JPH02311422A - Activator for choline acetyltransferase - Google Patents

Abstract

PURPOSE:To obtain the subject activator, composed of powder of Ligustici Radix and Paeoniae Radix which is a Chinese medicine formulation and useful for treating various disease caused by reduction in acetylcholine in biological tissues. CONSTITUTION:The objective activator obtained by decocting a mixture of Paeoniae Radix with Zeodoariae, Alismae Rhizoma, Hoelen, Cnidium and Ligustici Radix at (4 to 6):(4 to 6):(4 to 6):(4 to 6):(3 to 4):(3 to 4), especially 4:4:4:4:3:3 mixing ratio and removing residues. The abovementioned drug in an amount of 1 to 15g expressed in terms of weight of a dried extract powder can be administered in several portions a day to treat various diseases caused by reduction in acetylcholine, such as grave amyosthernia, Alzheimer's disease, Alzheimer type dementia or gastrointestinal dysfunction.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application J The present invention relates to an activity enhancer of choline acetyltransferase, which has an important role in acetylcholine synthesis in vivo.

[Prior art and problems] Acetylcholine is a combination of choline and acetyl coenzyme A (hereinafter referred to as
It is called acetyl-CoA. ) is a cholinergic nerve fiber transmitter synthesized by choline acetyltransferase, and is an extremely important in-vivo substance involved in various biological reactions. This acetylcholine is involved in the onset of various diseases.

For example, in myasthenia gravis, which is an autoimmune disease, the number of acetylcholine receptors in skeletal muscles decreases, and symptoms are alleviated by increasing the amount of acetylcholine in the interstitial sonabus.

Furthermore, in patients with Alzheimer's disease and Alzheimer's type dementia, a decrease in acedercholine in the cerebral cortex has been observed, and symptoms are said to improve by increasing the amount of acedercholine in the brain. .

Furthermore, acedercholine stimulates the secretion of gastric acid and enhances the motility of the gastrointestinal tract, so if the amount of acedercholine in the gastrointestinal tract is avoided, the decreased gastrointestinal function will be alleviated.

Therefore, a method of increasing acedercholine concentration in living tissues is viewed as a promising method for treating various diseases.

Acetylcholine is synthesized in all tissues in the body, and the following methods are currently used to increase acetylcholine concentration in tissues.

■Provides a precursor of acetylcholine, a precursor to narocholine, and promotes the biosynthesis of acedercholine.

■Activates choline acedertransferase activity and promotes acetylcholine biosynthesis.

■Inhibits the enzyme activity of cholinesterase, which is an enzyme that decomposes acetylcholine, thereby suppressing its decomposition.

However, with regard to (2), there is no drug with significant medicinal efficacy, and it has been desired to develop a drug that activates choline acetyltransferase activity.

[Means for Solving the Problems] The present inventors conducted intensive research to develop a drug that activates choline acetyltransferase activity, and as a result, they found that the drug, which is a Chinese herbal prescription, has an excellent activation effect. This discovery was made and the present invention was completed. That is, the present invention is a choline acetyltransferase activity activator (hereinafter referred to as the drug of the present invention) comprising Tokishakuyakusan.

The drug of the present invention has its constituent herbal medicines, amounts, extraction methods, etc. described in the classic Chinese herbal formula, Kaidou Koro, and is effective against cold sensitivity,
It is used to treat various diseases such as anemia and abdominal pain, but it was completely unknown until now that it had the effect of activating choline acetyltransferase activity.

The constituent crude drugs and composition ratios of the drug of the present invention are determined in accordance with the classical Chinese medicine, but the proportions of the constituent crude drugs vary in the classical Chinese medicine, and the crude drugs contained vary depending on the place of production, time of collection, natural conditions, etc. Since the amounts of the ingredients change, the mixing ratio of each component herbal medicine needs to be increased or decreased as appropriate.

Therefore, the drug of the present invention is
Return (4-6:4-6; 4-6:4-6:3-4:3-
Any mixing ratio may be used as long as it satisfies the range of 4).

Furthermore, a particularly preferable mixing ratio for the drug of the present invention is:
:3), and the drug of the present invention can be obtained by decocting this with 10 to 20 times the amount of water and removing the dregs.

In addition, considering portability + 11, ease of administration, etc.,
Add excipients, etc. to the dry extract powder obtained from the herbal medicine mixed in the ratio of 4.3.3) through the process of thermal extraction, overnight separation, concentration, and drying, and make granules according to the general rules for formulation. , capsules, tablets, and other dosage forms.

A specific example of the production of the drug of the present invention is as follows.

Specific example 1 Xunyaku 49, Ao, t49, Sawabashi 49, Kessei 4ri, Yoshu 39
, Add 220 d of water to 3 g of mixed herbal medicine for 1 hour.
Extraction was carried out by heating at 100°C, and the resulting extract was filtered and then spray-dried to obtain a dry extract powder with a weight of 3.89.

[Effects of the Invention] Next, the effects of the drug of the present invention on choline acetyltransferase activity will be explained using experimental examples.

Experimental example! SD old rats (15 to 20 months old) were divided into two groups (2-week administration group and control group), and the dried extract powder obtained in the specific example was mixed into their feed at a ratio of 19/9 in a day. It was administered orally with drinking water.

The control group received drinking water only. After finishing each stage of dry extract powder, the rat was decapitated, the brain was taken out, 0.2% polyoxoethylene (lO) ocdyl phenyl ether was added to the cerebral cortex, homogenized, and a mixed solution with the composition shown below was prepared. was added and incubated at 37°C for 15 minutes.

