JPS5940364B2 - Pharmaceutical extracts that act on the central nervous system - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a medicinal extract that acts on the central nervous system and is obtained from Zingibermio.

Ginger is a perennial herb that is widely cultivated in private homes and has been used as a condiment since ancient times. However, there is a legend that it makes you forget things if you eat it in large quantities, and little is known about its ingredients and pharmacological effects. unknown.

The present inventor thought that this "forgetfulness" phenomenon might be due to some central nervous system active ingredient contained in Japanese ginger, and as a result of continued extraction, analysis, and pharmacological research of Japanese ginger, we found that methanol and The present invention was completed after learning that water extraction process scratches contain components that significantly suppress the central nervous system. According to the present invention, Japanese ginger leaves washed with water and dried with air are used as the raw material, which is first digested with methanol and/or water. When methanol is used as an extraction solvent, for example, about 7
Add about 7 to 8 times the amount of 0% methanol and digest for 3 times at 50℃ for 3 hours, or if water is used, about 5 to 8 times the amount of drying.
Add 7 times the amount of water. Three digestions of 3 hours at 60° C. have been found to be most preferred.

However, the present inventor has discovered that methanol and water are selectively effective in extracting components that act on the central nervous system from ginger, and the above processing requirements during digestion are not critical. It's not a typical thing. In other words, the methanol concentration is preferably about 60 to 90.
%, most preferably about 70 to 80%, but a mixture of methanol and water in any proportion can be effectively used for the purpose of the present invention. Next, the methanol and/or water extract is filtered, and the solvent is distilled off under reduced pressure to obtain a dark brown candy-like extract of Japanese ginger.

In this case, the treatment temperature for solvent distillation must be kept at 60° C. or lower, otherwise the pharmacological activity of the extract will be significantly impaired due to decomposition of the extracted components as described below. In the case of methanol distillation, treatment at 50° C. or lower is most preferable for the same reason. When using the most preferable extraction conditions mentioned above,
The amount of extraction process scratches obtained is about 30 to 35% based on dryness when using methanol extraction, and about 32% when using water extraction.

Finally, the Miyoga extract is evaporated to dryness under reduced pressure to obtain a powdery extract.

For the same reason, the treatment temperature at this time is also kept at 60°C or lower, preferably at 50°C or lower. The Miyoga extract obtained in this way is a brown, non-hygroscopic powder that exhibits similar properties whether methanol, water, or a mixture thereof is used as the extraction solvent, and has a slightly pungent and bitter taste and a weak aroma. , readily soluble in water, methanol, physiological saline, ethanol (70%
), but it is hardly soluble in most other organic solvents such as ethanol (100%), acetone, ether, chloroform, benzene, petroleum ether, etc., and the pH of a saturated aqueous solution is 5.98. ~6.00.

Furthermore, the Namjoga extract of the present invention exhibits the following physiological effects that are exactly the same whether methanol or water is used as the extraction solvent.

Therefore, in the following description, these extracts will be simply referred to as the Namjoga extract according to the present invention without distinguishing between methanol and water, regardless of whether methanol or water is used as the extraction solvent. The extract according to the present invention is almost harmless to humans and suckling animals, and exhibits remarkable central nervous system depressing effects and hypotensive effects when administered orally or parenterally.

1. Acute Toxicity The acute toxicity of the Miyoga extract, calculated by the Richfield-Wilcoxon method using a group of ICR male mice weighing 16-227, is as follows.

Shown in Table 1? The extract of the present invention has extremely low toxicity and can be said to be almost non-toxic.

1. Pharmacological effects (1) Effect on locomotor activity of mice Using a group of ICR male mice weighing 20 to 25 years, the number of movements was recorded for each cage using Animex immediately before measurement, and then 100 mg of Miyoga extract was administered to the drug administration group. Soku/K9 dissolved in physiological saline was administered subcutaneously, and the number of movements over 60 minutes was measured over time and compared with that of the control group.

The decrease in the amount of exercise over time was more remarkable in the drug-administered group, and the decrease in exercise amount from 12 minutes after administration was particularly remarkable compared to the control group. (2) Analgesic effect by acetic acid stretching method The test drug was subcutaneously administered to a group of ICR male mice weighing 17 to 237 cm, and 15 minutes later, 0.1 ml/107% of 0.7% acetic acid was administered intraperitoneally. The inhibitory effect on stretching symptoms induced over a period of 10 to 20 minutes was investigated.

In addition, aminopyrine 60η/K9 (subcutaneous) was used as a control drug. The results are shown in Table 2. Analgesic effects were clearly observed in Miyoga extract using the acetic acid stretching method.

(3) Effect of hexobarbital Na on sleep duration The test drug was subcutaneously administered to a group of CR male mice weighing 18-22', and hexobarbital Na7Oll! fl/Kll was administered intraperitoneally, and the time to loss of righting reflex and the time to recovery (sleep duration) were measured.

