to the above prescription, were uniformly mixed, compression-molded by a compression molding machine, crushed by a crusher, and sieved to obtain a granule.

1 g of this granule contains 10 mg of 1-ephedrine hydrochloride, and 3.75 to 7.5 per day for an adult.
Take g in several divided doses. Example 4 According to the above formulation, and were dissolved in, and a solution of and was added and emulsified to obtain an injection.

[0029]

EFFECTS OF THE INVENTION According to the present invention, it is possible to provide a brain function improving agent which is highly safe and has a brain nerve cell protecting action.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Kazuhiro Goto 3586 Yoshihara, Ami-cho, Inashiki-gun, Ibaraki Prefecture Tsumura Co., Ltd.

Claims (5)

[Claims] 1. A brain function improving agent containing ephedrine or a salt thereof as an active ingredient. 2. The brain function improving agent according to claim 1, wherein the ephedrine is 1-ephedrine. 3. The brain function improving agent according to claim 1, wherein the salt of ephedrine is 1-ephedrine hydrochloride. 4. A brain function-improving agent containing mahuang or an extract thereof as an active ingredient. 5. The brain function improving agent according to any one of claims 1 to 4, which is a therapeutic agent for cerebrovascular disorders.