The reaction was stopped by adding 10 mM sodium hydrogen phosphate buffer, partitioned by adding 0.5% tetraphenylboron in acetonitrile, then 0.4% butyl PL3D in toluene, and the radioactivity in the toluene layer was removed by liquid non-tillation. It was measured with a counter and defined as choline acetyltransferase activity.

Mixed liquid composition 14G acetyl CoA 507
J2.5 Acetyl CoA
2500.1M Ethylenediaminetetraacetic acid-Naz
1000.4M Sodium Cyanide
500, l M choline bromide
1005, OM Sodium Chloride
100034M Sodium Hydrogen Phosphate
300 physostigmine-So,
10□ Bovine Serum Album No□-” - Menichi 10
0 (lzρ) As a result, the choline acetyltransferase activity in the control group was 1.55 ± 0.11 μ-/9/h, while that in the 2-week treatment group was 1.80 ± 0.24 μ-/h. 9
/h, and activation of enzyme activity was confirmed.

Furthermore, when the acute toxicity test of the drug of the present invention was carried out using ddY male mice, both
There were no deaths even after oral administration (dose limit).

From the above results, it was confirmed that the drug of the present invention activates the activity of choline acetyltransferase, has low toxicity, and is extremely safe.

Therefore, the drug of the present invention is useful for treating all diseases caused by a decrease in acetylcholine in living tissues.

Next, the dosage and formulation of the drug of the present invention will be explained.

The drug of the present invention can be administered to animals and humans as is or together with a conventional pharmaceutical carrier.

The dosage form is selected and used as appropriate,
Oral preparations such as tablets, capsules, granules, fine granules, and powders can be mentioned.

In order to exert the desired effect as an oral agent, the weight of the dry extract powder, which is the active ingredient of the drug of the present invention, for an adult is usually 1 to 159, although it varies depending on the age, body weight, and severity of the disease. It seems appropriate to take the drug in divided doses several times a day.

Oral agents include, for example, starch, lactose, sucrose, mannitol,
It is manufactured using conventional methods using carboxymethyl cellulose, corn starch, inorganic salts, etc.

In addition to the above-mentioned injection molding agent, 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 preparation. Specific examples of each are shown below.

[Binder 1 Starch, dextrin, arahia gum powder, gelatin,
Hydroquinopropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroquinpropylcellulose, crystalline cellulose, edylcellulose,
Polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroquinopropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroquinopropylcellulose.

[Surfactant Sodium colauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The drug of the present invention can also be administered as a suspension, emulsion, tablet, or elixir, and these various forms may contain flavoring agents and coloring agents.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited by this.

Example I ■Corn starch 44g ■Crystalline cellulose 44g ■Carboxymethylcellulose calcium toy ■Light anhydrous silicic acid 1g ■Magnenium stearate I9 1 and Hinoki Example 11 Sentomoyaoka @ 1009 total 2
009 According to the above recipe, ① to ② were uniformly kneaded and compressed using a tablet machine to obtain one tablet of 20019.

This tablet contains the compound 10011f obtained in Example I.
Adults should take IO to 25 tablets a day in several doses.

Example 2 ■ Crystalline cellulose 899 ■ Magnesium stearate 19 ■ Calcium carboxymethyl cellulose 109 ■ Powder obtained in specific example 1 1009 Total 200 g After uniformly mixing ■ and part of ■ according to the above recipe and compression molding. The mixture was pulverized, the remaining amounts of ① and ③ were added and mixed, and the mixture was compressed using a tablet machine to obtain 200 star tablets.

This tablet contains 100 j! of the powder obtained in Example 1! 9
It contains 10 to 25 tablets per day for adults, divided into several doses.

Example 3 ■ Crystalline cellulose 509 ■ 10% hydroquinepropyl cellulose ethanol solution 399 ■ Calcium carboxymethyl cellulose 109 ■ Magnesium stearate 10 0 Powder obtained in Example 1 101 Total 200 g Prepare ■, ■, and ■ according to the above recipe. After uniformly mixing, neutering by a conventional method, granulating with an extrusion granulator, drying and crushing, ① and ② were mixed, and compression molded with a key press to make some 200179 tablets. Obtained.

This tablet contains the powder 100 tablets obtained in Example 1, and is taken by adults in 5 to 40 tablets a day in several doses.

Example 4 ■Corn starch 399 ■Magnesium stearate 50? ■Carboxymethylcellulose calcium 109 ■Light silicic anhydride 1g Powder obtained in 1) 1ooy total
2009 According to the above recipe, (1) to (2) were uniformly mixed, compression molded using a compression molding machine, crushed using a crusher, and sieved to obtain granules.

This granule I9 contains powder 500 M9 obtained in Example 1.
It contains 4 to 209 doses per day for adults, divided into several doses.

Example 5 ■Crystalline cellulose 659 ■1O% hydroquinepropyl cellulose ethanol solution 359] Powder obtained from stem PI l 100g total
2009 According to the above recipe, ① to ② were uniformly mixed and made into a paste. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

This granule 19 contains 500 pieces of the powder obtained in Example 1, and is taken by adults in 2 to 5 g per day in several doses.

Example 6 ■Corn starch 999 ■Light silicic anhydride 19 ■Powder obtained in specific example 1 1009 Total 2009 ■~■ were mixed uniformly according to the above recipe, and 200 #
9 was filled into a No. 2 capsule.

This capsule! The capsules contain powder 1 obtained in Example I.
001119, and adults should take IO to 25 capsules a day in several doses.

Claims (1)

[Claims] Choline acetyl transferase activity activator consisting of Tokishakuyakusan