As is clear from Table 3, Miyoga extract 500m9/K
Subcutaneous administration of physiological saline solution No. 9 showed no significant difference from the control group in terms of time until loss of righting reflex.
In terms of sleep duration, a 57.4% increase in sleep duration was observed compared to the control group.

(4) Effect on body temperature The rectal temperature of male Wista rats weighing 140 to 160 mm was measured at 30 minute intervals using a thermistor (manufactured by Nihon Kohden).
Animals whose measured values varied by 0.50°C or less were selected and used as specimens.

Rectal temperature was measured every 30 minutes after intraperitoneal administration of the two test drugs, and aminopyrine (subcutaneously) was used as a control drug. A clear decrease in body temperature was observed with intraperitoneal administration of Miyoga extract, and extract 5
At 0m'/K9, 2.0+0 compared to the control group 1 hour after administration.
．． A drop in body temperature of 2°C was observed, after which it gradually recovered.
After 4 hours, the condition returned to normal. Similarly, after administration of 100-7 balls 9, a decrease in body temperature of 2.4 ± 0.2°C was observed compared to the control group after 1 hour, and it took 5 hours to recover, which was a stronger decrease in body temperature than with aminopyrine 100 mc/K9. The effect was observed.

(5) Effect on electroencephalogram Cats (male and female) weighing 2.5 to 3.5k9 were fixed in a brain stereotaxic apparatus of the University of Tokyo Brain Research Institute under ether anesthesia, and after inserting a tracheal cannula, the skull was exposed and subcortical. A hole was made in the skull at the electrode insertion site.

The animals were immobilized by intravenous administration of 5-10 m of gallamine triethiodide/K9, and the experiments were performed under artificial ventilation. The cortex is made of stainless steel (5 x 0.5 mm)
Unipolar guidance was performed from the frontal, parietal, temporal, and occipital cortices using needle electrodes, and the indifferent electrode was placed on the frontal bone. The deep electrode is made of stainless steel. Using enamel-insulated bipolar concentric electrodes, Jasper and Ajimon were tested. Marsan (The
National Research Council of Canada19
Published in 1954, “Stereotaxic Atlas of the Cat Brain”
According to the brain diagram, PL (posterior ventral nucleus), RF (reticular formation)
, Hippocampus (hippocampus), and Amy (amygdaloid nucleus).

After intravenous administration of Miyoga extract 3▼/Kg, spikes appeared in the VPL after 5 minutes, and low amplitude fast waves (20
~30Hz).

In HippO, HippOcampalOusal
A wave (100 to 200 μV, 4 to 7 Hz) appeared, and in Amy, the amplitude decreased somewhat and became a slow wave (5 to 7 Hz). There were also cases where spikes appeared in HippO. Approximately 10 minutes after administration, cortical electroencephalograms showed spindle burst-like waves (
150-250μV, 12-13Hz) increased and spread to the subcortex.

Approximately 20 to 30 minutes after administration, the frequency of spindle burst-like waves increased, and irregular slow waves (50 to 10
0 μV, 0.5-1.0 Hz) appeared more clearly, and the electroencephalogram began to show a somnolence pattern. These electroencephalogram changes were antagonized by intravenous administration of atropine sulfate 0.1Tf9/Kg. Furthermore, the brain wave changes recovered around 60 minutes. From the above, it is clear that Miyoga extract has a strong suppressive effect on the central nervous system.

(6) Blood pressure lowering effect The Japanese ginger extract according to the present invention also exhibits a unique effect on the circulatory system.

In other words, when Miyoga extract 1η/K9 is administered intravenously, blood pressure decreases immediately after administration, with a maximum of 17 to 34 m
A decrease in mHg was observed, and it gradually recovered after 5 minutes, returning to the level before administration; 3mf! ! /1<9, the drop starts immediately after administration, and the maximum level is 49 to 71 mmHg after 1 minute and 30 seconds.
It took about 16 minutes to recover;
In the case of 19/K9 administration, blood pressure decreases immediately after administration, shows a maximum decrease of 110 to 111 mmHg after about 2 minutes, and recovers in about 26 minutes. Moreover, this blood pressure lowering effect is α
- There is almost no effect even with pre-administration of torazoline, which is a protzka, and propranolol, which is a β-protzka, and it is suppressed by pre-administration of atropine, a peripheral parasympathetic nerve blocker, and diphenhydramine, an antihistamine. Therefore, it is thought to have effects similar to acetylcholine or histamine. However, the blood pressure lowering effect of this drug is suppressed by bilateral vagotomy, etc., so it is thought that not only peripheral acetylcholine and histamine-like effects but also central involvement is involved.

As mentioned above, the central nervous system depressing component contained in the Japanese artemisia inflorescence, which exhibits the above-mentioned pharmacological effects, is very easily transferred to methanol and water, but most other organic solvents such as ethanol (100%), acetone, It hardly migrates to ether, chloroform, benzene, petroleum ether, etc.

Furthermore, even if methanol or water is selected as the extraction solvent, if the treatment temperature is set to 80°C in the process of concentrating the extract, the activity will be reduced to about 1/3 or less when compared with the effect of suppressing peristaltic movement in the isolated intestinal tract. It has also been confirmed that a temperature of 50 to 60°C is the upper limit for maintaining activity. If you separate the water and methanol extracts and store them in the refrigerator, they will not lose their activity for several days, but if you do not separate the extracts, they will lose their activity very quickly. Furthermore, it has been confirmed that the product evaporated to dryness under reduced pressure is stable for a long period of time even at room temperature and does not lose its activity.Thus, in the present invention, it is possible to extract the active ingredients of the Japanese artemisia inflorescence using a specific solvent and extract it under specific temperature conditions. By combining the essential processing means of concentrating the liquid and evaporating the concentrated liquid to dryness under specific conditions, a medicinally useful extract of Miyoga can be industrially advantageously provided. Although it is possible to obtain a liquid that acts on the central nervous system by simply grinding and filtering the inflorescences, not only is the amount obtained extremely small, but it also quickly loses its activity, making it impossible to use as a medicine. It should be noted that, for the first time, the invention has made it possible to provide industrially advantageous pharmaceuticals that act on the central nervous system. The Japonica japonicum extract according to the present invention can be administered as a central nervous system depressant or antihypertensive agent by either oral administration or parenteral administration such as subcutaneously, intravenously, intramuscularly, intraperitoneally, etc.

When used as an antihypertensive agent, the dosage varies depending on the patient's age, health condition, weight, and other individual differences, but in general, intravenous administration is 1 to 2 T/K9 per day; oral administration is 10 to 20 T!
The dose is adjusted to around Zf7/Kg, which is increased or decreased depending on the symptoms, and in the case of other central nervous system depression such as sedation or analgesia, a smaller amount is selected as appropriate depending on the symptoms.

When administering the Namjoga extract of the present invention orally, it can be used in the form of tablets, capsules, powders, liquids, elixirs, etc., and when administering parenterally, it can be used in sterile liquid forms such as solutions or suspensions. Miyoga extract of the present invention? For this purpose, conventional solid or liquid non-toxic pharmaceutical carriers, excipients or auxiliaries can be incorporated. The present invention will be explained below with reference to Examples.

Example 1 Manufacture of extract of Japanese artemisia japonica Inflorescences of Japanese artemisia japonica were washed with water and dried with air at 40°C, 5 to 7 times the amount of water was added, and the mixture was digested 3 times for 3 hours at 60°C.
The digestion liquids were combined and filtered.

This filtrate was concentrated under reduced pressure at 60° C. until it became caramel-like, giving a dark brown candy-like waterworks scratch. The yield of engineered scratches based on dried Japanese trifoliate inflorescences was 32.0%. Next, the above-mentioned engineering scratches were further evaporated to dryness under reduced pressure at 60° C. or lower to obtain a dark brown powder of the Japanese ginger extract. Example 2 Manufacture of Samyoga japonica extract After washing the inflorescences of japonica japonica and drying with air, 7 times the amount of 70% methanol was added thereto, and the mixture was digested three times for 3 hours at 50°C.

The digestion liquids were combined, filtered, and concentrated under reduced pressure at 50° C. or lower to obtain a dark brown candy-like methanol extract. The yield was 35%. Next, the engineering scratches were evaporated to dryness under reduced pressure at 50° C. or lower to obtain a brown powdered extract of Japanese ginger. Example 3 The extract obtained in Example 1 was made into capsules and tablets by a conventional method.

(a) Production of capsules Miyoga extract 50T! Lactose 10 to 19
Add 0me and 2m of Aerosil and mix thoroughly, fill in a plug capsule, and add the active ingredient 50W19.
We made capsules containing the following.

(b) Manufacture of tablets Mix the Miyoga extract 2507, lactose 5457, and potato starch 10507 intimately,
This mixture was mixed with gelatin (1527)-glycerin (37
) The mixture was granulated using a mixture of water and water, and dried under reduced pressure at room temperature.

Next, the granules were compressed into tablets having a weight of 400η using a tablet machine. The contents per tablet were 50 mc of Japanese ginger extract, 109mc of lactose, and 210 mc of starch. Example 4 Using the Japanese ginger extract obtained in Example 2, an injection was prepared by a known method.

A 2% solution was obtained by dissolving the Miyoga extract in physiological saline and using aseptic procedures. After adjusting the pH to 5.0 to 5.5, it was filtered, sealed in an ampoule, and sterilized to obtain a solution containing 5 m of the active ingredient. I got an injection.

In initial clinical experiments using the above-mentioned various preparations of the Namyoga extract according to the present invention, the Namyouga extract has an excellent central nervous system depressing effect similar to that of chloropromacine, an effect of prolonging sleep time due to barbital drugs, and a hypotensive effect. etc.

Claims (1)

[Claims] 1. Digest inflorescences of Zingiber mioga with methanol and/or water, filter and boil at 60°C.
The candy-like extract obtained by concentrating under reduced pressure at the following temperature is further added to
A powdered pharmaceutical extract that acts on the central nervous system obtained by evaporation to dryness under reduced pressure at a temperature below 0°C.